Lynda Wyld · Christos Markopoulos

Marjut Leidenius · Elżbieta Senkus-Konefka Editors

Breast Cancer
Management for
Surgeons

A European
Multidisciplinary Textbook

123
Breast Cancer Management for Surgeons

rares1geo@gmail.com
Lynda Wyld
Christos Markopoulos
Marjut Leidenius
Elżbieta Senkus-Konefka
Editors

Breast Cancer
Management for
Surgeons
A European Multidisciplinary Textbook

rares1geo@gmail.com
Editors
Lynda Wyld Christos Markopoulos
The Medical School Department of Oncology Athens University Medical School
University of Sheffield Athens, Greece
Sheffield, United Kingdom
Elżbieta Senkus-Konefka
Marjut Leidenius Department of Oncology & Radiotherapy
Helsinki University Hospital Gdańsk Medical University Department of Oncology
Helsinki, Finland & Radiotherapy
Gdańsk, Poland

ISBN 978-3-319-56671-9    ISBN 978-3-319-56673-3 (eBook)

https://doi.org/10.1007/978-3-319-56673-3

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 V

Foreword

Foreword by: and are also robustly prepared to apply for the rel-
evant UEMS Exams. The superb textbook that you
Professor Vassilios Papalois have in your hands is testimony to this great effort.
Imperial College Healthcare NHS Trust, London, UK
Secretary General of the European Union of Medical I truly enjoyed reading each chapter that is written
Specialist (UEMS) most clearly and elegantly and addresses all ele-
ments of modern practice: evidence based
It is a great honour to offer this forward for this approach, multidisciplinary/ team work, state of
world class textbook for the multidisciplinary the art experience, expertise and clinical pathways
management of breast cancer for surgeons. I will as well as constructive use of technology.
first address with great pleasure the fact that this is
a European textbook reflecting the widely known I was particularly impressed by the fact that the
and well respected experience and expertise of textbook combines scientific accuracy and robust-
Colleagues across Europe with whom I had the ness with the authors’ genuine interest and truly
real privilege to work closely when I was President humane approach for the patients. The textbook is
of the Section of Surgery of the Union of European inspired by the Hippocratic (and pan-European!)
Medical Specialists (UEMS) and over the last two values of medical humanism.
years as UEMS Secretary General.
I believe that Colleagues of all specialties and ranks
The UEMS is an organisation with almost 60 years of who are actively involved in breast cancer treat-
history, representing, through their National Medi- ment will find this textbook a powerful ally and
cal Associations, 39 Countries in the EU and beyond, compelling navigator that will guide them through
a total of 1.6 million medical specialists. The UEMS the complexities of this ever evolving area of mul-
work on the ground is being done by 43 Specialist tidisciplinary practice that affects the lives of mil-
Sections that also collaborate though 15 Multidisci- lions of patients around the world.
plinary Joint Committees for areas of practice which
are of interest to more than one Section. Congratulations and Kudos to the Editors and the
Authors!
The UEMS prides itself for being an organisation
that develops real projects for real people in real life! Enjoy sailing through its pages!
The development of the UEMS European Training
Requirements (ETRs) and Exams are two flagship
projects for the UEMS. The ETRs and the Exams are
developed by the UEMS Sections in close collabora-
tion with the relevant European Scientific Societies.
This is being done through a truly wide and in depth
consultation across Europe that embraces Universi-
ties, Scientific Societies and Professional Colleges
and Associations; the final product has the review
and approval of the National Medical Associations
represented in the UEMS. I cannot really think of a
more robust process for developing such quality
control projects as the UEMS ETRs and Exams aim-
ing to advance and harmonise specialist practice in
Europe that will of course translate into top class
clinical care for patients.

The Divisions of Breast Surgery of the Section of

Surgery of the UEMS has been one of the most
active and productive players in the field of UEMS
ETRs and Exams. They have also gone one step fur-
ther and they have produced superb educational
material in support of Colleagues across Europe
who wish to ensure that their knowledge is up to
speed and meets the standards of the UEMS ETRs

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Preface from the UEMS – EBS – Division of
Breast Surgery

A few years ago, EUSOMA (the European Society This textbook, written by European-based breast
of Breast Cancer Specialists) published a position cancer specialists from all management disciplines
paper on “Guidelines on the standards for the involved in modern breast cancer care, will serve as
training of specialized health professionals deal- the syllabus for the EBSQ in breast surgery exam.
ing with breast cancer”. Theoretical and practical Breast surgeons have a leading role in the manage-
requirements for the training of a “breast sur- ment of patients with breast cancer, and all current
geon” were described in detail, as well as an necessary knowledge for evidence-­ based breast
assessment strategy – specialist exams – on how a cancer management is included in its chapters. Fur-
candidate could be qualified as a “specialist in thermore, this textbook will also serve as a helpful
breast surgery”. reference tool in everyday practice for everyone
involved in the care of breast cancer patients.
Following that, the UEMS (European Union of
Medical Specialists) expressed its support for pro- On behalf of the UEMS-EBS-Division of Breast
posals in the guidelines, and as a result, the breast Surgery, I would like to express my deep apprecia-
surgery working group was established in the tion to the editors and co-authors of the book for all
UEMS Section of Surgery, and the breast surgery their efforts and to Springer for this great edition.
examination was launched in 2010.
Professor Christos J. Markopoulos
The exam is part of the series of professional exam- President of the Division of Breast Surgery
inations offered by the European Board of Surgery at the Section of Surgery of the UEMS-EBS
(EBS) and results in the award of a European
Board of Surgery Qualification (EBSQ) in breast
surgery examination. Graduates of the exam may
use the post-nominal FEBS or Fellow of the Euro-
pean Board of Surgery. Considering the recog-
nized success of the project, the UEMS proceeded
in 2015 to officially upgrade the breast surgery
working group to a full division within the Euro-
pean Board of Surgery, the Division of Breast Sur-
gery, recognizing its status as an increasingly
important specialist group of surgeons.

The EBSQ in breast surgery exam is organized

twice per year, and respected and recognized
breast surgeons from all over Europe are invited to
act as examiners. In our common effort to improve
the quality of health services for breast cancer
patients across Europe, we strongly believe that the
EBSQ exams play an important role. A breast sur-
geon holding an EBSQ diploma has official recog-
nition that she/he meets EBSQ application
requirements with regard to specialist education,
training and experience and has up-to-date knowl-
edge of breast cancer management.

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 VII

Preface from the European Society of Surgical

Oncology

Half a million women develop breast cancer, and
100,000 women die of the disease each year in
Europe. This represents a massive health burden
but one where outcomes are steadily improving.
Outcomes continue to vary widely across Europe
due to differences in early detection and wide
variance in therapy schedules. Breast cancer sur-
geons play a leading role in the delivery of care to
women with breast cancer, and over 60% of breast
cancers are cured by surgery alone. However, the
increasingly complex treatment schedules require
that surgeons have in-depth knowledge of
evidence-­based multidisciplinary practice.
This textbook summarizes the expected knowl-
edge which any breast cancer surgeon has to pos-
sess in order to pass the exam.
I congratulate the editors and all contributors to
this ambitious editorial and educational project; it
is here to reassure all breast cancer patients that
they will receive the best management possible
today and to lay the foundations for future research.
Professor Riccardo A. Audisio
Immediate Past President of ESSO

Harmonization of outcomes across Europe

requires education, training and quality assurance.
Specialist breast units are being set up across
Europe as per European Parliament resolutions
and European guidelines for quality assurance. A
programme of breast unit quality assurance is in
progress in the EU at the moment. This critically
important action, implemented by the European
Union, would be entirely useless if there was no
quality assurance of surgical management and
training in breast surgery.

ESSO (the European Society of Surgical Oncol-

ogy) is committed to this task. Numerous courses
and masterclasses have been organized, specialists
have set up a network to facilitate training across
Europe, grants are available to train young breast
surgeons, and the UEMS examination is solidly in
place to certify competence and multidisciplinary
understanding.

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 IX

Contents

I Basic Science
1 Gross Anatomy of the Breast and Axilla........................................................................................................... 3
Peter Palhazi

Physiology and Developmental Stages of the Breast.............................................................................. 11

2 
Theodore G. Troupis, Adamantios Michalinos, George Skandalakis, and Panayiotis Skandalakis

3 Breast Cancer Epidemiology.................................................................................................................................... 19

R.M. Parks, M.G.M. Derks, E. Bastiaannet, and K.L. Cheung

Effect of Oestrogen Exposure, Obesity, Exercise and Diet

4 
on Breast Cancer Risk.................................................................................................................................................... 31
Eleni Th. Petridou, Marios K. Georgakis, and Constantine N. Antonopoulos

Hereditary Breast Cancer Genetics and Risk Prediction Techniques............................................. 43

5 
Helena Carley and Anju Kulkarni

II Screening, High Risk Lesions, and Risk ­Management

6 Screening for High-Familial-­Risk Women........................................................................................................ 59
Athina Vourtsis

7 Risk-Reducing Breast and Ovarian Surgery for Women at High Familial Risk........................ 69

Inkeri Schultz and Kerstin Sandelin

The Role of Breast Cancer Chemoprevention in High-Risk Women................................................ 79

8 
Lynda Wyld

9 Molecular Profiling of Breast Cancer and DCIS............................................................................................ 89

Christos Markopoulos

10 Pathology of High-Risk Breast Lesions.............................................................................................................. 103

Sarah E. Pinder and Abeer M. Shaaban

11 Ductal Carcinoma in Situ............................................................................................................................................. 115

Stacey A. Carter, Sarah E. Pinder, and Alastair M. Thompson

12 Imaging of the Breast.................................................................................................................................................... 127

Petra Steyerova

13 Breast Cancer Screening.............................................................................................................................................. 147

John Mathew and Mark Sibbering

III Early Breast Cancer: Diagnosis and ­Management

Clinical Presentation, Diagnosis and Staging of Breast Cancer........................................................ 159
14 
Janez Zgajnar

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X
Contents

15 Pathology of Breast Cancer....................................................................................................................................... 177

Frederique Penault-Llorca and Nina Radosevic-Robin

16 The Breast and Oncoplastic Multidisciplinary Team................................................................................ 193

Fiona MacNeill, Marios Konstantinos Tasoulis, Melissa Ley Hui Tan, and Andreas Karakatsanis

17 Surgery to the Breast: Mastectomy...................................................................................................................... 203

Petros Charalampoudis and Tibor Kovacs

18 Surgery to the Breast: Breast Conservation Techniques........................................................................ 213

Marjut Leidenius

19 Oncoplastic Breast-Conserving Therapy.......................................................................................................... 229

Elias E. Sanidas and Florian Fitzal

Fat Transfer in Oncoplastic and Reconstructive Breast Surgery....................................................... 245

20 
Riccardo Bonomi, I. Fabio Rapisarda, Gilles Toussoun, and Loraine Kalra

Breast Surgery after Primary Systemic Treatment..................................................................................... 255

21 
Thorsten Kuehn

Surgery for Locally Recurrent Breast Cancer................................................................................................. 263

22 
Roberto Agresti, Andrea Spano, Giulia Bianchi, and Giovanna Trecate

Management of the Axilla: Sentinel Lymph Node Biopsy.................................................................... 275

23 
Leif Bergkvist and Jan Frisell

Axillary Node Clearance.............................................................................................................................................. 285

24 
Tuomo J. Meretoja

25 Axillary Management in the Neoadjuvant Setting.................................................................................... 291

K. Wimmer, F. Fitzal, R. Exner, and M. Gnant

Axillary Reverse Mapping: ARM............................................................................................................................. 303

26 
Isabel T. Rubio, Ernest J.T. Luiten, and V. Suzanne  Klimberg

IV Reconstructive Surgery
27 Immediate Reconstruction: General and Oncological Considerations........................................ 315
Maria João Cardoso and Giuseppe Catanuto

Delayed Breast Reconstruction: General and Oncological Considerations.............................. 325

28 
Zoltán Mátrai

29 Breast Implants: Design, Safety and Indications for Use....................................................................... 355

Jana de Boniface and Inkeri Schultz

Specific Implant-Based Techniques for Breast Reconstruction......................................................... 365

30 
Lorna J. Cook and Michael Douek

Specific Autologous Flap Techniques................................................................................................................. 381

31 
Sinikka Suominen and Maija Kolehmainen

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 XI
Contents

Goldilocks Procedure.................................................................................................................................................... 393

32 
Fiona MacNeill

33 Nipple Reconstruction.................................................................................................................................................. 401

Valentina Lefemine and Kelvin F. Gomez

34 Complications of Breast Surgery and Their Management.................................................................... 411

Michalis Kontos and Christos Markopoulos

V Adjuvant Therapy for Early Breast Cancer

Adjuvant Endocrine Therapy.................................................................................................................................... 427
35 
Manuela Rabaglio and Monica Castiglione

36 Adjuvant Chemotherapy............................................................................................................................................. 439

Giuseppe Curigliano, Angela Esposito, and Carmen Criscitiello

Adjuvant Molecular Therapies in Breast Cancer......................................................................................... 447

37 
A. Prove, L.-A. Teuwen, and L. Dirix

Primary Systemic Therapy for Breast Cancer................................................................................................. 453

38 
Cornelia Liedtke and Hans-Christian Kolberg

39 Radiotherapy for Breast Cancer............................................................................................................................. 463

Barbara Alicja Jereczek-Fossa, Maria Cristina Leonardi, and Samantha Dicuonzo

VI Breast Cancer in Special Groups

Breast Cancer in Special Groups: Young Women with Early Breast Cancer............................... 487
40 
Rossella Graffeo and Olivia Pagani

Hereditary Breast Cancer............................................................................................................................................ 499

41 
Teresa Ramón y Cajal, Anna Virgili, and Nuria Dueñas

Breast Cancer in Special Groups: Breast Cancer in Pregnancy.......................................................... 511

42 
Matteo Lambertini, Hatem A. Azim Jr, and Fedro Alessandro Peccatori

Fertility Preservation in Women with Breast Cancer................................................................................ 521

43 
Anna Rachelle Mislang, Matteo Lambertini, and Laura Biganzoli

Breast Cancer in Older Patients.............................................................................................................................. 529

44 
Anne Shrestha and Lynda Wyld

Breast Cancer in the Male Patient......................................................................................................................... 541

45 
M. Umit Ugurlu and Bahadir M. Gulluoglu

Sarcoma of the Breast................................................................................................................................................... 551

46 
Erkki Tukiainen and Andrew Lindford

Desmoid (Aggressive) Fibromatosis of the Breast..................................................................................... 559

47 
Nicholas C. Eastley, Jaroslaw Krupa, and Robert U. Ashford

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XII
Contents

VII Advanced Breast Cancer

48 Locally Advanced Breast Cancer............................................................................................................................ 567
Elżbieta Senkus and Aleksandra Łacko

Metastatic Breast Cancer: Prognosis, Diagnosis and Oncological Management.................. 579

49 
Elżbieta Senkus and Aleksandra Łacko

50 The Role of Surgery in Metastatic Disease to the Bone.......................................................................... 595

Amit Kumar and Robert U. Ashford

Roles of Surgery and Modern Radiation Techniques in Metastatic

51 
Disease Affecting the Brain....................................................................................................................................... 603
Garth Cruickshank

Local Therapies for Liver Metastases from Breast Cancer.................................................................... 613

52 
Robert P. Jones, Hassan Z. Malik, and Carlo Palmieri

Role of Surgery in Lung Metastases from Breast Cancer....................................................................... 619

53 
Michael Shackcloth and Susannah Love

Surgery for Locally Advanced Breast Cancer................................................................................................. 625

54 
Jaroslaw Skokowski and Pawel Kabata

The Role of Surgery to the Primary Cancer in Stage IV Disease........................................................ 633

55 
Seema A. Khan and Patience Odele

56 Palliative Care..................................................................................................................................................................... 641

Tiina Saarto

Supportive Care................................................................................................................................................................ 649

57 
Renata Zaucha

VIII Survivorship
Breast Cancer Survivorship: Chronic Post-operative Pain
58 
and Sensory Changes.................................................................................................................................................... 659
Tuomo J. Meretoja

59  reast Cancer Survivorship: Psychological Distress, Body Image, Sexuality

B
and Importance of the Clinical Consultation................................................................................................. 663
Louise Fairburn, Christopher Holcombe, and Helen Beesley

Bone Health in Patients with Breast Cancer................................................................................................... 673

60 
Amy Kwan and Janet E Brown

Nursing Issues and the Role of the Specialist Nurse in Breast Care............................................... 681

61 
Victoria Harmer

62 Breast Cancer-Related Lymphedema.................................................................................................................. 689

Heli Kavola and Sinikka Suominen

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 XIII
Contents

IX Quality Assurance
63 Research and Audit in Advancing the Quality of Breast Cancer Care........................................... 703
Petra G. Boelens, Elma Meershoek-Klein Kranenbarg, Esther Bastiaannet,
Cornelis van de Velde, and Riccardo A. Audisio

X Appendix
64 MCQ Self-Test...................................................................................................................................................................... 715
Lynda Wyld and Christos Markopoulos

Erratum to: The Breast and Oncoplastic Multidisciplinary Team............................................................. E1

 Supplementary Information
 Index........................................................................................................................................................................................... 721

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Contributors

Roberto Agresti, MD Giulia Bianchi, MD
Fondazione IRCCS Istituto Nazionale dei Tumori Medical Oncology Unit
Surgery – Breast Surgery Unit Department of Medical Oncology
Milan, Italy Fondazione IRCCS Istituto Nazionale dei Tumori
roberto.agresti@istitutotumori.mi.it Milan, Italy
giulia.bianchi@istitutotumori.mi.it
Constantine N. Antonopoulos, MD, PhD, FEBVS
National and Kapodistrian University of Athens Laura Biganzoli, MD
Medical School, Department of Hygiene, Nuovo Ospedale-Santo Stefano Istituto Toscano Tumori
Epidemiology and Medical Statistics Department of Medical Oncology
Athens, Greece Prato, Italy
kostas.antonopoulos@gmail.com laura.biganzoli@uslcentro.toscana.it

Robert U. Ashford, MBBS, FRCS, MD Petra G. Boelens

University Hospitals of Leicester NHS Trust Department of Surgery
Department of Orthopaedics, Leicester Royal Infirmary Leiden University Medical Center
Leicester, UK Leiden, The Netherlands
Robert.Ashford@uhl-tr.nhs.uk P.G.Boelens@lumc.nl

Riccardo A. Audisio Jana de Boniface, MD, PhD

St Helens and Knowsley Teaching Hospitals NHS Trust Karolinska University Hospital
University of Liverpool, Department of Surgery Department of Breast and Endocrine Surgery
Liverpool, Merseyside, UK Stockholm, Sweden
raudisio@doctors.org.uk Jana.de-boniface@ki.se

Hatem A. Azim Jr, MD, PhD Riccardo Bonomi, MD

2BrEAST Data Centre, Department of Medicine Western Sussex Hospital Foundation Trust
Institut Jules Bordet, and l'Université Libre de Bruxelles Worthing Hospital
(U.L.B.) Worthing, West Sussex, UK
Brussels, Belgium riccardo.bonomi@wsht.nhs.uk
hatemazim@icloud.com
Janet E Brown, MD
Esther Bastiaannet, PhD University of Sheffield
Leiden University Medical Center Academic Unit of Clinical Oncology
Department of Surgery Sheffield, UK
Leiden, The Netherlands j.e.brown@sheffield.ac.uk
e.bastiaannet@lumc.nl
Maria-João Cardoso, MD, PhD
Helen Beesley, D.Clin.Psychol Champalimaud Foundation, Breast Unit
University of Liverpool Lisbon, Portugal
Institute of Psychology Health and Society maria.joao.cardoso@fundacaochampalimaud.pt
Liverpool, Merseyside, UK
h.c.beesley@liverpool.ac.uk Helena Carley, MBChB (Hons), BSc (Hons)
Guy’s and St. Thomas’ NHS Foundation Trust
Leif Bergkvist, MD, PhD Department of Clinical Genetics, Guy’s Hospital
Västmanland County Hospital Västerås London, UK
Center for Clinical Research Helena.carley@gstt.nhs.uk
Uppsala University and Department of Surgery
Västerås, Sweden
leif.bergkvist@ltv.se

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 XV
Contributors

Stacey A. Carter, MD Marloes Gertruda Maria Derks, MD
Baylor College of Medicine, Department of Surgery Leiden University Medical Center
Houston, TX, USA Department of Surgery
stacey.carter@bcm.edu Leiden, Zuid-Holland, The Netherlands
m.g.m.derks@lumc.nl
Monica Castiglione, MD
IBCSG (International Breast Cancer Study Group) Samantha Dicuonzo, MD
Berne, Switzerland European Institute of Oncology
monica.castiglione@bluewin.ch Milan, Italy
samantha.dicuonzo@ieo.it
Giuseppe Catanuto, MD, PhD
Azienda Ospedaliera Cannizzaro Luc Dirix
U.O.C. Multidisciplinare di Senologia Medical Oncology, EUSOMA Breast Unit
Catania, Italy Wilrijk Antwerp, Belgium
giuseppecatanuto@gmail.com luc.dirix@telenet.be

Petros Charalampoudis, MD, FRCS, FEBS Michael Douek, MD, FRCS

Guy’s and St. Thomas’ NHS Foundation Trust Guy’s and St. Thomas’ Hospital-London
King’s College London, Breast Unit Research Oncology
(Guy’s and St. Thomas’ NHS Foundation Trust) London, UK
Division of Cancer Studies (King’s College London) michael.douek@kcl.ac.uk
London, UK
Petros.Charalampoudis@gstt.nhs.uk Nuria Dueñas, MD
Hospital de Sant Pau
Kwok-Leung Cheung, DM, FRCSEd, FACS Department of Medical Oncology
University of Nottingham Barcelona, Catalonia, Spain
School of Medicine, Royal Derby Hospital Centre ndueñas@santpau.cat
Derby, UK
kl.cheung@nottingham.ac.uk Nicholas Eastley, MBCHB, BMedSci, MRCS
University Hospitals of Leicester NHS Trust
Lorna J. Cook, BA, MBBS, FRCS Department of Orthopaedics, Leicester Royal Infirmary
Guy’s and St. Thomas’ Hospital-London Leicester, UK
Lavant, West Sussex, UK neastley@doctors.org.uk
lorna.cook@kcl.ac.uk
Angela Esposito
Carmen Criscitiello Istituto Europeo di Oncologia
Istituto Europeo di Oncologia Division of Early Drug Development
Division of Early Drug Development for Innovative Therapies
for Innovative Therapies, Division of Pharmacy Division of Pharmacy
Milan, Italy Milan, Italy
carmen.criscitiello@ieo.it angela.esposito@ieo.it

Garth Cruickshank, PhD, MBBS, FRCS Ruth Exner, MD

University of Birmingham, Institute of Cancer and Department of Surgery and
Genomic Sciences and Department of Neurosurgery Comprehensive Cancer Center
Queen Elizabeth Hospital Birmingham Medical University of Vienna
Edgbaston, Birmingham, West Midlands, UK Vienna, Austria
g.s.cruickshank@bham.ac.uk ruth.exner@meduniwien.ac.at

Giuseppe Curigliano, MD, PhD Louise Fairburn, D.Clin.Psychol, MSc, BA (Hons)

Istituto Europeo di Oncologia Royal Liverpool and Broadgreen
Division of Early Drug Development University Hospitals NHS Trust
for Innovative Therapies Liverpool Cancer Psychology ­Service
Milan, Italy Prescot Street, Liverpool, UK
giuseppe.curigliano@ieo.it louise.fairburn@rlbuht.nhs.uk

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XVI
Contributors

Florian Fitzal, FEBS Christopher Holcombe, MD, FRCS

Medical University of Vienna
Department of Surgery and
Comprehensive Cancer Center
Vienna, Austria
florian.fitzal@meduniwien.ac.at
Royal Liverpool University Hospital
Department of Breast and Endocrine Surgery
Linda McCartney Centre
Liverpool, Merseyside, UK
chris.holcombe@rlbuht.nhs.uk

Jan Frisell, MD, PhD Barbara Alicja Jereczek-Fossa, MD, PhD

Department of Molecular Medicine and Surgery European Institute of Oncology
Karolinska Institutet Milan, Italy
Stockholm, Sweden barbara.jereczek@ieo.it

Department of Breast and Endocrine Surgery

Robert P. Jones, BSc (Hons), MBChB, PhD, MRCS
Karolinska University Hospital
University of Liverpool
Stockholm, Sweden
Institute of Translational Medicine
Jan.Frisell@ki.se
Liverpool, UK
robjones@liv.ac.uk
Marios K. Georgakis, MD
National and Kapodistrian University of Athens
Pawel Kabata, MD, PhD
Medical School, Department of Hygiene,
Department of Surgical Oncology
Epidemiology and Medical Statistics
Medical University of Gdansk
Athens, Greece
Gdansk, Poland
mgeorgakis91@gmail.com
pawel.kabata@gumed.edu.pl

Michael Gnant, MD
Loraine Kalra, MBBS, MS, MRCS, EBSQ
Department of Surgery and
Royal Victoria Infirmary
Comprehensive Cancer Center
Queen Victoria Road
Medical University of Vienna
Newcastle Upon Tyne NE1 4LP, UK
Vienna, Austria
dr_lorainekalra@hotmail.com
michael.gnant@meduniwien.ac.at

Andreas Karakatsanis, PhD
Kelvin Francis Gomez, MBChB, MD, FRSCEd
Department for Surgical Sciences
Nevill Hall Hospital
Uppsala University and Section for Endocrine
Department of Breast Surgery,
and Breast Surgery, Uppsala University Hospital
Abergavenny, Wales, UK
Uppsala, Sweden
Kelvin.gomez@wales.nhs.uk
Andreas.Karakatsanis@surgsci.uu.se

Rossella Graffeo, MD
Heli Kavola, MD, PhD
Institute of Oncology (IOSI) and
Helsinki University Hospital
Breast Unit of Southern Switzerland (CSSI)
Department of Plastic Surgery
Bellinzona, Switzerland
Helsinki, Finland
rossella.graffeogalbiati@eoc.ch
heli.kavola@hus.fi

Bahadir M. Gulluoglu, MD, FACS

Seema Ahsan Khan, MD
Marmara University School of Medicine
Co-leader Women’s Cancer Research Program
Department of General Surgery,
Robert H. Lurie Comprehensive Cancer Center
Breast and Endocrine Surgery Unit
Northwestern Hospital, Department of Surgery
Istanbul, Turkey
Chicago, IL, USA
bmgulluoglu@marmara.edu.tr
s-khan2@northwestern.edu

Victoria Harmer, DHC, MBA,

V. Suzanne Klimberg, MD
BSc(Hons) Dip, RN AKC
Breast Surgical Oncology, University of Arkansas
Breast Care, Imperial College Healthcare NHS Trust
for Medical Sciences (UAMS)
Department of Breast Care,
Winthrop P. Rockefeller Cancer Institute
Charing Cross Hospital
Division of Breast and Surgical Oncology
London, UK
Little Rock, AR, USA
Victoria.harmer@imperial.nhs.uk
klimbergsuzanne@uams.edu

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 XVII
Contributors

Hans-Christian Kolberg, MD Matteo Lambertini, MD
Marienhospital Bottrop gGmbH Institut Jules Bordet and l'Université Libre
Obstetrics and Gynecology/Breast Cancer Center/ de Bruxelles (U.L.B.), Breast Data Centre
Gynecologic Cancer Center Department of Medicine
Bottrop, Germany Brussels, Belgium
hans-christian.kolberg@mhb-bottrop.de matteo.lambertini85@gmail.com

Maija Kolehmainen, MD Valentina Lefemine, MD, FRCS

Helsinki University Hospital, Helsinki University Nevill Hall Hospital
Department of Plastic Surgery Department of Breast surgery
Helsinki, Finland Abergavenny, Wales, UK
Maija.kolehmainen@hus.fi Valentina.lefemine@wales.nhs.uk

Michalis Kontos, MD, PhD Marjut Leidenius, MD, PhD

National and Kapodistrian University of Athens Department Head, Helsinki University Hospital
1st Department of Surgery Comprehensive Cancer Center, Breast Surgery Unit
Athens, Greece Helsinki, Finland
Mchalis_Kontos@yahoo.com marjut.leidenius@hus.fi

Tibor Kovacs, PhD, FRCS, EBSQ Maria Cristina Leonardi, MD

Guy’s and St. Thomas’ NHS Foundation Trust European Institute of Oncology
Breast Unit, King’s College London Milan, Italy
London, UK cristina.leonardi@ieo.it
Tibor.Kovacs@gstt.nhs.uk
Cornelia Liedtke, MD, PhD
Jaroslaw Krupa, MD, PhD Klinik für Frauenheilkunde und Geburtshilfe
University Hospitals of Leicester NHS Trust Universitätsklinikum Schleswig-Holstein/
Department of Breast Surgery, Glenfield Hospital Campus Lübeck
Leicester, UK Lübeck, Germany
jaroslaw.krupa@uhl-tr.nhs.uk cornelia.liedtke@uksh.de

Thorsten Kuehn, MD Andrew Lindford, MBBS, MRCS, FEBOPRAS, PhD

Department of Gynecology Helsinki University Hospital
Esslingen, Germany Department of Plastic Surgery
kuehn.thorsten@t-online.de Helsinki, Finland
Andrew.lindford@hus.fi
Anju Kulkarni, MBBS, BSc, MD(Res), FRCP
Clinical Genetics, Guy’s Hospital Susannah Love, BA (Hons), MBBS, MRCS
London, UK Liverpool Heart and Chest Hospital
Anjana.kulkarni@gstt.nhs.uk Department of Thoracic Surgery
Liverpool, UK
Amit Kumar, BSc, MBBS, FRCS Ed (Tr & Orth) Susannah.love@lhch.nhs.uk
University Hospitals Leicester NHS Trust
Department of Orthopaedics Ernest J.T. Luiten, MD
Leicester, UK Amphia Hospital
mrakuamr@mac.com Department of Oncologic Breast Surgery
Breda, The Netherlands
Amy Kwan, MBBS, BSc eluiten@amphia.nl
University of Sheffield
Academic Unit of Clinical Oncology Fiona MacNeill, MD, MBBS, FRCS, FEBS
Sheffield, UK Royal Marsden Hospital
amy.kwan@sheffield.ac.uk London, UK
fiona.macneill@rmh.nhs.uk
Aleksandra Łacko, MD, PhD
Department of Clinical Oncology
Wroclaw Medical University
Wrocław, Poland
olalacko@wp.pl

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XVIII
Contributors

Hassan Z. Malik, MBChB, MD Olivia Pagani, MD

School of Cancer Studies Institute of Oncology (IOSI) and
Institute of Translational Medicine Breast Unit of Southern Switzerland (CSSI)
University of Liverpool Bellinzona, Switzerland
North Western Hepatobiliary Unit Olivia.Pagani@eoc.ch
Aintree University Hospital
Liverpool, UK Peter Palhazi, MD
hassan.malik@aintree.nhs.uk Department of Anatomy
Histology and Embryology, Semmelweis University
Christos Markopoulos, MD, PhD Budapest, Hungary
Medical School - National and Kapodistrian peterpalhazi@gmail.com
University of Athens
2nd Department of Propedeutic Surgery - Breast Unit Carlo Palmieri, MBBS, PhD
Athens, Greece Molecular and Clinical Cancer Medicine
cmarkop@hol.gr Institute of Translational Medicine
University of Liverpool
John Mathew, DM, FRCS Liverpool, UK
Royal Derby Hospital, Breast Unit
Liverpool and Merseyside Breast Academic Unit
Derby, UK
The Linda McCartney Centre
John.Mathew2@pbh-tr.nhs.uk
Royal Liverpool University Hospital
Liverpool, UK
Zoltán Mátrai, MD, PhD, FEBS
National Institute of Oncology Academic Department of Medical Oncology
Center of Surgical Oncology Clatterbridge Cancer Centre NHS Foundation Trust
Department of Breast and Sarcoma Surgery Wirral, UK
Budapest, Hungary C.Palmieri@liverpool.ac.uk
matraidoc@gmail.com
Ruth Parks, BMedSci, MBBS, MRCS
Elma Meershoek-­Klein Kranenbarg University of Nottingham, School of Medicine
Datacenter, Department of Surgery Royal Derby Hospital Centre
Leiden University Medical Center Derby, UK
Leiden, The Netherlands ruth.parks@nhs.net
w.m.meershoek-klein_kranenbarg@lumc.nl
Fedro Alessandro Peccatori, MD, PhD
Tuomo J. Meretoja, MD, PhD Fertility and Procreation Unit
Helsinki University Hospital Division of Gynecologic Oncology
Comprehensive Cancer Center European Institute of Oncology
Breast Surgery Unit Milan, Italy
Helsinki, Finland fedro.peccatori@ieo.it
tuomo.meretoja@hus.fi
Frederique Penault-Llorca, MD, PhD
Adamantios Michalinos, MD, PhD Departments of Pathology and Biopathology
Department of Anatomy Jean Perrin Comprehensive Cancer Centre
National and Kapodistrian University of Athens Clermont-Ferrand, France
Helsinki, Finland frederique.penault-llorca@clermont.unicancer.fr
amichalinos@hotmail.com
Eleni Th. Petridou, MD, MPH, PhD
Anna Rachelle Mislang, MD, FRACP (Australia) National and Kapodistrian, University of Athens
Nuovo Ospedale-Santo Stefano Istituto Toscano Tumori Medical School, Department of Hygiene,
Department of Medical Oncology Epidemiology and Medical Statistics
Prato, Italy Athens, Greece
amislang@uslcentro.toscana.it epetrid@med.uoa.gr

Patience Odele, MD
Northwestern Hospital
Department of Surgery
Chicago, IL, USA
patience.odele@northwestern.edu

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 XIX
Contributors

Sarah E. Pinder, MBChB, FRCPath Kerstin Sandelin, MD, PhD

King’s College London, Guy’s and Department of Breast and Endocrine Surgery
St. Thomas’ Hospitals Karolinska University Hospital
Research Oncology, Cancer Division, Guy’s Hospital Stockholm, Sweden
London, UK
Department of Molecular Medicine and Surgery
sarah.pinder@kcl.ac.uk
Karolinska Institutet
Stockholm, Sweden
A. Prove
kerstin.sandelin@karolinska.se
Medical Oncology, EUSOMA Breast Unit
Wilrijk, Antwerp, Belgium
Elias E. Sanidas, MD, FACS
Heraklion Medical School
Breast Unit-Medical Oncology
Heraklion, Crete, Greece
Sint-Augustinus Cancer Centre
Iridium Network, Antwerp, Belgium Asklipeion Private Hospital
annemie.prove@gza.be Department of Surgery
Heraklion, Crete, Greece
Manuela Rabaglio, MD eliassanidas@gmail.com
IBCSG (International Breast Cancer Study Group) and
University Hospital – Inselspital Berne Inkeri Schultz, MD, PhD
Department of Medical Oncology Karolinska University Hospital
Bern, Switzerland Department of Reconstructive Plastic Surgery
manuela.rabaglio@ibcsg.org Stockholm, Sweden

Department of Molecular Medicine and

Nina Radosevic-Robin, MD
Surgery at Karolinska Institutet
Jean Perrin Comprehensive Cancer Centre
Stockholm, Sweden
Department of Pathology and Biopathology
inkeri.leonardsson-schultz@karolinska.se
Clermont-­Ferrand, France
nina.robin@clermont.unicancer.fr
Elżbieta Senkus, MD, PhD
Medical University of Gdańsk
Teresa Ramón y Cajal, MD, PhD
Department of Oncology and Radiotherapy
Hospital de Sant Pau
Gdańsk, Poland
Department of Medical Oncology
elsenkus@gumed.edu.pl
Barcelona, Catalonia, Spain
tramon@santpau.cat
Abeer M. Shaaban, MBChB, PhD, FRCPath
Queen Elizabeth Hospital Birmingham
Fabio Rapisarda, MD, MSc, MCh, FEBS
Department of Histopathology
Western Sussex Hospital Foundation Trust
Birmingham, West Midlands, UK
Lyndhurst Road
a.shaaban@bham.ac.uk
Worthing, West Sussex, UK
fabio.rapisarda@gmail.com
Michael Shackcloth, MD
Liverpool Heart and Chest Hospital
Isabel T. Rubio, MD
Department of Thoracic Surgery
Breast Surgical Oncology
Liverpool, UK
Hospital Universitari Vall d’Hebron
Michael.shackcloth@lhch.nhs.uk
Breast Cancer Center
Barcelona, Catalonia, Spain
Anne Shrestha, BMedSci, MBChB, MRCS, PGCME
irubio@vhio.net
The Medical School, Department of Oncology and
Metabolism, University of Sheffield
Tiina Saarto, MD, PhD
Sheffield, UK
Helsinki University and Helsinki University Hospital
shrestha.anne@gmail.com
Comprehensive Cancer Center
Helsinki, Finland
tiina.saarto@hus.fi

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XX
Contributors

Mark Sibbering, FRCS L-A Teuwen

Royal Derby Hospital, Breast Unit Hospital: GZA Sint-Augustinus
Derby, UK Center for Oncological Research
mark.sibbering@nhs.net Wilrijk, Antwerp, Belgium
laure-anne@teuwen.com
George Skandalakis
Department of Anatomy Alastair M. Thompson, ALCM, BSc,
National and Kapodistrian University of Athens MB ChB, MD, FRCSEd
Athens, Greece University of Texas MD Anderson Cancer Center
gskandalakis@hotmail.com Houston, TX, USA
AThompson1@mdanderson.org
Panayiotis Skandalakis, MD, PhD
Department of Anatomy Gilles Toussoun
National and Kapodistrian University of Athens Chirurgie Plastique, Reconstructrice et Esthetique
Athens, Greece Polyclinique du Val de Saone
skantakis@yahoo.gr Macon, France
dr.gilles.toussoun@gmail.com
Jaroslaw Skokowski, MD, PhD
Medical University of Gdansk Giovanna Trecate, MD
Department of Surgical Oncology Radiology and Magnetic Resonance Unit
Gdansk, Pomorskie, Poland Department of Radiology
jskokowski@gumed.edu.pl Fondazione IRCCS Istituto Nazionale dei Tumori
Milan, Italy
Andrea Spano, MD giovanna.trecate@istitutotumori.mi.it
Fondazione IRCCS Istituto Nazionale dei Tumori,
Surgery – Plastic and Reconstructive Surgery Theodore G. Troupis, MD, PhD
Milan, Italy Department of Anatomy, National and Kapodistrian
andrea.spano@istitutotumori.mi.it University of Athens
Athens, Greece
Petra Steyerova, MD ttroupis@gmail.com
General University Hospital Prague
Clinic of Radiology Erkki Tukiainen, MD, PhD
Breast Cancer Screening and Diagnostic Centre Department of Plastic Surgery, Töölö Hospital
Prague, Czech Republic Helsinki University Hospitals
steyerovap@gmail.com Helsinki, Finland
erkki.tukainen@hus.fi
Sinikka Suominen, MD, PhD
Department of Plastic Surgery M. Umit Ugurlu, MD, FEBS
Helsinki University Hospital Marmara University, School of Medicine
Helsinki, Finland Department of General Surgery
Maltepe, Istanbul, Turkey
Helsinki University, Plastic Surgery
Helsinki, Finland Breast and Endocrine Surgery Unit
sinikka.suominen@hus.fi Fevzi Cakmak M. Marmara Universitesi Pendik EAH
Istanbul, Turkey
Melissa Ley Hui Tan, FRCS umit.ugurlu@marmara.edu.tr
Royal Marsden Hospital
London, UK Cornelis van de Velde
Melissa.Tan@rmh.NHS.UK Department of Surgery
Leiden University Medical Centre
Marios Konstantinos Tasoulis, PhD Leiden, The Netherlands
Royal Marsden Hospital c.j.h.van_de_velde@lumc.nl
London, UK
Marios.Tasoulis@RMH.NHS.UK

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 XXI
Contributors

Anna Virgili, MD Lynda Wyld, MBChB, PhD, FRCS

Hospital de Sant Pau, Department of Medical Oncology E Floor, The Medical School
Barcelona, Catalonia, Spain Department of Oncology and Metabolism
avirgili@santpau.cat University of Sheffield
Sheffield, UK
Athina Vourtsis, MD, PhD l.wyld@sheffield.ac.uk
Diagnostic Mammography Center
Athens, Greece Renata Zaucha, MD, PhD
vourtsis@mammography.gr Clinical Center of the Medical University of Gdansk
Department of Oncology and Radiotherapy
Kerstin Wimmer, MD Gdansk, Poland
Department of Surgery and rzaucha@gumed.edu.pl
Comprehensive Cancer Center
Medical University of Vienna Janez Zgajnar, MD, PhD
Vienna, Austria Institute of Oncology Ljubljana
kerstin.wimmer@meduniwien.ac.at Department of Surgical Oncology
Ljubljana, ­Slovenia
jzgajnar@onko-i.si

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 1 I

Basic Science
Contents

Chapter 1 Gross Anatomy of the Breast and Axilla – 3

Peter Palhazi

Chapter 2 Physiology and Developmental Stages

of the Breast – 11
Theodore G. Troupis, Adamantios Michalinos,
George Skandalakis, and Panayiotis Skandalakis

Chapter 3 Breast Cancer Epidemiology – 19

R.M. Parks, M.G.M. Derks, E. Bastiaannet,
and K.L. Cheung

Chapter 4 Effect of Oestrogen Exposure, Obesity,

Exercise and Diet on Breast Cancer Risk – 31
Eleni Th. Petridou, Marios K. Georgakis,
and Constantine N. Antonopoulos

Chapter 5 Hereditary Breast Cancer Genetics and

Risk Prediction Techniques – 43
Helena Carley and Anju Kulkarni

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 3 1

Gross Anatomy of the Breast

and Axilla
Peter Palhazi

1.1 Overview – 4

1.2 Fascial and Ligamentous Structure – 4

1.3 Blood Supply – 5

1.4 Innervation – 6
1.5 Muscles of the Anterior Chest Wall – 7

1.6 Lymphatic Drainage – 7

1.7 The Anatomy of the Axilla – 9

1.8 Summary – 9

References – 9

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_1

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 4 P. Palhazi
1.1 Overview
1 Numerous sweat and sebaceous glands can be found among
The female breast is located on the chest wall between the
second and sixth or seventh ribs, lateral to the sternum and
medial to the anterior axillary line [1]. It is associated poste-
riorly with the fascia of the pectoralis major, serratus ante-
rior, abdominal external oblique and the most cranial part of
the rectus abdominis muscles. Its ideal shape is classically
described as a combination of cone and hemisphere. Its vol-
ume is determined by the amount of fatty and glandular tis-
sue. The glandular tissue is less dominant until the second
half of pregnancy. The gland becomes fully developed during
lactation. The fatty and glandular tissue is suspended by the
fascial-ligamentous system and the skin envelope. The quan-
tity, quality and relationship of these four factors determine
the shape of the breast.
The glandular tissue consists of 15–20, radially located
lobes (. Fig. 1.1). They are separated from each other by cell-
poor, fibrous, interlobular bundles. The lobes consist of lob-
ules. Each lobule has its own duct. The lobules are surrounded
by dense fibrous tissue with a significant amount of fatty tis-
sue. The 15–20 main ducts branch and finally terminate in
the terminal duct lobular unit (TDLU) that secretes milk
during lactation.
The nipple-areola complex (NAC) is located on the most
prominent part of the breast mound. Most textbooks state that
there are 15–20 main ducts with 15–20 ductal orifices on the
top of the nipple. According to classical anatomical descrip-
tions, each lobe has its own main duct and orifice; however,
some publications state less, 5–9 nipple ductal orifices. Possi-
ble explanations for the discrepancy may be the sebaceous
glands that mimic the appearance of ducts but do not contrib-
ute to the ductal lobular infrastructure or that some ducts
bifurcate shortly after emerging from the nipple [2]. The ducts
have a zone which expands (lactiferous sinus) directly under-
neath the nipple [3]. They serve as a milk reservoir during
lactation; however, recent studies doubt their existence [4].
The pigmented areola contains several prominences. They are
TDLU-s
main lactiferous duct
..      Fig. 1.1  The lactiferous ducts of a premenopausal breast lobe are
filled with plastic. Blue colour indicates the ductal structure, while white
colour indicates the TDLUs
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modified accessory glands, so-called glands of Montgomery.
these, which keep the NAC lubricated and protected.
The breast can be divided practically into six portions.
According to horizontal and vertical axes, four quadrants can
be differentiated. The central substance is located behind the
areola, while an extension of the breast extends into the axilla
(Spence’s tail).
1.2 Fascial and Ligamentous Structure
The breast integrates into the superficial fascial system [5] of
the trunk, which is located between the chest musculature
and the skin. The superficial fascia of the breast encases the
glandular tissue with its anterior and posterior lamella. The
anterior lamella is located superficial to the gland at varying
distances from the dermis. It is important to note that the
superficial fascia of the breast is not a unified demarcation
sheet, but a pitted cloak-like structure. The anterior lamella
has clinical significance during skin-sparing mastectomies.
The posterior lamella covers the undersurface of the gland
and continues as Scarpa’s fascia [6] inferiorly. Between the
posterior lamella and the pectoral fascia, the retromammary
space (Chassaignac’s bursa) can be found [7]. This space con-
tains fine areolar tissue, which can be dissected bluntly and
serves as a pocket during sub-glandular breast augmentation.
The main suspensory ligaments of the breast course from
the pectoral fascia through the glandular tissue to the skin.
These are the so-called Cooper’s ligaments [8]. These liga-
ments have three distinct segments (deep, middle, superfi-
cial) created by the aforementioned anterior and posterior
lamella of the superficial fascia of the breast. The deep seg-
ment is between the pectoral fascia and the posterior lamella,
the middle segment is between the posterior and anterior
lamella, and the superficial segment is between the anterior
lamella and the skin (. Fig. 1.2). Cooper’s ligaments have sig-
nificant oncologic importance. Their deep segment anchors
the breast to the pectoral fascia, so total removal of the gland
is facilitated by removal of the pectoral fascia. A tumour may
also infiltrate these ligaments causing skin retraction, which
is an important diagnostic sign of breast cancer. By contrac-
tion of the pectoralis major muscle, this skin sign can be pro-
voked, which is an important clinical indicator of malignancy.
The posterior lamella of the superficial fascia continues as
Scarpa’s fascia inferiorly. The anterior lamella also connects
to the posterior lamella at the level of the fifth rib. This junc-
tion is fixed to the pectoral fascia, because the posterior
lamella and the pectoral fascia get close to each other side to
side. From this point several strong ligaments can be observed
towards the dermis of the inferior pole and also the inframam­
mary fold. They are considered the inframammary fold liga-
ments [9]. This anatomical feature may explain the fixed
position of the inframammary fold during ageing.
There is a clinically important fibrous septum in the
breast, called the septum fibrosum (. Fig. 1.3, Modified from
Wuringer) [10].
Gross Anatomy of the Breast and Axilla
5 1
It is located horizontally at the level of the fifth rib towards
the nipple. It divides the glandular tissue into an upper and
lower part. It is reinforced medially and laterally by vertical
horns. The medial horn of the septum fibrosum attaches para-
sternally between the second and fifth rib, while the lateral
horn attaches to the lateral margin of the pectoralis major
muscle. The septum fibrosum contains neurovascular struc-
tures supplying the NAC and gland. The thoracoacromial and
deep branches of the lateral thoracic artery travel on the cra-
nial side of this septum, while the fourth – rarely the fifth and
sixth – intercostal artery perforator travels on the caudal side
of it. The lateral cutaneous branches of the fourth intercostal
nerve travel also along this septum. The breast can be dis-
sected bluntly along this septum from the posterior side, so
the blood supply can be preserved to the NAC during surgery.

1.3 Blood Supply

One can divide the arterial system of the breast into superfi-
cial and deep groups. Deep vessels penetrate the breast mainly
along the septum fibrosum in the posterior to anterior direc-
tion, while the superficial ones travel in the subcutaneous
layer towards the NAC (. Fig. 1.4). The superficial and deep
 

..      Fig. 1.2  Ligaments in between the skin and the anterior lamella of

the superficial fascia of the breast. A superficial branch of the second
internal mammary artery perforator is also seen

Clavicle
Pectoral fascia

Retromammary
Pectoralis space
major

Thoracoacromial
artery

Intercostal
artery 4

Intercostal
artery 5
Fibrous septum

Inframammary
fold ligament

..      Fig. 1.4  Blood supply of the breast. Superficial and deep branches

..      Fig. 1.3  Schematic representation of a lateral cross-sectional view of the lateral thoracic vessels (A), second and third internal mammary
of the fibrous septum of the breast vessel perforators (B, C), fourth intercostal vessel perforators (D)

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 6 P. Palhazi

vessels create an anastomosing subdermal net underneath
1 the areola that supplies the NAC. One of the most important
aspects of the vascular anatomy is the blood supply to the
NAC.  Blood supply of the NAC is beautifully described in
relation to oncoplastic surgery in the work of van Deventer
and colleagues (2004) [11]. Surgeons should be aware of the
common patterns and how they may vary.
The second to fourth internal mammary artery perfora-
tors belong to the superficial group. After piercing the chest
wall, they get into the subcutaneous tissue, where they travel
further towards the nipple. They are the dominant blood sup-
ply of the NAC [12], although there may be considerable
anatomic variation in the number and direction of NAC
feeding vessels which may account for some instances of
cervical plexus [8]. The anterior cutaneous branches of the
intercostal nerves pierce the chest wall parasternally, and
then they travel superficially to laterally and innervate the
medial part of the breast.
The lateral cutaneous branches pierce the chest wall in
the mid-axillary line and then travel towards the NAC to
innervate the outer part of the breast. The upper pole
receives its sensory innervation from the supraclavicular
nerves.
From a surgical point of view, the most important point
is to preserve the sensory innervation of the NAC, which
is ensured most commonly by the deep division of the
lateral cutaneous branches of the fourth intercostal nerve
laterally (. Figs. 1.5 and 1.7) and by the third and fourth

nipple necrosis following surgery. anterior cutaneous branches (superficial course) medially.
The breast receives its blood supply laterally from the lat- The aforementioned deep division of the lateral cutane-
eral thoracic artery. It travels under the lateral margin of the ous branches travels in the pectoral fascia and then cen-
pectoralis major muscle, then passes round the margin and trally pierces the gland and innervates the NAC from
gets into the substance of the breast. It has two main branches. posteriorly [13].
One of them stays deep (deep group), the other becomes The exclusively vasomotor sympathetic fibres reach the
superficial (superficial group) and both travel towards the breast along the aforementioned nerves and vessels, while
nipple. parasympathetic fibres do not run to the breast, because
The thoracoacromial artery (deep group) arises directly secretion is hormonally regulated.
from the axillary artery and then branches underneath the
pectoralis minor muscle. Its pectoral branches supply the
upper pole of the breast.
The second to sixth intercostal artery perforators belong
to the deep group of arteries. They are in general smaller, ran- ACB
dom vessels supplying the base of the breast. Sometimes some
of these arteries can be more prominent, in particular the
fourth intercostal artery perforator. It travels in the axis of the
central parenchyma and supplies it. Sometimes this artery
travels underneath the parenchyma and passes round the
inferior pole of the breast. In particular, the fifth to sixth inter-
LCB
costal artery perforators are located in the area of the infra-
mammary fold. Although they are smaller branches, their
significance is enormous, because they serve as the blood sup-
ply to the inferior pole of the breast and hence are important
in supporting inferior nipple pedicles during breast surgery.
The veins of the breast also have superficial and deep
groups. The deep veins accompany the deep arteries. The
superficial veins accompany the superficial arteries and are
superficial to them. They create a superficial venous system.
The venous blood flows towards the axillary, internal mam-
mary and intercostal veins. The venous plexus underneath
the areola is called the areolar venous plexus. These venous
plexuses may become more apparent after augmentation sur-
gery because of increased venous stasis.

1.4 Innervation

The sensory innervation of the breast is provided by the ante-

rior and lateral cutaneous branches of the second to sixth ..      Fig. 1.5  Figure demonstrating a schematic of the nerve supply to
intercostal nerves and the supraclavicular branches of the the breast

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Gross Anatomy of the Breast and Axilla
..      Fig. 1.6  Muscles of the chest wall in the area of the breast
footprint. Serratus anterior (A), pectoralis major (B), abdominal external
oblique (C) and rectus abdominis muscles (D)
1.5 Muscles of the Anterior Chest Wall
The most dominant muscle on the chest wall is the pectoralis
major muscle (. Fig. 1.6). It originates from the clavicle, the
 
sternum, the sixth to seventh ribs and the abdominal wall
and inserts into the crest of the greater tubercle of the
humerus [7]. Further fibres may originate from the fascia of
the rectus abdominis muscle or from the upper part of the
abdominal external oblique muscle. The blood supply of the
pectoralis major muscle is from the pectoral branches of the
thoracoacromial artery and branches of the lateral thoracic
artery and the intercostal artery perforators. It is innervated
by the medial and lateral pectoral nerves. The medial branch
pierces the pectoralis minor muscle, which is often visible
during dissection under the pectoralis major muscle. The lat-
eral branch passes round the pectoralis minor muscle medi-
ally and then reaches the pectoralis major muscle. Ideally
these nerves should be preserved during axillary surgery.
The pectoralis minor muscle lies underneath the pectora-
lis major muscle, originates from the third to fifth ribs and
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7 1
..      Fig. 1.7  The lateral cutaneous branch of the fourth intercostal
nerve in a right-sided breast
inserts to the coracoid process of the scapula. Blood supply
and innervation are the same as for the pectoralis major
muscle.
The serratus anterior muscle covers the lateral thoracic
wall, originates from the first nine ribs with alternating
laces with the abdominal external oblique muscle and
inserts to the medial margin of the scapula. Its upper part
is supplied by the lateral thoracic artery, and its lower pole
is supplied by the thoracodorsal artery. It is innervated by
the long thoracic nerve, which travels down covered by the
muscle fascia and innervates each lace by separate nerve
branches.
1.6 Lymphatic Drainage
The lymphatic drainage of the breast is provided by four
communicating lymphatic plexuses. The superficial network
is located in the layers of the skin: the cutaneous plexus
drains the lymph of the dermis and the subcutaneous plexus
drains the lymph of the subcutaneous tissue. The deep net-
work consists of the fascial plexus (located in the pectoral
fascia) and the glandular plexus (drains the gland). Density
of the lymphatic vessels is the highest directly underneath the
areola in the subcutaneous layer [14] (Sappey’s subareolar
plexus). The cutaneous plexus with perforating branches, the
glandular plexus along the ducts and the fascial plexus along
 8 P. Palhazi
1
Supraclavicular
lymph nodes
Humeral (lateral)
lymph nodes
Central lymph
nodes
Apical lymph
nodes
Axillary
lymph nodes Subscapular
(posterior) lymph
nodes
Pectoral
(anterior) lymph
nodes
..      Fig. 1.8  Figure showing the lymph node groupings in the axilla
the connective tissue fibres connect directly to Sappey’s sub-
areolar plexus.
The lymph drainage of the breast is provided on one hand
by the lymph vessels from the Sappey’s subareolar plexus and
on the other hand by the direct efferents from the glandular
tissue.
The primary drainage is towards the axilla by the lateral
efferents, which is responsible for 75% of the breast drainage
[15].
One can divide the axillary lymph nodes anatomically
into five groups: anterior, posterior, lateral, apical and central
(. Fig.  1.8). The anterior lymph nodes are underneath the
 
lateral margin of the pectoralis major muscle, along the lat-
eral thoracic vein. Their afferents drain directly the glandular
tissue.
The posterior lymph nodes lay on the posterior wall of the
axilla, along the thoracodorsal bundle. The lateral lymph
nodes are located laterally in tight topographic relationship
with the distal axillary vein. They receive the lymph of the
upper limb (except the lymph vessels, which accompany the
cephalic vein). The central lymph nodes are located centrally,
close to the axillary base, behind the pectoralis minor muscle,
and receive afferents from the aforementioned lymph nodes
(anterior, posterior, lateral). The apical lymph nodes are
located in the apex of the axilla, on the medial side of the
proximal axillary vein. These lymph nodes receive their affer-
ent from all of the aforementioned lymph nodes and the
cephalic vein accompanying lymph nodes. The efferent vessels
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Subclavian
lymphatic trunk
Right lymphatic
duct
of the apical lymph nodes unite to form the subclavian lymph
trunk. This trunk opens into the right lymphatic duct on the
right and into the thoracic duct (sometimes directly into the
venous angle) on the left.
Berg’s classification [16] of the lymph nodes is in wide-
spread clinical practice as opposed to the anatomical clas-
sification. Berg defined three groups of axillary lymph
nodes according to their position relative to the pectoralis
minor muscle. Level I lymph nodes are located laterally to
the lateral margin of the muscle. Level II lymph nodes are
located behind the muscle. Level III lymph nodes are
located medially to the medial-superior margin of the mus-
cle. Level I lymph nodes correspond to the anatomical ante-
rior, posterior and lateral lymph nodes. Level II lymph
nodes are the central lymph nodes and some of the apical
lymph nodes. Level III lymph nodes are the apical lymph
nodes. It is important to note that Berg’s classification uses
just the pectoralis minor muscle as a reference point, as
opposed to the anatomical classification, which uses fixed
anatomical landmarks. That is why the positioning of the
arms has enormous consequences during surgeries of the
breast and axilla, marking of the sentinel lymph node and
radiation therapy. Changing the arm position changes the
lymph node levels, which are relative to the pectoralis
minor muscle.
The remaining 25% of the lymph drainage splits among
the so-called extra-axillary efferents, which serve as second-
ary efferent pathways. They play a significant clinical role,
Gross Anatomy of the Breast and Axilla
when the primary lymph efferent vessels close up or become
blocked by previous surgery or tumour emboli, and these
secondary efferents become the main direction of lymph
drainage.
The medial lymph efferent vessels arise mainly from the
deep plexuses and drain the lymph towards those lymph
nodes, which accompany the internal mammary artery. Fur-
thermore, they form subcutaneous anastomosis with the
lymph vessels of the opposite breast [17]. These intermam-
mary connections explain the appearance of metastasis on
the contralateral side in women who have undergone previ-
ous axillary surgery. The posterior [15] intercostal lymph
nodes also receive lymph from the breast. The efferent vessels
of the fascial plexus – piercing the pectoral muscles (transpec-
toral or Grossman’s path) [18] between the pectoralis minor
and major muscles – run to the apical lymph nodes directly
(particularly from the cranial part of the breast) or through
the lymph nodes along the thoracoacromial vessels indi-
rectly.
Sometimes the lymph drainage of the breast courses
towards the sub-diaphragmatic plexus through the abdomi-
nal wall (Gerota’s paramammaris path) [19]. These pathways
may explain some cases of liver metastases.
1.7 The Anatomy of the Axilla
The axilla is a pyramid-like hole with four walls between the
chest and the arm. Its anterior wall consists of the pectoralis
minor and major and subclavius muscles, while its posterior
wall consists of the subscapularis, teres major and latissimus
dorsi muscles. The medial wall is created by the lateral tho-
racic wall, while the lateral wall is created by the structures of
the arm.
The axillary pyramid opens with incision of the axillary
fascia. The aforementioned lymph nodes, vessels and nerves
form a complex network in the axillary fat.
The intercostobrachial nerve is the lateral cutaneous
branch of the second intercostal nerve, which travels from
the second intercostal space obliquely through the axilla
between the anterior and central lymph nodes, and then it
anastomoses with the medial brachial cutaneous nerve. It
participates in sensory innervation of the medial part of the
upper arm. The long thoracic nerve travels downwards, cov-
ered by the fascia of the serratus anterior muscle. It inner-
vates the serratus anterior muscle with motor nerves. Total
injury to the nerve leads to a so-called winged scapula. The
thoracodorsal nerve runs along with the subscapular, thora-
codorsal vessels along the posterior wall of the axilla and
innervates with motor nerves the latissimus dorsi muscle.
The axillary vessels are important landmarks during axil-
lary surgery. Approaching the axilla, the main landmark is
the axillary vein, which is the most anterior and most medial
part of the neurovascular bundle supplying the arm. The axil-
lary vein travels along the lateral wall, close to the posterior
rares1geo@gmail.com
9 1
wall, towards the apex of the axilla. The lateral thoracic artery
and vein and the direct branches of the axillary artery and
vein travel along the inferior edge of the pectoral minor mus-
cle. They run among the anterior lymph nodes and supply the
serratus anterior, pectoralis major, subscapular muscles and
the mammary gland in part. They also supply the anterior,
central and posterior lymph nodes with small branches. The
thoracodorsal artery and vein, the subscapular artery and the
direct branches of the axillary vein run deeply, in tight topo-
graphical relationship with the posterior lymph nodes along
the posterior wall of the axilla. They supply the latissimus
dorsi muscle and, with small branches, the posterior and lat-
eral lymph nodes.
1.8 Summary
The anatomy of the breast and axilla is complex, and under-
standing it is vital for successful breast and axillary surgery.
Knowledge of the blood supply and its anatomic variants has
special relevance in the era of oncoplastic and reconstructive
surgery.
References
1. Westreich M. Anthropomorphic breast measurement: protocol and
results in 50 women with aesthetically perfect breasts and clinical
application. Plast Reconstr Surg. 1997;100(2):468–79.
2. Love SM, Barsky SH. Anatomy of the nipple and breast ducts revis-
ited. Cancer. 2004;101(9):1947–57.
3. Williams PL, Warwick R, Dyson M, Bannister LH, editors. Gray’s anat-
omy. 37th ed. New York: Churchill Livingstone; 1989.
4. Ramsay DT, Kent JC, Hartmann RA, Hartmann PE.  Anatomy of the
lactating human breast redefined with ultrasound imaging. J Anat.
2005;206(6):525–34.
5. Lockwood TE.  Superficial fascial system (SFS) of the trunk and
extremities: a new concept. Plast Reconstr Surg. 1991;87(6):1009–18.
6. Scarpa A. Sull' ernie: memorie anatomico-chirurgiche. 2nd ed. Milano:
d. reale Stamperia; 1820.
7. Romrell LJ, Bland KI. Anatomy of the breast, axilla, chest wall, and
related metastatic sites. In: Bland KI, Copeland EM, editors. The
breast comprehensive management of benign and malignant dis-
ease. 2nd ed. Philadelphia: WB Saunders Company; 1998.
8. Cooper AP. On the anatomy of the breast. London: Longman, Orme,
Green, Brown and Longmans; 1840.
9. Bayati S, Seckel BR. Inframammary crease ligament. Plast Reconstr
Surg. 1995;95(3):501–8.
10. Würinger E, Mader N, Posch E, Holle J. Nerve and vessel supplying
ligamentous suspension of the mammary gland. Plast Reconstr
Surg. 1998;101(6):1486–93.
11. van Deventer PV. The blood supply to the nipple–areola complex of
the human mammary gland. Aesthetic Plast Surg. 2004;27:393–8.
12. Michelle le Roux C, Kiil BJ, Pan WR, Rozen WM, Ashton MW. Preserv-
ing the neurovascular supply in the Hall-Findlay superomedial
pedicle breast reduction: an anatomical study. J Plast Reconstr Aes-
thet Surg. 2010;63(4):655–62.
13. Schlenz I, Kuzbari R, Gruber H, Holle J. The sensitivity of the nipple-­
areola complex: an anatomic study. Plast Reconstr Surg. 2000;105(3):
905–9.
 10 P. Palhazi
14. Tanis PJ, Nieweg OE, Valdés Olmos RA, Kroon BB.  Anatomy and
1 physiology of lymphatic drainage of the breast from the perspec-
tive of sentinel node biopsy. J Am Coll Surg. 2001;192(3):
399–409.
15. Turner-Warwick RT. The lymphatics of the breast. Br J Surg. 1959;46:
574–82.
16. Berg JW. The significance of axillary node levels in the study of breast
carcinoma. Cancer. 1955;8(4):776–8.
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17. Perre CI, Hoefnagel CA, Kroon BB, Zoetmulder FA, Rutgers EJ. Altered
lymphatic drainage after lymphadenectomy or radiotherapy of the
axilla in patients with breast cancer. Br J Surg. 1996;83(9):1258.
18. Grossman F.  Ueber die axillaren Lymphdrusen. Berlin: C.  Vogts
Buchdruckerei (E. Ebering). Inaug. Dissert. Berlin; 1896.
19. Gerota D.  Zur technik der Lymphgefassinjection. Eine neue Injec-
tionmasse fur Lymphgefasse. Polychrom Injection. Anat Anz.
1896;12:216.
 11 2

Physiology and Developmental
Stages of the Breast
Theodore G. Troupis, Adamantios Michalinos, George Skandalakis,
and Panayiotis Skandalakis

2.1 Introduction – 12

2.2 Breast Development – 12

2.2.1 Prenatal Development – 12
2.2.2 Congenital Anomalies – 13
2.2.3 Infant Breast – 13
2.2.4 Peripubertal Breast – 14
2.2.5 Adult Breast, Pregnancy and Lactation – 14
2.2.6 The Postmenopausal Breast – 16

2.3 Conclusions – 16

References – 17

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_2

rares1geo@gmail.com
 12 T.G. Troupis et al.
2.1 Introduction
Our knowledge about normal breast development is incom-
2 plete. Due to limited tissue availability, much of our knowl-
edge derives from mouse models, which may not be fully
equivalent [1, 2]. Knowledge about normal breast develop-
ment is important as there are links to the genesis of numer-
ous breast pathologies, including breast cancer, and how to
treat them [3]. Many pathways which regulate developmental
organogenesis are also implicated in tumorigenesis and thus
may be targets for anticancer drugs [4].
Breast development can be separated into five stages: pre-
natal, infant, peripubertal, adult (including pregnancy and
lactation) and postmenopausal. These stages are controlled
by intrinsic genetic information and are under tight hor-
monal control.
This chapter will focus only on physiology and develop-
mental stages of the breast for humans.
2.2 Breast Development
2.2.1 Prenatal Development
Breast development begins after development of the three
principal embryonal axes (lateral-­medial, dorsal-ventral and
anterior posterior) and fetus segmentation has occurred [5].
Arbitrarily, prenatal breast development can be divided into
two stages: development of a primary bud (first trimester)
and development of a rudimentary gland (second and third
trimester). The ductal system originates from the nipple and
is a derivative of the ectoderm, while the breast stroma is
derived from the underlying mesoderm. Both those stages
..      Fig. 2.1  a The milk lines in a
generalized mammalian embryo. a b
Mammary glands form along
these lines. b Common sites of
formation of supernumerary
nipples or mammary glands
along the course of the milk line
in human (Reproduced from
Skandalakis et al. [22]; with
permission)
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are hormonally independent, and genes determining the ini-
tiation of breast development have not yet been defined in
human [6]. The common theory that the breast is a modified
sweat gland is not supported by good-quality data [6].
The first breast progenitor cells can be identified during
the 4th–6th week of gestation [6], while the first structure cor-
responding to the breast is the mammary band, a thickened
area of differentiated ectoderm surrounding the origin of the
limbs and extending down to the future inguinal or even
femoral areas. Subsequently, at about the 7–8 mm fetal length
stage, this mammary band involutes, leaving a narrow crest of
tissue called the breast primordium. The nipple-areola com-
plex and ductal system are derived from this primordium. No
direct evidence connects nipple development with the mam-
mary band, yet the fact that the nipples of many mammals
arise along its course and that human accessory nipples and
breasts appear along this line justifies the name «mammary
line» [7] (. Fig. 2.1). Soon after the appearance of the nipple,
a condensation of mesoderm is seen below the nipple [7, 8].
At about 10 mm fetal length, the cell population of the breast
primordium differentiates between central (progenitors of
luminal cells) and peripheral cells (progenitors of myoepithe-
lial cells) [9]. Luminal cells are milk producers, while myoepi-
thelial cells are epithelial cells with contractile capabilities that
promote milk ejection. Notably, myoepithelial cells maintain a
central role throughout breast development, from the earliest
stages of gestation. They are necessary for maintenance of the
mammary epithelium’s physical integrity, the establishment of
polarity of the normal bilayered breast epithelium, turnover of
the extracellular matrix and control of several aspects of breast
physiology, including the rate of cell division, polarization of
secretion-related molecules and configuration of the breast
epithelium’s basal membrane [9]. At 14 mm fetal length, the
Physiology and Developmental Stages of the Breast
mesoderm has been differentiated into four discrete layers:
From the first layer (capsular), the smooth muscle of the nip-
ple will be produced; from the second zone (dense, vascular),
the smooth muscle of the nipple; from the third zone (loose),
the connective tissue of the lobules; and from the fourth zone,
the interlobular fat and the capsular connective tissue [7].
Simultaneously, the primordium moves ventrally from its
original dorsolateral position to the anterolateral thoracic
wall. This movement is secondary to and dependent on somite
development.
At 16  mm fetal length, the mammary band has disap-
peared, while the breast primordium has almost sunk inside
the mesoderm, while at 55  mm fetal length, the primitive
nipple appears as a well-circumscribed mass of cells at the
apex of an elevation. Nipple formation is almost complete at
90 mm fetal length with keratinization of the superficial cells
of the mammary bud. Superficial cells are easily discernible
since, in contrast to periderm, they are CK14 negative [5].
At this point, the first stage of fetal breast development is
complete. At 170  mm fetal length, the primordium of the
ducts appears as solid cellular outgrowths that arise from the
deep surface of the mammary bud. They pierce the first two
layers of the mesoderm, without being invested by them and
receive a covering from the third layer [7]. Transformation of
these solid outgrowths into lobules occurs through desqua-
mation and lysis of the central cells. Ducts are further
branched and acquire several terminal branches. At this
stage, at 300 mm fetal length, two discrete cell populations are
seen inside the ducts: luminal and myoepithelial. Separation
into lobes has already begun with fibrous septa originating
from the fourth layer of the mesoderm [9]. At 330 mm fetal
length, the development of the fetal breast is almost complete
with completion of canalization of the tubules and their orga-
nization into groups of ducts separated into lobules. Lobules
are covered by two cell layers, one cuboidal and one flattened.
The zones of the mesoderm have completed their differentia-
tion. Dense vascular plexuses at the end of the ductal struc-
tures have appeared and drain into vascular lakes in the
second layer of the mesoderm. The mammary gland is
enclosed in a thin capsule of connective tissue with a similar
appearance to a series of small sebaceous gland related to the
mammary ducts. No hair follicles are seen at the nipple. At
this point male and female mammary glands are not discern-
ibly different.
2.2.2 Congenital Anomalies
Most congenital anomalies and variations originate during
this prenatal period of development. The ulnar-mammary
syndrome that manifests as aplasia or hypoplasia of the breast
and anomalies of the ipsilateral limb is attributed to absence
of the T-box transcription factor (TBX3) gene [5].
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13 2
Isolated amastia or hypoplasia of the breast without other
pectoral defects is rarer, and athelia (congenital absence of
the nipple only) without amastia is an extremely rare situa-
tion. No responsible genes for the aforementioned conditions
have been found.
Accessory nipples and accessory breasts are a relatively
common phenomenon, with an incidence of 1–5%. They
develop along the mammary line and require no treatment
except if they become symptomatic, usually during lactation.
European populations usually present with supernumerary
nipples below the normal nipple and Japanese populations
usually above. Juvenile or virginal hypertrophy of the breast
and fibroadenomas are better explained as anomalies associ-
ated with breast development and are not correlated with any
hormonal abnormality.
Gynecomastia is an acquired rather than a congenital
situation. It is often caused by drugs or by oestrogen regula-
tion in cirrhotic patients. Gynecomastia is secondary to duc-
tal and stromal development but not to lobular development
due to the immaturity of the male breast [5, 8, 10, 11].
Deformities of the thoracic wall are often accompanied by
deformities of the breast. They are often explained as secondary
to rib morphogenesis abnormalities. They should be treated in
an individualized manner, with respect to patient’s other abnor-
malities, symptoms and life expectancy. Commoner are a
depressed chest (pectus excavatum), protruding chest (pectus
carinatum/pigeon breast) and mixed deformities [10]. The
most well-known syndrome is Poland’s syndrome, character-
ized by:
55 Absence of costal cartilages and a portion of the third or
third and fourth rib
55 Absence of the nipple or breast with accompanying
hypoplasia
55 Absence of subcutaneous fat
55 Absence of axillary hair
55 Absence of the pectoralis minor muscle
55 Absence of costosternal part of the pectoralis major
muscle [8]
2.2.3 Infant Breast
During intrauterine life, the fetal breast is under hormonal
control of oestrogen and progesterone produced by the pla-
centa. Oestrogens promote tissue development, growth of the
network of breast ducts and fat deposition, while progesterone
promotes lobuloalveolar differentiation. Oestrogen receptors
are found to be expressed in the infant breast tissue from birth
to 2–3  months of age [12]. Oestrogen and p ­ rogesterone are
inhibitors of prolactin synthesis. Immediately after birth, fetal
prolactin increases temporarily which leads to breast develop-
ment and milk production, commonly referred to as «witch’s
milk» [13, 14].
 14 T.G. Troupis et al.
Soon after birth, the breast involutes rapidly and remains
as such until puberty. Until puberty, the only change is ductal
elongation in accordance with body size. There is no further
2 maturation [15]. Soon after birth, the nipple everts due to an
increase in stroma, and areola pigmentation increases [16].
The infant breast contains lobular structures, dilated ducts,
apocrine secretions, extra-medullary haematopoiesis and the
presence of myoepithelial cells [17].
McKiernan and Hull [18] investigated the infant breast
and stated that most infants have palpable breasts and are
capable of milk production on gentle palpation. They also
stated that breast development corresponds to gestational age
and not body size, and thus breasts are not usually palpable
in preterm infants.
Anbazhagan and colleagues [19], taking the above con-
siderations into account, stated that the infant breast can be
categorized into three different morphologic types:
55 Type I: Rudimentary ductal system, single elongated
ducts, no branching or less than two dichotomous
branchings and two layers of epithelium
55 Type II: More than two dichotomous branchings, no
terminal lobules and few budlike projections lined by
stratified epithelium
55 Type III: Branching ductal system and developed termi-
nal lobules
They also classified functional status into five different grades:
55 Type I: Whole ductal system lined by luminal cells,
single layer of myoepithelial cells and loose intralobular
connective tissue
55 Type II: Cystic dilation of the ducts. Secretory- and
apocrine-type epithelium
55 Type III: Most ductal system shows cystic dilation.
Existence of grossly dilated lobules and apocrine meta-
plasia
55 Type V: A complete involuted gland
55 Type IV represents a transition between types III and V
According to these authors, [20] these differences might be
caused by different levels of maternal oestrogen during intra-
uterine life.
2.2.4 Peripubertal Breast
Soon after birth, low GnRH levels and consequently low FSH
and LH levels lead to low oestrogen and progesterone levels.
The breast therefore remains inactive until puberty [15].
Probably due to secondary mediators, breast development
restarts before levels of sex hormones can be discriminated
between the sexes [11]. At adrenarche, an increase of
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a­ ndrogens and pregnenolone restarts breast maturation. In
men a transient breast enlargement might become clinically
important, yet it will soon involute [15]. In women, menarche
signifies oestrogen production that, in cooperation with
androgens, will continue to stimulate breast development.
Amphiregulin, human growth factor, epidermal growth fac-
tor and insulin growth factor have all been proposed as para-
crine mediators of oestrogen effects. Microscopically, the
ducts become elongated, the epithelium becomes thicker and
the stromal tissue increases. Immature ducts undergo branch-
ing and extend into underlying tissue giving rise to a segmen-
tal pattern. Subsegmental and terminal ducts eventually give
rise to acini. Acini from a single terminal duct surrounded by
fibrous tissue constitute the functional unit of the breast: the
terminal duct lobular unit (TDLU). Four types of lobule are
recognized: Type 1 comprise short terminal ducts ending in a
cluster of secretory cells, the alveoli. Types 2 and 3 comprise
ducts ranching into several ductules and an increasing num-
ber of alveoli. Type 4 is seen in women that have gone through
pregnancy and lactation and will be discussed later [16].
By age 15, the central breast is shaped. After that, and
until the first pregnancy, it expands peripherally acquiring
the form of the nulliparous adult breast [5, 11, 13, 15]. Until
the first pregnancy, the breast is under the hormonal control
of the menstrual cycle. During the menstrual cycle, the breast
size increases in the luteal phase due to stromal swelling
rather than further duct development. Yet functional changes
have been observed through an increase in mitoses and
apoptosis during the luteal phase of the cycle [15]. Notably in
a mature breast, the glandular component constitutes less
than 20% of the whole breast.
Macroscopically, Marshall and Tanner [21] classified the
prepubertal breast into five categories (. Fig. 2.2):
55 First (prepubertal): Elevation of the papilla
55 Second (breast bud): Development of a small mound
beneath an enlarged areola
55 Third: Further enlargement of the breast and areola, with
the breast beginning to take on a small adult form, but
with no separation of the contour of the areola
55 Fourth: Further enlargement of the nipple and areola to
form a secondary projection above the level of the rest of
the breast
55 Fifth: Fully mature adult breast
2.2.5 Adult Breast, Pregnancy and Lactation
Breast epithelium can be considered immature in nulliparous
women [15] since the mammary gland reaches complete
maturity only during pregnancy and lactation. [14] During
pregnancy, changes in oestrogen and progesterone prepare
Physiology and Developmental Stages of the Breast
15 2
the breast for milk production through breast enlargement,
growth of the ductal system and alveoli differentiation [6].
Specifically, during the first trimester, there is an increase in
alveoli/lobule numbers while luminal cells acquire the
appearance of secretory cells. During the second trimester,
duct histology is established and ductules have begun
­differentiating into alveoli. During the third trimester, lumi-
nal cells are enlarged and filled with droplets of lipids and
I
adipophilin. Notably during this period, the breast is inca-
pable of lactation because, under the influence of oestrogens
and progesterone, prolactin levels are very low [13, 15].
Immediately post-partum, maternal oestrogen and pro-
gesterone levels decrease. Normal suckling results in a dimi-
nution of dopamine levels through complex reflexes in the
hypothalamus. Those two physiologic actions result in prolac-
tin production from the anterior hypophysis. Suckling also
II
results in oxytocin production from the posterior hypophysis.
Prolactin is necessary for further mammary gland growth and
development, production and delivery of the milk. Oxytocin
results in contraction of myoepithelial cells and milk ejection.
Oxytocin is also important in mating and maternal behaviour
[13]. Suckling also activates local reflexes that lead to milk
ejection through myoepithelial cell contraction and duct
opening without the intercession of oxytocin. Stressful situa-
tions can cease milk production through interaction of both
central and local mechanisms [13]. Prolactin increase inhibits
III
oestrogen and progesterone secretion, explaining the contra-
ceptive effects of lactation [13] (. Fig. 2.3).
 

Histologically during lactation there is an increase in the

IV
V
..      Fig. 2.2  Diagram showing the Tanner stages of breast develop-
ment. I Tanner I: No glandular tissue. II Tanner II: Primary formation of
breast bud, little glandular tissue, widening of areola. III Tanner III: Breast
elevation. Areola still follows shape of the breast. IV Tanner IV: Further
breast elevation. Areola and papilla projecting from the breast. V Tanner
V: Adult breast. Final breast size. Areola follows shape of the breast but
papilla projects
number of lobules while the mammary gland has less fat. The
acini are dilated and filled with milk fat globules. These
changes are not homogenous throughout the breast: Active
and dilated acini can coexist with inactive ones [5].
At a cellular level, luminal cells are activated during lacta-
tion and can produce three times their weight in milk.
During lactation myoepithelial cells form an almost com-
plete layer in the ducts and ductules. Immediately post-par-
tum, tight junctions between basal layer cells are tightened to
allow milk delivery [13, 14].
After each pregnancy when the child is weaned and suck-
ling stops, the gland undergoes rapid involution and soon after
acquires a puberty-like histological appearance. This involution
is a two-stage process and has a rapid but reversible phase for
the first 48 h and a slower but irreversible one [6]. Involution is
not complete since after each pregnancy the breast is left with a
number of differentiated lobes [13]. Higher differentiation after
each pregnancy is probably the mechanism behind the cancer-
protective effect of pregnancy and lactation.

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 16 T.G. Troupis et al.

Estrogen Progesterone Hypothalamus

stimulation of stimulation of
duct growth formation of
2 secretory alveoli Block of
prolactin-
inhibiting
hormone
Anterior
pituitary
Neural stimulus Posterior
from suckling pituitary
Prolactin
release
Oxytocin
release
Milk protein
and fat
a b c synthesis

Milk
letdown e

..      Fig. 2.3  Development of the mammary duct and hormonal control along these lines. b Young adult. c Adult. d Lactating adult. e Postlacta-
of mammary gland development and function. a Newborn, the milk tion (From Skandalakis et al. [22]; with permission)
lines in a generalized mammalian embryo. Mammary glands form

2.2.6 The Postmenopausal Breast
Following menopause, oestrogen and progesterone levels fall
dramatically, and this leads to significant changes in breast
histology. Lobules and ducts involute and reduce in number,
intralobular stroma is replaced by collagen and glandular
epithelium, and interlobular stroma regresses and is replaced
by fat [13]. Furthermore many ducts lose their two-layered
appearance and present only a single, regressed layer of cells.
Acini are more affected by postmenopausal involution than
ducts which usually retain their integrity [5, 15]. A positive
side effect of connective tissue replacement by fat is that the
breast becomes less dense, increasing the diagnostic value of
mammography.
2.3 Conclusions
Despite extensive research, many aspects of normal breast
development at the cellular and molecular level remain
obscure. Much of our knowledge derives from mouse mod-
els. While information obtained is valuable considering simi-
larities between mouse and human development, analogy
cannot be wholly reliable.
Yet research on normal breast development can be useful
in research into various breast diseases, especially breast
cancer. Knowledge of hormone dependency has led to
­
­ evelopment of hormonal therapy. Knowledge about the
d
development of the mammary gland during pregnancy and
lactation has explained their protective effects.
Considering ethical limitations, it is hard to augment the
availability of human breast tissue specimens. Constant
research on sophisticated experimental animal models will
probably remain our most important source of information
in the future.
Key Points
55 Breast development is a continuum that begins
prenatally and does not complete until pregnancy
and lactation. Schematically it can be separated
into prenatal, infant, peripubertal and adult stage.
Complete maturation does not occur until
pregnancy and lactation.
55 Breast development occurs through interaction
between epithelial and mesenchymal elements.
55 Apart from intrinsic regulation, breast develop-
ment is highly dependent on hormonal regula-
tion.
55 A number of diseases including breast cancer can
be understood through a developmental prism.
55 Disturbances in breast development are a
sensitive marker of some systemic diseases or
hormonal dysregulation.

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Physiology and Developmental Stages of the Breast
17 2
References 11. Gusterson BA, Stein T. Human breast development. Semin Cell Dev
Biol. 2012;23(5):567–73. doi:10.1016/j.semcdb.2012.03.013.
12. Keeling JW, Ozer E, King G, Walker F.  Oestrogen receptor alpha
1. Cardiff RD, Wellings SR.  The comparative pathology of human
in female fetal, infant, and child mammary tissue. J Pathol.
and mouse mammary glands. J Mammary Gland Biol Neoplasia.
2000;191(4):449–51. doi:10.1002/1096-9896(2000)9999:9999<::AID-
1999;4(1):105–22.
PATH661>3.0.CO;2-#.
2. Robinson GW, Karpf AB, Kratochwil K.  Regulation of mammary
13. Johnson M.  Anatomy and physiology of the breast. In: Manage-
gland development by tissue interaction. J Mammary Gland Biol
ment of breast diseases. Berlin Heidelberg: Springer; 2010. p. 1–36.
Neoplasia. 1999;4(1):9–19.
14. Hassiotou F, Geddes D. Anatomy of the human mammary gland: cur-
3. Osin PP, Anbazhagan R, Bartkova J, Nathan B, Gusterson BA. Breast
rent status of knowledge. Clin Anat. 2013;26(1):29–48. doi:10.1002/
development gives insights into breast disease. Histopathology.
ca.22165.
1998;33(3):275–83.
15. Drife JO.  Breast development in puberty. Ann N Y Acad Sci.

4. Sternlicht MD.  Key stages in mammary gland development: the
1986;464:58–65.
cues that regulate ductal branching morphogenesis. Breast Cancer
16. Javed A, Lteif A.  Development of the human breast. Semin Plast
Res. 2006;8(1):201. doi:10.1186/bcr1368.
Surg. 2013;27(1):5–12. doi:10.1055/s-0033-1343989.
5. Howard BA, Gusterson BA. Human breast development. J Mammary
17. McKiernan J, Coyne J, Cahalane S. Histology of breast development
Gland Biol Neoplasia. 2000;5(2):119–37.
in early life. Arch Dis Child. 1988;63(2):136–9.
6. Macias H, Hinck L. Mammary gland development. Wiley Interdiscip
18. McKiernan J, Hull D. Breast development in the newborn. Arch Dis
Rev Dev Biol. 2012;1(4):533–57. doi:10.1002/wdev.35.
Child. 1981;56:525–9.
7. Hughes ES. The development of the mammary gland: arris and gale
19. Anbazhagan R, Bartek J, Monaghan P, Gusterson BA.  Growth and
lecture, delivered at the Royal College of Surgeons of England on
development of the human infant breast. Am J Anat. 1991;192(4):
25th October, 1949. Ann R Coll Surg Engl. 1950;6(2):99–119.
407–17. doi:10.1002/aja.1001920408.
8. Skandalakis J.  Embryology and anatomy of the breast. In: Breast
20. Anbazhagan R, Nathan B, Gusterson BA.  Prenatal influences and
augmentation. Berlin/Heidelberg: Springer; 2009. p. 3–24.
breast cancer. Lancet. 1992;340(8833):1477–8.
9. Jolicoeur F. Intrauterine breast development and the mammary myo-
21. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in
epithelial lineage. J Mammary Gland Biol Neoplasia. 2005;10(3):199–
girls. Arch Dis Child. 1969;44(235):291–303.
210. doi:10.1007/s10911-005-9581-9.
22. Skandalakis J, et al. Skandalakis’ surgical anatomy. Athens: Paschal-
10. Dixon JM, Mansel RE. ABC of breast diseases. Congenital problems
ides Medical Edition; 2004.
and aberrations of normal breast development and involution. BMJ.
1994;309(6957):797–800.

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 19 3

Breast Cancer Epidemiology

R.M. Parks, M.G.M. Derks, E. Bastiaannet, and K.L. Cheung

3.1 Introduction – 20

3.2 The Pattern – 20

3.2.1 Worldwide – 20
3.2.2 Incidence: Key Patterns – 20
3.2.3 Variation Within Continents – 21
3.2.4 Incidence Patterns Over Time – 21
3.2.5 Immigration – 21

3.3 Risk Factors Associated with Breast Cancer – 21

3.3.1 Relative Risk Greater Than or Equal to 4 (RR ≥ 4) – 22
3.3.2 Relative Risk of Less Than 4 (RR < 4) – 23
3.3.3 Exogenous Hormones – 23
3.3.4 Physical Activity – 24
3.3.5 Diet – 24
3.3.6 Obesity – 24
3.3.7 Alcohol – 25
3.3.8 Smoking – 25
3.3.9 Summary – 25

3.4 Prevention – 25

3.5 Breast Cancer Survival – 25

3.5.1 Western Countries – 25
3.5.2 Developing Countries – 25

3.6 Intervention Strategies – 27

3.6.1 Future Directions – 27
3.6.2 Data Collection – 27
3.6.3 Causation Versus Association – 27
3.6.4 Strategies to Deal with Prevention – 27

References – 27

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_3

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 20 R.M. Parks et al.
3.1 Introduction
Breast cancer accounts for 25% of all female cancers diag-
nosed worldwide [1]. However, there is a large global dispar-
ity between continents and countries in its incidence as well
as mortality.
3 Breast cancer is the most common cause of cancer death
in women worldwide. Although globally more women are
surviving breast cancer with improved awareness, implemen-
tation of screening programmes and superior treatments,
there are still vast differences in both incidence and mortality
internationally as well as within nations [2]. A minority of
breast cancers are due to known genetic mutations. Most
breast cancers are termed «sporadic» and are associated with
a number of factors, some potentially modifiable. As more
evidence-based literature is available on the relevance of these
risk factors to breast cancer, it will be possible to understand
the differences between causation and association of these
factors. With this is mind, targets for preventative healthcare
are highlighted, and possible interventions can be made with
the overall aim to improve survival in breast cancer outcomes.
This chapter will set out the pattern of worldwide varia-
tion in the incidence and mortality of breast cancer and
describe their changes over time. We will then discuss factors
influencing the incidence and potential causes of breast can-
cer. This chapter will then consider the effects these identified
factors have on breast cancer in our population, thus identi-
fying potential targets for preventative healthcare.
3.2 The Pattern
Global disparities in breast cancer incidence and mortality
remain, despite improvements over time in developing coun-
tries with respect to screening and treatment of breast cancer.
3.2.1 Worldwide
Breast cancer is the most common cancer worldwide for
females, and the second most common cancer overall, with
..      Fig. 3.1  Number of new
cases and deaths per 100,00 150
women in the USA (Source:
National Cancer Institute [7])
100,000 females
100
Number per
50
0
1992
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more than 1,676,000 new cases diagnosed in 2012 worldwide.
This accounts for 25% of all female cancers and 12% total of all
cancers [1]. According to the World Health Organization
(WHO) [3], out of 8.2 million cancer deaths in 2012, 521,000
of these were due to breast cancer. This compares to 1.59 mil-
lion deaths from lung cancer and 695,000 deaths from colorec-
tal cancer. Although breast cancer is thought to be a disease of
the developed world, almost 50% of breast cancer cases and
58% of deaths occur in less-developed countries [3, 4].
3.2.2 Incidence: Key Patterns
Western Countries
Breast cancer incidence and mortality rates are fairly consis-
tent within the Western developed nations such as the UK,
Canada and the USA with an incidence per 100,000 women
at 129.2, 99.7 and 123.1, respectively [5, 6].
According to US Breast Cancer Statistics published in
2016, there is a 12% lifetime incidence of developing breast
cancer for women in the USA. It is estimated that in 2016,
over 246,000 new cases of invasive breast cancer will be diag-
nosed in US women [7] (. Fig.  3.1). Female breast cancer
represented 14.6% of all new cancer cases in the USA.
Data from the Global Burden of Cancer Study
(GLOBOCAN) suggests that approximately 464,000 new
cases of breast cancer were diagnosed in Europe in 2012. This
accounts for 29% of all female cancers and 13% of all cancers
in Europe [8] (. Fig. 3.2).
According to the European Cancer Observatory (EUCAN),
incidence of breast cancer in Europe is 94.2 per 100,000 with
rates as low as 63.4 per 100,000 in Central and Eastern Europe
and as high as 126.8 per 100,000 in Western Europe [9].
For the most up-to-date data, please visit the GLOBOCAN
[2] or EUCAN websites [10].
Developing Countries
The incidence of breast cancer is lower in less economically
developed parts of the world such as some Asian and African
countries when compared to Western nations, with an esti-
mated overall incidence for Africa at 28.0 per 100,000 women
and 29.6 per 100,000 women for Asia [11].
New cases
Deaths
1995 1998 2001 2004 2007 2010 2013
Year
Breast Cancer Epidemiology
21 3

Incidence Mortality

28.8% 16.8%
Other and unspecified
Breast Breast

40.8% 464 Other and unspecified 131

658 13.0%
45.1% Colorectum
351 102

99
205
44 52 Lung
66 119 Colorectum 12.7%
99
Pancreas
12.7% Stomach
Ovary 5.6% 6.7%
Lung

4.1%
Corpus uteri 7.4%
6.1%

..      Fig. 3.2  Distribution of the expected cases and deaths for the five most common cancers in females in Europe 2012 (Reprinted from Ferlay
et al. [9] with permission from Elsevier)

3.2.3 Variation Within Continents 3.2.5 Immigration

It is apparent that in both the developed and developing world,
there is much variation between different regions and even
countries within a continent. To give an example, in Europe
the incidence of breast cancer in Bosnia is reported at 49.1 per
100,000, compared to 142.8 per 100,000 in Denmark [10]. It is
hypothesised variation may be due to better registration of
data in these countries, high socio-economic status and better
access to healthcare (including screening) [12].
3.2.4 Incidence Patterns Over Time
Studies on migrants globally have demonstrated that,
although initially the incidence of breast cancer of the
country of origin is retained, within two or three genera-
tions, the incidence of the new country is ultimately adopted
[19–21]. This suggests that some environmental factors
have an impact on the overall incidence of breast cancer,
which we will explore later in this chapter. Another theory
would be that women moving to more economically devel-
oped countries have better access to healthcare facilities
such as screening and, therefore, appear to have a higher
incidence.

In the USA, breast cancer incidence rates began decreasing at

the beginning of the twenty-first century, dropping by 7%
from 2002 to 2003 alone. One theory was the reduced use of
hormone replacement therapy [13]. Contrary to the situation
in the USA, breast cancer incidence rates in Europe have
increased since the late 1970s, by 50% between 1979–1981
and 1998–2000 and then by 10% between 1998–2000 and
2011–2013 [14]. A similar pattern is seen in Japan with the
incidence of breast cancer rising more than twofold from
1959–1960 to 1983–1987 [15–18]. We can speculate that this
is due to a number of factors including an increased life
expectancy of the general population and changes in lifestyle
factors (e.g. obesity).
3.3  isk Factors Associated with Breast
R
Cancer
As previously eluded to, there are multiple potential risk fac-
tors which may contribute to the risk of breast cancer. The
importance of these risk factors is measured by determining
the relative risk (RR), defined as the ratio of the breast cancer
probability occurring in the exposed group to the probability
in a comparable but nonexposed group. These are grouped
below into those with a relative risk of less than 4 and those
with a RR of greater than 4.
. Table 3.1 provides a summary of these risk factors.

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 22 R.M. Parks et al.

If all women younger than 65 years of age are compared

..      Table 3.1  Summary of breast cancer risk factors
with women aged over 65, the relative risk of breast cancer
Relative risk ≥4 Relative risk <4 between both groups is 5.8 [24].

Female gender Other family history Genetic Mutations

3 Increasing age
Past history of breast cancer
Past history of other
high-risk pathology
Previous radiation therapy
The most well-known genes for increased susceptibility to
Personal history of benign
breast disease breast cancer are BRCA1 and BRCA2 although the number of
other significant genes is increasing as global genetic consor-
Significant family history
tia analyse more genomes (reviewed in 7 Chap. 6). The risk
Younger age at menarche of developing breast cancer by age 70, if either BRCA1 or
BRCA2 genes are present, is between 46% and 65%. The rela-
Older age at menopause tive risk of breast cancer for carriers of BRCA mutations has
been quoted to be as high as more than 200 below age 40 and
Older age at first pregnancy
15 for ages 60–69 years [25].
Use of hormone replacement For more information, please see 7 Chap. 6.

therapy
Although the majority of cases of known genetic muta-
Use of oral contraceptives tions are found in women with a significant family history,
Lack of physical activity
this is not always the case. For example, it is well recog-
nised that younger patients with triple-negative breast can-
Diet lacking in vegetable cer are highly likely to harbour a genetic mutation such as
Increased alcohol intake BRCA1 [26]; around 10–30% of women under the age of 60
diagnosed with «triple-negative» breast cancer will have a
Smoking
genetic mutation. Some specific national variation in rates of
gene carriage accounts for higher than average breast cancer
rates in certain populations (so-called founder mutations).
The best known of these is in the Ashkenazi Jewish popu-
3.3.1  elative Risk Greater Than or Equal
R lation, but founder mutations are also described elsewhere
to 4 (RR ≥ 4) such as in Iceland and Spain.

Female Gender
The risk of females developing breast cancer is approximately
100 times greater than for males [22].
Age
The most important risk factor in the development of breast
cancer after female gender is increasing age. It is estimated
that there is a 1 in 1732 probability of developing breast can-
cer in the next 10 years for a woman with a current age of 20.
This rises to 1 in 69 for individuals aged 40 and 1 in 26 for
individuals aged 70 years [23] (. Fig. 3.3).
 
Past History of Breast Cancer
Women who have had previous breast cancer are at two to
five times increased risk of developing a second primary
breast cancer [27].
Past History of High-Risk Pathology
Previous proliferative lesions with atypia, such as atypical
ductal hyperplasia (ADH) or atypical lobular hyperplasia
(ALH), increase the risk of developing breast cancer up to five
times higher than normal [28–30] (reviewed in 7 Chap. 11).

..      Fig. 3.3  Absolute risk of

developing breast cancer by
4.5
age [23]
Odds of dedveloping breast cancer in

4
3.5
3
next 10 years

2.5
2
1.5
1
0.5
0
0 10 20 30 40 50 60 70 80
Age

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Breast Cancer Epidemiology
23 3
Radiation Therapy in a study by the Collaborative Group on Hormonal Factors
Women who have been previously treated with radiation in Breast Cancer [39] where they examined data from 117
therapy, for example, for lymphoma, leukaemia or bone epidemiological studies encompassing 118,964 women
tumours in childhood, are at greater risk of developing breast with invasive breast cancer compared to 306,091 women
cancer. It is shown that treatments with moderate- to high-­ without. They concluded that the risk of breast cancer
dose therapeutic chest radiation (≥20 Gy) have an elevated increased by a factor of 1.050 for every year younger at
risk of breast cancer, and this does not plateau with increas- menarche and by a factor of 1.029 for every year older at
ing age [31]. menopause.
As a result, enhanced screening or surveillance with MRI An inverse association between parity and HR-positive
or mammography (depending on age) is offered to these breast cancer has been shown. An increasing number of
women in some countries, for example, in Canada [32], and pregnancies have been shown to decrease the risk of breast
risk-reducing mastectomy is even discussed in some countries. cancer [40, 41]. Risk estimates ranged from 0.5 to 0.8 [42].
There is some evidence to suggest that exposure to lower However, women who give birth to their first child after age
doses of radiation during diagnostic procedures or occupa- 30 have a higher risk for breast cancer than nulliparous
tional hazards may increase the risk of breast cancer; how- women. It is speculated that a full-term pregnancy at an early
ever, studies have been biased by other risk factors [33–35]. age may reduce the likelihood of tumour initiation by caus-
ing further maturation of breast epithelial cells, while a full-­
term pregnancy at a later age may promote the growth of
3.3.2 Relative Risk of Less Than 4 (RR < 4) existing tumour cells The reduction in breast cancer risk
associated with an increasing number of pregnancies was
Family History more consistently seen for oestrogen receptor (ER)-positive
Although there is clearly a genetic relationship involving the breast cancer [43, 44]. Increased age at first birth led to
incidence of breast cancer, it is estimated that only approxi- increased risk of breast cancer with the relative risk estimated
mately 3–10% of breast cancers are inherited [22–24]. Having to range from 1.4 to 2.6.
a positive family history of breast cancer, without a known There is less evidence to support lactation history and
genetic mutation, does increase the risk of breast cancer, with relationship to HR-positive breast cancer. Some studies have
a relative risk of 1.5–2 [24]. For all women, having a first- reported a protective effect of breast-feeding, but overall this
degree female relative with breast cancer approximately remains unclear and may only be related to ER-positive can-
doubles the risk of breast cancer, with risk increasing with cer [45, 46].
younger age of the relative’s diagnosis [36]. Cancer Research
UK suggests that the risk of developing breast cancer for an
identical twin, where the first twin has already developed 3.3.3 Exogenous Hormones
breast cancer, is 1 in 3, compared to overall lifetime risk of
approximately 1  in 8 [27]. Risk increases with number of Hormone Replacement Therapy
relatives affected, age at diagnosis, occurrence of bilateral or
Concurrent use of hormone replacement therapy (HRT) is
multiple ipsilateral tumours and male breast cancers in the
significantly associated with an increased risk of HR-positive
family. However, it is difficult to tell if the underlying influ-
breast cancer. Two large observational studies published in
ence is genetic or environmental.
2002 and 2003 showed that current use of HRT was associ-
History of Benign Breast Disease ated with an increased incidence and mortality from breast
cancer. The effect was greater in oestrogen-progestin combi-
Research has shown that non-proliferative breast lesions
nations, compared to other combinations of HRT [47, 48].
such as breast cysts, duct ectasia or fat necrosis are not linked
Following the publication of these two studies, the use of
with an increased risk of developing breast cancer at a later
HRT in the USA dropped by 38% between 2002 and 2003,
date. Proliferative lesions without atypical cells, such as fibro-
leading to a drop in breast cancer incidence of 7% [13].
adenomas or multiple intraductal papillomas, increase the
risk of breast cancer development by up to two times [37].
Oral Contraceptives
Reproductive Factors A meta-analysis comparing oral contraceptive users versus
These elements can be largely grouped into those which non-users found a non-significant increase in breast cancer
cause greater or lesser lifetime exposure to sex hormones. It risk associated with ever use of oral contraceptives (RR 1.08
is hypothesised that greater exposure to oestrogens and 95% CI 0.99–1.17). Dose-response analysis showed that
androgens increases the likelihood of breast cancer. every 10  years use of the oral contraceptive was associated
Due to a longer duration of regular menstrual cycles with a 14% increase in breast cancer risk [49].
and therefore longer lifetime exposure to the above-men- A recent systematic review examined progesterone-only
tioned hormones, younger age at menarche and older age at formulations of contraceptives and effect on breast cancer
menopause are associated with increased risk of hormone incidence and reported no association between progesterone-­
receptor (HR)-positive breast cancer [38]. This was shown only formulations and breast cancer risk [50].

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 24
R.M. Parks et al.

3.3.4 Physical Activity
Increased physical activity may reduce the risk of breast can-
cer. Studies have suggested that physical activity results in a
lower ratio of oestrogen metabolites which have been shown
to be associated with a decreased risk of breast cancer [51, 52].
3 A literature review identified that the highest level of
physical activity (at least 150 min of vigorous physical activity
per week) was associated with a relative risk of 0.88 for all
breast cancers compared to the lowest level of physical activ-
ity [53]. Another literature review found that a lack of p
­ hysical
activity increased the risk of breast cancer. Moderate recre-
ational physical activity, defined as about 3–4 hours of walk-
ing per week, may reduce breast cancer incidence [54].
3.3.5 Diet
Robust evidence for the role of diet in the risk of developing
breast cancer is scarce. A primary prevention trial found that
among postmenopausal women, a low-fat diet did not result in
a statistically significant reduction in breast cancer risk over an
average follow-up of 8 years. However, there were non-signifi-
cant trends suggesting a reduced risk, and, therefore, the
authors concluded that follow-up over a longer period of time
may provide significant results [55]. A retrospective study
using data from a cohort of 91,779 women found that greater
consumption of a plant-based diet was associated with a
reduced risk (RR 0.85) of breast cancer, particularly in
HR-positive tumours [56].
3.3.6 Obesity
High BMI is associated with a higher risk of breast cancer
in the postmenopausal population [57, 58]. In addition,
longer duration of obesity has been shown to be associated
with an increased risk of breast cancer in older adults [59].
Another study showed that this increased risk was associ-
ated with increased exposure to sex hormones, specifically
oestrogens.
Women aged 55  years and older with a BMI in the 80th
centile have a relative risk of 1.2 for developing breast cancer,
compared to patients within the 20th centile [58, 60] (. Fig. 3.4).

Experimental Control Risk Ratio Risk ratio

Study or subgroup Events Total Events Total Weight IV, Random, 95% CI IV, Random, 95% CI
1.2.1 Overweight
Barlow 2006 1408 237278 1864 332255 9.3% 1.06 [0.99, 1.13]
Kerlikowske 2008 1505 93717 1697 119504 9.3% 1.13 [1.06, 1.21]
Lee 2006 542 17154 843 27107 7.0% 1.02 [0.91, 1.13]
Sellers 2002 702 12916 567 13205 7.0% 1.27 [1.14, 1.41]
Setiawan 2009 1053 26172 1488 40272 8.7% 1.09 [1.01, 1.18]
Sonnenschein 1999 47 966 55 1955 1.2% 1.73 [1.18, 2.53]
Suzuki 2006 436 16805 692 29359 6.4% 1.10 [0.98, 1.24]
Tehard 2006 244 9039 735 30744 5.3% 1.13 [0.98, 1.30]
Subtotal (95% CI) 414047 594401 54.2% 1.12 [1.06, 1.18]
Total events 5937 7941
Heterogeneity: Tau2= 0.00; Chi2 = 15.98, df = 7 (P = 0.03); l2 = 56%
Test for overall effect: Z = 3.94 (P < 0.0001)

1.2.2 Obese
Barlow 2006 977 160573 1864 332255 8.8% 1.08 [1.00, 1.17]
Kerlikowske 2008 1244 73894 1697 119504 9.0% 1.19 [1.10, 1.27]
Lee 2006 348 11110 843 27107 6.2% 1.01 [0.89, 1.14]
Sellers 2002 381 6428 567 13205 6.0% 1.38 [1.22, 1.57]
Setiawan 2009 729 17983 1488 40272 8.2% 1.10 [1.01, 1.20]
Sonnenschein 1999 48 1020 55 1955 1.2% 1.67 [1.14, 2.45]
Suzuki 2006 156 5659 692 29359 4.2% 1.17 [0.99, 1.39]
Tehard 2006 58 2074 735 30744 2.3% 1.17 [0.90, 1.52]
Subtotal (95% CI) 278741 594401 45.8% 1.16 [1.08, 1.25]
Total events 3941 7941
Heterogeneity: Tau2= 0.01; Chi2 = 20.20, df = 7 (P = 0.005); l2 = 65%
Test for overall effect: Z = 3.92 (P < 0.0001)

Total (95% CI) 692788 1188802 100.0% 1.14 [1.09, 1.19]

Total events 9878 15882
Heterogeneity: Tau2= 0.00; Chi2 = 37.70, df = 15 (P = 0.0010); l2 = 60%
Test for overall effect: Z = 5.67 (P < 0.00001) 0.5 0.7 1 1.5 2
Favours experimental Favours control
Test for subgroup differences: Chi2 = 0.65, df = 1 (P = 0.42), I2 = 0%

..      Fig. 3.4  Forest plot of odds ratio estimates of breast cancer in postmenopausal period by obesity (Reprinted from Cheraghi et al. [60].
Originally published under an Open Access CC BY license)

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Breast Cancer Epidemiology
Although historically most studies of premenopausal
women have not found such a relationship between obesity
and incidence of breast cancer [61], newer studies have found
that the inverse may be true [62].
3.3.7 Alcohol
A pooled analysis of 53 studies including more than 58,000
women with breast cancer showed that daily consumption of
about 50  g is associated with a relative risk of 1.5 (95% CI
1.3–1.6) compared with women who reported drinking no
alcohol [63].
3.3.8 Smoking
Allen and colleagues found that the impact of smoking on
breast cancer was confounded by alcohol use. When restrict-
ing the analysis to subjects who reported no alcohol intake,
smoking was not associated with breast cancer [64].
3.3.9 Summary
This section of the chapter has presented a number of poten-
tial risk factors which may impact on the incidence of breast
cancer. Overall, it is recognised that most of these factors
relate to exposure to oestrogen. In addition, there are other
factors such as genetic mutations and radiation exposure
which are associated with an increased risk for breast cancer
but which are not related to oestrogen exposure.
In the next section of this chapter, we will discuss how we
can use knowledge of these aforementioned risk factors to
aid in the prevention of breast cancer.
3.4 Prevention
Due to the complex aetiology of breast cancer, often an inter-
action between genetic and lifestyle factors, prevention may
be equally complex and challenging.
There are clear guidelines and well-researched preven-
tion/intervention strategies currently in use for women with
an increased risk of breast cancer, including prophylactic
surgery, chemoprevention and extra screening. These are dis-
cussed at length in other chapters of this book. Please refer to
7 Chaps. 7 and 9, for further information.
 
Unfortunately, unlike work done on prevention of risk
from genetic mutations as above, evidence supporting pre-
ventative intervention of environmental factors in those at
risk of breast cancer is lacking. This is presumed to be due
to the complexity and feasibility of such types of trials; a
large group of participants with long follow-up is required.
There are few current prevention studies in the literature with
incidence and/or mortality as outcome measures. Instead,
a number of prevention strategies and their feasibility are
presented.
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25 3
Three studies showed positive health benefits from enrol-
ment onto a physical activity programme [53, 54, 65].
However, evidence showing the impact of physical activity
on the incidence of breast cancer is currently lacking.
3.5 Breast Cancer Survival
Data on 5-year survival rates from breast cancer is lacking in
some parts of the world. Survival in the Western world is
fairly consistent with rates for the USA, Canada and the UK
at 89.7%, 88% and 86.6%, respectively [5, 6, 14]. Survival fig-
ures for African and Asian countries vary considerably from
as low as 12.5% in the Gambia to as high as 80.9% in China
and 84.7% in Japan [11, 12, 66, 67]. Estimated breast cancer
mortality worldwide taken from GLOBOCAN data in 2012
is shown in . Fig. 3.5 [68].
3.5.1 Western Countries
Mortality in the UK, Canada and the USA is reported per
100,000 women at 24.8, 18.0 and 21.9, respectively [5, 6]. This
compares to estimated rates of 16.0 and 8.1 per 100,000
women for Africa and Asia, respectively [11].
The population-based EUROCARE data system collected
data for over 114,000 women with a first primary breast can-
cer in Europe. In the paper by Allemani and colleagues [69],
10-year survival exceeded 70% in most regions, but was only
54% in Eastern Europe with the highest values in Northern
Europe at about 75%.
De Angelis and colleagues and Sant and colleagues [70,
71] analysed the EUROCARE data to estimate 5-year can-
cer survival in Europe between 1999 and 2007. Over this
time period, 5-year relative survival increased throughout
Europe for all cancer types. Breast cancer had a 5-year rela-
tive survival of 81.8% overall, with rates varying from 74.3%
in Eastern Europe to 87.7% in Northern Europe. For all
regions, survival peaked at 45–54 years of age and then fell.
For current data please refer to the GLOBOCAN [2] and
EUCAN websites [10].
3.5.2 Developing Countries
The evidence base for survival rates in Africa is hampered by
a number of issues including a lack of registration to data-
bases, lack of access to health services, a lack of pathological
diagnosis or true differences in risk factors. As such, it is not
possible to estimate overall survival from breast cancer for
Africa as a whole continent. The pivotal CONCORD study
published in Lancet Oncology in 2008 [72] estimated survival
based on 101 population-based cancer registries in 31 coun-
tries worldwide. According to CONCORD data [72], there
were four population-based cancer registries in Asia exam-
ined, all based in Japan, giving a 5-year survival of 81.6%. A
population-based study published by Sankaranarayanan and
 3
26
R.M. Parks et al.

rares1geo@gmail.com
> 18.1
15.2 – 18.1
13.1 – 15.2
10.1 – 13.1
< 10.1

No data Not applicable

..      Fig. 3.5  Estimated breast cancer mortality worldwide in 2012 (Reproduced with permission from Ferlay et al. [68])
Breast Cancer Epidemiology
colleagues in Lancet Oncology in 2010 [72] estimated cancer
survival from 25 population-based cancer registries world-
wide. They gave an estimated 5-year survival for China,
Singapore and Turkey of >76% and India, the Philippines and
Thailand of between 47% and 63%.
Survival Patterns Over Time
In the USA, over the past two decades, survival rates have
been increasing. They have improved on average by 1.9% per
year for each year between 2004 and 2013 [8]. Survival for
the whole of Europe increased over time from 78.4% in
1999–2001 to 82.4% in 2005–2007.
In China 5-year survival rose from 53.8% in 1995–1999 to
80.9% in 2005–2009. Five-year survival increased in Malaysia
and Japan but at a slower pace from 64.8% to 67.8% and
81.8% to 84.2%, respectively [4, 11, 66, 67]. Like incidence,
5-year survival from breast cancer shows global variation.
In the remainder of this chapter, we will discuss possible
interventions to minimise mortality from breast cancer.
3.6 Intervention Strategies
We have outlined some potential methods for preventing the
occurrence of breast cancer, but as previously mentioned
there are a number of genetic and other factors beyond the
control of the individual, for which risk-tailored screening
and more formal risk reduction interventions such as risk-­
reducing surgery and even chemoprevention (for the high-­
risk group) may be offered. These are dealt with in detail in
7 Chaps. 7, 8, and 9.
3.6.1 Future Directions
The main challenge at present is to decrease global disparity
in all aspects of breast cancer care. The WHO promotes com-
prehensive national cancer control programmes involving
prevention, early detection, diagnosis, treatment, rehabilita-
tion and palliative care [2]. The European Union Commission
project Horizon 2020 [73] is an EU research and develop-
ment programme targeting many areas including breast can-
cer research across the EU.
3.6.2 Data Collection
It has been highlighted throughout this article that it is diffi-
cult to make global comparisons of incidence and survival
between countries due to lack of available data in developing
countries. There is a lack of cancer registries in Africa and
Asia, and where they are available, they may not be represen-
tative of the continent as a whole, due to such great diversity
of health, access to healthcare and lifestyle factors. Therefore,
attempts to have representative and standardised national
cancer registries should be made.
rares1geo@gmail.com
27 3
3.6.3 Causation Versus Association
A number of risk factors that are associated with the devel-
opment of breast cancer have been identified. Whether these
factors are a direct cause of breast cancer or simply an asso-
ciation can be difficult to decipher. More global studies look-
ing at risk factors and the incidence of breast cancer would
be beneficial to increase our understanding of these associa-
tions.
3.6.4 Strategies to Deal with Prevention
There is a lack of data on the outcomes of preventative strate-
gies, for example, implementation of exercise and diet
regimes. Key factors should be focused upon as targets for
prevention in order to maximise cost-effectiveness of such
interventions and potentially have significant impact on inci-
dence and outcomes of breast cancer.
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 31 4

Effect of Oestrogen Exposure,

Obesity, Exercise and Diet
on Breast Cancer Risk
Eleni Th. Petridou, Marios K. Georgakis, and Constantine N. Antonopoulos

4.1 Introduction – 32
4.1.1 Endogenous Oestrogens and Proxy Measurements
of Oestrogen Exposure – 32
4.1.2 Exogenous Hormone Administration – 33

4.2 Effect of Obesity and Exercise – 35

4.2.1 Obesity – 35
4.2.2 Exercise – 36
4.2.3 Underlying Mechanisms for Obesity and Exercise – 36

4.3 Effects of Diet – 36

4.3.1 Macronutrients and Food Items – 37
4.3.2 Dietary Patterns – 37
4.3.3 Micronutrients – 37
4.3.4 Alcohol Consumption – 37
4.3.5 Non-alcoholic Beverages – 38

4.4 Conclusions – 38

References – 39

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_4

rares1geo@gmail.com
 32 E.T. Petridou et al.
4.1 Introduction
Oestrogens, the primary female sex hormones, are mainly
involved in the formation of female sex organs and second-
ary sex characteristics, including breast development, control
of the menstrual cycle and reproduction. Concerning their
effect on breast tissue, oestrogens are directly responsible for
inducing the ductal component of breast development, as
4 well as for fat deposition and connective tissue growth.
Therefore, they are highly linked to female breast growth
during puberty and breast maturation during pregnancy
which lead to lactation and breast-feeding. Over and beyond
their physiological central role in breast epithelial tissue
growth, however, oestrogens are also involved in breast carci-
nogenesis through a proliferative impact on breast tissue.
Breast cancer, the most common type of cancer among
women both in the developed and the developing world, is on
the increase. Genetic risk factors account for a steadily
increasing proportion of disease causation as scientists
develop a better understanding of the numerous potent,
moderate and minor impact genes and polymorphisms on
risk (see 7 Chap. 5). Interestingly, lifestyle factors, including
physical activity, weight and diet, seem to contribute most to
the observed increase in the frequency of female breast can-
cer. Hence, identification of factors implicated in oestrogen-
induced carcinogenicity and recommendations on modifiable
behaviours are elements of paramount importance for cancer
prevention programmes. This chapter aims to summarize
current evidence on the impact of exposure to oestrogens,
use of exogenous pharmaceutical agents related to female
hormones, obesity, exercise and diet on breast cancer risk and
outcome; to present potential gains in breast cancer preven-
tion where behaviour modification is to be achieved at popu-
lation level; and to introduce domains for further research.
4.1.1  ndogenous Oestrogens and Proxy
E arche according to the largest to-date study of 120,000 breast
Measurements of Oestrogen Exposure
Endogenous Oestrogens
Among oestrogens, oestradiol, the most biologically active
oestrogen during reproductive years, and oestrone, the major
circulating oestrogen after menopause, comprise the most
well-studied female hormones. Oestradiol may be found in
the circulation either bound to sex hormone-binding globu-
lin and albumin or in an unbound form; free and albumin-
bound oestradiol is thought to be highly active and readily
available to breast tissue. On the other hand, oestrone can be
directly converted to oestradiol either in the peripheral adi-
pose tissue or by sulphatase and 17-beta-dehydrogenase
intracellularly in breast cells [1].
Early evidence regarding the association between circulat-
ing oestrogen levels and breast cancer risk was derived from
case-control studies despite their inherent limitations on
account of oestrogen levels after diagnosis and via heteroge-
neous assessment methodologies (direct measurement, extrac-
rares1geo@gmail.com
tion or mass spectroscopy). Subsequently, these results were
confirmed in large prospective studies, and an association
between high circulating oestrogen levels and risk of breast
cancer in postmenopausal women was established. A recent
meta-analysis of these studies, encompassing 4302 breast can-
cer cases, showed that in postmenopausal women incremental
quantiles of oestradiol levels (E2) increased breast cancer risk
by a factor of two (OR for highest vs. lowest quantile = 2.15) [2];
a similar effect was also reported for oestrone (E1; OR = 1.81).
Indeed, this study confirmed findings from an older pooled
analysis [3], which had shown an increase in risk of postmeno-
pausal breast cancer by increasing quantile of free oestradiol,
bioavailable oestradiol, total oestradiol, oestrone and oestrone
sulphate. Interestingly, more recently diverse effects by levels of
hormone receptor expression of the tumour were shown, par-
ticularly the elevated risk of postmenopausal breast cancer by
increasing circulating oestrogen levels pertained only to the
hormone receptor-positive tumours [4], providing evidence for
a biologically plausible explanation on the action of oestrogens
via these receptors. The data for premenopausal women are
limited due to cyclical variations in hormone levels during
reproductive years making these studies challenging. Despite
this a recent pooled analysis of seven prospective studies
showed an increased risk of premenopausal breast cancer when
concentrations of total oestradiol (OR = 1.19), free oestradiol
(OR = 1.17) and oestrone (OR = 1.27) were doubled [5].
 roxies of Endogenous Oestrogen Exposure:
P
Early Age at Menarche and Late Age at
Menopause
Menarche signals the onset of exposure to ovarian hormone
cycling, whereas menopause signals its cessation and the
transition to a hypo-oestrogenemic environment. Evidence
suggesting that earlier menarche and later menopause
increase the breast cancer risk is consistent and quantified to
a 5% increase in the risk with a 1-year decrease of age at men-
cancer cases [6]. Adolescents with an earlier menarche have
been shown to have increased urinary oestrogens around
puberty, indicating increased exposure to ovarian hormones
at a time of high breast tissue responsiveness [7]. There is also
evidence that earlier menarche may determine circulating
oestrogen levels even later in women’s life, at the menopausal
transition [8].
Conversely, breast cancer risk in postmenopausal women
decreases by 2.9% by 1-year increment of age at menopause
[6]. Possible reasons for the protective effect of earlier meno-
pause seem to be the abrupt decrease of circulating sex hor-
mone levels during menopause [9] and the shorter overall
period of exposure to cycling endogenous hormones. The
evidence for a decreased breast cancer risk conferred in case
of surgical menopause via bilateral oophorectomy is compel-
ling [10]. In particular, a 50% lower risk was observed among
women with oophorectomy before the age of 45 years [11],
whereas the risk did not seem to decrease among women
after hysterectomy with preservation of the ovaries [12].
Effect of Oestrogen Exposure, Obesity, Exercise and Diet on Breast Cancer Risk
 roxies of Endogenous Oestrogen Exposure:
P oestrogen, from higher than 100 μg to a considerably decreased
Childbearing
Nulliparous women are known to be at increased breast cancer
risk compared to parous women [13], but this effect is more
complex than initially thought. In particular, prospective stud-
ies have found that there is a transient increased risk after
delivery among parous compared to same-age nulliparous
women for a short-term period calculated up to 15 years [14].
Eventually, however, this effect reverses with a long-­lasting
protection of parous women for the rest of their lives and a
further modestly decreased level of risk for every subsequent
pregnancy. Thus, the cumulative breast cancer risk is overall
decreasing with parity, given that breast cancer is more com-
mon among older women, and the increased risk following a
pregnancy is extended to a period until the 40th to 50th year of
age when baseline breast cancer rates are generally lower [15].
A younger age at first pregnancy is associated with
decreased breast cancer risk [13, 16]. Although varying by
study, each additional year of age at first childbearing leads to
an increased premenopausal and postmenopausal breast
cancer risk of 5% and 3%, respectively [16]. Additionally,
women bearing their first child after 35  years compared to
those with a first full-time pregnancy before 20 years, show
an increased breast cancer risk of 30% [13].
The mechanisms underlying the parity-breast cancer
associations relate to lifetime and parity-induced changes in
the breast tissue. Before childbearing, the breast tissue of a
woman of reproductive age contains a large number of undif-
ferentiated glandular epithelial cells, characterized by higher
proliferation and division rates and a stronger malignant
potential, whose differentiation is gradually evolving. Parity
promotes the differentiation of these cells making them more
resistant to carcinogenic stimuli, thus decreasing the risk of
breast cancer [17]. An earlier pregnancy indicates an earlier
differentiation of glandular epithelial cells and thus a short-
ened period of exposure of undifferentiated cells to potential
carcinogenic factors.
4.1.2 Exogenous Hormone Administration
Given the proliferative effects of oestrogens on breast tissue,
the widespread use of exogenous hormones has rationally
drawn research attention. Hormone regimens are mainly
administered either as oral contraceptives (OC) during repro-
ductive years, as part of infertility treatment, or as meno-
pausal hormone replacement therapy (HRT). Another
interesting new and unexplored research field is the effect for
breast cancer risk of hormone medications for feminization
in transgender individuals.
Oral Contraceptives
Oral contraceptives (OCs), introduced in the 1960s, represent
the most common form of hormonal contraception reaching
an 82% ever use among US women [18]. The ­majority of OCs
contain both an oestrogen and a synthetic progestin. OC syn-
thesis over time has undergone a major change in the dose of
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33 4
20–30 μg of ethinyloestradiol in the currently most frequently
used OC.
The findings regarding a potential association with breast
cancer risk remain rather inconsistent, despite the vast num-
ber of publications. Overall, a moderately higher breast can-
cer risk among OC users is found restricted to premenopausal
breast cancer and recent use. In a recent meta-analysis of 44
case-control and cohort studies, the overall risk of breast can-
cer among OC users was 1.08 (95% CI, 1.003–1.165); the
high heterogeneity between studies, though, raised concerns
regarding the robustness of the findings [19]. The results sup-
ported a stronger association with recent OC use (<5 years,
OR  =  1.21) gradually attenuating with longer period since
last use (5–10  years, OR  =  1.17; 10–20  years, OR  =  1.13;
>20 years, OR = 1.02). The findings, showing increased risk
in premenopausal and generally younger women [20, 21],
but not in postmenopausal women [22], shown in previous
studies, were also confirmed in the meta-analysis.
Furthermore, OC have been associated with a comparably
increased risk of premenopausal breast cancer in both parous
(OR = 1.24) and nulliparous women (OR = 1.29); among par-
ous women, however, the association is stronger in those
who started OC use before their first full-term pregnancy
[20]. A large pooled analysis [22], entailing worldwide avail-
able data up to 1996 on the association of breast cancer with
OC use, showed an approximate 20% increased risk only
among women under 45  years who were recent OC users.
The risk was independent of the duration of use, but disap-
peared 10 years after OC quitting. No dose-response pattern
in terms of duration of OC use seemed to apply [19], and no
interaction with other breast cancer risk factors, such as BMI
or family history, was evident [22].
The effect of OC on breast cancer risk seems to be medi-
ated by either ethinyloestradiol or synthetic progestin deriva-
tives of 19-nortestosterone that possess estrogenic activity
[23]. Only a few studies have, however, examined the effect by
oestradiol dose or progestin compound. A case-control study
of younger women (20–44 years old) with breast cancer (1640
cases, 1492 controls) showed that those who used OC with
ethinyloestradiol doses >35 μg were at higher risk compared
to users of OC with lower doses, an effect more profound
among women <35  years. The risk did not differ by recent
progestin compounds, whereas pills with high progestin and
oestrogen potency significantly increased the risk [21]. In
conclusion, the reduction of oestradiol dose may have led to
a decrease in the risk of breast cancer associated with OC use;
more studies are needed, however, on the type of OC used
and tentative associations with breast cancer subtypes.
Ovarian-Stimulating Agents
The emergence of infertility as a public health issue during
the last decades and the use of ovarian-stimulating agents for
its treatment rationally raised concerns regarding the tenta-
tive negative long-term effects of these agents. Ovarian-­
stimulating agents encompass oestrogen receptor modulators,
like clomiphene citrate and tamoxifen, FSH, hCG, human
 34 E.T. Petridou et al.
menopausal gonadotrophin and GnRH analogues, and are
typically administered during the follicular phase of the men-
strual cycle aiming to stimulate ovulation. More frequently,
ovarian-stimulating agents are used in complex protocols in
the context of the controlled ovarian hyperstimulation phase
of assisted reproductive technologies. Despite their definite
effect on modifying circulating oestrogen and progesterone
levels, however, current evidence, as synopsized by two recent
4 meta-analyses, does not support any effect of ovarian-stimu-
lating agents on the risk of subsequent breast cancer [24, 25].
The lack of association seemed to be robust independently of
the drug used or the cycles of administration, whereas when
used in the context of in vitro fertilization, no effect was evi-
dent when comparisons pertained to either women of the
general population or women with history of infertility.
Hormone Replacement Therapy
HRT use was initiated in the 1960s, became popular in the
developed world and reached its peak in the late 1990s.
Oestrogen/progestogen combination is the most common form
of HRT used for women with a natural menopausal transition,
as opposed to oestrogen-only therapies used for hysterecto-
mized women [26]; progestogens were used to protect the
endometrium against the proliferative effects of unopposed
oestrogens [27]. Most early scientific reports from observa-
tional studies showed beneficial effects of HRT on women’s
health [28]. The initial promising findings were thereafter
reversed in the Women’s Health Initiative (WHI) randomized
controlled trial, published in 2002 [29]. The trial was termi-
nated early due to increasing rates of adverse health outcomes
among postmenopausal women using oestrogen plus progesto-
gen therapy [29–31]. Questions were raised about the safety of
HRT given that trial findings for increasing risk of cardiovascu-
lar disease, breast cancer and dementia outweighed the reported
beneficial action against fractures and colon cancer [29–31].
Summarizing the results of epidemiologic studies on HRT
effects is challenging, given the wide variation in doses, pat-
terns of use and the varying combinations of different oestro-
gen and progestogen compounds over time. A meta-­analysis,
pooling results from 51 observational studies, showed a higher
breast cancer risk among women using HRT, increasing with
longer duration of use (RR  =  1.35 among HRT users of
>5 years) [32]; the summary findings were later confirmed in
the large Nurses’ Health Study [33], the Million Women Study
[34] and the WHI trial [30]. Previous studies had shown an
increased risk primarily for in situ and not invasive cancer [35,
36] supporting a hypothesis that the higher breast cancer risk
among HRT users was due to the most intense surveillance for
breast cancer. Recent studies, however, confirmed a significant
increase also for invasive breast cancer [32, 35, 36]. The effect is
stronger for women of lower weight and BMI [32], possibly on
account of lower baseline oestrogen levels among lean women
and the abrupt increase following HRT administration.
Additionally, Asian and women with high breast density seem
to be more susceptible to the tumorigenic effects of HRT [37].
Concerns about the diverse effects of different types of
HRT on breast cancer risk were initially raised after publication
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of the differential Women’s Health Initiative oestrogen-­only
and combined oestrogen-progesterone trials among 10,739
hysterectomized women [38] and 16,608 naturally menopausal
women, respectively. Indeed, combined therapy with oestro-
gen and progestogen exerts a more pronounced breast cancer
risk compared to «monotherapy» with oestrogen [29]. Despite
the evidence for a causative association in the combined ther-
apy arm, the oestrogen-only arm also showed a sizeable,
though marginally significant, inverse association with breast
cancer risk (RR = 0.77, 95% CI: 0.59–1.01). The WHI study,
however, enrolled women many years after menopause (mean
age 64 years) with a relatively high proportion of overweight
women (BMI ≥ 30 kg/m2 in 45% of study subjects) [38] and a
short follow-up (7.1 years), as the study was terminated due to
the increased risk of adverse effects.
In terms of type of oestrogen or type of progestogen used,
data were mainly contributed by European studies, with a
higher variability in the formulas used. The Million Women
Study showed no difference between conjugated oestrogen
and ethinyloestradiol [34], whereas the French E3N study
showed that the increased risk of breast cancer among com-
bined HRT users is restricted to those receiving synthetic pro-
gestins and not progesterone or dydrogesterone [39], possibly
on account of their increased androgenic action [40]. Despite
the rationale that the route of oestrogen administration could
change their effect due to differences in their metabolism,
contemporary studies do not support differential effects of
oral, transdermal or implanted oestrogens [34, 39].
The association of HRT with the risk of breast cancer-­
specific histology is an emerging research field within pathol-
ogy. Generally, the findings are consistent towards an association
of combined oestrogen-progesterone therapy with the risk of
oestrogen and progesterone receptor-positive breast cancer but
not with receptor-negative tumours [41–44]. Regarding partic-
ular histology, the WHI did not show any specific association of
combined HRT with ductal or lobular carcinomas, even though
the study was relatively underpowered [30]. Other studies show,
however, a trend for stronger associations with lobular carcino-
mas, compared to ductal tumours [45, 46].
Conclusively, after myths on the overall protective effects
of HRT have been debunked and replaced with well-­
established findings on a relationship between breast cancer
risk and use of combined oestrogen-progesterone HRT, its
use dropped dramatically; current guidelines recommend
HRT only for relief of severe menopausal symptoms and
deceleration of bone mass loss in the lowest possible dose
and for the shortest possible time period [26, 47, 48].
Feminizing Therapy in Transgender
Individu als
Since the beginning of the 1900s, societal awareness (and
more recently acceptance) of transgender individuals consid-
ering themselves «trapped in their own body» has developed.
Cross-sex hormonal treatment is now recommended as an
important component of the endocrine regimen in transsex-
ual people [49]. In male-to-female individuals, the treatment
comprises combined administration of anti-androgens or
Effect of Oestrogen Exposure, Obesity, Exercise and Diet on Breast Cancer Risk
GnRH ­analogues to block the activity of androgens or sup-
press the gonadotrophin axis on androgen production,
respectively. In addition oestrogens are administered to pro-
mote the development of female characteristics. The negative
findings of the oestrogen-only therapies on breast cancer risk
in hysterectomized women in the WHI trial [38], along with
the lack of evidence on increased risk of breast cancer among
women with Turner’s syndrome receiving HRT for long peri-
ods [50], provided indirect evidence that cross-sex therapies for
male-to-female individuals may not lead to an increased breast
cancer risk among transsexuals. To date, up to 30 years of fol-
low-up studies on transgender individuals seem to confirm
initial findings, showing no evidence for increased risk of breast
cancer among either male-to-female or female-to-­male indi-
viduals [51–53]. Follow-up and further research is warranted to
allow exploration of specific epidemiological parameters.
4.2 Effect of Obesity and Exercise
Overweight and obesity are expanding on a worldwide basis,
reaching levels of 60–70% of the adult population in devel-
oped countries; alarmingly increasing are also the rates in
developing countries. In the USA, the impact of overweight
and obesity has been estimated to account for 20% of cancer
deaths in women, a trend that has been implied as a cause of
the concurrent overall breast cancer incidence increase [54].
The association between obesity and breast cancer risk varies
by menopausal status. The findings regarding weight change
throughout a woman’s lifetime, implicating also the beneficial
role of physical activity, are also interesting. The common
proposed mechanism for both of these associations pertains
to oestrogenic activity, whereas other factors may prove to be
equally or more important, particularly in respect to the more
aggressive tumour immunophenotypes. Among them, insu-
lin, insulin-like growth factor-I (IGF-I) and leptin, as well as
angiogenic and a range of other transcription factors, have
been implicated in the obesity-breast cancer association [55].
4.2.1 Obesity
 he Bimodal Role of Adiposity Among
T change) [64]. It is worth noting, however, that periods of poten-
Premenopausal and Postmenopausal Women
A vast number of studies have explored the association between
BMI and breast cancer risk showing a differential pattern
depending on menopausal status. Specifically, adiposity has
been associated with a decreased risk in premenopausal but
increased risk in postmenopausal women [56]. A 15% decrease
per 5 kg/m2 increase in BMI has been recorded for premeno-
pausal cancer; according to the Nurses’ Health Study, the effect
of BMI on premenopausal breast cancer risk could be explained
by the BMI at the age of 18 years [57]. It has also been sug-
gested that this effect in premenopausal women could be
mediated by obesity-related amenorrhea and subsequent lower
exposure to endogenous oestrogen levels in these women [58].
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35 4
1.8
1.6
1.4
RR
1.2
1
20 25 30 35 40
BMI
..      Fig. 4.1  Dose-response meta-analysis for the association between
BMI and risk of breast cancer in postmenopausal women (From Xia
et al. [60]
On the other hand, a strong increase of around 12% per
5 kg/m2 BMI increment in breast cancer risk has been reported
in obese postmenopausal women [59]. In a meta-­analysis, the
authors found that obesity contributed to increased breast can-
cer risk in a nonlinear dose-response manner in postmeno-
pausal women, and it is important to realize that body weight
control may be a crucial process to reduce breast cancer sus-
ceptibility (. Fig. 4.1) [60]. Interestingly, the higher risk may
primarily apply for oestrogen and progesterone receptor-posi-
tive tumours [61]. Family history of breast cancer and HRT
seem to modify this association; particularly, having a relative
with breast cancer strengthened the effect of a high BMI [62],
whereas among HRT users this effect was moderate [63].
Weight Change
A number of studies have assessed the effect of weight change
during lifetime on breast cancer risk. The majority of studies
pertain to postmenopausal breast cancer and show an increased
risk with weight gain after 18 years of age; the effect over adult-
hood is estimated at 5% per 5  kg of weight gain [56, 64].
Furthermore, weight gain after menopause has been also found
to independently increase breast cancer risk (OR: 1.18 for
weight gain of at least 10 kg compared to women with no weight
tial weight loss have not been taken into account. The published
data for premenopausal breast cancer are limited. In one report
no effect was found [65], whereas another study showed a mar-
ginally significant decrease in breast cancer risk among women
reporting weight loss since the age of 18 years [66].
Central Adiposity
Of interest is also the association of breast cancer with fat dis-
tribution, besides overall adiposity. Central adiposity is linked
to metabolic-hormonal changes leading to insulin resistance,
as well as hyperandrogenemia and excess conversion of
peripheral androgens to oestrogens. Waist-to-hip ratio is con-
sidered a reliable measure of central adiposity and has been
 36 E.T. Petridou et al.
consistently associated with postmenopausal breast cancer
[56, 67]. Again findings for premenopausal breast cancer
remain inconsistent and inconclusive; as contrasted to BMI,
however, two meta-analyses have shown an increased risk of
premenopausal cancer in women with central adiposity [67,
68]. The results were heterogeneous, though, whereas the
effect seemed to be stronger among women of Asian origin.
4 or a shortened luteal phase. Lastly, in puberty, vigorous activity
4.2.2 Exercise
Physical activity is considered an established primary breast
cancer prevention strategy for both premenopausal and post-
menopausal women [69]; indeed, sustained regular activity
throughout life seems to provide the highest benefit [70].
Noticeably, it has been estimated that elimination of physical
inactivity would result in a decrease of breast cancer incidence
by 10% [71]. The first study aiming to assess this association,
using a detailed lifetime physical activity assessment, showed a
58% decreased risk of breast cancer among premenopausal
women with an average of 3.8 h of exercise per week, compared
to those who reported no exercise [72]. Similarly, a decreased
risk by 45% for breast cancer in postmenopausal women in the
highest physical activity category was found [73]. A large
recent meta-analysis summarizing evidence from 31 cohort
studies confirmed the results and showed an overall 13%
decrease in risk among women reporting the highest versus the
lowest level of physical exercise. A dose-response pattern was
recorded, and the overall estimate was stronger for premeno-
pausal women and women with normal BMI values, compared
to overweight, and confined to oestrogen/progesterone recep-
tor-negative tumours [74]. Interestingly, in a systematic review
of the literature, occupation-related, household, recreational
and walking-­associated physical activity all seemed to inde-
pendently decrease the risk for breast cancer [75].
4.2.3  nderlying Mechanisms for Obesity
U  nti-inflammatory and Other Protective
and Exercise
The adverse effects of obesity and the beneficial actions of
physical activity are generally considered to be exerted via
common mechanisms. The proposed actions could be gener-
ally synopsized as (a) exposure to oestrogens, (b) changes in
insulin-related factors and adipokines and (c) anti- or pro-­
inflammatory actions and other protective mechanisms.
These are described below.
Exposure to Oestrogens
Body fat in postmenopausal women is a main source of oes-
trogen secretion via aromatization of androgens [76].
Therefore, the higher oestrogen levels in obese postmeno-
pausal women seem to be responsible for the increased risk
of breast cancer after menopause; similarly, the observed
protective effects of physical activity seem to be mainly medi-
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ated by the subsequent body fat loss associated with regular
exercise in this age group.
Physical activity, in premenopausal women, where the
association between adiposity and breast cancer risk is reversed,
seems to act via independent mechanisms. Specifically, high
levels of physical exercise in reproductive years are associated
with reduced levels of circulating oestradiol and progesterone,
possibly because of irregular or anovulatory menstrual cycles
could delay the onset of menarche, which has been associated
with a decreased risk of breast cancer.
Downregulation of Insulin-Related Factors
Physical activity may prevent breast tumour development by
lowering levels of the hormones insulin and insulin-like
growth factor-I (IGF-I) [77]. Decreased insulin upregulates
sex hormone-binding globulin (SHBG), leading to lower
levels of bioavailable oestradiol [78]; it also seems to decrease
the bioavailability of IGF-I [79]. IGF-I acts as a mitogen in
breast epithelial cells, promoting transformation and sup-
pressing apoptosis [80]; consequently, lower circulating lev-
els of IGF-I are associated with a decreased breast cancer
risk [81].
Benefits on Obesity-Related Adipokine Levels
Adipose tissue is considered an endocrine organ which pro-
duces and secretes adipokines, involved in the mediation of
inflammatory diseases and obesity. In a recent study, adipo-
nectin, leptin, visfatin and resistin were all found to be risk
factors for breast cancer in postmenopausal females. In par-
ticular, leptin, resistin and visfatin levels were positively cor-
related with TNM staging, tumour size, lymph node
metastasis and histological grading in postmenopausal sub-
groups [82]. As a result, physical exercise and its inhibitory
effect upon adipose tissue provide downregulatory signals for
decreased adiponectin secretion.
A
Mechanisms
Chronic inflammation is now considered a key process in
carcinogenesis, and physical activity has been known to sup-
press increased levels of inflammation, whereas obesity is
now recognized as a chronic inflammatory disorder [83, 84].
Other proposed protective mechanisms of exercise against
breast cancer risk include an exercise-induced decrease in
breast density, reduction in oxidative stress, enhancement of
immune function, promotion of tumour suppressor genes
and intracellular anticarcinogenic pathways [85].
4.3 Effects of Diet
Diet has been associated with the development or progres-
sion of major human cancers, including breast, prostate and
colorectal tumours. It is a modifiable factor, which has been
Effect of Oestrogen Exposure, Obesity, Exercise and Diet on Breast Cancer Risk
the subject of intensive research interest as it provides a win-
dow for preventive intervention strategies, due also to the
immense interest of lay people in associating their dietary
habits with cancer risk and breast cancer risk, in particular.
4.3.1 Macronutrients and Food Items
Among macronutrients and food items, dietary fibre has been
proposed to reduce breast cancer risk via decreasing reab-
sorption of oestrogens in the gastrointestinal system [86], yet
evidence remains inconclusive [87, 88]. Regarding fat intake,
there are experimental studies suggesting that an increased fat
intake could induce mammary gland tumours in rodents
[89]. On a molecular level, fatty acids could influence the car-
cinogenic process through mechanisms related to modifica-
tions of cell membrane structure, metabolic effects and impact
on translational signals and gene expression [87]; findings
from humans, however, do not seem to strongly support this
hypothesis [87, 88, 90]. Regarding other food groups, high
dietary intake of carbohydrates has been suggested to increase
breast cancer via induced hyperinsulinemia.
Many studies on the association of specific dietary factors
with breast cancer have been published showing conflicting
results, notably inverse, positive or null associations [91].
Briefly, consumption of fruit, vegetables and fish, as well as
soy-based food and isoflavone intake, seems to be associated
with decreased breast cancer risk, possibly on account of their
antioxidant effects and the decrease in oestrogen levels related
to soy-based food. Meat intake, apart from being associated
with colorectal cancer, has been also found in some studies to
increase breast cancer risk, but the evidence is limited [87, 88].
4.3.2 Dietary Patterns
A lower breast cancer incidence has been encountered by
women who live in Mediterranean countries compared to
those in Northern European countries, such as the UK or the
USA; in this context, the Mediterranean pattern of diet has
been considered as a tentative contributing factor. In the small
MeDiet study, study subjects were randomized into a dietary
intervention group (n = 58) following a traditional, controlled
Mediterranean diet for 6 months and a control (n = 57) group,
which continued to follow their regular diet. At baseline, no
significant difference was observed in urinary levels of indi-
vidual oestrogens comparing intervention and control
women. After 6 months, however, whereas no major change
was noted in the control group, as expected, women in the
intervention group showed a significant reduction (over 40%,
p < 0.02) of total oestrogen levels [92]. These findings need to
be further confirmed in the hope that this strategy may be
part of breast cancer prevention strategies. A number of stud-
ies have also explored whether the so-called Western diet,
traditionally including high red and processed meats, refined
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37 4
grains, potatoes and starches, snacks, sweets, fried foods and
soft drinks, impacts on breast cancer risk; the majority, how-
ever, have not found statistically significant associations [87].
4.3.3 Micronutrients
Evidence regarding the association of micronutrients with
breast cancer risk in both premenopausal and postmenopausal
women is not consistent. Despite the reported antioxidant
effects of vitamin C, vitamin E and selenium, most cohort stud-
ies do not confirm these results. By contrast, the protective effect
of vitamin A and retinol intake seems to merit further research
[93] taking into account variations in absorption, metabolism
and excretion of carotenoids between individuals [94].
Regarding other micronutrients, higher dietary folate
intake has been associated with decreased breast cancer risk,
especially among women reporting higher alcohol con-
sumption indicating an interactive effect [95]. Similarly, a
higher dietary intake of methionine, but not vitamin B6 and
B12, has been proposed to have an inverse association, espe-
cially for postmenopausal women [96]. These molecules are
considered essential for DNA synthesis, repair and methyla-
tion, and their deficiency could lead to DNA instability and
proneness to carcinogenic mutations [97]. Lastly, there are
some suggestions of an inverse association between vitamin
D, as well as calcium intake and breast cancer risk [98, 99],
which were not confirmed, however, in the results of a ran-
domized trial assessing the link between use of combined
calcium and vitamin D supplementation with breast cancer
risk [100].
4.3.4 Alcohol Consumption
Alcohol consumption is considered to be causally related to
breast cancer risk, with a 7–10% increase in risk for each 10 g
(~1 drink) of alcohol daily consumption by premenopausal
or postmenopausal women [101]. A dose-response pattern is
noted with heavy drinking increasing the risk by approxi-
mately 60% and enhanced associations for hormone receptor-­
positive tumours [102]. Proposed mechanisms include the
effect of alcohol on circulating oestrogen levels and the carci-
nogenic role of ethanol metabolites or the effect of alcohol on
epithelial-mesenchymal transition, epithelium-stroma inter-
action and epigenetic regulation of gene expression in the
breast [101]. Alcohol consumption may cause a rise in oes-
trogen levels by promoting aromatase activity that converts
androgens to oestrogens, inhibiting oestrogen degradation,
decreasing melatonin secretion that inhibits oestrogen
­production and ­increasing hepatic redox state that results in
a decrease in steroid metabolism. Additionally, acetaldehyde
and free radicals, alcohol metabolites, may cause DNA dam-
age promoting carcinogenesis. Lastly, the decrease in folate
levels due to antagonism by alcohol may contribute to breast
cancer development [101].
 38 E.T. Petridou et al.
4.3.5 Non-alcoholic Beverages
Caffeine was implicated in breast tumorigenesis, on account
of an observation that coffee consumption reduction was
associated with regression of fibrocystic breast disease [103].
The results of subsequent large cohort studies are synopsized
in a recent meta-analysis [104] showing no association. Of
note, however, are suggestions for a small inverse association
4 specific for green tea consumption and its association with
breast cancer incidence and recurrence, possibly on account
of its antioxidant actions [105], which does not apply for
black tea consumption [106].
4.4 Conclusions
Breast cancer remains the leading type of malignancy in
women worldwide with a profoundly higher incidence in the
developed compared to developing countries. Increasing
trends have been evident in Western communities for several
decades. Lifestyle changes leading to obesity and physical
inactivity, higher alcohol consumption and variable use of
Factor
Physical inactivity
Overweight (BMI 25-29.9 kg/m2) vs. normal (<25 kg/m2)*
Obese (BMI >=30 kg/m2) vs. normal (<25 kg/m2)*
Light vs. no alcohol consumption
Moderate vs. no alcohol consumption
High vs. no alcohol consumption
.9
* Refers only to postmenopausal breast cancer
..      Fig. 4.2  Summary effects of the three major modifiable lifestyle risk factors, namely, physical inactivity, obesity and alcohol consumption, on
the risk of breast cancer. The effect estimates are obtained from three latest meta-analyses on each topic [71, 102, 108]
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exogenous oestrogens are believed to have contributed to the
observed increase of the disease. Higher oestrogen exposure,
indicated by proxies, such as earlier age at menarche, later
menopause and adverse childbearing patterns, has been wit-
nessed in parallel [107]. There is no strong evidence that
other macro- or micronutrients are clearly included in the
aetiology of the disease.
Intense research over the last few decades has broadened
our understanding of the aetiology of the disease and revealed
modifiable factors offering applicable preventive targets
(. Fig. 4.2). According to the World Cancer Research Fund,
40% of postmenopausal breast cancers would have been pre-
vented, where it is possible to reduce alcohol consumption,
physical inactivity and obesity [41]. In order to formulate
public health recommendations and tangible prevention
guidelines, future research should focus on specific compo-
nents of modifiable risk factors, such as type and timing of
physical activity, and their geographical, ethnical and cul-
tural customization. Indispensable is further exploration of
the model of oestrogen- or other hormone-induced carcino-
genesis, the findings of which should be clinically integrated
into breast cancer prevention and control programmes.
Effect size (95% CI)
1.33 (1.26, 1.42)
1.10 (1.06, 1.13)
1.18 (1.12, 1.25)
1.04 (1.01, 1.07)
1.23 (1.19, 1.28)
1.61 (1.33, 1.94)
1 2
Effect of Oestrogen Exposure, Obesity, Exercise and Diet on Breast Cancer Risk
39 4

Key Points transgender individuals do not seem to increase

55 Oestrogens are involved in breast carcinogenesis by
exerting proliferative effects on breast epithelial 55
tissue.
55 High levels of serum oestrogens have been linked
with increased risk of breast cancer, especially
among postmenopausal women. 55
55 Proxies of high lifetime exposure to endogenous
oestrogens, like early menarche and late meno-
pause, are associated with increased risk of breast 55
cancer, whereas premenopausal oophorectomy
seems to decrease the subsequent risk.
Childbearing and young age at first pregnancy
decrease the lifetime risk for breast cancer.
55 Well-documented findings support the finding
that the use of combined oestrogen-progesterone
hormone replacement therapy (HRT) increases
the risk for breast cancer in postmenopausal 55
women.
55 Oral contraceptives, ovarian stimulation for 55
infertility treatment and hormone therapy for
breast cancer risk.
A bimodal pattern has been observed regarding the
association of obesity with breast cancer, with an
increased risk for postmenopausal and a decreased
risk for premenopausal women.
Physical exercise decreases the risk of breast cancer
in a dose-response pattern, thus comprising a target
for preventive strategies.
Body fat comprises the main source of oestro-
gens in postmenopausal women via aromatiza-
tion of androgens, and this is thought to be the
main mechanism underlying the aggravat-
ing effect of obesity, as well as the protec-
tive action of exercise. Other mechanisms
include the IGF-I system, adipokines and inflam-
mation.
Alcohol consumption is a well-established risk
factor for breast cancer.
There is no consistent evidence regarding associa-
tion with other dietary patterns.

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4
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 43 5

Hereditary Breast Cancer

Genetics and Risk Prediction
Techniques
Helena Carley and Anju Kulkarni

5.1 Mechanisms of Oncogenesis – 44

5.2 DNA Sequence Alterations and Their Effects – 44

5.3 Somatic Mutations in Oncogenesis – 45

5.4 Constitutional Mutations in Oncogenesis – 46

5.5 Hereditary Breast Cancer ­Susceptibility – 47

5.6 High-Penetrance Genes – 48

5.6.1 BRCA1 and BRCA2 – 48
5.6.2 TP53 – 49
5.6.3 STK11 – 49
5.6.4 PTEN – 49
5.6.5 CDH1 – 49

5.7 Moderate-Penetrance Mutations – 49

5.7.1 PALB2 – 50
5.7.2 ATM – 50
5.7.3 CHEK2 – 50

5.8 Low-Penetrance Alleles – 50

5.9 Risk Prediction – 50

5.10 Tools in Risk Prediction – 50

5.11 Gene Sequencing Technologies – 51

5.12 Gene Panel Testing in Breast Cancer – 52

5.13 Conclusion – 53

References – 54

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_5

rares1geo@gmail.com
 44 H. Carley and A. Kulkarni
5.1 Mechanisms of Oncogenesis
Cancer develops due to a series of insults to cellular DNA
which enable the cell to escape the tightly controlled pro-
cesses governing cell proliferation and acquire new capabili-
ties to permit unregulated cell division, to sustain tumour
growth and to acquire metastatic potential [1]. Hanahan and
Weinberg summarise the «hallmarks of cancer» as the ability
to disrupt cellular energetics; initiate cell proliferation; resist
growth inhibitory signals; escape immune system destruc-
5 tion and apoptosis, cellular immortality and the potential to
sustain angiogenesis; invade tissues; and metastasise [1, 2].
In the normal cellular equilibrium, proto-oncogenes reg-
ulate cell proliferation, whilst tumour suppressor genes
(TSGs) act as the cellular «brake», by regulating cell cycle
checkpoint controls, cell cycle progression, DNA damage
repair and the promotion of apoptosis.
In oncogenesis, the tumour-initiating event is DNA dam-
age, causing a mutation in a gene critical to cell cycle regula-
tion. Gain-of-function mutations in proto-oncogenes form
oncogenes. These disrupt the function of the wild-type allele,
acting in a dominant manner, to permit uncontrolled cellular
proliferation. Alternatively, mutations may occur in tumour
suppressor genes (TSGs), allowing aberrant cells to proceed
through the cellular cycle unchecked. In general, TSGs act
recessively and as such, loss-of-function mutations in both
alleles are required for oncogenesis [3].
Following the initial DNA-damaging event, the tumour cell
is then exposed to tumour-promoting stimuli, which induce
clonal proliferation. Genetic instability ensues due to further
accumulation of DNA damage, with new mutations providing
a selective advantage to the growing population of tumour cells
[4]. The tumour-associated stroma is harnessed to provide a
supportive framework upon which tumour cells can evade the
immune response, develop a vasculature and metastasise [5].
5.2  NA Sequence Alterations and
D tide sequence [6]. Variants of uncertain significance (VUS)
Their Effects
A mutation is any irreversible alteration to the DNA sequence
[6]. Changes of the DNA sequence at the base or codon level take
the form of substitutions, insertions or deletions. If a change in
the DNA sequence results in a change to the amino acid being
encoded, this is termed a «non-synonymous change» and may
manifest as a change to the protein structure. Non-synonymous
changes can be further characterised as missense mutations, in
which a different amino acid is encoded; non-sense mutations, in
which a premature stop codon is encoded; or sense mutations, in
which a stop codon is changed to a normal amino acid. Single
base substitutions are called point mutations. Base insertions or
deletions, «indels», have the potential to cause significant changes
to the protein structure, if they occur «out of frame», that is, not
in multiples of three. Frameshift mutations affect all subsequent
codons in the protein sequence until a stop codon is reached [3].
Mutations may also occur due to more substantial changes
in chromosomal integrity which impact on multiple genes,
rares1geo@gmail.com
such as copy number variations (CNVs) or chromosomal
rearrangements. CNVs consist of duplicated or deleted chro-
mosomal material, which may span multiple genes. The func-
tional consequences depend on the ability of the residual
chromosomes to carry out normal gene functions in the pres-
ence of additional or missing copies of the gene. CNVs occur-
ring without functional consequences are termed benign
CNVs. Rearrangements occur when chromosomal material
is inserted, inverted or translocated and can cause genes to be
aberrantly switched on or off [3].
A polymorphism is a change in the DNA sequence, which
occurs at a population frequency of greater than 1% [6]. A single
nucleotide polymorphism (SNP) describes a single base change
in the nucleotide sequence. Whilst some polymorphisms may
be considered a part of normal genetic variation, genome-wide
association studies (GWAS) have been used to identify lower-
penetrance common SNPs which are statistically associated
with disease [7]. GWAS compare genetic variation between
cases and controls to detect SNPs and copy number variations
(CNVs) and thereby identify areas of the genome implicated in
disease aetiology. Such studies have been used in breast cancer
to detect previously unknown susceptibility loci, several of
which can be linked to specific breast cancer subtypes [7, 8].
A variant is any change in a DNA sequence, which is dif-
ferent to an accepted reference DNA sequence [9]. As, strictly
speaking, this definition includes both mutations and poly-
morphisms, the American College of Medical Genetics and
Genomics (ACMG) suggests that all DNA sequence changes
be termed variants. These should then be classified according
to their pathogenicity, using the 5-tier classification system
outlined in . Table 5.1 [6]. Variants are graded from patho-
genic to benign based on evidence in the scientific and medi-
cal literature, population and disease databases and in silico
(computational) analyses, which help determine the pre-
dicted functional effect on the protein structure, the pre-
dicted effect at the splice site, the location within the gene
and the degree of evolutionary conservation of the nucleo-
occur where there is insufficient evidence to establish a vari-
ant as clearly pathogenic or clearly benign.
Mutations may be described as either constitutional or
somatic. Constitutional mutations are also known as germline
mutations. These are present in gametes prior to fertilisation
..      Table 5.1  Five-tier classification of variants as proposed by
the American College of Medical Genetics and Genomics
(ACMG) [6]
Variant class Pathogenicity
1 Pathogenic
2 Likely pathogenic
3 Uncertain significance
4 Likely benign
5 Benign
Hereditary Breast Cancer Genetics and Risk Prediction Techniques
and therefore present in every cell of the individual resulting
from that embryo. They are highly heritable between genera-
tions. Germline mutations occurring in an oncogene or
tumour suppressor gene (TSG) cause an inherited cancer pre-
disposition and the individual will usually have a high lifetime
risk of cancer development.
Most cancers, however, develop from somatic mutations,
which arise in dividing cells post-fertilisation. Somatic muta-
tions are present only in descendants of that cell and are not
heritable between generations [10].
5.3 Somatic Mutations in Oncogenesis
Individuals accrue somatic mutations in cells throughout
their lifetime (. Fig. 5.1). In a tumour cell, somatic mutations
 
are identified as either driver or passenger mutations. A
driver mutation is a cancer-causing mutation, which gives the
cell a selective growth advantage in tumourigenesis. Passenger
mutations co-exist alongside driver mutations but do not
contribute to cancer development and confer no survival
benefit. Both driver and passenger mutations are replicated
throughout the clonal population descending from the initial
tumour cell. Chemotherapy resistance mutations begin as
passenger mutations, initially providing no advantage to the
growing tumour. Once challenged with chemotherapy, they
offer a selective advantage upon which a subclone can develop
and can then be considered driver mutations. This may man-
ifest phenotypically as cancer recurrence [10].
DNA damage
Apoptosis
DNA damage DNA damage
repaired not repaired
Key
Passenger mutation
Driver mutation
..      Fig. 5.1  The cell accumulates both passenger and driver somatic
mutations which are replicated in a clonal population with each mitosis.
Driver mutations contribute to cancer development. The cell may repair
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45 5
Intratumoural heterogeneity is a feature of breast tumour
tissues, in which several genetically diverse subclones of cells
exist within the tumour tissue. For example, The Cancer
Genome Atlas performed whole exome sequencing of 510
breast tumours and identified over 30,000 somatic mutations
[11]. Of these, they found that mutations in only three genes,
PIK3CA, TP53 and MAP3K1, occurred in more than 10%
tumours. Cells with mutations offering the greatest advantage
to the growing tumour are selected by way of evolutionary
pressure [12]. Gene expression in breast cancer tumours may
also be modified by epigenetic changes, which lead to aberrant
gene regulation without altering the DNA sequence. Examples
of epigenetic changes include hypermethylation of gene pro-
motor regions or changes to the structure of the DNA-protein
packaging complex, chromatin. Both of these mechanisms
may lead to silencing of tumour suppressor genes (TSGs) [12].
Somatic mutations in cancer are collated in the Catalogue
Of Somatic Mutations In Cancer (COSMIC) database
(7 http://cancer.sanger.ac.uk/cosmic) [13]. This is a publicly
searchable online database, which combines mutation data
with evidence from the published scientific literature [14].
Somatic mutations in breast cancer may be useful indica-
tors of treatment response and prognosis. However, intratu-
moural heterogeneity poses a challenge for tumour profiling
and may explain why some patients fail to respond to targeted
treatments. For example, the American Society of Clinical
Oncology (ASCO) and the College of American Pathologists
recommend that molecular profiling of breast tumours for oes-
trogen and progesterone receptor positivity requires only 1% of
DNA damage not Malignant
repaired, loss of cell cycle cell
control
DNA damage or trigger cell death by apoptosis. If DNA damage repair is
deficient, mutations accumulate causing genomic instability and loss of
cell cycle control, and the cell acquires malignant potential
 46 H. Carley and A. Kulkarni
tumour nuclei to express positivity by immunohistochemistry
[15] which, it may be argued, fails to take into account the
variation within the tumour. Furthermore, discrepancies exist
between the molecular profiles of primary and metastatic
tumours suggesting a need for multiple biopsies during sys-
temic treatment to optimise treatment design and minimise
the emergence of chemotherapy-resistant clones [12].
5.4 Constitutional Mutations
5 in Oncogenesis
Hereditary cancers occur due to a constitutional mutation in
a gene critical to cell cycle regulation with a second driver
mutation triggering tumourigenesis.
a
Key
Mutation
Tumour
b
..      Fig. 5.2  a Non-hereditary cancer. Somatic mutations occur in cells
post-fertilisation, with a later age at cancer diagnosis. b Hereditary
cancer. Germline mutation present in all cells from conception. Only
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Alfred Knudson first provided evidence in 1971 for
hereditary cancer syndromes by studying cases of familial
retinoblastoma [16, 17]. He found that individuals with bilat-
eral retinoblastomas developed these at a younger age than
individuals with unilateral retinoblastomas. Not all individu-
als with a family history developed retinoblastomas, yet reti-
noblastomas could be observed in their offspring. This was
suggestive of the presence of a germline mutation for which a
further «hit» or mutation was required for tumour develop-
ment. Where unilateral cases occurred at a later age, these
were due to two somatic mutations, which took more time to
accumulate. Knudson proposed his «two-hit hypothesis» in
which two loss-of-function mutations were required for
tumour development (. Fig. 5.2). RB1 was later identified as
the first tumour suppressor gene (TSG).
Time
Time
one somatic mutation is required for tumour initiation, resulting in
earlier onset of disease
Hereditary Breast Cancer Genetics and Risk Prediction Techniques
47 5
Although it is now believed that multiple hits may be the remainder being more common low-penetrance alleles
required for cancer development, Knudson’s model still (. Fig.  5.3) [19]. This corresponds with the UK National
 

forms the basis for understanding the mechanism of cancer Institute of Health and Care Excellence’s (NICE) definitions,
development in inherited cancer syndromes. where those at high risk have a lifetime breast cancer risk of
>30% and those at moderate risk have a lifetime breast
­cancer risk of 17–29% [20].
5.5 Hereditary Breast Cancer ­Susceptibility The majority of genes implicated in hereditary breast can-
cers occur due to protein truncating mutations in genes
The Utah Population Database demonstrated an increased active in the DNA damage repair pathway [19]. Breast cancer
familial risk of breast cancer in first-, second- and third-­ susceptibility genes have been identified using three main
degree relatives compared to population risk, providing evi- techniques: linkage analysis studies, mutation screening of
dence for a significant genetic contribution to breast cancer candidate genes and genome-wide association studies
development [18]. Genes implicated in the development of (GWAS). Linkage analysis studies are useful in large families
breast cancer can be considered in terms of their penetrance, with multiple affected relatives whereby regions of the
or their likelihood of causing disease, as high, moderate or genome co-segregating in affected family members can be
low penetrance. High-penetrance genes are rare and typi- analysed for highly penetrant cancer susceptibility genes
cally cause a greater than fourfold increased risk compared [21]. Mutation screening of candidate genes has developed
to the general population (. Table  5.2). Moderate- alongside our understanding of oncogenesis and, in particu-
 

penetrance genes cause a two-to fourfold increased risk with lar, the DNA damage repair pathway.

..      Table 5.2  Summary of clinical features of high-­penetrance hereditary breast cancer genes

Gene Syndrome Population Breast cancer risk Median age Special Other features
frequency tumour type

BRCA1 Hereditary 1/400 to 1/800 High BRCA1 60% BRCA1 BRCA1 Ovarian cancer
and breast and by age 70 42 years triple-­ Pancreatic cancer
BRCA2 ovarian cancer (95% CI BRCA2 negative, Prostate cancer
44–75%) 45 years basal tumours (males)
BRCA2 55%
by age 70
(95% CI
41–70%)

TP53 Li-Fraumeni 1/5000 to High a 33 years Often HER2 Sarcoma

syndrome 1/20,000 positive Brain tumours
Adrenocortical
carcinomas
May have multiple
primaries

STK11 Peutz-Jeghers 1/155,000 High 45% by age 44 years Mucocutaneous

syndrome 70 (95% CI pigmentation
27–68%) Hamartomatous
polyps
Increased risk of GI,
ovarian, pancreatic
cancer and adenoma
malignum of uterine
cervix
Gonadal tumours

PTEN Cowden 1/200,000 High 77% by age 42 years Increased Macrocephaly

syndrome 70 (95% CI incidence of Learning difficulties
59–91%) benign breast Thyroid cancer
disease Endometrial cancer
Gastrointestinal cancer
Renal cell cancer

CDH1 Hereditary Unknown High 39% by age 53 years Invasive Gastric cancer
diffuse gastric 80 (95% CI lobular breast
cancer 12–84%) cancer

aOverall lifetime cancer risk in males is 73%, whereas in females it approaches 100% due to the significant risk of breast cancer in women

rares1geo@gmail.com
 48 H. Carley and A. Kulkarni
..      Fig. 5.3  Schematic represen-
tation of genetic modifiers of
breast cancer risk. Genes can be
grouped into rare, high-pene-
trance mutations, moderate- 16
penetrance mutations and
low-penetrance alleles. The
approximate location of known
genes is shown with respect to STK11
8 TP53
allele frequency and relative risk
CDH1
Relative risk
5 4
PTEN
2 PALB2
1
0.0001
5.6 High-Penetrance Genes
5.6.1 BRCA1 and BRCA2
The BRCA1 and BRCA2 genes were identified as breast can-
cer predisposition genes in the mid-1990s by linkage analysis
studies [22, 23]. In an intact DNA damage repair response,
the BRCA1 and BRCA2 proteins form part of a complex
recruited to the site of DNA double strand breaks to accu-
rately repair DNA damage by homologous recombination.
Homologous recombination uses an intact complementary
strand as a template to faithfully restore the DNA sequence.
In contrast, BRCA-deficient cells repair DNA damage by
non-homologous repair pathways, prone to error, causing
genomic instability [24, 25].
BRCA1 and BRCA2 carrier frequency is estimated to be
around 1/400 to 1/800 in the general population [26–28]. In
certain populations, carrier frequency may be significantly
higher due to a founder effect, whereby rare mutations are
seen at relatively high frequencies within small, genetically
isolated populations. One example is the Ashkenazi Jewish
population, in which three common founder mutations,
BRCA1_185delAG, BRCA1_5382insC and BRCA2_6174delT,
combine to give an overall carrier risk of 1  in 40  in the
Ashkenazi Jewish population. [29, 30]. The proportion of
hereditary breast cancers in this group is significantly elevated
compared to that of the general population. In Iceland, the
BRCA2_999del5 founder mutation occurs in 0.4% of the
population and is responsible for the majority of inherited
breast cancer risk in this country, accounting for 8.5% breast
Rare, high
penetrance BRCA1
mutations
BRCA2
Moderate
penetrance
mutations
ATM CHEK2
Low penetrance alleles
0.01 1
Allele frequency
cancers, 7.9% ovarian cancers and 2.7% prostate cancers [31].
It should be noted that founder mutations in populations
from resource-poor settings are less well described.
A prospective analysis as part of the EMBRACE study
reported breast cancer risk by age 70 as 60% (95% confidence
interval (CI) 44–75%) in BRCA1 and 55% (95% CI 41–70%)
in BRCA2 carriers, respectively. Ovarian cancer risk was 59%
(95% CI 43–76%) in BRCA1 and 16.5% (95% CI 7.5–34%) in
BRCA2 carriers [32]. Median age at diagnosis of breast can-
cer in BRCA1 mutation carriers was 42 years and in BRCA2
mutation carriers, 45 years [32].
Within the BRCA1 and BRCA2 genes, thousands of vari-
ants have been identified, occurring across the entire coding
regions of the gene. Most pathogenic mutations involve the
formation of a truncated BRCA1 or BRCA2 protein and occur
as a result of non-sense mutations, frameshift mutations,
splice site mutations or larger-scale rearrangements [21, 33].
Pathologically, invasive breast tumours in BRCA1 muta-
tion carriers often display a basal epithelial phenotype [34] and
characteristically stain negative by immunohistochemistry for
oestrogen receptors (ER), progesterone receptors (PR) and
human epidermal growth factor receptor 2 (HER2), so-­called
triple-negative tumours (TNT). A large analysis of breast
tumour datasets showed that ER positivity was negatively pre-
dictive of BRCA1 mutations. TNTs were identified in 67.3% of
BRCA1 mutation carriers under 50  years old and 57.7% in
those over 50 years and in 13% of BRCA2 mutation carriers
under 50% and 23.5% in those over 50 years. TNTs were highly
predictive of BRCA1 mutations at any age and modestly pre-
dictive of BRCA2 mutations in individuals over 50 years [35].
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Hereditary Breast Cancer Genetics and Risk Prediction Techniques
5.6.2 TP53
Germline loss-of-function mutations in the tumour suppres-
sor gene, TP53, cause the cancer predisposition syndrome
Li-Fraumeni Syndrome (LFS) [36]. LFS is characterised by
childhood- and adult-onset tumours comprising soft tissue
and bone sarcomas, early-onset breast cancer, brain (espe-
cially choroid plexus) tumours and adrenocortical carcino-
mas, although the spectrum of reported tumours is diverse.
One report calculated a population frequency of TP53 germ-
line mutations as 1 in 5000 [37] although more conservative
estimates have suggested this is closer to 1  in 20,000 [38],
with a de novo mutation rate of between 7% and 20% [39].
Lifetime cancer risk in LFS approaches 100% in females and
73% in males. This gender discrepancy is largely due to the
high risk of female breast cancer in LFS [40]. Breast cancer in
LFS typically occurs in premenopausal females, with an aver-
age age of onset of 33 years [41]. The risk ratio for breast can-
cer development in TP53 mutation carriers is 6.4 (95% CI
4.3–9.3) [42], and 31% of carriers develop a further tumour
in the contralateral breast [41]. Pathologically, breast tumours
in TP53 germline mutation carriers tend to demonstrate
HER2 overexpression [43]. TP53 mutation carriers may
develop multiple primaries, with approximately 30% devel-
oping a second tumour within a radiation field within a mean
of 10.7  years, suggesting the need for carefully scheduled
treatments plans in LFS [41].
The TP53 mutation carrier rate in women with early-­
onset breast cancer (<30 years of age), who have no family
history of relevant cancers, is estimated to be between 5%
and 8%, and McCuaig and colleagues (2012) recommend
BRCA1/2-negative breast cancer patients under 30  years
be offered TP53 testing [44]. The Chompret Criteria can
also be used to indicate individuals appropriate for TP53
mutation testing. Recent revisions to the Chompret
Criteria recommend testing is based on family history, a
personal history of breast cancer under age 31, the occur-
rence of multiple primary tumours and the occurrence of
rare tumours [41].
5.6.3 STK11
Germline mutations in the tumour suppressor gene, STK11
(previously known as LKB1), give rise to Peutz-Jeghers syn-
drome (PJS). STK11 is a serine threonine kinase involved in
cell polarity and regulation of downstream effectors of the
mTOR (mammalian target of rapamycin) signalling pathway
[45]. Population frequency is believed to be around 1  in
155,000 although estimates vary [46]. Peutz-Jeghers syn-
drome (PJS) is characteristically associated with mucocuta-
neous pigmentation, hamartomatous polyps and an
increased risk of a variety of cancers, which may include
gastrointestinal, pancreatic, breast, gonadal and gynaeco-
logical cancers. Female breast cancer risk in PJS is 45% (95%
rares1geo@gmail.com
49 5
CI 27–68%) by age 70  years with an overall cancer risk of
85% (95% CI 68–96%) [47]. A meta-analysis suggested an
average age of onset of breast cancer in STK11 carriers of
44 years [48].
5.6.4 PTEN
PTEN is a tumour suppressor gene, which antagonises and
suppresses the PI3K-AKT-mTOR pathway [49]. Germline
mutations in PTEN cause PTEN hamartoma tumour syn-
drome, which includes Cowden syndrome (CS) [50].
Prevalence is believed to be between 1 in 200,000 and 1 in
250,000 [51]. CS is an autosomal dominant hamartoma
syndrome comprising macrocephaly, mucocutaneous
lesions and an increased benign and malignant tumour
risk, particularly thyroid, breast, endometrial, renal and
colorectal cancers [52]. Benign breast disease is also found
in PTEN gene mutation carriers. A cohort of 154 PTEN
mutation carriers found that 47% of the 55 female carriers
had fibrocystic breast disease. Breast cancer occurred in
34% of female carriers, occurring at a median age of
42 years, with 48% of breast cancers occurring bilaterally.
The cumulative risk of breast cancer by age 70 was 77%
(95% CI 59–91%) [53]. In an international, multicentre
cohort of germline PTEN mutation carriers, the cumula-
tive risk of breast cancer was 67% by age 60 years, giving a
five- to sevenfold increased risk compared to the general
population [54].
5.6.5 CDH1
CDH1 encodes the glycoprotein E-cadherin, which has an
important role in maintaining cell-cell adhesion and cell
polarity [55]. Germline CDH1 mutations were identified by
linkage analysis to cause hereditary diffuse gastric cancer
[56]. Germline CDH1 mutations have also been associated
with development of lobular breast cancer, with a cumula-
tive breast cancer risk by age 80 of 39% (95% CI 12–84%),
giving a risk ratio of 6.6 [57]. This older data is supported
by a 2015 study of breast cancer risk in individuals with
CDH1 germline mutations which estimated breast cancer
risk of 42% by age 80 (95% CI 23–68%) [58]. A recent
review by Corso and colleagues (2016) identified 14
reported cases of CDH1-­associated breast cancer without a
family history of diffuse gastric cancer and suggested the
concept of «hereditary lobular breast cancer» as its own
clinical entity [55].
5.7 Moderate-Penetrance Mutations
Several genes have been proposed as harbouring moderate-­
penetrance mutations.
 50 H. Carley and A. Kulkarni
5.7.1 PALB2
PALB2 interacts with BRCA1 and BRCA2 at the site of DNA
damage as part of DNA damage repair by homologous
recombination [59]. Bi-allelic mutations in PALB2 are asso-
ciated with the childhood autosomal recessive condition,
Fanconi anaemia, whilst germline heterozygous mutations in
PALB2 are associated with an increased risk of breast cancer.
Risk of breast cancer in PALB2 mutation carriers borders the
moderate- to high-penetrance risk group. Antoniou and col-
5 leagues (2014) suggested PALB2 mutations confer a high risk
of breast cancer, finding an up to ninefold increased risk in
mutation carriers under 40 and a cumulative lifetime risk of
35% (95% CI 26–46%) by age 70 [60]. However, age, birth
cohort and family history influenced this risk. Their analysis
suggested breast cancer risk was modified by other genetic
and environmental factors precluding attempts to provide a
single estimate of breast cancer likelihood in all mutation
carriers and leading to the suggestion that family history and
genotype be considered in risk estimations. Other studies
have estimated a lower risk, and wide confidence intervals
noted on meta-analysis mean that PALB2 is still considered a have their risk assessed through a three-generation family
moderate-penetrance allele [19].
5.7.2 ATM
The ataxia telangiectasia mutated (ATM) gene is activated in
response to DNA damage. ATM regulates downstream tar-
gets, including, amongst others, p53 and CHEK2, important
in cell cycle regulation, and BRCA1-mediated DNA damage
repair [61]. Bi-allelic loss-of-function mutations in ATM
cause the autosomal recessive condition, ataxia telangiecta-
sia, characterised by ataxia, immune dysfunction, radiation
sensitivity and cancer predisposition. Heterozygote loss-of-­
function mutations in ATM have been associated with
increased risk of breast cancer. A recent meta-analysis of 19
studies by Marabelli and colleagues (2016) estimated the
cumulative breast cancer risk in heterozygote ATM carriers
to be 32.8% by age 80 (95% CI 24.5–40.3%) [62].
5.7.3 CHEK2
Constitutional mutations in CHEK2 are associated with
increased breast cancer risk. A protein truncating founder
mutation, CHEK2_1100delC, has been identified in North
European populations and is estimated to confer a twofold
increased breast cancer risk in women [63]. A recent report
has suggested it may also increase the risk of gastric, renal,
sarcoma and prostate cancer [64].
Other genes, such as MRE11, NBN and RAD50, exist
within the same DNA damage repair system and have been
implicated as increasing breast cancer risk although this evi-
dence of association is more limited.
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5.8 Low-Penetrance Alleles
Low-penetrance variants account for around 14% of the
genetic contribution to breast cancer [65]. These variants
occur with relatively common frequency within the general
population and are expected to operate in polygenic models
with multiple weak associations contributing to cancer risk
[66]. Pathogenic variants have been identified in CASP8 and
TFGR1 genes. In addition, multiple susceptibility loci have
been identified, some of which can be mapped to individual
genes, such as FGFR3 and TNRC9. However, other loci map
to several genes and some loci cannot be mapped to gene
coding regions at all. The mechanisms by which these sus-
ceptibility loci function in breast cancer risk are incompletely
understood [21].
5.9 Risk Prediction
All individuals with breast cancer and particularly those at
risk of a hereditary cancer predisposition syndrome should
history [67]. This may be conducted as part of assessment at a
specialist breast cancer family history clinic or clinical genet-
ics consultation. Referral guidelines to clinical genetics ser-
vices for suspected hereditary breast cancer are available in
the UK from NICE [20] and in the USA, from the National
Comprehensive Cancer Network (NCCN) [68]. The consen-
sus from the European 14th St Gallen International Breast
Cancer Conference is that individuals with breast cancer
diagnosed at less than 40 years, those with a strong family his-
tory, or individuals diagnosed at less than 50 years with a tri-
ple-negative tumour, without a family history of breast cancer,
should be considered for BRCA1 and BRCA2 testing [69].
Decision support tools have been developed to enable
clinicians to identify patients who need further assessment
by clinical genetics services. For example, Guy’s and St
Thomas’ regional genetics service has developed an interac-
tive decision support tool and hereditary cancer reference
guide, accessible as a smartphone application («App») or via
desktop (7 www.ubqo.com/cancergenetics) [70]. This aims
to simplify the referral process so that at risk individuals can
be identified and appropriately referred whilst individuals
with low risk can be reassured.
5.10 Tools in Risk Prediction
The Manchester scoring system (MSS) uses information
from the family history to calculate the probability of finding
a pathogenic BRCA1 or BRCA2 mutation [71]. An updated
model was proposed in 2009, which incorporates tumour
histology and hormone receptor status [72]. The MSS has the
advantage of being quick and simple to use in a clinical set-
ting but is not recommended for use in founder populations
or populations in which breast cancer is rare [71]. The UK
Hereditary Breast Cancer Genetics and Risk Prediction Techniques
NICE guidelines recommend BRCA1 and BRCA2 testing in
individuals with a carrier probability of ≥10%, which equates
to a MSS score of ≥15 [20].
In addition, various computerised models have been
designed. Examples of such models include Claus, Gail,
Tyrer-Cuzick or IBIS, BRCAPro and BOADICEA. All mod-
els are limited by accessibility, the requirement for user data
entry, which can be time-consuming and the reliance on self-­
reported family history information, which may be limited
or inaccurate [73]. The models are calibrated to different
population datasets and incorporate additional risk factor
assessments to different degrees.
The Gail model was proposed in 1989, based on data from
the Breast Cancer Detection Demonstration Project (BCDDP)
in which data was gathered for approximately 300,000 indi-
viduals undergoing annual mammographic breast cancer
screening [74]. This model incorporates six risk factors,
including age, age at menarche and first live birth, number of
previous breast biopsies, history of atypical hyperplasia and
breast cancer occurrence in first-degree relatives. The original
model predicts the probability of in situ and invasive breast
cancer development in an individual undergoing annual
screening, but updates to this model predict the absolute risk
of invasive breast cancer occurrence and in addition adjust
the model to predict cancer occurrence in black women [75].
Neither model accounts for high-risk genes such as BRCA1 or
BRCA2 mutation carriers. A systematic review demonstrated
that the early Gail models had limited ability to predict indi-
vidualised risk [76], possibly due to its failure to account for
high-risk groups [73]. A systematic review of the Gail model
with further updates has demonstrated improved accuracy
compared to the original model [77].
The Claus Model, proposed in 1991, uses data from the
Cancer and Steroid Hormone study, a case-control study of
4730 confirmed breast cases [78]. The model combines infor-
mation on breast cancer occurrence in mothers and sisters of
index cases and the age at diagnosis. This is used to estimate
which cases are expected to be high-risk gene mutation car-
riers and the estimated age-specific and cumulative lifetime
risk of breast cancer development in carriers. The model was
updated in 1993 to include the occurrence of ovarian cancer
in the family history [79]. The dataset is restricted to white,
North American subjects, which may limit its widespread
generalisability, and it does not address the extended family
history or other recognised breast cancer risk factors [73].
Following the identification of BRCA1 and BRCA2, the
Tyrer-Cuzick or IBIS model was developed to incorporate
genetic risk factors with hormonal and reproductive risk fac-
tors to predict individual breast cancer risk. Genetic risk was
based upon the possibility of a BRCA1 or BRCA2 mutation
plus a second low-penetrance gene to acknowledge and
account for other unknown influencers of genetic risk.
Family history included first- and second-degree relatives
with a history of breast or ovarian cancer, bilateral breast can-
cer and the age at diagnosis. Additional personal risk factors
included age, height, body mass index (BMI), age at men-
arche, first live birth and menopause, parity and the presence
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51 5
of atypical hyperplasia or lobular carcinoma in situ [80]. It
has recently (2013) been updated to include the impact of
Ashkenazi Jewish ancestry, third-degree relatives, male breast
cancers and hormone replacement therapy use. It calculates
the lifetime risk of breast cancer and the risk of gene carriage.
The BRCAPro model was developed to determine the
likelihood of being a BRCA1 or BRCA2 mutation carrier
[81]. This model uses detailed information in the family his-
tory such as breast cancer in first- and second-degree rela-
tives, ages at diagnoses, bilateral breast cancer, ovarian cancer
and the presence of male breast cancers. In addition, the
model also gives weight to unaffected relatives. Extensions to
the model enable an overall risk of breast cancer develop-
ment to be calculated, and three different population datasets
can be used to estimate mutation frequency [73]. Limitations
to the model include the absence of non-hereditary risk fac-
tors, and the model does not account for more complex
genetic susceptibility mechanisms.
The Breast and Ovarian Analysis of Disease Incidence
and Carrier Estimation Algorithm (BOADICEA) model was
developed to account for genetic and polygenic influences in
familial breast cancer occurring in addition to BRCA1 and
BRCA2 [82, 83]. The dataset was based on the Anglican
Breast Cancer Study, which comprised 1484 confirmed breast
cancer cases and 156 multiple case families and included
information about BRCA1 and BRCA2 mutation status. The
model included detailed family history information includ-
ing breast cancer diagnoses in first-, second- and third-­
degree relatives and ages at diagnoses, bilateral cancer,
ovarian cancer and male breast cancer. Aside from age, it did
not include any non-hereditary risk factors. BOADICEA
provides likelihood of breast cancer development in women
with a family history of breast and ovarian cancer. In addi-
tion, the model can predict BRCA1 and BRCA2 mutation
probability and provides an assessment of polygenic
­modifiers of breast cancer risk in mutation carriers. An
extension to the BOADICEA model has recently been pro-
posed to incorporate PALB2, CHEK2 and ATM protein
truncating variants into its risk assessment [84].
It is accepted that there is no single perfect breast cancer
risk assessment model to date, and it is proposed that differ-
ent models should be employed depending on an individual’s
risk factor profile [73, 85].
5.11 Gene Sequencing Technologies
Genetic testing may be diagnostic or predictive. Diagnostic
testing is a full screen of the relevant gene(s) performed in an
individual with cancer, to help guide further treatment
options and identify at risk family members. Predictive test-
ing is a targeted test looking for a specific gene mutation pre-
viously identified in another family member. It is usually
performed in an asymptomatic individual with a high familial
risk of being a mutation carrier. Predictive testing can allow
identification of at-risk individuals before they become symp-
tomatic, so that through increased screening, ­surveillance
 52 H. Carley and A. Kulkarni
and access to prophylactic treatments, cancer may be pre-
vented or diagnosed at an early stage. However, gene pene-
trance in most cancer susceptibility genes is less than 100%,
meaning that not all mutation carriers will develop cancer.
Likewise, even with screening and risk-reducing treatments,
not all cancers will be preventable; therefore, pretest genetic
counselling is recommended, particularly in the predictive
setting, to avoid post-decision regret and minimise adverse
psychological effects on the individual and family.
Single gene testing has been the diagnostic approach tradi-
5 tionally adopted by clinical geneticists. Where successful, this
has the advantage of facilitating a speedy and cost-­efficient
diagnosis; however, it relies on the existence of a limited num-
ber of known candidate genes which can be mapped to a
clinical phenotype. Longitudinal sequencing of multiple can-
didate genes is slow and cumulatively expensive, often involv-
ing a number of different techniques such as Sanger
sequencing, fluorescence in situ hybridisation (FISH), array
comparative genome hybridisation (array CGH) and Multiplex
Ligation-dependent Probe Amplification (MLPA) [86–88].
The introduction of next-generation sequencing (NGS)
has revolutionised gene testing. NGS is an umbrella term
used to describe several sequencing platforms in which the
approach is to sequence millions of DNA fragments simulta-
neously [89]. When a fragment is sequenced, it is termed a
«read». Each fragment is sequenced numerous times to give
sufficient read depth to account for sequencing errors, varia-
tion in coverage and adequate coverage of both wild-type
and mutant alleles in heterozygous states. The average
required sequencing depth is 30–40 reads. The DNA frag-
ments are aligned and analysed by bioinformatic techniques
to identify variation in the DNA sequence from an expected
reference sequence. Variants are then filtered and interpreted
to determine clinical significance and pathogenic variants
validated by resequencing and functional analysis [90].
Sanger sequencing techniques are limited in their ability
to detect only base pair substitutions and small insertions or
deletions, with larger deletions and rearrangements requir-
ing additional techniques such as FISH, array CGH and
MLPA. NGS techniques have the advantage of being able to
detect both smaller sequence changes and larger deletions
and rearrangements [89].
Sequencing in NGS may be limited to certain areas of
interest in a targeted panel approach or may be extensive,
such as in «whole exome sequencing» (WES) or «whole
genome sequencing» (WGS). Targeted gene panel testing
involves enriching the protein coding regions (exons) of dis-
ease-related genes with specific probes so that only these
areas are sequenced, reducing the likelihood of incidental
findings. Panel sequencing is a time- and cost-efficient
method of sequencing for conditions in which several candi-
date genes exist compared to multiple attempts to elucidate a
molecular diagnosis by single gene testing [91].
WES searches for variants within all exons, thought to
comprise around 1% of the whole genome [90]. WES is of
lower cost than WGS and can be sequenced to a higher depth.
WGS searches for variants within the whole genome, without
rares1geo@gmail.com
requiring knowledge of prior genes and therefore can be said
to operate «hypothesis-free». Since WGS explores non-­
coding areas of the genome, which are felt to be increasingly
important in disease, it may detect previously unrecognised
gene associations, allowing detailed characterisation of gene
interactions and detect actionable targets for drug-therapies.
A further benefit of WGS and WES is the ability to reanalyse
the data in light of new information and the potential to dis-
cover digenic or polygenic associations [90].
Both WGS and WES techniques require detailed clinical
phenotype information to interpret variants. Filtering and
analysis of potential disease-causing variants is labour-­
intensive, and there is a high chance of revealing variants of
uncertain significance. In addition, WGS and WES may
detect pathogenic variants in known disease-causing genes
unrelated to the test indication. Disclosure of such incidental
findings to the patient poses ethical challenges. The American
College of Medical Genetics and Genomics have issued
guidelines to suggest 56 genes for which there are manage-
ment implications, which should be reported to the patient if
detected as incidental findings. This list includes BRCA1,
BRCA2, TP53, STK11, PTEN and other non-breast cancer
susceptibility genes [92]. WGS and WES currently require
confirmation with Sanger sequencing techniques, and cost
and storage of the large amounts of data generated by each
technique are problematic [90].
5.12 Gene Panel Testing in Breast Cancer
As genetic testing technology expands, it is becoming
increasingly easy for clinicians to test large panels of genes,
some of which may have only modest association with
increased breast cancer risk [19]. The finding of a variant in a
low- or moderate-penetrance allele poses dilemmas for clini-
cians due to the relative rarity of cancer susceptibility genes,
the paucity of evidence regarding ongoing management and
the consequent lack of an actionable management plan.
Whilst it is likely that gene panel testing will increase the
detection rate of pathogenic mutations, the detection rate of
variants of uncertain significance is also likely to increase
[93]. Even in well-described genes, such as BRCA1 and
BRCA2, the variations of uncertain significance (VUS) rate
can range from 2.1% to 20% depending on the laboratory
and population under study [93, 94]. The detection of a VUS
can cause confusion amongst families and health care pro-
viders and may cause distress to patients [95]. The NCCN
suggests that multigene testing should be considered only
where there is strong clinical suspicion of a hereditary cancer
susceptibility gene, despite the exclusion of high-penetrance
gene mutations, or where there is suspicion that more than
one cancer susceptibility gene may be contributing to cancer
risk [68]. Fecteau and colleagues (2014) recommend that as
part of pretest counselling, informed consent for multigene
testing includes a discussion of high-, moderate- and low-­
risk genes and the implications of finding both causative
mutations and VUS [96].
Hereditary Breast Cancer Genetics and Risk Prediction Techniques
..      Fig. 5.4  Algorithm to guide
management of BRCA1/2-nega-
tive women with breast cancer.
BC breast cancer, OC ovarian
cancer, CBC contralateral breast
cancer, RRM risk-reducing
mastectomy, NHS BSP UK National
Health Service’s Breast Screening
Programme. *Following a
negative BRCA1/2 mutation
testing, the family history should
be reassessed based on the
breast cancer diagnoses alone.
**There is no screening cut-off
age according to NHS BSP
higher-risk programme
53 5
Woman with unilateral
breast cancer and
negative BRCA1/2 test
Low-moderate risk family
history
· <30% lifetime risk of CBC
· RRM not indicated based High risk family history
on genetic risk (excluding OC diagnoses*)
· Annual mammograms
from diagnosis to 49 years
of age followed by NHS BSP

Age at diagnosis ≤45 years Age at diagnosis >45 years

· ≥30% lifetime risk of CBC · <30% lifetime risk of CBC

· RRM appropriate · RRM not indicated based

depending on prognosis, on genetic risk
woman’s preferences and
· Annual mammograms
co-morbidities - discuss
from diagnosis to 59 years
with oncologist/breast
of age followed by NHS BSP
surgeon
· Annual MRI from 30 to
49 years of age and annual
mammograms from 40
years of age onwards**

The high-, moderate- and low-risk variants identified to
date are expected to account for around 28% of excess famil-
ial risk of breast cancer [97]. There is the likely possibility
that further disease-modifying genes exist which have not
yet been identified. Metcalfe and colleagues (2009) studied
cancer risk in BRCA1/2 mutation-negative families in which
there were at least two breast cancers diagnosed under
50 years of age or three breast cancers diagnosed at any age
[98]. Women in these families had a fourfold increased risk
of breast cancer compared to the general population.
Reiner and colleagues (2013) provided further evidence
of elevated cancer risk in BRCA1/2 mutation-negative fami-
lies [99]. They found that women who developed a primary
mutation carriers: 5% for no relatives with breast cancer, 22%
if a second-degree relative and 30% if a first-degree relative
has a history of breast cancer, although this was less than the
contralateral breast cancer risk in BRCA1/2 gene mutation
carriers of 53% [100]. These studies demonstrate that regard-
less of mutation status, family history should be considered
an important ongoing risk factor.
At Guy’s and St Thomas’ regional genetics service, an
algorithm has been developed to help clinicians determine
appropriate risk-reducing options, based on the above litera-
ture and UK NICE guidance [20], for the management of
women with breast cancer who test negative for BRCA1/2
gene mutations, as shown in . Fig. 5.4.

breast cancer at a young age, or those with a first-degree rela-

tive with breast cancer, remained at high risk of developing a
contralateral breast cancer. Specifically, a woman diagnosed
before age 55 years with a first-degree relative with bilateral
breast cancer had a 10-year risk of contralateral breast cancer
of 15.6% compared to 18.4% in BRCA1/2 mutation carriers.
Nilsson and colleagues (2014) similarly found that, in a
cohort of women diagnosed with breast cancer under the age
of 41  years, a family history of breast cancer increased the
15-year cumulative risk of contralateral breast cancer in non-­
5.13 Conclusion
The identification of BRCA1 and BRCA2 in the 1990s enabled
a revolution in the care of familial breast cancer. Further
progress in our understanding of the genetic factors that con-
tribute to breast cancer development will be increasingly
important, particularly if our clinical interpretation of gene
variants is to keep pace with sequencing technologies.

rares1geo@gmail.com
 54 H. Carley and A. Kulkarni
However, the major challenge lies in translating advances in
our understanding of genetic susceptibility into improved
patient outcomes in breast cancer care. The UK government’s
100,000 Genomes Project aims to define new hereditary
breast cancer susceptibility genes by performing whole
genome sequencing (WGS) of individuals with familial
breast cancer. In addition, WGS will be performed on both
tumour and blood samples of 25,000 cancer patients to iden-
tify somatic mutations driving cancer development [101].
As access to technology increases, the threshold for breast
5 cancer susceptibility testing falls, allowing the identification
of women with a specific constitutional gene mutation early
in the patient pathway and enabling personalised manage-
ment. With the unprecedented advances in sequencing tech-
nology in recent years, it may be envisaged that, in the not so
distant future, all women with breast cancer, irrespective of
their family history, will undergo testing at the point of diag-
nosis for relevant cancer predisposition mutations. Significant
challenges remain ahead in developing a risk prediction tool
which incorporates all modifiers of risk, including gene
mutations of differing penetrance, family history and hor-
monal, reproductive and lifestyle factors, and thereby appro-
priately informs mutation carrier testing, risk of breast cancer
development and risk-reducing management options.
The current model of delivering genetic testing will need
to evolve to meet this changing need and the provision of
testing is likely to extend to include specialties outside of
Clinical Genetics. Development of such services will require
close partnership between primary and secondary care clini-
cians, clinical geneticists and commissioning bodies. All pro-
fessionals involved in gene testing need an appreciation of
the challenges involved in interpreting genetic test results,
and clinical genetics services will need to work closely with
secondary care to provide education, advice and supervision
in this regard. Furthermore, gene testing can have significant
psychosocial consequences both for individuals and their
families and prompt complex ethical and confidentiality
issues. Such individuals will continue to require specialist
input from clinical genetics services that have specific exper-
tise in these areas.
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 57 II

Screening, High Risk

Lesions, and Risk
­Management
Contents

Chapter 6 Screening for High-Familial-Risk Women – 59

Athina Vourtsis

Chapter 7 Risk-Reducing Breast and Ovarian Surgery for

Women at High Familial Risk – 69
Inkeri Schultz and Kerstin Sandelin

Chapter 8 The Role of Breast Cancer Chemoprevention

in High-Risk Women – 79
Lynda Wyld

Chapter 9 Molecular Profiling of Breast Cancer and DCIS – 89

Christos Markopoulos

Chapter 10 Pathology of High-Risk Breast Lesions – 103

Sarah E. Pinder and Abeer M. Shaaban

Chapter 11 Ductal Carcinoma in Situ – 115

Stacey A. Carter, Sarah E. Pinder, and Alastair M. Thompson

Chapter 12 Imaging of the Breast – 127

Petra Steyerova

Chapter 13 Breast Cancer Screening – 147

John Mathew and Mark Sibbering

rares1geo@gmail.com
 59 6

Screening for High-Familial-­
Risk Women
Athina Vourtsis

6.1 Introduction – 60

6.2 Breast MRI – 60

6.2.1 Sensitivity, Specificity and Cancer Detection Rates with 
MRI Screening – 60
6.2.2 Interval Cancer Rates in MRI – 62
6.2.3 Decline in Mortality Rate: Survival Rate – 62

6.3 Mammography – 63

6.4 Breast Ultrasound – 63

6.5 Screening During Pregnancy and Lactation – 64

6.6 Current Recommendations – 64

6.7 Conclusions and Future Perspectives – 65

References – 65

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_6

rares1geo@gmail.com
 60 A. Vourtsis
6.1 Introduction
In comparison to the general population, women with a fam-
ily history of breast cancer have an increased risk of develop-
ing the disease. This lifetime risk varies according to the
number of affected relatives, the degree of relation and the
age they were diagnosed. A number of reliable risk assess-
ment tools are available to quantify risk [1–3].
1. According to the American Cancer Society, the criteria
for designating women at high familial risk for breast
cancer are: women with a known mutation in BRCA1 or
BRCA2 or their untested first-degree relatives; women
with Li-Fraumeni syndrome, Cowden’s syndrome,
6 Bannayan-Riley-Ruvalcaba syndrome, hereditary diffuse
gastric cancer or Peutz-­Jeghers syndrome and their
first-degree relatives (see 7 Chap. 5 for further details);
and women having a lifetime risk equal to or greater than
20–25% according to BRCAPRO or other family history-
based models [4]. Other expert bodies, such as the UK
NICE guidelines, have slightly different thresholds [5].
Breast cancers in BRCA1 mutation carriers are predomi-
nantly triple-negative cancers that tend to grow quickly with
well-circumscribed and pushing margins and without micro-
calcifications, making diagnosis with mammography diffi-
cult. In addition the prevalence of ductal carcinoma in situ
(DCIS) is rare. Suspicious lesions in BRCA2 mutation carri-
ers have a higher chance of being diagnosed on mammogra-
phy compared to BRCA1 carriers [6]; they have the same
immunophenotypic pattern as sporadic cancers with similar
rates of ductal, lobular and ER+ cancers and DCIS, suggest-
ing that personalised screening depending on gene mutation
type may be appropriate. The age at which screening com-
mences should also be varied by mutation type bearing in
mind the earlier onset of cancers in BRCA1 and TP53 gene
carriers than for BRCA2 carriers.
Early guidelines for women with a high familial risk rec-
ommended screening by clinical breast examination (CBE)
and annual mammography starting at the age of 25–30 years
[7]. However, mammography screening alone was shown to
have a low sensitivity ranging from 14% to 59% in this very
young age group, resulting in two-thirds of breast cancers not
being diagnosed in a timely manner and being detected as
interval cancers before the next screening round [8]. Results
from prospective cohort studies have shown magnetic reso-
nance imaging (MRI) has improved performance in the
detection of breast cancer in high-risk women compared to
X-ray mammography [9]. The emerging evidence that MRI is
far more sensitive than mammography led to the endorse-
ment of its use by international societies for the surveillance
of high-familial-risk women [10]. MRI, in combination with
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mammography, performed on an annual basis is an effective
imaging protocol for this particular high-risk population
[11]. However, a debate is ongoing regarding whether annual
surveillance is adequate, especially in BRCA1 carriers, since
2–14% of women present with palpable interval breast can-
cers after a negative MRI in the past year [11–15]. This may
relate to the very high proliferation rate of triple-negative
breast cancers. . Figure  6.1 presents a series of mammo-
grams of a patient diagnosed with a triple-negative, node-
positive breast cancer, which emerged 3 months before her
annual follow-up with mammogram, indicating the rapid
growth of these tumours (see . Fig.  6.1). The evidence for
these different imaging modalities in high-risk women is
reviewed below.
6.2 Breast MRI
Breast MRI provides the highest diagnostic sensitivity of
the three modalities for screening high-risk women with
evidence suggesting that an additional 30% of cancers
would have been diagnosed as interval cancers between
screening rounds if a multimodality approach had not
been employed [16]. . Table 6.1 summarises the results of
the main studies [9, 11, 15–21] comparatively examining
the sensitivity/specificity of mammography, breast US and
MRI (see . Table 6.1).
6.2.1  ensitivity, Specificity and Cancer
S
Detection Rates with MRI Screening
The overall sensitivity of MRI in women at high familial risk
varies between different studies from 71% to 100%. Importantly
the sensitivity is not modified by the density of the breast [24].
A meta-analysis of 11 studies showed a sensitivity of 77% for
the performance of MRI alone and 94% when MRI was com-
bined with mammography, compared to 39% for mammogra-
phy alone [22]. One of the explanations that has been given
regarding the variation between published studies is the
unusual MRI imaging features in this group. Frequently, these
tumours demonstrate benign kinetic features and often pres-
ent with non-mass like enhancement [23]. Additionally, these
lesions appear with smooth, non-­infiltrative borders, without
architectural distortion or space-­occupying effects on T1- or
T2-weighted images. Consequently, the specificity of MRI in
these populations varies between 79% and 95%. These partic-
ular features give an explanation for the lower detectability
of familial breast cancer and emphasises that the significance
of this type of finding should not be underestimated when
­identified [23].
Screening for High-Familial-Risk Women
2010 2011 2012
..      Fig. 6.1  Mammography in a 52-year-old woman with three sisters
diagnosed with breast cancer at ages 45, 49 and 55 years old. Digital
mammography was performed annually for the past 5 years. Within
9 months since the last mammogram, the patient presented with a
The cancer detection rate reported for MRI alone in dif-
ferent prospective cohort studies ranges from 8.2 to 15.9 per
1000 [9, 11, 16, 18, 22]. Different studies demonstrate similar
or increased detection rates in BRCA1 and BRCA2 mutation
carriers and their first-degree relatives compared to women
with a family history of breast/ovarian cancer with no docu-
mented mutation [24]. Additionally, the detection rate of
MRI varied among different age groups. Chiarelli and col-
leagues identified a higher cancer detection rate for MRI
alone in women who were over 50  years old compared to
women younger than 50 years old [25]. A number of studies
have suggested that in high-risk women, MRI has an increased
sensitivity in identifying multifocal and multicentric disease,
compared to breast ultrasound and mammography [11, 24].
The ability of MRI to detect breast cancers, virtually unin-
fluenced by the density of breast parenchyma in familial
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61 6
2013 2014
palpable mass. Mammography revealed a mass measuring 2.7 × 1.6 cm,
with indistinct borders (rightmost panels). Histopathological examina-
tion showed a triple-negative breast cancer with one positive sentinel
node
high-risk women [21], led the National Institute for Health
and Care Excellence [5] and the GC-HBOC [26] to recom-
mend annual MRI alone, and not in combination with mam-
mography, for familial high-risk women between the ages of
30 and 39, who do not have a prior diagnosis of the disease. It
has been recommended by some that the starting age for MRI
screening should be adjusted according to the age of diagno-
sis in the youngest affected relative, with MRI screening com-
mencing 5  years earlier than this age, and according to the
type of mutations (BRCA1, BRCA2 or TP53) as age-­specific
risks vary [27]. UK NICE guidelines advise MRI screening
should commence at age 20 in TP53 gene carriers compared
to age 30 in BRCA gene carriers [5]. Most recommendations
suggest continuing intensified surveillance, including MRI, at
least until the age of 50. Nevertheless, Sardanelli and col-
leagues found that the effectiveness of MRI continues even

62 A. Vourtsis

..      Table 6.1  Results of the main studies comparatively examining the sensitivity/specificity of mammography, breast US and MRI

Sensitivity % Specificity %

Studies Country Sample Age No of MRI Mammog- Ultrasound MRI Mammog- Ultrasound
size range cancers raphy raphy

Warner Canada 236 25–65 22 77 36 33 95 99 96

(2004)

Kriege The Nether- 1909 25–70 50 80 33 Not 90 95 Not

(2004) lands examined examined

Kuhl (2005) Germany 529 30+ 43 91 33 40 97 97 91

Leach United 649 35–49 35 77 40 Not 81 93 Not

6 (2005) Kingdom examined examined

Lehman USA – interna- 390 25+ 4 100 25 Not 95 98 Not

(2005) tional examined examined
consortium

Weinstein USA 609 25–80 20 71 33 17 79 94 88

(2009)

Kuhl (2010) Germany 687 25–71 27 93 33 37 98 99 98

Sardanelli Italy 501 25+ 52 91 50 52 97 99 98

(2011)

Riedl (2015) Austria 559 22–83 40 90 38 38 89 97 97

after the age of 50 [24]. However, cost issues must also be
taken into account by health funding agencies when develop-
ing guidelines.
6.2.2 Interval Cancer Rates in MRI
The rates of interval cancers in familial high-risk patients
undergoing MRI surveillance may be as high as 40% [11].
Annual MRI surveillance is associated with a significant
increase in the incidence of smaller size cancers in BRCA2
carriers. However, this was less frequently observed in
BRCA1 carriers, where some women presented with palpable
interval cancers, between 6 and 12  months after a normal
annual screening MRI [28]. This observed difference might
be due to the faster rate of tumour growth in BRCA1 carriers,
given the fact that BRCA1-associated cancers are frequently
triple negative and of basal phenotype, which are usually
high grade and with a very high proliferation index [22].
Interestingly, Tilanus-Linthorst and colleagues [29] reported
a significant difference in the doubling time of tumours
between BRCA mutation carriers and noncarriers. The
reported doubling time for carriers was 45 days compared to
84  days for noncarriers [29]. Therefore, some high-risk
screening programmes recommend 6-month surveillance
with CBE and/or breast ultrasound in addition to regular
annual screening with MRI or alternating MRI and mam-
mography every 6 months, so BRCA1 carriers are offered a
shorter interval between screening rounds.
6.2.3 Decline in Mortality Rate: Survival Rate
Despite the higher sensitivity of MRI compared to mammog-
raphy, it remains unclear whether MRI leads to decreased
mortality from breast cancer. Up until now, no randomised
trial has been designed to directly compare mortality reduc-
tion offered by mammography versus MRI; the existing evi-
dence is only indirect and further research is urgently needed.
The estimated indirect benefit that has been achieved
from MRI surveillance is derived from downstaging of
breast cancer, where the small size and noninvasiveness of
breast cancers have been used as reasonable proxy indices
for cancer survival [11]. In BRCA1-associated breast cancer
diagnosed in an MRI-based surveillance programme, the
10-year survival rate for cancers less than 1  cm was 93%,
compared to 58% for cancers measuring from 1 to 2 cm [30].
Documented evidence has shown that BRCA1 tumours are
more aggressive and that size is not an ideal criterion for
improved survival since these tumours tend to metastasize
early and small tumours may often already have positive
lymph nodes [31]. According to earlier studies, BRCA1
patients had a 73–74% 5-year survival [32, 33]. Nevertheless,
a more recent study reported a 10-year survival equal to
81%; data suggested that once prognostic factors are taken
into account, the outcome among carriers is similar to non-
carriers [34].
Apart from the high cost, the most important problems
regarding breast MRI are its low specificity, high false-­
positive recall rates and low sensitivity for detecting DCIS;

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Screening for High-Familial-Risk Women
nevertheless, the latter seems of minor importance since
DCIS is rare in BRCA 1 carriers. With continual improve-
ments in MRI technology, specificity has improved. In addi-
tion, mammography and second look ultrasound
substantially increases the specificity of MRI [35]. Modern
MRI units, with high field strength, with a minimum stan-
dard of at least 1.5 Tesla, a dedicated bilateral breast coil,
quality control visits on a regular basis and experienced radi-
ologists are some of the requirements for high-quality MRI
screening. In addition, substantial reporting expertise is
needed and some health systems recommend double reading
to ensure quality. Furthermore MRI examination is not fea-
sible in certain women due to claustrophobia or contraindi-
cations, such as pacemakers, metallic implants, morbid
obesity (many scanners have a weight limit), inability to lie
prone for up to an hour or renal dysfunction precluding the
use of contrast agents [36]. Cost prohibits its use for many
health economies in the world.
In a recently published work, Kuhl and colleagues intro-
duced an ultra-fast, 3-min, breast MRI for cancer screening.
The results of this study showed that ultra-fast breast MRI
substantially reduces the time of image acquisition as well as
it decreases the reading time and cost of the exam, displaying
a comparable sensitivity and specificity to that of conven-
tional MRI in the screening setting [37].
6.3 Mammography
Randomised controlled trials have shown that in general
population mammography is the only screening modality
that reduces breast cancer-specific morbidity and mortality
[38, 39]. The sensitivity of mammography varies depending
on the pattern of breast tissue and can range from as high as
98% in fatty breasts to as low as 30–40% in women with
dense breasts [40].
Although screening mammography has been suggested
in women with high familial breast cancer risk under the age
of 50, its efficacy has been disappointing in BRCA carriers
[15, 25]. Several studies have demonstrated low sensitivity in
BRCA mutation carriers, leading to a high rate of interval
cancers, ranging from 29% to 50%, while 40–56% of patients
had nodal involvement at the time of diagnosis, and 20–78%
of invasive tumours were larger than 1 cm in size [9, 41].
The lower performance of mammography in this group
of women compared to the general population has been
attributed to several factors; one of them is the early onset of
disease associated with these mutations, at a time in a woman’s
life when breast density is high. This adversely affects mam-
mographic sensitivity. It should be declared that there is a
concern if the benefit of the reduction in the mortality rate
among younger carriers outweighs the potential increased
risks caused by radiation injury, since implicated genes (such
as BRCA1/BRCA2) are involved in the DNA repair mecha-
nism [42]. This is a cause for special concern in TP53 gene
carriers, and guidelines generally recommend MRI screening
only for such women.
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63 6
Another study by Kriege and colleagues​[15] highlighted
the higher sensitivity of mammography compared to MRI for
detecting DCIS in women with a familial or genetic predis-
position. In contrast, mammography had a lower sensitivity
for the detection of invasive cancers (40.0%) compared to the
sensitivity of MRI (71.1%); however, the specificity and posi-
tive predictive value of MRI in this study were lower than
those of mammography.
Consequently, surveillance solely with X-ray mammogra-
phy in young women with a high familial risk is not ­adequate,
and additional modalities such as MRI or breast ultrasound
with high-frequency linear transducers are recommended.
The results from published studies are encouraging, as the
implementation of a multimodality approach has demon-
strated a high performance level in detecting the disease at an
earlier stage [43].
Additionally the results of the digital mammographic
imaging screening trial (DMIST) suggest that digital mam-
mography could overcome some of the limitations of screen-­
film mammography [44]. In digital mammography, the
X-ray transmission can be varied to enhance the visualisa-
tion and conspicuity of subtle anatomical changes that have
developed on the background of dense breast parenchyma.
Studies have shown the higher sensitivity of digital versus
conventional mammography in the detection of microcalci-
fication and subtle masses that have developed in the con-
tour of the breast tissue if the image contrast is adjusted [45].
Therefore, whenever possible, digital mammography should
be implemented rather than conventional screen-film mam-
mography for intensified surveillance of women with high
familial risk [25, 46].
Due to the limitations of X-ray mammography in this set-
ting, alongside the increased availability and great improve-
ment in MRI, a new strategy for the surveillance of high-risk
women younger than 40 has been widely adopted. In 2013
the German Consortium of Hereditary Breast and Ovarian
Cancer (GC-HBOC) followed later by the United Kingdom
(NHS breast screening programme, NHSBSP) modified their
screening guidelines, which suggested not to perform mam-
mography in women under the age of 40 without a prior
diagnosis of breast cancer and instead undertake high-­quality
breast MRI screening [5].
The evolution of digital mammography has opened the
pathway for the development of digital breast tomosynthe-
sis (DBT), which provides a series of thin slices covering
the entire breast parenchyma and therefore improves breast
imaging. Currently, however, no studies have demonstrated
the value of replacing digital mammography with DBT in
women at high familial risk, and further studies are war-
ranted.
6.4 Breast Ultrasound
Supplemental screening with handheld breast ultrasound
after mammography in women with dense breasts increases
the detection rate for cancer by 2.7–4.6 per 1000 [47].
 64 A. Vourtsis
Importantly, cancers identified with US have been noted to be
particularly small invasive cancers with negative lymph nodes.
However, breast ultrasound screening in familial high-risk
women, in combination with MRI, has been shown to have
only a limited value for the detection of the disease [25, 48].
Handheld ultrasound was not designed for screening but
for assisting in the differential diagnosis of a palpable or a
mammographically detected lesion. Factors hampering the
use of ultrasound as a screening modality include operator
dependence, variability between different operators, small
field of view with the risk of not scanning the entire breast,
shortage of qualified personnel to conduct and interpret the
exams, lack of standardisation scanning protocols and false-­
6 positive findings [49].
Standard breast ultrasound is currently offered in the
GC-HBOC screening programme at 6-month intervals [26].
Using US in addition to other screening modalities may also
be beneficial in detecting additional impalpable cancers [11]
and in the detection of multifocal disease when compared
with mammography [24].
Recently, three-dimensional automated breast ultrasound
systems have been developed and have opened a new era in
ultrasound breast screening. The second-generation Automated
Breast Ultrasound System (ABUS) has been FDA approved for
screening as a substitute for handheld ultrasound [47]. The
automated imaging process of ABUS is faster to acquire and
requires less training than handheld ultrasound. Women toler-
ate it well; according to the study by Zintsmaster and colleagues
[50], ABUS was substantially more comfortable than digital
mammography and had high patient satisfaction ratings. ABUS
overcomes the limitations of handheld ultrasound, as it is oper-
ator independent and is based on an automated high-resolution
reverse transducer which produces high-volume reconstructed
coronal slices that allow better visualisation of architectural dis-
tortions due to multifocal or multicentric disease. Thus, evalu-
ating the efficacy and cost-effectiveness of ABUS in familial
high-risk women might be a promising consideration for future
research.
The contribution of breast ultrasound screening should
be considered when there is lack of availability of breast MRI,
e.g. due to costs and in women who are unable to tolerate or
have contraindications for MRI.
An additional contribution of ultrasound to the screen-
ing process is the correlation of sonographic findings with
the MRI-detected lesions and guiding their biopsy.
Identifying the lesion allows real-time imaging that is less
expensive, and in experienced hands, biopsy of the lesion
under guidance is easily performed. Additionally, the proba-
bility of malignancy increased in the lesions that were
detected on MRI and visualised later by ultrasound [51];
thus, ultrasound can be used to increase the specificity of
MRI. A short follow-­up with breast ultrasound after 6 months
is accurate, easier and less expensive to perform for lesions
identified on ultrasound that have been characterised with
MRI as probably benign.
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6.5  creening During Pregnancy
S
and Lactation
The changes that occur during pregnancy and lactation make
the diagnosis of breast cancer difficult. In the general popula-
tion, breast ultrasound is particularly valuable in differentiat-
ing malignant lesions from benign breast conditions during
pregnancy, as published studies have reported 100% ­sensitivity
and a 100% negative predictive value [52]. Although mam-
mography is considered safe during pregnancy, it is usually
avoided during this period in view of the perceived risks due
to the exposure to ionising radiation [53]. Mammography is
however performed when there is a high suspicion or histo-
logically proven malignancy [52]. In such cases, the use of
lead apron shielding can substantially decrease the dose to the
uterus [54].
During lactation, the increased breast volume decreases
the sensitivity of mammography; therefore, mammogra-
phy screening is performed 3 months after discontinuation
of lactation. There are no existing guidelines about screen-
ing of high-risk women during lactation; nevertheless, it
has been suggested that screening mammography can be
offered as early as 3 months after delivery in this subgroup
of women [52].
In addition, MRI is avoided during pregnancy. The fact
that contrast agents cross the placenta raises concerns that
gadolinium in the amniotic fluid may exert toxic effects to
the foetus. However, no data has been reported on terato-
genic effects of gadolinium-based contrast agents in humans
[55]. On the contrary, during lactation MRI can be safely
performed; however, due to diagnostic challenges imposed
by hypervascularity, its use is mainly limited to the preopera-
tive staging of breast cancer.
6.6 Current Recommendations
The EUSOMA recommendations, issued in 2010, have
underlined the role of genetic counselling in the assessment
and definition of familial high risk (inherited predisposition)
for breast cancer. High-risk women include BRCA1, BRCA2,
TP53 and other high-risk mutation carriers, their first-degree
relatives and women from untested families with a 20–30%
lifetime breast cancer risk; annual MRI screening should be
offered to them. MRI should be conducted in facilities and
programmes following a strictly defined protocol. The age of
commencement for annual MRI screening may optimally
range from 20 to 30 years depending on mutational type; the
upper age limit also remains debatable. Annual MRI is also
performed in women already diagnosed with breast cancer;
MRI should also be performed within 3 months before pro-
phylactic mastectomy to detect any occult breast cancer.
X-ray mammography should be avoided in TP53 mutation
carriers and women below 35 years of age, but may be con-
sidered from age 35 [27].
Screening for High-Familial-Risk Women
In the recent ACR Appropriateness Criteria for Breast
Cancer Screening [56], mammography begins at the age of
25–30 years or 10 years before the age at diagnosis of a first-­
degree relative; nevertheless, the age at onset of screening should
not be younger than 25. Mammography and MRI are comple-
mentary examinations; both should be performed. On the other
hand, ultrasound is performed if a patient cannot undergo MRI.
6.7 Conclusions and Future Perspectives
Evidence derived from published studies has indicated that
breast cancer arising in familial high-risk women is an entity
with distinct radiological and pathological features com-
pared to cancers arising in the general population. Therefore,
its surveillance needs a multimodal strategy tailored accord-
ing to the subject’s age, breast density, mutation status, acces-
sibility of screening modalities and coexisting personal or
medical conditions.
Among all imaging modalities, breast MRI seems to be
far more sensitive for the surveillance of women with BRCA1
mutations, whereas mammography provides a satisfactory
accuracy in BRCA2 mutation carriers. Breast ultrasound
plays an important role in the intervals between screening
rounds in the context of a multimodality strategy and when
MRI and/or mammography are contraindicated. Notably,
none of these modalities alone seem to provide the optimal
solution; in a multimodality approach, the limitations of each
method are ultimately diminished, offering the best possible
approach to this population group.
The evaluation of imaging modalities as screening tools
for familial high-risk women is an intensively investigated
field. Future studies addressing the role of emerging modali-
ties such as DBT or ABUS seem promising. Studies further
assessing the improvement in mortality rates, as well as aim-
ing to shape the optimal multimodality screening regimens,
are anticipated.
Key Facts
1. MRI and mammography are effective screening
modalities in high-risk women and reduce breast
cancer-­specific mortality.
2. BRCA1 gene carriers often have cancers which may
appear benign on imaging due to their pushing
borders, and care is needed in their assessment.
3. Optimal screening protocols vary with age with
MRI being more appropriate in younger women
with dense breasts.
4. For high-risk women, a multimodal approach is
optimal and may overcome the limitations of the
different modalities.
5. New strategies show promise: digital breast
tomosynthesis and automated breast ultrasound
(ABUS) may be helpful and are under evaluation.
rares1geo@gmail.com
65 6
6. Women should be counselled about the pros and
cons of screening – the impact of cumulative
radiation doses, unnecessary procedures and
over-diagnosis and the fact that screening does
not guarantee early diagnosis – and all appropriate
risk reduction strategies should be discussed
(chemoprevention, risk-reducing surgery, lifestyle
modification).
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13. Tilanus-Linthorst MM, Obdeijn IM, Hop WC, Causer PA, Leach MO,
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14. Chereau E, Uzan C, Balleyguier C, Chevalier J, de Paillerets BB, Caron
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15. Kriege M, Brekelmans CT, Boetes C, Besnard PE, Zonderland HM,
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19. Weinstein SP, Localio AR, Conant EF, Rosen M, Thomas KM, Schnall
MD.  Multimodality screening of high-risk women: a prospective
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22. Warner E, Messersmith H, Causer P, Eisen A, Shumak R, Plewes
D. Systematic review: using magnetic resonance imaging to screen
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671–9.
23. Schrading S, Kuhl CK. Mammographic, US, and MR imaging pheno-
types of familial breast cancer. Radiology. 2008;246(1):58–70.
24. Sardanelli F, Podo F, D’Agnolo G, Verdecchia A, Santaquilani M,
Musumeci R, et al. Multicenter comparative multimodality surveil-
lance of women at genetic-familial high risk for breast cancer (HIB-
CRIT study): interim results. Radiology. 2007;242(3):698–715.
25. Chiarelli AM, Prummel MV, Muradali D, Majpruz V, Horgan M, Carroll
JC, et al. Effectiveness of screening with annual magnetic resonance
imaging and mammography: results of the initial screen from the
ontario high risk breast screening program. J Clin Oncol.
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26. Rhiem K, Schmutzler RK. Genetic risk factors exemplified by familial
breast cancer. Forum. 2015;30(2):139–42.
27. Sardanelli F, Boetes C, Borisch B, Decker T, Federico M, Gilbert FJ,
et al. Magnetic resonance imaging of the breast: recommendations
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28. Foulkes WD, Chappuis PO, Wong N, Brunet JS, Vesprini D, Rozen F,
et al. Primary node negative breast cancer in BRCA1 mutation carri-
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29. Tilanus-Linthorst MM, Kriege M, Boetes C, Hop WC, Obdeijn IM,
Oosterwijk JC, et al. Hereditary breast cancer growth rates and its
impact on screening policy. Eur J Cancer. 2005;41(11):1610–7.
30. Moller P, Stormorken A, Jonsrud C, Holmen MM, Hagen AI, Clark N,
et al. Survival of patients with BRCA1-associated breast cancer diag-
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31. Kurian AW, Sigal BM, Plevritis SK.  Survival analysis of cancer risk
reduction strategies for BRCA1/2 mutation carriers. J Clin Oncol.
2010;28(2):222–31.
32. Moller P, Evans DG, Reis MM, Gregory H, Anderson E, Maehle L, et al.
Surveillance for familial breast cancer: differences in outcome accord-
ing to BRCA mutation status. Int J Cancer. 2007;121(5):1017–20.
33. Heemskerk-Gerritsen BA, Brekelmans CT, Menke-Pluymers MB, van
Geel AN, Tilanus-Linthorst MM, Bartels CC, et al. Prophylactic mas-
tectomy in BRCA1/2 mutation carriers and women at risk of heredi-
tary breast cancer: long-term experiences at the Rotterdam family
cancer clinic. Ann Surg Oncol. 2007;14(12):3335–44.
34. Huzarski T, Byrski T, Gronwald J, Gorski B, Domagala P, Cybulski C,
et al. Ten-year survival in patients with BRCA1-negative and BRCA1-
positive breast cancer. J Clin Oncol. 2013;31(26):3191–6.
35. Giess CS, Raza S, Birdwell RL. Patterns of nonmasslike enhancement
at screening breast MR imaging of high-risk premenopausal
women. Radiographics. 2013;33(5):1343–60.
36. Berg WA, Blume JD, Adams AM, Jong RA, Barr RG, Lehrer DE, et al.
Reasons women at elevated risk of breast cancer refuse breast MR
imaging screening: ACRIN 6666. Radiology. 2010;254(1):79–87.
37. Kuhl CK, Schrading S, Strobel K, Schild HH, Hilgers RD, Bieling
HB.  Abbreviated breast magnetic resonance imaging (MRI): first
postcontrast subtracted images and maximum-intensity projec-
tion-­a novel approach to breast cancer screening with MRI.  J Clin
Oncol. 2014;32(22):2304–10.
38. Nystrom L, Andersson I, Bjurstam N, Frisell J, Nordenskjold B, Rutqvist
LE. Long-term effects of mammography screening: updated overview
of the Swedish randomised trials. Lancet. 2002;359(9310):909–19.
39. Berg WA, Gutierrez L, NessAiver MS, Carter WB, Bhargavan M, Lewis
RS, et al. Diagnostic accuracy of mammography, clinical examina-
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40. Kolb TM, Lichy J, Newhouse JH. Occult cancer in women with dense
breasts: detection with screening US--diagnostic yield and tumor
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M, et  al. The development of interval breast malignancies in
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 69 7

Risk-Reducing Breast and

Ovarian Surgery for Women at
High Familial Risk
Inkeri Schultz and Kerstin Sandelin

7.1 Introduction – 70

7.2 Risk-Reducing Interventions – 70

7.3 Efficacy of Risk-Reducing Mastectomy – 70

7.4 Efficacy of Bilateral Risk-Reducing

Salpingo-Oophorectomy – 71

7.5 Technical Considerations – 71

7.5.1 Mastectomy – 71
7.5.2 Skin Incisions – 71

7.6 Breast Reconstruction – 74

7.6.1 Implant-Based Reconstruction – 74
7.6.2 Autologous Reconstruction – 74

7.7 Risk-Reducing Bilateral Salpingo-­Oophorectomy – 74

7.8 Psychosocial Considerations – 75

7.9 Surveillance After Risk-Reducing Surgery – 76

7.10 Conclusion – 76

References – 76

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_7

rares1geo@gmail.com
 70 I. Schultz and K. Sandelin
7.1 Introduction
To date removal of the target organs is the only highly effec-
tive preventive method available for women with an increased
risk of breast and ovarian cancer.
In a meta-analysis of 10 studies, the mean cumulative
cancer risk for mutation carriers at age 70  years for breast
cancer was 57% for BRCA1 and 49% for BRCA2 mutation
carriers. The mean cumulative risk for ovarian cancer was
40% for BRCA1 and 18% for BRCA2 gene carriers [1].
Higher-risk estimates were found in the Ashkenazi Jewish
population of Israel [2]. In addition, the calculated risk of
contralateral breast cancer 25 years after the first breast can-
cer diagnosis is 44% for patients from BRCA1-positive fami-
lies and 33.5% for patients from BRCA2-positive families in a
7 large retrospective, multicentre cohort study [3].
7.2 Risk-Reducing Interventions
Risk-reducing strategies include surveillance, chemopreven-
tion and risk-reducing surgery of the breasts, ovaries and fal-
lopian tubes. A multidisciplinary and multiprofessional team
including genetic counsellors, oncologists, psychologists,
breast surgeons, gynaecologists and reconstructive plastic
surgeons should provide a service and advise families and
individuals at high risk. An objective estimation of risk and
information about different surveillance and surgical options
are key issues that need to be covered. In proportion to the
level of risk for an individual woman and her age, active sur-
veillance is offered at regular intervals according to national
or international protocols [4]. Countries with established
guidelines recommend risk-reducing strategies primarily to
individuals at greatly increased risk, both asymptomatic and
those with a history of breast cancer. Breast imaging, at 6- or
12-month intervals, including mammography, ultrasound
and magnetic resonance imaging (MRI), is usually recom-
mended although not strongly evidence based (see 7 Chap. 6).
Ovarian cancer screening can be done by measurements of
CA125 and transvaginal ultrasound although without evi-
dence of improved survival [5]. Two trials set out to evaluate
the efficacy of ovarian cancer screening have failed to show
improved survival in both unselected women aged
50–74 years [6] and in women with an estimated >10% life-
time risk of ovarian or fallopian tube cancer [7]. The US
National Comprehensive Cancer Network’s recommenda-
tions for surveillance for BRCA1 and BRCA2 mutation carri-
ers include information about «breast awareness» starting at
the age of 18, clinical breast exam every 6–12 months from
the age of 25, annual breast screening using MRI from age 25
to 29 years and annual breast MRI and mammography from
30 to 75 years. After the age of 75 years, they recommend that
surveillance should be considered on an individual basis [8].
These recommendations are similar to most national proto-
cols [4]. However, while much of this is evidence based,
clinical breast examination has not been proven to be effec-
tive in trials.
rares1geo@gmail.com
Any woman who considers risk-reducing surgery has to
be accurately informed about different surgical options. In
the decision-making process, the significant reduction in
cancer risk associated with RRM and RRSO must be weighed
against other factors, including the need for breast recon-
struction, the risk of complications related to surgery, the
effect of the surgery on a woman’s body image and sexuality
and the irreversibility of the decision. The decision is mostly
patient driven, the uptake varies between countries and
socioeconomic factors also play a role in the decision pro-
cess. In contemporary reports, the percentage of women who
choose risk-reducing surgery varies from 18–51% for bilat-
eral RRM to 51–75% for RRSO, and acceptance of RRM in
the mutation carriers’ population has gradually increased
over time. Most centres report a higher uptake of RRSO than
RRM [9–13].
Rates of breast reconstruction after prophylactic mastec-
tomy by country ranged from 50.0% in China to 85.7% in
France in an international review. Overall 69% of the women
had a breast reconstruction after RRM, 72% with implants, 21%
had autologous reconstruction and 5.5% had a combined pro-
cedure, implant and autologous. Younger women and those
without a previous diagnosis of breast cancer were more likely
to have breast reconstruction than older women or those with a
previous diagnosis of cancer [11].
7.3 Efficacy of Risk-Reducing Mastectomy
Bilateral (RRM) [14] has been estimated to reduce breast
cancer incidence by more than 90% in BRCA mutation car-
riers [15–17]. The Cochrane Database of Systematic
Reviews update from 2010 concluded that RRM is effective
in reducing both the incidence of and death from breast
cancer, but should be considered only for women at very
high risk of breast cancer. Evidence regarding the effect of
contralateral mastectomy after a previous breast cancer on
survival was considered insufficient at that time [18]. The
effect of contralateral surgery is complex as the biology and
stage of the ipsilateral cancer will have a strong impact on
prognosis.
A meta-analysis from 2014 concluded that CRRM is
associated with a decreased metachronous breast cancer
incidence but not improved survival among patients with
elevated familial/genetic risk and that CRRM should not be
recommended to patients with unilateral breast cancer with-
out a known elevated risk [19]. Other studies focusing on
BRCA1/2 mutation carriers have indicated a survival advan-
tage after CRRM. Evans and co-authors compared 105 female
BRCA1/2 mutation carriers with unilateral breast cancer
who underwent CRRM to controls and reported a signifi-
cantly improved 10-year overall survival of 89% in the CRRM
compared to 71% in the non-CRRM group [20]. A retrospec-
tive analysis comparing survival rates in BRCA mutation car-
riers from Canada and the USA having had breast cancer
showed that after 20 years, survival was 88% among women
who had undergone CRRM and 66% among those who had
Risk-Reducing Breast and Ovarian Surgery for Women at High Familial Risk
not [21]. Improved overall survival after CRRM compared to
patients who remained under surveillance has also been
reported from the Netherlands, especially in breast cancer
patients under the age of 40, in patients with cancer grade 1/2
and/or no triple-negative phenotype and in patients not
treated with adjuvant chemotherapy [22]. Today most inter-
national guidelines recommend CRRM to high-risk individ-
uals according to the same indications as for bilateral RRM in
asymptomatic women. The effect on survival of CRRM in the
short term is small but increases after 20 years [21]. Measuring
the absolute survival benefit is complicated. The Society of
Surgical Oncology in 2007 suggested the following three
potential indications for CRRM: risk reduction, problems in
surveillance due to dense breasts and symmetry issues, thus
in a much broader context than simply risk reduction
(7 http://www.surgonc.org/resources/consensus-statements/
 
position-statement-on-prophylactic-mastectomy). The
American Society of Breast Surgeons has updated their rec-
ommendations in 2016 [23].
7.4  fficacy of Bilateral Risk-Reducing
E lous mastectomy should be performed, preserving the
Salpingo-Oophorectomy
Ovarian cancer is the fifth leading cause of cancer-related
deaths among women overall. Similar to breast cancer, inci-
dence rates are highest in European and North American
countries and lowest in African and Asian countries [24].
Bilateral salpingo-oophorectomy prevents ovarian cancer in
average risk women, when performed at the same time as
hysterectomy for benign disease. There is also substantial evi-
dence supporting the efficacy of RRSO salpingo-oophorec-
tomy [9] in mutation carriers whereby the risk of ovarian
cancer is reduced by 80% [15, 25]. Furthermore, the risk for
breast cancer is considered to be reduced by 50% in BRCA1
and BRCA2 carriers after RRSO if performed before meno-
pause [17, 26], and an association with decreased mortality
after breast cancer if oophorectomy is performed after breast
cancer in women with a BRCA1 mutation has been reported
[27]. This has recently been disputed by Heemskerk-
Gerritsen and colleagues who did not find any risk reduction
in their study and postulated that the reduced risk after
RRSO in BRCA1/2 mutation carriers may have been overes-
timated because of bias [28]. There may be some theoretical
basis to this in BRCA1 carriers who largely develop oestro-
gen-insensitive breast cancers.
7.5 Technical Considerations
7.5.1 Mastectomy
Before performing a RRM, magnetic resonance imaging
(MRI) is recommended to detect possible malignancies pre-
operatively. Unanticipated breast malignancies have been
found in 5–10% of breast specimens from risk-reducing mas-
tectomies [29–31]. As all mastectomies result in incomplete
rares1geo@gmail.com
71 7
removal of all breast tissue, it is important to inform women
that breast cancer can still occur after RRM. The frequency of
breast cancer after RRM is difficult to estimate as surgical
technique varies and the duration of follow-up often is
­limited. A review of 24 observational studies published in
2014 reported that after 6044 bilateral RRM, primary breast
cancers occurred in 21. In addition four patients had distant
metastases with an unknown primary site [30]. Breast tissue
is common in biopsy samples from the superficial tissue
plane in specimens after mastectomy and was found in 76%
of 206 specimens in one study [32]. A superficial facial plane
separating breast tissue from subcutaneous fat is usually
either not present or poorly defined in many women, making
complete breast tissue removal technically impossible. A his-
tological study found such a plane to be absent in 44% of
resection specimens, and when found, it was often micro-
scopically too thin and delicate to be detectable macroscopi-
cally [33]. The existence of a consistent and distinct layer of
subcutaneous tissue with a median thickness of 1.0 cm has
been confirmed in a pathology study, by microscopic exami-
nation and measurement [34]. For risk reduction, a meticu-
subcutaneous layer and if possible the internal mammary
perforators. Preservation of the inframammary fold improves
the results after reconstruction of the breast but may leave a
small volume of residual breast tissue.
Few women undergoing bilateral RRM choose mastec-
tomy only [11]. The goal for most BRCA1 and BRCA2 muta-
tion carriers is removal of as much glandular breast tissue as
possible and restoration of a breast mound that looks as natu-
ral as possible. This influences the choice of skin incision.
7.5.2 Skin Incisions
The concept of «skin-sparing mastectomy» [35] was intro-
duced in 1991 by Toth and Lappert [36]. Instead of the con-
ventional elliptical mastectomy incision including the
nipple-areola complex (NAC) [37] and skin overlaying the
tumour, they described modified skin incisions for the mas-
tectomy, to facilitate or improve the outcome of a subsequent
breast reconstruction. This technique included removal of
the NAC.  Many retrospective reports have confirmed the
oncological safety of the technique for patients with breast
cancer [38–41]. Nipple-sparing mastectomy (NSM) is a fur-
ther development of the surgical technique aiming to
improve the cosmetic outcome and reduce the psychological
impact. There is still an ongoing debate regarding the risk of
occult cancer or of later developing cancer in residual breast
tissue in the nipple. Early accounts of subcutaneous mastec-
tomy describe leaving up to a 1 cm plaque of breast tissue
under the areola [42, 43]. Modern techniques include a sub-
areolar biopsy specimen and leaving a minimal amount of
tissue in the nipple. This is done by removing the entire core
of the nipple [30]. Many reports indicate a low risk of pri-
mary breast cancer after NSM for women with breast cancer.
In a study from the Mayo Clinic by Hartmann and col-
 72 I. Schultz and K. Sandelin

leagues, 575 women with a family history of breast cancer
underwent bilateral RRM with a nipple-sparing technique
that included leaving residual tissue under the NAC and 64
women – standard mastectomies. The median length of fol-
low-up was 14 years. There was no significant difference in
the incidence of breast cancer between the groups, and of the
seven women who developed a breast cancer during follow-
up, only one had a cancer in the nipple [16]. In the review of
6044 bilateral RRM and cancer incidence after prophylactic
surgery mentioned above, most of the mastectomies were
SSM or NSM, but the majority of the cancers did not develop
near the NAC [30].
Risks of NSM have to be discussed with the patient pre-
inadequate blood supply leading to skin desquamation or
necrosis of the nipple-areola complex with possible need for
debridement or excision of the NAC are other problems of
concern.
In women with small- to moderate-sized breasts, NSM is
often the preferred option. There are no widely accepted cri-
teria for NSM to be performed. Relative contraindications
include smoking history, larger breast size and ptosis. Many
different skin incisions are used, and placement can vary
depending mostly on the surgeon’s preference: periareolar
with or without a lateral extension; different radial incisions
as, for example, a lateral «lazy-S»; submammary, omega type;
or transareolar (see . Fig. 7.1). In a review of 48 studies by

operatively. A positive biopsy specimen from the nipple base Munhoz and colleagues [44], the most common incision was
may necessitate removal of the NAC. Surgical morbidity and radial, followed by periareolar, inframammary, mastopexy
7
..      Fig. 7.1  a Wise-pattern
a b
incision b Radial incision, «lazy-S»
c Periareolar incision, may be
extended medially, laterally or
both («omega incision») d
Submammary fold incision,
extended laterally (Used with
permission from Lucy Bai.
Illustration credit: Lucy Bai)

c d

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Risk-Reducing Breast and Ovarian Surgery for Women at High Familial Risk
73 7
..      Fig. 7.2  a Before bilateral a b
RRM b After RRM and reconstruc-
tion with permanent implants,
submammary incision with lateral
extension (same patient as a) c
Before bilateral RRM, the patient
has previously undergone
reduction mammoplasty and lost
much weight d After RRM and
reconstruction with permanent
expander, Wise-pattern incision
(same patient as c) (Photos used
with permission from Medicinsk
Bild, Karolinska University
Hospital, Stockholm, Sweden)

c d

and transareolar. Wijayanayagam and colleagues [45] found
that the radial incision had the greatest likelihood of avoiding
ischaemia of the nipple-areola complex in a series of 64 con-
servative mastectomies. However, the scar from this incision
is prominent and the NAC is often displaced by the scar.
Inframammary incisions are generally the least conspicuous,
but in a larger-sized breast it can be difficult to remove all
ditional mastectomy incision with removal of the NAC but
leaving more skin than when no reconstruction is planned.
The nipple can be retransplanted as a full-thickness skin graft
at the end of the operation. A skin-reducing mastectomy
using a Wise-pattern incision is another alternative, often
suitable for women with larger-sized or ptotic breasts (see
. Figs.  7.1 and 7.2). The NAC can be saved or removed

breast tissue. Total or partial loss of the nipple has been
reported in 4.4–23% of patients. The risk for NAC complica-
tions and displacement is reduced when the incision is placed
at a distance from the NAC. In a review of 500 nipple-sparing
mastectomy procedures, the periareolar incision was an
independent predictor of complications, and the inferolateral
inframammary fold incision was associated with a decreased
risk of total and ischemic complications [46].
In woman with large or very ptotic breasts, a reduction of
the skin envelope is needed. This can be achieved using a tra-
depending on the size of the breast. In some women, a de-­
epithelialized dermal flap created by the skin between the
inframammary fold and the upper lines of the resection may
be used. This flap can be sutured to the detached lower bor-
der of the pectoralis major muscle, thus creating a wide
dermo-muscular pocket for an implant [47, 48].
After previous breast augmentation with subpectoral
implants, the mastectomy can be performed leaving the
implant and surrounding capsule in place. After the skin- or
NAC-sparing mastectomy, the skin envelope can either be

rares1geo@gmail.com
 74 I. Schultz and K. Sandelin

reduced or left unchanged depending on breast size. An superior for reconstruction in women with a previous breast
alternative is placing an expander in the implant pocket. A cancer who have undergone chest wall irradiation, where an
retrospective review of cancer patients with pre-existing sub- implant-based reconstruction may cause major surgical chal-
pectoral implants compared placing an immediate tissue lenges and more revisional surgeries. The free flaps are con-
expander [49] to implant-sparing mastectomy followed by sidered superior to implant-based reconstruction for many
delayed implant exchange [50] and found more complica- patients due to the resulting soft natural breast mound and
tions in the tissue expander group [51]. the longevity of the aesthetic results. The complexity associ-
ated with autologous breast reconstruction must be remem-
bered, with increased operative times, involved microsurgical
7.6 Breast Reconstruction techniques and potential for surgical morbidity at two sepa-
rate sites. In the Swedish national inventory of bilateral RRM,
7.6.1 Implant-Based Reconstruction one site solely performed autologous reconstructions. Their
complication rate was higher, and their need of blood trans-
Reconstruction using permanent implants is the most fusion exceeded that compared to the implant-based cohort
straightforward method that enables a cosmetically satisfac- [29]. When compared for costs and complications, LD flaps
7 tory result in women with small breasts (. Fig. 7.2). Elasticity were more costly but not associated with more complications
 

of the pectoralis major muscle will be the size-limiting factor than the implant-based reconstructions in 50 UK patients
in many patients. After finishing the mastectomy, a subpecto- (19/50 were RRM, the remaining had a personal history of
ral pocket is created for the implant by lifting the pectoralis breast cancer) [58]. Techniques for reconstruction vary
major muscle from underlying pectoralis minor muscle and depending on local traditions between countries and regions.
chest wall. Electrocautery is useful for this dissection, and the A high frequency of autologous flaps has been reported from
surgeon positioned on the cephalad side of the arm helps giv- Helsinki, Finland, where a majority of patients chose LD flaps
ing a good view of the caudal portion of the pocket. Lateral or free flaps. They report 25 out of 80 breasts reconstructed
coverage of the implant can be achieved by mobilising the with different free flaps such as the transverse rectus abdomi-
serratus anterior muscle. An acellular dermal matrix [7] or a nis musculo (TRAM)-cutaneous flaps, superficial inferior
synthetic mesh can be used to increase the size of the sub-­ epigastric abdominal (SIEA) perforator flaps, transverse
muscular pocket and improve the projection in the caudal myocutaneous gracilis (TMG) flaps, deep inferior epigastric
part of the breast. ADMs are matrix grafts derived from allo- perforator flaps and 20/80 with LD flaps. Three of the free
genic and xenogenic dermis intended to provide a scaffold flaps were lost, and among 31 implant-based reconstructions,
for the patient’s own cells. Some patients may benefit from four implants were lost [59]. Low frequencies of complica-
this, but it is still a controversial technique associated with tions after autologous reconstructions in the risk-reducing
high costs and possible increased complication rates [52, 53]. setting have been reported by others. A one-­step procedure
Long-term follow-up regarding quality of life has been pub- for bilateral RRM and RRSO has also been described, starting
lished but is lacking regarding cosmetic outcomes [54]. with salpingo-oophorectomy using open laparoscopy then
In women with larger breast sizes, an expander-based recon- bilateral immediate or delayed breast reconstruction with
struction is needed. This technique has been widely used for DIEP flaps. This was performed in eight patients with a mean
reconstruction after bilateral RRM with good results, relatively duration of the entire procedure of 524 minutes and no flap
low complication rates and high patient satisfaction [29, 35, 55]. loss [60]. There are no long-term follow-up studies after
Regardless of the chosen reconstruction mode, RRM is a autologous breast reconstructions in mutation carriers, but
major surgical event and women need extensive preoperative these techniques are appealing alternatives for some, espe-
information about the extent of the procedure, the risk for cially younger and healthy women resulting in reconstructed
complications and the possibility of revision surgeries. breasts without need for corrections and changes of implants
Smoking, high body mass index and preoperative irradiation later in life. However as the median age of this subgroup is
are well-known predictors of complications [56]. Tobacco relatively younger than in cancer patients, many do not have
users should be encouraged to stop smoking at least 4 weeks adequate donor site volumes for autologous bilateral recon-
before and 4 weeks after surgery, as this substantially reduces structions.
the risk for complications [57].

7.7  isk-Reducing Bilateral Salpingo-­

R
7.6.2 Autologous Reconstruction Oophorectomy

Free flap reconstructions are less frequently used for bilateral Today most guidelines recommend RRSO at the ages 35–40 or
RRM, whereas the latissimus dorsi (LD) flap in combination after completion of childbearing for mutation carriers. It [9] is
with implants is well suited for women with larger breast vol- the most effective prevention mode for ovarian cancer in BRCA
umes and higher body mass index. However, free flaps are ­mutation carriers. The surgery is usually undertaken laparo-

rares1geo@gmail.com
Risk-Reducing Breast and Ovarian Surgery for Women at High Familial Risk
scopically with minimal surgical morbidity. However side
effects related to premature surgical menopause are common,
may be very distressing and should be actively managed. These
include vasomotor symptoms, loss of libido, vaginal dryness
and dyspareunia, increased relative risk for cardiovascular
events, osteoporosis, psychosexual and cognitive dysfunction
in premenopausal women. Women may not always be ade-
quately counselled about these side effects which may have a
negative impact on quality of life and relationships. Hormone-­
replacement therapy may be used until approximately
50 years of age with little impact on the degree of breast can-
cer risk reduction [61]. Bone density monitoring with DEXA
scans and appropriate use of calcium and vitamin D supple-
ment +/− bisphosphonates may be useful especially if HRT is
not used. Sexual dysfunction may be helped with oestrogen
creams or simple vaginal ­moisturisers.
A recent hypothesis proposes that many ovarian cancers
(especially high-grade serous histotype) may arise from the
distal part of the fallopian tube. Furthermore epidemiologic
data show a decreased risk of ovarian cancer following tubal
ligation or salpingectomy. In the future, bilateral salpingec-
tomy with ovarian retention (BSOR) [62] might become a
prevention strategy for premenopausal high-risk women for
whom RRSO is recommended, but are reluctant to have their
ovaries removed due to hormonal implications. For these
women, BSOR might be useful as a temporary measure [63–
65], but currently this is not recommended outside of clinical
trials.
7.8 Psychosocial Considerations
The decision process for any woman opting for an ablative
procedure includes both emotional and cognitive under-
standing of what this entails. The permanent effects that
these procedures involve need to be fully communicated. The
multiprofessional and multidisciplinary team can facilitate
and offer information and support in its special field of
expertise. They need to balance the substantial risk-reducing
effect against the small possibility of leaving residual breast
tissue behind. As interpreting risk is a difficult and highly
subjective matter, decision aids have been developed [66, 67].
The reported incidence of breast cancer occurring in muta-
tion carriers varies depending on surgical technique and
time of follow-up but is reported to be very low as discussed
earlier. Further health-related quality of life outcomes such as
body image changes, physical and sexual wellbeing and psy-
chosocial changes that may occur should be considered and
discussed.
Regarding RRSO and RRM, the overall goal for the
patient, apart from risk reduction, is to reduce cancer anxi-
ety. The reported outcomes after RRSO confirm this reduc-
tion of anxiety levels and post-operative problems relate
more to menopausal symptoms from urogenital tract and
sexual disturbances than regrets of having undergone the
rares1geo@gmail.com
75 7
surgery. An information gap between patients and caregiv-
ers preoperatively has been described, and women have
reported a preoperative lack of information regarding
impact of RRSO on body image, sex life and their risks for
coronary heart disease [68].
While most women are highly motivated once they
come for a surgical consultation, there are a number of
issues that they need to comprehend and reflect upon.
Most studies reporting patient-related outcomes after RRM
include women who have had reconstructive surgery of
their breasts. Few studies on RRM in purely asymptomatic
patients exist comparing reconstructed versus only mas-
tectomised patients. In studies including high-risk patients
with breast cancer generally, patients who had not opted
for reconstruction reported higher satisfaction rates and
less anxiety and bodily problems [69–71]. When evaluat-
ing the literature, it becomes clear that the instruments
used are often not validated and not breast specific and that
the sample sizes are small [72]. However, the results are
quite unanimous in their findings. Moreover, it is difficult
to deduce what role on decision-­making the physicians
play [72]. Halloway and colleagues conducted semi-struc-
tured interviews with 40 high-risk women 3  years after
surgery and focused on two themes: looking different and
feeling different. The authors concluded that although
women find the procedure satisfactory in reducing the
cancer risk and anxiety, careful preoperative information is
mandatory as they reported being unprepared for the lack
of sensation on their breasts, the severity of the meno-
pausal symptoms and the impact on sexuality [68]. From
the same research group, a prospective analysis comprising
women who had either undergone RRM and RRSO or
RRSO only reported few regrets and little negative impact
on psychosocial functioning [73].
Satisfaction with both outcome and the decision-making
is generally high in reported studies also when being asked
long-term post-operatively, but enjoyment of sex was nega-
tively impacted on in 75% of the patients [74]. Character and
emotional traits like vulnerability and high cancer distress
preoperatively correlated with decreased quality of life post
RRM and reconstruction [71]. In a prospective study using a
bespoke instrument, Gopie and colleagues showed in Dutch
women that RRM and reconstruction did not affect sexual
relationships if these were considered satisfying preopera-
tively [75]. However, body image deteriorated especially if
cancer distress was high preoperatively.
Outcome studies reveal that patients’ motives for CRRM
are risk reduction and to achieve symmetry and improved
cosmesis [21]. Prospective studies looking at complications
following CRRM report that the surgical challenge is the can-
cer side and that of achieving a satisfactory result after adju-
vant treatment. Especially when radiotherapy is needed to
one side as part of cancer treatment, multiple revision surger-
ies are often necessary. Otherwise outcome measures are
similar to those after bilateral RRM [76, 77].
 76 I. Schultz and K. Sandelin

7.9  urveillance After Risk-Reducing

S 11. Semple J, Metcalfe KA, Lynch HT, Kim-Sing C, Senter L, Pal T, et al.
International rates of breast reconstruction after prophylactic mas-
Surgery tectomy in BRCA1 and BRCA2 mutation carriers. Ann Surg Oncol.
2013;20(12):3817–22.
Guidelines for surveillance after risk-reducing surgery are less 12. Metcalfe KA, Birenbaum-Carmeli D, Lubinski J, Gronwald J, Lynch H,
consistent than for mutation carriers who have not under- Moller P, et al. International variation in rates of uptake of preven-
tive options in BRCA1 and BRCA2 mutation carriers. Int J Cancer.
gone surgery. In a survey of surveillance schemes from 22
2008;122(9):2017–22.
centres in 16 countries in Asia, Australia, Europe and North 13. Garcia C, Wendt J, Lyon L, Jones J, Littell RD, Armstrong MA, et al.
America, most centres offered annual clinical breast exam, Risk management options elected by women after testing positive
while four centres offered annual MRI, primarily for substan- for a BRCA mutation. Gynecol Oncol. 2014;132(2):428–33.
tial residual breast tissue after RRM. Only four centres offered 14. Beesley H, Holcombe C, Brown SL, Salmon P. Risk, worry and cosme-
sis in decision-making for contralateral risk-reducing mastectomy:
specific gynaecological surveillance after RRSO [4].
analysis of 60 consecutive cases in a specialist breast unit. Breast.
2013;22(2):179–84.
15. Rebbeck TR, Kauff ND, Domchek SM. Meta-analysis of risk reduction
7.10 Conclusion estimates associated with risk-reducing salpingo-­oophorectomy in
BRCA1 or BRCA2 mutation carriers. J Natl Cancer Inst. 2009;101(2):
7 To conclude BRCA1 and BRCA2 mutations carry a high risk 80–7.
16. Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG,
for cancer in both breasts and ovaries/fallopian tubes. et al. Efficacy of bilateral prophylactic mastectomy in women with a
Prophylactic mastectomy and salpingo-oophorectomy sub- family history of breast cancer. N Engl J Med. 1999;340(2):77–84.
stantially reduce the cancer risk and improve survival. All 17. Domchek SM, Friebel TM, Singer CF, Evans DG, Lynch HT, Isaacs C,
mutation carriers should be offered counselling by a multi- et al. Association of risk-reducing surgery in BRCA1 or BRCA2 muta-
tion carriers with cancer risk and mortality. JAMA. 2010;304(9):
professional team about risks and surgical options.
967–75.
18. Lostumbo L, Carbine NE, Wallace J. Prophylactic mastectomy for the
prevention of breast cancer. Cochrane Database Syst Rev. 2010;(11):
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implications of risk-reducing mastectomy and reconstruction. Eur J
Surgl Oncol. 2016;42(1):45–50.
59. Koskenvuo L, Svarvar C, Suominen S, Aittomaki K, Jahkola T.  The
frequency and outcome of breast cancer risk-reducing surgery in
finnish BRCA1 and BRCA2 mutation carriers. Scand J Surg.
2014;103(1):34–40.
60. Hunsinger V, Marchac AC, Derder M, Hivelin M, Lecuru F, Bats AS,
et al. A new strategy for prophylactic surgery in BRCA women: com-
bined mastectomy and laparoscopic salpingo-oophorectomy with
immediate reconstruction by double DIEP flap. Ann Chir Plast
Esthet. 2016;61(3):177–82.
61. Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, et al.
Effect of short-term hormone replacement therapy on breast can-
cer risk reduction after bilateral prophylactic oophorectomy in
BRCA1 and BRCA2 mutation carriers: the PROSE study group. J Clin
Oncol. 2005;23(31):7804–10.
62. Daly MB, Dresher CW, Yates MS, Jeter JM, Karlan BY, Alberts DS, et al.
Salpingectomy as a means to reduce ovarian cancer risk. Cancer
Prev Res (Phila). 2015;8(5):342–8.
63. Yates MS, Meyer LA, Deavers MT, Daniels MS, Keeler ER, Mok SC,
et al. Microscopic and early-stage ovarian cancers in BRCA1/2 muta-
tion carriers: building a model for early BRCA-associated tumori-
genesis. Cancer Prev Res (Phila). 2011;4(3):463–70.
64. Greene MH, Mai PL, Schwartz PE. Does bilateral salpingectomy with
ovarian retention warrant consideration as a temporary bridge to
risk-reducing bilateral oophorectomy in BRCA1/2 mutation carri-
ers? Am J Obstet Gynecol. 2011;204(1):19.e1–6.
 78 I. Schultz and K. Sandelin
65. Swanson CL, Bakkum-Gamez JN. Options in prophylactic surgery to
prevent ovarian cancer in high-risk women: how new hypotheses of
fallopian tube origin influence recommendations. Curr Treat
Options in Oncol. 2016;17(5):20.
66. Collins IM, Bickerstaffe A, Ranaweera T, Maddumarachchi S, Keogh
L, Emery J, et al. iPrevent(R): a tailored, web-based, decision support
tool for breast cancer risk assessment and management. Breast
Cancer Res Treat. 2016;156(1):171–82.
67. Culver JO, MacDonald DJ, Thornton AA, Sand SR, Grant M, Bowen
DJ, et  al. Development and evaluation of a decision aid for BRCA
carriers with breast cancer. J Genet Couns. 2011;20(3):294–307.
68. Hallowell N, Baylock B, Heiniger L, Butow PN, Patel D, Meiser B, et al.
Looking different, feeling different: women’s reactions to risk-reduc-
ing breast and ovarian surgery. Familial Cancer. 2012;11(2):215–24.
69. Frost MH, Schaid DJ, Sellers TA, Slezak JM, Arnold PG, Woods JE,
et al. Long-term satisfaction and psychological and social function
following bilateral prophylactic mastectomy. JAMA. 2000;284(3):
319–24.
7 70. Dowdy SC, Stefanek M, Hartmann LC. Surgical risk reduction: pro-
phylactic salpingo-oophorectomy and prophylactic mastectomy.
Am J Obstet Gynecol. 2004;191(4):1113–23.
71. Metcalfe KA, Esplen MJ, Goel V, Narod SA. Psychosocial functioning
in women who have undergone bilateral prophylactic mastectomy.
Psycho-Oncology. 2004;13(1):14–25.
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72. Razdan SN, Patel V, Jewell S, McCarthy CM.  Quality of life among
patients after bilateral prophylactic mastectomy: a systematic review
of patient-reported outcomes. Qual Life Res. 2016;25(6):1409–21.
73. Heiniger L, Butow PN, Coll J, Bullen T, Wilson J, Baylock B, et al. Long-
term outcomes of risk-reducing surgery in unaffected women at
increased familial risk of breast and/or ovarian cancer. Familial Can-
cer. 2015;14(1):105–15.
74. Gahm J, Wickman M, Brandberg Y.  Bilateral prophylactic mastec-
tomy in women with inherited risk of breast cancer–prevalence of
pain and discomfort, impact on sexuality, quality of life and feelings
of regret two years after surgery. Breast. 2010;19(6):462–9.
75. Gopie JP, Mureau MA, Seynaeve C, Ter Kuile MM, Menke-Pluymers
MB, Timman R, et al. Body image issues after bilateral prophylactic
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for hereditary breast cancer. Familial Cancer. 2013;12(3):479–87.
76. Unukovych D, Sandelin K, Liljegren A, Arver B, Wickman M, Johans-
son H, et al. Contralateral prophylactic mastectomy in breast cancer
patients with a family history: a prospective 2-years follow-up study
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cer. 2012;48(17):3150–6.
77. Unukovych D, Sandelin K, Wickman M, Arver B, Johansson H, Brand-
berg Y, et al. Breast reconstruction in patients with personal and fam-
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 79 8

The Role of Breast Cancer

Chemoprevention in High-Risk
Women
Lynda Wyld

8.1 Introduction – 80

8.2 Induced Premature Menopause – 80

8.3 Selective Oestrogen Receptor Modulators (SERMs) – 81

8.3.1 Tamoxifen Studies – 81
8.3.2 Aromatase Inhibitors – 84

8.4 Indications for Chemoprevention – 84

8.5 Risk Stratification Techniques – 84

8.6 Agents Targeting Non-oestrogenic Pathways – 84

8.6.1 Cox-2 Inhibitors – 85
8.6.2 Retinoids – 85
8.6.3 PARP Inhibitors – 85
8.6.4 Epidermal Growth Factor Receptor (EGFR)-Directed Therapies – 85

8.7 Summary – 85

References – 86

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_8

rares1geo@gmail.com
 80 L. Wyld
8.1 Introduction
Breast cancer is the most common cancer to affect females in
the developed world with 1 in 8 developing the disease. Some
women are at an even higher risk due to their genetic make-
up [1, 2], lifestyle or atypias such as ADH or LCIS [3]. Whilst
those at highest risk may wish to undergo risk-reducing mas-
tectomy (BRCA1 or BRCA2 gene carriers), for others, this is
unacceptable, and other risk-reducing strategies and/or
enhanced surveillance are more appropriate. These strategies
may include lifestyle modification to reduce known risk fac-
tors such as weight control, exercise, reducing alcohol, and
oestrogen-containing medication consumption (birth con-
trol pills and HRT), but pharmacological interventions tar-
geting the carcinogenic pathway of breast cancer development
may also be effective [4]. These pathways are complex, result-
ing in the development of numerous breast cancer subtypes.
8 Most of the research in this field has focussed on the role of
oestrogen in the genesis of oestrogen receptor-­ positive
(ER  +  ve) cancers and how this pathway may be blocked.
More recently some of the less common subtypes and regula-
tory pathways have become the focus of chemoprevention
research, but as yet, no randomised clinical trial data exists to
support their use [5].
The role of oestrogen in the genesis of breast cancer has
long been recognised [6]. The link between the incidence of
breast cancer and increased lifetime oestrogen exposure as a
result of early menarche, late menopause, or women who have
higher levels of endogenous (e.g. obesity) or exogenous (e.g.
HRT, birth control pills) oestrogen is widely established in epi-
demiological research. In terms of biological plausibility, oes-
trogen acts as both an inducer and promoter of breast
carcinogenesis by stimulating cellular proliferation of breast
epithelial cells and possibly by direct genotoxicity [6]. Similarly,
males with hereditary conditions associated with raised oestro-
gens or an altered oestrogen to testosterone ratio (Klinefelter’s
syndrome) are at increased breast cancer risk [7].
It is therefore logical that interventions to reduce the oes-
trogenic stimulation of breast tissue may reduce the risk of
breast cancer development and in particular the development
of oestrogen-sensitive breast cancer. A number of strategies
have been used to interfere with this carcinogenic mechanism:
induction of early menopause, selective oestrogen receptor
modulators (SERMs) and aromatase inhibitors (AIs).
Most of these strategies have proven to be effective to
varying degrees in reducing the risk of developing breast
cancer. However, to date, evidence of increased overall sur-
vival in such trials is lacking. Whilst oestrogen-sensitive
breast cancer subtypes (luminal A and B [8]) account for 70%
of all cases, they tend to have a relatively good prognosis with
high breast cancer-specific survival rates and lengthy disease-
free survival times. Interventions to reduce the risk of devel-
oping such cancers may fail to show an overall survival
benefit unless they have large sample sizes and long follow-
up periods [9]. Data for tamoxifen with relatively lengthy
follow-up has so far failed to show an overall survival benefit,
probably as a result of drug-related adverse events counter-
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acting any cancer-specific survival advantage, combined with
a low event rate. However, with other more recent trials of
newer SERMS and AIs with better side effect profiles, such
long-term follow-up is not yet available. In addition compli-
ance with these agents both within and outside of trials is
poor [10], possibly as low as only 10% [11], due to the adverse
side effect profiles of many of these agents and the fact that
they may be perceived as «cancer drugs» [11]. This may also
have impacted on the efficacy of trial interventions and may
limit clinical utility.
Other subtypes of breast cancer such as Her2-positive
and the triple-negative (TNC) subtypes have higher mortal-
ity rates and shorter disease-free survival times. Their pre-
vention would therefore have a much greater impact on
survival and would be detectable after shorter trial follow-up.
However, research into pharmacological strategies to reduce
the risks of these cancers is at a very early stage with recent
interest in ErbB2 family receptor inhibition (trastuzumab
and lapatinib), metformin, COX-2 inhibitors, statins,
bisphosphonates and PARP inhibitors [12] in the prophylac-
tic setting, but there is no mature human trial data at present.
These strategies are reviewed below.
8.2 Induced Premature Menopause
Arrest of ovarian oestrogen synthesis before menopause is
associated with an approximate halving of the risk of breast
cancer which may be more marked the earlier it is performed,
but this must be balanced against the risks of very early
menopause. This may be achieved by either surgical oopho-
rectomy or use of gonadotropin-releasing hormone (GnRH)
agonists. In a risk reduction setting, surgery is primarily used
for women at increased risk of both breast and ovarian can-
cer as a result of BRCA1 or BRCA2 gene carriage. Numerous
studies have confirmed this finding with a breast cancer risk
reduction of ~50% on meta-analysis [13]. The addition of
HRT to abrogate the consequences of premature menopause
is not associated with a sigificant restitution of risk [14] and
improves quality of life.
However, carriers of the BRCA1 and, to a lesser extent,
BRCA2 gene mutations have a substantially elevated breast
cancer risk well before completion of childbearing and at an
age when surgical oophorectomy would also risk significant
adverse effects (osteoporosis, vaginal atrophy, hot flushes).
Use of the selective oestrogen receptor modulator (SERM)
tamoxifen may be an option for these very young women but
may be associated with significant adverse effects, and there
is no trial data on its efficacy below the age of 35. Other
SERMS and AIs are not effective in premenopausal women.
Medically induced menopause with GnRH agonists would
logically be expected to induce a similar but reversible effect
to oophorectomy, but they are not used routinely in a risk
reduction setting at present. There is evidence of their likely
efficacy [15] in this setting, but no large-scale preventative
trials have been performed. One proposal is to use GnRH
agonists combined with low-dose oestrogen and testosterone
The Role of Breast Cancer Chemoprevention in High-Risk Women
to offset the adverse effects of ovarian suppression without
abolishing risk reduction. A small pilot study (n = 8 BRCA1
gene carriers) of such a protocol has demonstrated signifi-
cant reduction of mammographic density (a surrogate for
breast cancer risk) without detrimental effects on quality of
life or bone mineral density [16]. This may be an option for
women who are not yet ready to undergo surgical risk reduc-
tion, but clinical trials would be needed before such regimes
could be offered.
8.3  elective Oestrogen Receptor
S domised to tamoxifen or placebo for 8  years. On interim
Modulators (SERMs)
This class of drugs acts as both agonists and antagonists of the
oestrogen receptor depending on the target tissue, exhibiting
anti-oestrogenic effects on breast tissue and pro-­oestrogenic
effects on bone and the uterus. There are a number of such
drugs which have been evaluated in the risk reduction setting
(. Table 8.1). They vary in their relative efficacy, trial inclu-
 
sion criteria, primary outcome and side effects.
8.3.1 Tamoxifen Studies
Use of tamoxifen in the prophylactic setting was first suggested
by the results of numerous adjuvant tamoxifen versus placebo
trials for women with breast cancer. A reduced risk of new pri-
mary breast cancer was noted in the contralateral breasts of
81 8
these women when given tamoxifen for 5 years. A relative risk
of 0.62 was found on meta-analysis of these trials [17]. It was
proposed that the same effect might hold in the setting of
women who had never had breast cancer in the first place. There
have been four major trials to assess the efficacy of tamoxifen in
a purely risk reduction setting: the first being the UK Royal
Marsden study [18], which started in 1986, followed several
years later by three much larger studies in the USA (NSABP-P1
[19]), Italy [20] and Europe/Australia (IBIS-1 [21]).
The Royal Marsden study recruited almost 2500 women,
at normal population breast cancer risk. They were ran-
analysis at the end of the treatment period, whilst there was a
reduced incidence of ER + ve cancers in the treated arm [22],
this did not reach statistical significance until late planned
analysis after 200 breast cancer events in 2007 after a median
follow-up of 13 years [18]. At this time there was a significant
difference in ER + ve breast cancer incidence with a hazard
ratio of 0.61. No significant difference was noted in the risk of
other breast cancer subtypes or in overall survival. This result
is not surprising, given the small sample size and the predict-
ably low event rate in a cohort of relatively young (median
age 47), normal risk women.
The NSABP-P1 trial [19, 23] which commenced in 1992
was much larger (over 13,000 women) and recruited high-­risk
women (either as a result of age over 60 or according to Gail
criteria) to 5 years of tamoxifen or placebo with a primary end
point of breast cancer incidence and secondary end points of
breast cancer death, all causes of death and treatment-related

..      Table 8.1  Overview of randomised trials comparing breast cancer chemoprevention agents and placebo

Name Menopausal Risk setting Key trials Significant Side effects

status breast cancer
risk reduction

SERM

Tamoxifen Pre and post High risk and normal NSABP-P1, IBIS-1, Yes, ER+ only Thromboembolism,
population risk Marsden, Italian endometrial cancer, hot
flushes

Raloxifene Post Normal population risk MORE, CORE, RUTH Yes, ER+ only Thromboembolism,
with osteoporosis or endometrial cancer, hot
CHD flushes

Lasofoxifene Post Normal population risk PEARL Yes, ER+ only Thromboembolism,
with osteoporosis endometrial cancer, hot
flushes

Arzoxifene Post Normal population risk GENERATIONS Yes, ER+ only Thromboembolism,
with osteoporosis endometrial cancer, hot
flushes

Aromatase Inhibitor

Anastrozole Post High risk IBIS-II Yes, ER+ only Joint pains, hot flushes,
loss of bone density

Exemestane Post High risk MAP-3 Yes, ER+ only Joint pains, hot flushes,
loss of bone density

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 82 L. Wyld
side effects. The trial demonstrated a reduction in invasive
breast cancer incidence of 49% at 5  years’ follow-up but no
significant reduction in overall mortality (but only 9 deaths
occurred so the event rate was too low for meaningful analysis
[23]). Treatment-related side effects were increased including
an increased risk of deep venous thrombosis and a doubling of
the rate of endometrial cancer [23]. Subsequent longer-term
follow-up of the P1 trial participants (7 years) confirmed these
findings [19].
The IBIS-I study also recruited a large cohort of high-risk
women and similarly showed a significant reduction in the risk
of ER  +  ve breast cancer which persisted beyond the 5-year
treatment period out to 96 months of follow-up [21]. Again no
survival benefit was seen. Rates of endometrial cancer were
elevated on tamoxifen (RR 1.55). Adjuvant tamoxifen studies
have shown increased endometrial cancer mortality rates and
an association with adverse endometrial cancer biology in
tamoxifen-treated women [24] after 5 years of treatment, so this
8 is not surprising. Rates of thromboembolic disease (DVT, PE,
retinal vein occlusion) were almost doubled in treated women.
These trials did not therefore lead to widespread adoption
of tamoxifen prophylaxis although it was approved by the US
FDA on the basis of the NSABP-P1 data in 1998 [25]. It is
effective in ER + ve breast cancer risk reduction, but the lack
of survival advantage even on long-term follow-up and con-
cerns about significant side effects have made its use contro-
versial. Uptake rates are generally low both within and
outside of trials [26].
Other SERMS
Due to concerns about the adverse effects of tamoxifen, other
SERMs have been evaluated in trials: raloxifene, lasofoxifene
and arzoxifene have been studied in postmenopausal women
often with the dual aim of treating osteoporosis and reducing
breast cancer risk. The first such agent to be evaluated was
raloxifene in the CORE/MORE trial which commenced in
1994 and compared raloxifene with placebo in women at
normal breast cancer risk recruited because they had a diag-
nosis of osteoporosis. It confirmed a significant reduction in
breast cancer risk, confined to ER  +  ve breast cancer (59%
risk reduction) [27]. Side effects were similar to tamoxifen
with a significant increase in thromboembolic events but
lower rates of endometrial cancer than tamoxifen and a sig-
nificant protective effect on bone density.
The RUTH trial also compared raloxifene and placebo in
a trial designed to assess the impact on coronary heart disease
(CHD) in normal breast cancer risk women with a history of
..      Fig. 8.1  Risk management algorithm. The risk level for chemopre-
vention for the USA is a 5-year risk of 1.66 using the Gail risk model or if
LCIS is present. In the UK, it is advised that high-risk women (30%
lifetime risk) should be offered such treatment and moderate-risk
(lifetime risk 17–29%) women should be considered for it. A number of
risk calculation resources are available to assist with these assessments:
the IBIS-11 risk calculator, the BOADICCEA on line algorithm or the Gail
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CHD and found a similar reduced risk of breast cancer after
5  years of treatment with a hazard ratio of 0.56. Again this
was confined to reducing the risk of ER+ breast cancers, and
there was an increased risk of thromboembolic events [28].
The relative efficacies of raloxifene and tamoxifen were
directly compared in the STAR trial (NSABP-P2) which ran-
domised over 19,000 high-risk women to either drug for
5  years. Follow-up at 81  months confirmed that raloxifene
has a better side effect profile than tamoxifen with very little
endometrial cancer risk and a lower DVT risk but was less
effective at breast cancer prevention with a 38% risk reduc-
tion for raloxifene versus 50% for tamoxifen [29].
It is thus clear that raloxifene is effective at breast cancer
risk reduction, less so than tamoxifen, but has a better safety
profile. No study has shown a benefit in overall survival out-
comes so far, as would be expected, as none of the above
studies were powered for this outcome. New agents have
therefore been developed to enhance efficacy and improve
the side effect profile of this drug class.
Lasofoxifene was compared to placebo in the PEARL trial.
This recruited population breast cancer risk women with
osteoporosis [30]. After follow-up of approximately 5 years,
lasofoxifene showed a greater protective effect against breast
cancer than either tamoxifen or raloxifene (hazard ratio 0.19),
a significant protective effect against vertebral fracture and a
reduced risk of stroke and CHD but an increased risk of
venous thromboembolism. Survival rates were non-signifi-
cantly slightly lower with low-dose lasofoxifene. The drug was
granted European Medicines Agency approval in 2008 but
was never launched clinically, and US FDA approval was
denied in 2009, and the drug is now undergoing further trial
evaluation but is not yet in routine clinical use. Overview of
SERM trials suggests that lasofoxifene may have the highest
efficacy in breast cancer prevention [31].
Most recently, arzoxifene has been assessed in the
GENERATIONS trial [32]. Breast cancer risk reduction was
not as striking as for lasofoxifene, although still significant. Its
efficacy for prevention of osteoporosis was not sufficient to
trigger further commercial development by its manufacturer.
In the UK at present, tamoxifen is the only recommended
agent for use in premenopausal women at moderate or high
breast cancer risk, and raloxifene or tamoxifen is recom-
mended for postmenopausal women (. Fig.  8.1). This is
based on efficacy within trial populations as tamoxifen is the
only agent with proven efficacy in the premenopausal setting.
The other SERMs have only been assessed in postmenopausal
women.
algorithm. Whilst the US guidelines permit calculation of whether
treatment is appropriate at a particular age (based on the 5-year
predicted risk at the time), UK guidelines do not give any recommen-
dation leaving this open to interpretation. There is no trial data to
support tamoxifen use below age 35. Various risk calculator pro-
grammes such as IBIS permit age based 5-year risks to be calculated to
help with this decision
The Role of Breast Cancer Chemoprevention in High-Risk Women
83 8

Moderate/High risk
premenopausal

Under age 35 Over age 35

History of No history of
thromboembolic disease thromboembolic disease
No chemoprophylaxis or personal or family or endometrial cancer or
history enometrial cancer prior hysterectomy

No chemoprophylaxis 5 years of tamoxifen

b
Moderate/High risk
post-menopausal

History of No history of
thromboembolic thromboembolic
disease disease

Consider 5 years of
exemestane or anastrazole Previous hysterectomy Uterus in tact
with appropriate BMD
monitoring

Consider 5 years of Consider 5 years of

tamoxifen raloxifene

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 84 L. Wyld

8.3.2 Aromatase Inhibitors ASCO guidelines, updated in 2013 [39], recommend use
of tamoxifen in premenopausal women over the age of 35
Whilst SERMs act directly by binding to the oestrogen receptor, (there is no trial data on women under this age) or raloxifene
aromatase inhibitors reduce oestrogenic stimulation to breast tis- or exemestane if they are postmenopausal if they have a
sue by reducing systemic oestrogen synthesis. Theoretically they 5-year absolute risk of greater than or equal to 1.66% based
would be expected to reduce the risk of ER+ breast cancer. There on the use of the National Cancer Institute breast cancer risk
have been two large trials to evaluate their efficacy in a risk reduc- assessment tool (Gail model) or have been diagnosed with
tion setting: IBIS-11 (anastrozole) and MAP-3 (exemestane). lobular carcinoma in situ. A past history of DVT, stroke, TIA
The potential benefit of aromatase inhibitors for breast or a personal or familial risk of endometrial cancer would
cancer prevention was first suggested by the ATAC study, contraindicate use of tamoxifen. Raloxifene is not contrain-
comparing adjuvant tamoxifen versus anastrozole, in women dicated by a history of endometrial cancer. In the UK, the
with early ER-positive breast cancer. This demonstrated a National Institute for Health and Care Excellence (NICE) has
greater percentage reduction in rates of new primary cancers also recommended use of tamoxifen or raloxifene for risk
in women taking anastrozole compared with tamoxifen [33]. reduction in high- and moderate-risk women depending on
Consequently the drug was evaluated in the purely risk-­ their risk of side effects and their menopausal status [40]. A
reducing setting. The IBIS-II trial was launched to evaluate summary of risk management is shown in . Fig. 8.1.  

the role of 5  years of anastrozole versus placebo in almost

8 4000 high-risk women based either on their family history or
the presence of atypias or DCIS (if treated by unilateral mas- 8.5 Risk Stratification Techniques
tectomy). The trial demonstrated a significant risk reduction
for breast cancer compared to placebo with a hazard ratio of Breast cancer risk calculation for women is a complex process
0.47. The benefit was confined to ER  +  ve breast cancers. with multiple factors interacting including the woman’s age,
Once again there was no overall survival difference, but very her family history, gene test results (if available), lifestyle fac-
few deaths had occurred at the time of first publication (at tors (such as obesity, HRT use, reproductive history) and
7  years’ follow-up). Adverse effects included arthralgia and whether she has been diagnosed with an atypia or a previous
hot flushes. Women on anastrozole demonstrated a small invasive or non-invasive cancer. Deciding about which risk
percentage reduction in bone mineral density during the reduction strategy is appropriate and acceptable for an indi-
study, and this could be prevented by co-administration of a vidual woman may be helped by the use of a range of tools such
bisphosphonate in a bone protection sub-study nested within as the IBIS-II risk calculator [41], the BOADICEA risk tool
the main protocol [34]. [42] and the Gail model [43] on line tool, all of which are easily
The aromatase inhibitor exemestane has also been evalu- assessable and factor in familial issues and/or lifestyle issues to
ated in the primary prevention setting in the MAP-3 trial [35]. varying degrees. There is also increasing interest in more com-
Findings confirmed a significant breast cancer risk reduction. plex risk estimation using multigene arrays or gene signatures
The drug was generally well tolerated with a small negative [44] (single nucleotide polymorphisms) either alone or com-
impact on quality of life [36] and little difference in compli- bined with mammographic breast density scores [45]. In addi-
ance rates between the exemestane and placebo groups sug- tion there are now specially developed decision support
gesting good patient tolerability. Again no survival difference algorithms to inform about relative risks and benefits of using
has yet been observed, but again the event rate is still low. chemoprevention drugs [46]. One such online tool is
iPREVENT [47] which allows integration of risk derived using
the IBIS-II or BOADICEA tools and the impact of various risk
8.4 Indications for Chemoprevention reduction strategies (risk-reducing surgery, chemoprevention,
screening) for presentation to the patient in an easy-to-read
The use of chemoprevention is somewhat controversial with format. Tools such as this may help women weigh up the often
some arguing that no trials have yet shown a survival advan- complex issues and trade-offs involved in making these choices.
tage, and therefore such drug treatment is unwarranted until
this has been directly proven [37]. There are justified con-
cerns about the adverse effects of tamoxifen in this setting 8.6 Agents Targeting Non-oestrogenic
and concerns about low compliance and uptake. However Pathways
agents that reduce the risk of ER + ve breast cancer will inev-
itably need to have long follow-up and very large sample sizes Non-oestrogen-sensitive subtypes of breast cancer are not
to be powered for survival outcomes due to the low death rate prevented by use of SERMs, AIs or oophorectomy, and,
and prolonged disease-free survival of these cancers [9]. It although less common than ER+ cancers, they have a dispro-
has been estimated that chemoprophylaxis may ultimately portionate impact on mortality rates as they carry a worse
result in an 18% mortality reduction once very long-term prognosis. They include Her2-positive cancers and triple-­
follow-up of prevention trials is available [38]. negative cancers. A number of strategies have been explored

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The Role of Breast Cancer Chemoprevention in High-Risk Women
to reduce their incidence and these are reviewed below. None
of these are in clinical practice at present, some are undergo-
ing clinical trials and some are at the preclinical stage.
8.6.1 Cox-2 Inhibitors
These have been the focus of numerous studies to prevent
cancers of various types, with the main focus being colorectal
polyps in patients with hereditary polyposis syndromes.
There is also some evidence to support their efficacy in reduc-
ing the risk of breast cancer, including ER-ve subtypes. A
large case control study found significantly reduced breast
cancer rates in women on NSAIDs and even more so in selec-
tive COX-2 inhibitors with a risk reduction of 46% seen with
rofecoxib [48]. Meta-analysis of these clinical studies, which
included data on nearly 3 million women given either aspirin
or other non-specific NSAIDS or selective COX-2 inhibitors,
indicated that a relative breast cancer risk reduction of 0.88 is
achieved [49]. There is also laboratory-based evidence in
murine studies showing reduced rates of tumour develop-
ment in animals treated with COX-2 inhibitors [50]. Clinical
trials have however been halted following evidence of cardiac
toxicity in some patients on COX-2 inhibitors.
Metformin
Metformin is widely used to treat type 2 diabetes where it
acts to induce uptake of glucose into muscle so lowering
blood glucose levels. There is evidence that the drug may
have wide-ranging impacts on various components of the
regulatory machinery of the cancer cell, either directly or
indirectly [51] so may potentially be effective across the
breast cancer subtype spectrum. As yet there have been no
randomised trials of clinical efficacy in the risk reduction set-
ting, but meta-analysis of cohort and case control studies has
suggested a risk reduction of 0.83 (0.71–0.97) [52] which was
significant, but other studies have found only a modest non-­
significant trend in favour of the drug [53]. There are the
usual caveats about bias in observational studies and so ran-
domised trials would be needed, although the modest effect
size likely to be seen suggests such a trial might need to be
prohibitively large and with very long follow-up. Several
smaller prevention trials looking at surrogate end points in
high-risk women are currently ongoing [54].
8.6.2 Retinoids
Retinoids are synthetic vitamin A derivatives and have been
studied for efficacy in breast cancer prevention for the past 2
decades. Probably the earliest trial was carried out in a cohort
of 3000 women with previous early breast cancer randomised
to fenretinide or placebo (secondary prevention). Whilst
showing no effect overall, in premenopausal women it showed
a significant risk reduction in the incidence of new primary
rares1geo@gmail.com
85 8
breast cancers (relative risk 0.62, 95% CI, 0.46–0.83) [55].
Risks were slightly increased in postmenopausal women. At
present in the primary prevention setting, there is insufficient
evidence to support their use.
8.6.3 PARP Inhibitors
Poly ADP-ribose polymerase inhibitors (PARP inhibitors,
olaparib, veliparib) are effective drugs for treating BRCA
mutant breast cancers and have been shown in a BRCA1
mutant mouse model to delay the onset of breast cancer sig-
nificantly and improve survival [56]. It is far too soon to say
whether this will translate into clinical use as a risk reduction
strategy.
8.6.4  pidermal Growth Factor Receptor
E
(EGFR)-Directed Therapies
The drugs gefitinib and lapatinib have been evaluated in ani-
mal models and found to delay development of ER-negative
tumours significantly [5]. There are presently no human tri-
als underway.
8.7 Summary
With the relentless increase in rates of breast cancer in the
developed world, strategies to reduce the burden of this disease
are urgently needed. There is good evidence to support the use
of SERMS and AIs in reducing rates of ER + ve breast cancer,
but both drug classes are associated with side effects which may
limit their use. Active research is ongoing to search for new
agents to reduce risks with better side effect profiles and for
agents to reduce the risks of non-oestrogen-­sensitive cancers.
Key Points
1. Significant breast cancer risk reduction may be
achieved with use of 5 years of SERMS or aromatase
inhibitors in postmenopausal women.
2. Tamoxifen is the only agent proven in trials to be
effective in premenopausal women.
3. Benefits must be weighed against the side effects
of thromboembolic disease and endometrial
cancer for SERMS and osteoporosis for aromatase
inhibitors.
4. Serms and ais only act to reduce risks of ER+ve
breast cancer.
5. New agents are under evaluation to reduce risks of
other subtypes with NSAIDS and metformin
showing some promise.
6. No agent has yet demonstrated a survival
­advantage.
 86 L. Wyld

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 89 9

Molecular Profiling of Breast

Cancer and DCIS
Christos Markopoulos

9.1 Introduction – 90

9.2 Multigene Assays in Invasive Breast Cancer:

Prognostication – 90
9.2.1 Oncotype DX Breast Recurrence Score Assay – 90
9.2.2 MammaPrint – 91
9.2.3 Prosigna (PAM50) – 92
9.2.4 EndoPredict – 93
9.2.5 Breast Cancer Index – 93
9.2.6 Insight Dx Mammostrat – 93
9.2.7 Breast IHC4 Assay – 93

9.3 Prediction of Adjuvant Chemotherapy Benefit – 93

9.4 Prediction of Chemotherapy Benefit in the 

Neoadjuvant Setting – 95

9.5 Inclusion in International BC Treatment Guidelines – 95

9.6 Concordance of Risk Assignment by Different Tests – 95

9.7 Decision Impact and Cost-Benefit Analysis – 96

9.8 Molecular Profiling and Tools for DCIS – 96

9.8.1 Clinical Management Uncertainties – 96
9.8.2 The Oncotype DX Breast DCIS Score – 96

9.9 Future Tools – 97

9.10 Conclusions – 97

References – 97

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_9

rares1geo@gmail.com
 90 C. Markopoulos

9.1 Introduction ultimate goal in using these MGAs is to offer chemotherapy

only to patients who are likely to benefit from it while sparing
The last decade has witnessed a dramatic shift in the way we other patients an unnecessary treatment.
perceive breast cancer (BC). It is no longer regarded as a
single disease entity with varying histological features and
clinical behaviours but rather as a heterogeneous group of 9.2  ultigene Assays in Invasive Breast
M
diseases characterised by distinct molecular profiles. Initial Cancer: Prognostication
cDNA microarray analyses revealed several intrinsic BC sub-
types [1, 2]; and subsequent studies using a variety of molec- Since 2004, several MGAs have become available to clini-
ular approaches (e.g. genomic DNA copy number arrays, cians treating early-stage invasive BC. This chapter discusses
DNA methylation analysis, exome sequencing) have demon- seven such MGAs: Oncotype DX® Breast Recurrence Score
strated a more complex picture with significant heterogeneity Assay (21-gene assay), MammaPrint® (70-gene panel,
within each intrinsic subtype [3]. «Amsterdam Signature»), Prosigna® (PAM50), EndoPredict®
The realisation that BC is not a single entity and that mul- (EP/EPclin Scores), Breast Cancer IndexSM, Insight® Dx
tigene assays (MGAs) can provide insights regarding tumour Mammostrat® and the Breast IHC4 Assay (. Table 9.1).
 

biology has transformed treatment decision-making in early-­

stage BC. While until approximately a decade ago, clinicians
based their treatment recommendations on traditional clini-
copathological prognostic factors such as age, lymph node
status, tumour size and grade, as well as on single-gene
9 molecular analysis such as oestrogen receptor (ER) and
human epidermal growth factor receptor 2 (HER2), nowa-
days, an increasing number of clinicians are also making use
of molecular-based MGAs to gain prognostic and predictive
(i.e. indicative of benefit to chemotherapy) information in
order to guide adjuvant treatment decisions (. Fig. 9.1). The  
Clinico-pathological characteristics
1970s
Increased complexity of molecular input over time
9.2.1  ncotype DX Breast Recurrence Score
O
Assay
The Recurrence Score assay is a quantitative real-time reverse
transcriptase polymerase chain reaction (qRT-PCR)-based
assay performed on RNA extracted from formalin-fixed
paraffin-embedded (FFPE) tissue samples, which was devel-
oped using three cohorts of patients with early BC and long-­
term follow-up [4, 5]. The assay, which is performed in a
central laboratory, provides a Recurrence Score result (range,
0–100), based on expression of 21 genes (16 cancer-related, 5
reference genes), which represents a point estimate of the
10-year risk of distant recurrence [4, 5]. The Recurrence
Score result is used to categorise patients into three
Recurrence Score groups: low, intermediate and high

(. Table 9.2) [4, 5].

 

Single-gene analysis (ER, PR, HER2) The assay was analytically validated [6] and then clini-
cally validated as a prognosticator [4, 5, 7–10] according to
2004 published guidelines for biomarker validation [11, 12]. The
prognostic utility of the assay in ER+ node-negative early BC
Multi-gene assays (up to ~100 genes) patients treated with endocrine therapy alone was validated
in four prospective studies, all of which used archival FFPE
2010s tissue samples: analysis of patients receiving 5  years of
tamoxifen in the National Surgical Adjuvant Breast and
Next-generation sequening of cancer gene
panels (up to ~several hundred genes)
Bowel Project (NSABP) trial B14 study, analysis of node-­
negative patients in transATAC (the translational arm of the
ATAC trial), the Kaiser Permanente case-control study and
Whole exome sequencing
(all coding regions of known the Japan BC Research Group cohort study [4, 7–9]. The
genes: ~3´107 base pairs) assay was also validated in node-positive patients (in node-­
positive patients in transATAC and the tamoxifen-treated
Whole genome sequencing arm in the Southwest Oncology Group study [SWOG] 8814)
(~3´109 base pairs) [7, 10]. Notably, the Recurrence Score result predicts late
recurrence (beyond 5  years) [13], which has become clini-
cally relevant with the recent evidence for the benefit of
10 years of tamoxifen treatment in ER+ patients [14, 15].
Several recent outcome studies with consistent results have
further validated the Recurrence Score assay. The ongoing Trial
Assigning Individualized Options for Treatment (TAILORx)
..      Fig. 9.1  The increasing complexity of clinical decision-making in phase III study examines the non-inferiority of endocrine treat-
early-stage breast cancer ment alone vs endocrine therapy plus ­ chemotherapy in

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Molecular Profiling of Breast Cancer and DCIS
91 9

..      Table 9.1  Overview of currently available multigene assays in breast cancer

Assay Manufacturer Tissue Technological Number of genes Indication (patient/

sample platform tumour
characteristics)a

Oncotype DX Genomic Health, Inc., FFPE tissue qRT-PCR 21 HR+

Breast Recur- Redwood City, CA (16 cancer-related HER2-negative
rence Score and 5 reference genes)
Assay

MammaPrint Agendia BV, Fresh Microarray 70 Tumour size ≤5 cm

Amsterdam, The frozen /
Netherlands FFPE tissue

Prosigna NanoString FFPE tissue Hybridisation-based 58 Postmenopausal

(PAM50) Technologies Inc., (for the Prosigna (50 classifiers HR+
Seattle, WA assay) and 8 reference genes)

EndoPredict Sividon Diagnostics, FFPE tissue qRT-PCR 11 HR+

Cologne, Germany (8 cancer-related HER2-negative
and 3 reference genes)

Breast Cancer bioTheranostics, Inc., FFPE tissue qRT-PCR 2 independent biomarkers: ER+
Index San Diego, CA the HOXB13:IL17BR ratio Node-negative
and a 5-gene molecular
grade index

Insight Dx Clarient Diagnostic FFPE tissue IHC 5 ER+

Mammostrat Services, Inc.,
Aliso Viejo, CA

Breast IHC4 Assay is performed at FFPE IHC 4 ER+

Assay local laboratories

Abbreviations: ER oestrogen receptor, FFPE formalin-fixed, paraffin-embedded, HER2 human epidermal growth factor receptor 2, HR
hormone receptor, IHC immunohistochemistry, qRT-PCR quantitative reverse transcriptase polymerase chain reaction
aIf not stated otherwise, the assay is indicated for both node-negative and node-positive patients, all ages, etc

­ode-negative hormone receptor (HR)  +  patients with

n early BC who have had surgery, no systemic therapy, and
Recurrence Score results of 11–25. All patients with scores >25 long-term follow-up [20]. MammaPrint, which is performed
received endocrine therapy plus chemotherapy, and those with by a central laboratory (in the Netherlands/USA), is
scores <11 received only endocrine therapy. Only findings from microarray-­based and assesses the expression of genes that
the non-randomised arm with patients with results <11 have regulate the cell cycle, invasion, metastasis and angiogenesis
been reported thus far, and they show that these patients have to classify patients as having either a good or poor prognosis
excellent clinical outcomes (rate of freedom from distant recur- (. Table 9.2) [20].
 

rence at 5 years, 99.3%; overall survival at 5 years, 98.0%) [16].
The TAILORx findings are consistent with results from the
endocrine therapy-only-­treated patients (node-positive/high-
risk node-negative) with Recurrence Score results ≤11  in the
West German Study Group (WSG) Plan-B study [17]. In addi-
tion, two recently presented large cohort studies (the Clalit study
and the Surveillance, Epidemiology, and End Results [SEER]-
based analysis) confirm and extend the results of TAILORx and
WSG Plan-B by demonstrating excellent clinical outcomes in
node-negative low (<18) Recurrence Score patients [18, 19].
9.2.2 MammaPrint
MammaPrint is a 70-gene expression profile signature devel-
oped using a cohort of 78 patients <55  years with ER+,
HER2-negative or HER2-positive, as well as triple-negative
MammaPrint was first validated with fresh frozen tissue
samples from the tumour bank of the Netherlands Cancer
Institute [21]. Several additional validation studies (using
various cohorts) followed (i.e. the TRANSBIG Consortium,
which was an independent validation study, the prospective
MicroarRAy PrognoSTics in Breast CancER study [RASTER]
and hospital tissue banks including the Massachusetts
General Hospital) [22–29]. Subsequently, the assay has also
been optimised and analytically validated for FFPE tissue,
and equivalence to the assay on fresh frozen tissue was dem-
onstrated [30].
Primary analysis from the prospective MINDACT study
(Microarray In Node-negative and 1–3 positive lymph node
Disease may Avoid ChemoTherapy study) has recently been
presented [31]. MINDACT included patients with all BC
phenotypes and investigated whether patients classified as
low-risk by MammaPrint can be spared chemotherapy. Only

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 92 C. Markopoulos

..      Table 9.2  Summary of the utility of currently available multigene assays in breast cancer

Assay Patient classification Prognosis Prediction of Prediction of Prediction of

late recurrence adjuvant neoadjuvant
chemotherapy chemotherapy
benefit benefit

Oncotype DX Low-risk (score <18) Yes Yes Yes Yes

(Recurrence Score) Intermediate-risk (score,
18–30)
High-risk (score ≥31)

MammaPrint Low-risk Yes No No Yes

High-risk

Prosigna (PAM50)a Node-negative: Yes Yes No Yes

(risk of recurrence   Low-risk (score, 0–40)
[ROR], Prosigna score)   Intermediate-risk (score,
41–60)
  High-risk (score, 61–100)
1–3 positive nodes:
  Low-risk (score, 0–40)
  High-risk (score, 41–100)

9 EndoPredict (EP and EP: Yes Yes No Yes

EPclin scores)   Low-risk (score <5)
  High-risk (score ≥5)
EPclin:
  Low-risk (score <3.3)
  High-risk (score ≥3.3)

Breast Cancer Index Low-risk (score <5) Yes Yes No Yes

Intermediate-risk (score,
5–<6.4)
High-risk (score ≥6.4)

Insight Dx Mam- Low-risk (score ≤0) Yes No No No

mostrat (prognostic Medium-risk (score,
index) 0–<0.7)
High-risk (score ≥0.7)

Breast IHC4 Assay Low-risk Yes No No Yes

High-risk

Abbreviations: H:I HOBXB13:IL17BR

aAlso provides intrinsic subtype classification

those whose MammaPrint risk assessment was discordant
with their Adjuvant! Online (a tool that assesses risk based
on clinical factors)-based risk assessment were randomised
to receive or not receive chemotherapy. The first results from
MINDACT suggest that patients with high-risk according to
Adjuvant! Online and low-risk according to MammaPrint
have excellent clinical outcomes without adjuvant chemo-
therapy [31], thus further validating (level 1A evidence)
MammaPrint as a prognosticator and thus allowing women
to be spared chemotherapy in 14% of the tested population.
technique to assess 58 genes (50 cancer-related, 8 reference
genes) [32]. The assay can be performed locally (using the
Nanostring nCounter DX Analysis System) and provides a BC
intrinsic subtype based on the similarity of gene expression to
prototypical expression and risk of recurrence (ROR) score
(Prosigna score; range, 0–100), which is calculated based on a
subset of 54 genes (46 cancer-related, 8 reference genes), a pro-
liferation score and the tumour size. The ROR score is used to
classify node-negative patients into low-, intermediate- and
high-risk groups, and node-positive (1–3 positive nodes)
patients into low- and high-risk groups [32] (. Table 9.2).

The Prosigna assay was first validated as a prognosticator

9.2.3 Prosigna (PAM50)
The Prosigna assay, performed on RNA extracted from FFPE
tissue, is based on PAM50 (a 50-gene set originally developed
to classify intrinsic BC subtypes [1]) and uses a hybridisation
using samples from ER+ endocrine therapy-treated post-
menopausal patients with node-negative/node-positive early
BC in the Austrian Breast and Colorectal Cancer Study
Group (ABCSG)-8 trial [33]. Several additional validation
studies included samples from transATAC, transATAC plus

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Molecular Profiling of Breast Cancer and DCIS
ABCSG-8, and the NCIC CTG MA2.1 trial [34–36]. The
ROR score was shown to predict early (years 0–5) and late
(years 5–10) recurrence in a dataset from the transATAC trial
(including node-negative and node-positive patients) [37].
9.2.4 EndoPredict
EndoPredict is an 11-gene (8 cancer-related, 3 reference genes)
qRT-PCR-based assay performed on RNA extracted from FFPE
tissue. The assay, which can be performed by local laboratories,
calculates a continuous risk score, EP (range, 0–15) [38]. When
combined with nodal status and tumour size, an EP clinical
score (EPclin) is calculated. The EP and EPclin scores are used
to classify postmenopausal ER+ HER2-negative early BC
patients who are treated with endocrine therapy into low- and
high-risk groups (. Table 9.2) [38]. EndoPredict was validated
independently using archived samples from two randomised
trials (ABCSG-6 and ABCSG-8) [38]. Additional analyses on a
cohort including patients from these two randomised trials
who were treated with endocrine therapy for only 5 years dem-
onstrated that EP and EPclin were predictive of both early (first
5 years) and late (years 5–10) risk of recurrence [39].
9.2.5 Breast Cancer Index
The Breast Cancer Index is a qRT-PCR-based assay per-
formed on RNA extracted from FFPE samples. The assay is
performed by a central laboratory and provides a Breast
Cancer Index score, which is calculated by combining 2 sig-
natures: a two-gene ratio, HOBXB13:IL17BR (H:I) in which
the 2 genes are independent biomarkers, and a molecular
grade index (MGI) that includes 5 genes related primarily to
proliferation [40]. The Breast Cancer Index was developed
because the MGI and the H:I ratio were shown to provide
complementary prognostic information [40]. The Breast
Cancer Index is a continuous score (range, 0–10) that is used
to classify patients into low-, intermediate- and high-risk
groups (. Table 9.2) [41]. The continuous score was validated
in patients from the prospective Stockholm trial, an institu-
tional cohort (University of Pittsburgh Medical Center) and
in a case-control study conducted among Kaiser Permanente
patients [41–43]. Analyses using patients from the Stockholm
trial and the transATAC study demonstrated that the Breast
Cancer Index can also predict late (years 5–10) distant recur-
rences in ER+ node-negative patients [44, 45].
9.2.6 Insight Dx Mammostrat
Mammostrat is an immunohistochemistry (IHC)-based assay
performed on FFPE samples that measures levels of five bio-
markers (SLC7A5, HTF9C, p53, NDRG1, and CEACAM5),
which are independent of one another and do not directly
measure proliferation or HR status. These markers were iden-
tified as the minimal panel able to predict recurrence risk in a
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93 9
discovery cohort and validated in node-negative ER+ patients
in two initial independent cohorts [46]. The assay provides a
risk score that is used to classify patients into low-, medium-
or high-risk groups (. Table  9.2) [46]. The assay was then
validated using samples from patients with ER+ endocrine
therapy-treated node-negative and node-­positive disease in
institutional cohorts, in the NSABP B14 and B20 trials, as well
as in the Tamoxifen versus Exemestane Adjuvant Multicenter
(TEAM) phase III trial [47–50]. Analyses assessing the per-
formance of the assay over time using patients from the
Edinburgh Breast Conservation Series and the TEAM trial
showed that the prognostic utility of Mammostrat is limited
to early recurrences (first 5 years) [51].
9.2.7 Breast IHC4 Assay
The IHC4 assay evaluates levels of four biomarkers by IHC
including ER, progesterone receptor (PR), Ki-67 and HER2 on
FFPE samples and can be performed in local pathology labo-
ratories. The assay provides an IHC4 score and can be com-
bined with clinicopathological information on nodal status,
tumour size, grade, age and type of endocrine treatment to
provide a more powerful prognosticator (IHC4 + C) [52]. The
assay was developed using patients from the transATAC study
and validated as a prognosticator in a second separate cohort
[52]. As in Mammostrat, an analysis assessing the performance
of the assay over time (using the Edinburgh Breast Conservation
Series and the TEAM trial) showed that the prognostic utility
of IHC4 is only for early recurrences (first 5 years) [51]. As the
assay is performed at local laboratories, known issues with pre-
cision/reproducibility of IHC testing present a challenge that
has yet to be overcome, although a very recent UK study com-
paring four centres suggested that IHC4  +  C is tolerant of
variation in staining and scoring methods [53].
9.3  rediction of Adjuvant Chemotherapy
P
Benefit
The ability of an assay to predict adjuvant chemotherapy benefit
can be determined in appropriately designed prospective trials
or in archived samples from clinically relevant prospective ran-
domised trials by using a statistical test for the interaction
between chemotherapy treatment and risk group classification.
The predictive ability of Oncotype DX in ER+ early BC
patients was tested using archival samples from the ran-
domised NSABP B20 (node-negative patients) and SWOG
8814 (node-positive patients) studies [10, 54]. In both stud-
ies, high Recurrence Score patients derived a large benefit
from chemotherapy (NSABP B20, 10-year distant recurrence-­
free [DRF] rates of 88% vs 61%; SWOG 8814, 10-year
disease-­free survival [DFS] rates of 55% vs 43%); low
Recurrence Score patients derived minimal, if any, benefit
(NSABP B20, 10-year DRF rates of 96% vs 97%; SWOG 8814,
10-year DFS rates of 64% vs 60%) [10, 54]; and the statistical
test for interaction between the Recurrence Score result and
 94 C. Markopoulos

chemotherapy treatment was significant. Also, in both stud-
ies, intermediate Recurrence Score patients did not derive a
significant benefit from chemotherapy, although a clinically
relevant effect could not be ruled out [10, 54]. The question
of whether intermediate Recurrence Score patients (scores,
11–25) benefit from adjuvant chemotherapy is being
addressed in the randomised arm of the ongoing TAILORx
study (results are expected in 2017).
MammaPrint was evaluated in samples from a pooled
study series (not a randomised trial) where tissue samples
were not reanalysed [27]. The study showed that in the
MammaPrint high-risk group, breast cancer-specific survival
and distant disease-free survival were significantly longer for
patients treated with endocrine therapy plus chemotherapy
vs those treated with endocrine therapy alone, whereas for
the low-risk group, this difference was not statistically sig-
nificant [27]. Nonetheless, the interaction test for survival
was nonsignificant [27], suggesting that the assay is not pre-
dictive. The MINDACT study (from which first results have
just been presented [31]) was not specifically designed to
evaluate the predictive ability of MammaPrint [55].
Mammostrat was evaluated using samples from NSABP
B20; however, the interaction test was not significant [47].
The ROR was studied using samples from the prospective
NCIC CTG MA2.1 trial, which randomised patients to dif-
ferent chemotherapy regimens including doxorubicin, cyclo-
phosphamide and paclitaxel; dose-intense cyclophosphamide,
epirubicin and fluorouracil; and dose-dense, dose-intense
epirubicin, cyclophosphamide and paclitaxel (i.e. all arms
involved chemotherapy treatment). The study found that the
ROR was not predictive of treatment benefit; however, this
study compared different chemotherapy regimens and did
not have a non-chemotherapy arm [36].
In conclusion, at present, the Oncotype DX Recurrence
Score assay is the only assay included as a predictive assay in
international BC guidelines (. Table 9.3).

9 ..      Table 9.3  Summary of inclusion of multigene assays in international guidelines for breast cancer treatment

St. Gallen 2015 [68] ESMO 2015 [69] ASCO 2016a [70] NCCN (version
1.2016) [71]

Oncotype DX Majority endorsement for Included as a tool Panel found sufficient evidence Included as the
prognostic (first 5 years, the that may help in to support clinical utility best-validated
panel was divided almost treatment (evidence for the recommenda- prognostic and
equally about prognostic decisions tion, high-­quality; strength of predictive factor
value beyond 5 years) and the recommendation, strong)
predictive utility

MammaPrintb Majority endorsement for Included as a tool —c Acknowledged as a

prognostication (first 5 years that may help in clinically validated
only). No majority endorse- treatment prognosticator
ment for predictive utility decisions

Prosignab Majority endorsement for
prognostication (first 5 years
and beyond). No majority
endorsement for predictive
utility
Included as a tool Panel found sufficient evidence Acknowledged as a
that may help in to support clinical utility clinically validated
treatment (evidence for the recommenda- prognosticator
decisions tion, high-­quality; strength of
the recommendation, strong)

EndoPredict Majority endorsement for
prognostication (first 5 years,
the panel was divided almost
equally about prognostic
value beyond 5 years). No
majority endorsement for
predictive utility
Included as a tool Panel found sufficient evidence —
that may help in to support clinical utility
treatment (evidence for the recommenda-
decisions tion, intermediate-­quality;
strength of the recommenda-
tion, moderate)

Breast Cancer Index Majority endorsement for
prognostication (first 5 years,
the panel was divided almost
equally about prognostic
value beyond 5 years). No
majority endorsement for
predictive utility
— Panel found sufficient evidence —
to support clinical utility
(evidence for the recommenda-
tion, intermediate-­quality;
strength of the recommenda-
tion, moderate)

Abbreviations: ASCO American Society of Clinical Oncology, ESMO European Society for Medical Oncology, FDA Food and Drug Administra-
tion, FFPE formalin-fixed, paraffin-embedded, NCCN National Comprehensive Cancer Network
aMammaPrint, Mammostrat and IHC4 were considered and their use was not supported by the ASCO panel
bReceived US FDA clearance. Note that MammaPrint received FDA clearance for the assay using fresh frozen samples and more recently on

the assay that uses FFPE sample

cThe panel awaits results of the prospectively conducted MINDACT

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Molecular Profiling of Breast Cancer and DCIS
9.4 Prediction of Chemotherapy
Benefit in the Neoadjuvant
Setting
The ability of an assay to predict response to neoadjuvant
therapy is clinically relevant, as for some patients, ­neoadjuvant
chemotherapy may be an «overtreatment». The Recurrence
Score assay was assessed in four neoadjuvant studies, in
which pathological complete responses (pCR) were observed
95 9
9.5 I nclusion in International BC Treatment
Guidelines
MGAs have been included in international BC treatment
guidelines for approximately a decade. At present, Oncotype
DX is included in all major international guidelines [68–71],
whereas the other MGAs are included in some of them. There
are also differences in the endorsement of MGAs with respect
to the clinical utility of the assays (. Table  9.3). National

only in intermediate/high Recurrence Score patients [56–59], guidelines also differ in their endorsement of MGAs.
suggesting a role for the Recurrence Score in this setting.
MammaPrint was also evaluated in four neoadjuvant studies 9.6  oncordance of Risk Assignment by
C
investigating MammaPrint alone or in combination with the
Different Tests
80-gene BluePrint® molecular subtyping assay (Agendia), all
of which demonstrated that tumours with high-risk by
The increasing use of MGA in BC and the growing number
MammaPrint were more sensitive to neoadjuvant chemo-
of available MGAs led to an interest in comparing risk clas-
therapy [60–63]. One study each for the Prosigna,
sifications on the same tumour samples using different
EndoPredict, Breast Cancer Index and IHC4 assays has
MGAs. Several such studies have recently been published/
recently been published suggesting that these assays can also
presented, comparing Oncotype DX classification to those by
predict response to neoadjuvant chemotherapy [64–67]. No
MammaPrint, Prosigna and EndoPredict, as well as one
Mammostrat studies in this setting have been published to
study comparing three MGAs (PAM50, Oncotype DX, and
date.
IHC4) in patients from the transATAC trial (. Table  9.4)  

..      Table 9.4  Direct comparison of risk classification by different multigene assays

Study (reference) Assays compared Number of samples Main results

included

Poulet [72] Oncotype DX 67 In the low-risk group by MammaPrint: 66%, 31% and 3% were low-,
MammaPrint intermediate- and high-risk by Oncotype DX, respectively
In the high-risk group by MammaPrint: 45%, 50% and 5% were low-,
intermediate- and high-risk by Oncotype DX, respectively

Denduluri [73] Oncotype DX 53 In the low-risk group by MammaPrint: 77%, 18% and 5% were low-,
MammaPrint intermediate- and high-risk by Oncotype DX, respectively
In the high-risk group by MammaPrint: 39%, 45% and 16% were low-,
intermediate- and high-risk by Oncotype DX, respectively

Alvarado [74] Oncotype DX 52 In the low-risk group by Prosigna: 79%, 18% and 4% were low-,
Prosigna intermediate- and high-risk by Oncotype DX, respectively
In the intermediate-­risk group by Prosigna: 65%, 29% and 6% were
low-, intermediate- and high-risk by Oncotype DX, respectively
In the high-risk group by Prosigna: 57%, 29% and 14% were low-,
intermediate- and high-risk by Oncotype DX, respectively

Varga [75] Oncotype DX 34 In the low-risk EP score group: 82%, 18% and 0% were low-,
EndoPredict intermediate- and high-risk by Oncotype DX, respectively
In the high-risk EP score group: 26%, 35% and 39% were low-,
intermediate- and high-risk by Oncotype DX, respectively
In the low-risk EPclin score group: 58%, 26% and 16% were low-,
intermediate- and high-risk by Oncotype DX, respectively
In the high-risk EPclin score group: 27%, 33% and 40% were low-,
intermediate- and high-risk by Oncotype DX, respectively

Dowsett [34] Oncotype DX 940b Correlation coefficients for the 3-way comparisons:
PAM50a   Oncotype DX vs IHC4, r = 0.64
IHC4   IHC4 vs PAM50, r = 0.48
  Oncotype DX vs PAM50, r = 0.39

Acs [76] Oncotype DX 106 Correlation coefficient, r = −0.0737

Mammostrat Concordance in risk assignment, 60%

aPerformed using PAM50 not the commercial Prosigna assay

bOf the patients included in the study, 940 had all 3 scores

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 96 C. Markopoulos
[34, 72–76]. All of the studies were consistent in showing dif-
ferences in risk classification between the assays. Overall,
Oncotype DX classified fewer patients as high-risk compared
to the other evaluated assays. Also, a wide range of Recurrence
Score results were observed in each of the risk classifications,
as determined by the comparator MGA.  Thus, these direct
comparisons demonstrate that MGAs do not provide
­interchangeable information.
9.7  ecision Impact and Cost-Benefit
D a reproducible manner [101, 102]. Thus, the common treat-
Analysis
Understanding the impact of MGAs on treatment decisions
is key for health economics (HE) analysis. For the Recurrence
Score assay, over 20 studies (performed all over the world)
have consistently demonstrated that approximately 30% of
treatment decisions that were based on clinicopathological
factors were changed after receiving the Recurrence Score
results, leading to a net reduction in chemotherapy use (for
9 review/meta-analyses and select studies, see [77–81]). The
impact of MammaPrint and Prosigna on adjuvant ­treatment
decisions was demonstrated in two recently published stud-
ies each (MammaPrint, Austrian and South African;
Prosigna, Spanish and German) and that of EndoPredict and
IHC4 + C in one recently published study each (EndoPredict,
German; IHC4  +  C, UK) [82–87]. For the Breast Cancer
Index and Mammostrat, no such studies have been pub-
lished.
MGAs present an opportunity to offer chemotherapy
only to BC patients who are likely to benefit from it and
spare chemotherapy and its associated costs, both direct and
indirect (cost of treatment itself and cost of managing
treatment-­related toxicity), from all other patients. As such,
they have the potential for cost-effectiveness/cost saving.
HE studies were conducted for some of the available MGAs,
particularly for those that have been commercially available
for the longest period (Oncotype DX and MammaPrint).
For Oncotype DX, multiple studies have demonstrated cost-
effectiveness/cost saving (for select studies, see [77, 78, 88–
92]), and for MammaPrint, such studies suggested
cost-effectiveness in the evaluated countries [82, 93–96].
For EndoPredict, a recent HE study showed cost saving
from the perspective of the German healthcare system [97],
and for the Breast Cancer Index, a recent HE study showed
cost saving from a US third-party payer perspective [98].
There are no HE assessments for the other qRT-PCR- or
microarray-based MGAs. IHC-based assays are associated
with considerably lower costs compared to assays using
other platforms. Some HE studies comparing Oncotype DX
to Mammostrat or IHC4 suggest that Mammostrat/IHC4
are more cost-effective than Oncotype DX [99, 100]; how-
ever, the body of evidence supporting IHC-based assays is
still currently limited.
rares1geo@gmail.com
9.8 Molecular Profiling and Tools for DCIS
9.8.1 Clinical Management Uncertainties
There is continuing uncertainty surrounding the optimal
treatment approach in DCIS, stemming from inability to reli-
ably predict local recurrence risk from standard clinicopath-
ological characteristics such as age, tumour size, architectural
growth pattern, grade and the presence of comedonecrosis,
alongside an ongoing challenge to determine DCIS grade in
ment approach (breast-conserving surgery [BCS] followed
by radiotherapy) could well be «overtreatment» in cases
where surgery would have been adequate or where DCIS
would have remained indolent and «under-treatment» in
high-risk patients for whom tamoxifen (for ER+ patients)
and/or mastectomy would have been a better treatment
option [103]. The Van Nuys Prognostic Index (VNPI) was
developed in 1996 [104] and updated in 2003 (University of
Southern California [USC]/VNPI) [105], to serve as a guide
for DCIS treatment using a score based on clinicopathologi-
cal characteristics (age, tumour size, tumour margins and
pathologic classification [i.e. nuclear grade, comedonecro-
sis]). A very recent retrospective longitudinal cohort study
reported that a clinicopathological-based score (characteris-
tics included age, tumour size and nuclear grade) is predic-
tive of survival benefit conferred by radiotherapy following
BCS, although further study is warranted [106]. Notably,
integration of gene expression information such as Genomic
Grade Index (as a replacement for nuclear grade) into USC/
VNPI improved its prognostic value, while integrating Ki-67
levels did not [107].
MGAs have not yet been as broadly investigated for pos-
sible clinical utility in treatment decisions (e.g. need for mas-
tectomy or radiotherapy) in DCIS patients as they have in
patients with invasive BC.  At present, the Oncotype DX
Breast DCIS Score is the only MGA available to refine risk
assessment and guide treatment decisions in DCIS.
9.8.2 The Oncotype DX Breast DCIS Score
The Oncotype DX Breast DCIS Score, which uses the
Oncotype DX qRT-PCR platform, was developed based on
five datasets (including DCIS and invasive carcinoma data)
[108]. The assay measures the expression of 12 of the 21
genes used in the Oncotype DX Breast Assay (for invasive
cancer). These include 7 cancer-related genes (5 prolifera-
tion genes, PR and GSTM1) and 5 reference genes used for
normalisation [108]. The DCIS Score algorithm uses nor-
malised gene expression to calculate the DCIS Score
(range, 0–100), which represents the 10-year risk for local
recurrence (DCIS or invasive carcinoma) and the 10-year
risk for developing local invasive carcinoma. The DCIS
Molecular Profiling of Breast Cancer and DCIS
Score is used to categorise patients into low (score <39),
intermediate (score, 39–54) and high (score ≥55) DCIS
risk groups [108].
The DCIS Score has been validated as a prognosticator in
two studies. The first was a prospective-retrospective study
[108] using archived samples from patients in the Eastern
Cooperative Oncology Group (ECOG) E5194 study, which
evaluated local recurrence rates in DCIS patients treated with
BCS alone [109]. The second study (population-based, con-
ducted by the Ontario DCIS group in Canada) involved a
real-world cohort of DCIS patients who had BCS alone and
negative margins [110]. In both studies, the DCIS Score
result was statistically significantly associated with the risk
for any local recurrence (E1594: hazard ratio [HR], 2.31
[adjusted for tamoxifen use]; P  =  0.02; the Ontario study:
HR, 2.15; P  <  0.001) as well as with invasive recurrence
(E1594: HR, 3.68; P  =  0.01; the Ontario study: HR, 1.78;
P  =  0.04) [108, 110]. Multivariate analyses in both studies
showed that the DCIS Score was an independent prognosti-
cator [108, 110].
The DCIS Score has been available since December 2011.
Two recent decision impact studies conducted in the USA
showed that its use led to a significant reduction in radio-
therapy recommendations [111, 112], and two US-based HE
analyses suggested cost-effectiveness/cost saving for this
assay [113, 114].
9.9 Future Tools
The currently available MGAs have undoubtedly shifted the
treatment paradigms in BC with an increasing focus being
placed on tumour/host biology rather than clinicopathologi-
cal characteristics. Ongoing and future efforts aim at devel-
oping improved prognostic and predictive tools (including
tools to predict response to specific therapeutic regimens)
overall and particularly for BC subtypes that are currently
underserved. Efforts are also being made to advance other
aspects of personalised medicine including identifying early
response to specific chemotherapies and development of
individualised monitoring of BC in order to detect relapses
early. To this end, methodologies such as high-throughput
sequencing (whole exome/genome sequencing), proteomics,
metabolomics and tissue microarray analysis (e.g. for deter-
mining tumour-infiltrating lymphocytes [TILs]) are being
examined, alongside the required bioinformatics and statisti-
cal tools.
As an example, triple-negative BC is inadequately
addressed by currently available MGAs. Consequently,
attempts are ongoing to develop tools to aid in prognostica-
tion and prediction of response to treatment using different
approaches, such as development of signatures containing
mRNA and long non-coding RNAs (lncRNA) [115, 116], or
identifying tumour-infiltrating lymphocyte (TIL) profiles for
rares1geo@gmail.com
97 9
predicting response to neoadjuvant chemotherapy [117].
Another recent example involves the newly Food and Drug
Administration (FDA)-approved palbociclib (CDK 4/6 inhib-
itor), a promising drug in ER+ HER2-negative BC. A 20-gene
palbociclib sensitivity signature was identified, as well as an
87-gene signature for functional retinoblastoma loss (a known
marker of palbociclib resistance) [118]. Such signatures,
which still need to be further validated, could help select
patients for palbociclib treatment.
9.10 Conclusions
MGA developments and their application in BC have trans-
formed the landscape in BC treatment, minimising over- and
under-treatment. Increasingly complex molecular tools will
undoubtedly continue this transformation in the upcoming
years, eventually enabling high-level personalised medicine
for all BC patients.
Key Points
55 Multigene assays (MGAs) are increasingly used in
treatment decisions in patients with invasive early
breast cancer.
55 MGAs differ with respect to the technological
platform used, their development and their utility
in clinical practice.
55 Oncotype DX Breast Cancer Assay is the first MGA
validated to predict benefit to adjuvant chemo-
therapy in ER+ early-stage breast cancer.
55 Direct comparison of MGAs demonstrates that
they do not provide interchangeable information.
55 At present, only one MGA, the Oncotype DX
Breast DCIS Score, has been validated as a
prognosticator for patients with DCIS.
55 Ongoing and future efforts aim at advancing
other aspects of personalised medicine including
identification of response to specific endocrine or
chemotherapy agents and development of
individualised monitoring of breast cancer
patients.
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2014;16(6):488.
118. Migliaccio I, Piazza S, Verardo R, Guarducci C, Bonechi M, Ciani Y,
et  al. Identification of gene expression signatures of palbociclib
(PD) response in breast cancer (BC). Ann Oncol. 2015;26(Supple-
ment 3):iii15–24.
 103 10

Pathology of High-Risk
Breast Lesions
Sarah E. Pinder and Abeer M. Shaaban

10.1 Introduction – 104

10.2 Flat Epithelial Atypia (FEA) – 104

10.2.1 Histology – 105
10.2.2 Significance of FEA – 105

10.3 Atypical Ductal Hyperplasia (ADH) – 106

10.3.1 Histology – 106
10.3.2 Significance of ADH – 107

10.4 Lobular Neoplasia – 107

10.5 Histology – 107

10.5.1 ALH and Classical LCIS – 107
10.5.2 Pleomorphic LCIS – 107
10.5.3 LCIS with Necrosis – 109

10.6 In Situ Carcinoma with Mixed Ductal

and Lobular Features – 109

10.7 Significance of LCIS – 109

10.8 Radial Scar/Complex Sclerosing Lesions – 110

10.9 Histology – 110

10.10 Significance of Radial Scars/Complex Sclerosing Lesions – 110

10.11 Intraductal Papilloma – 111

10.12 Histology – 111

10.13 Significance of Intraductal Papilloma – 112

10.14 Management of High-Risk Lesions – 112

References – 113

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_10

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 104 S.E. Pinder and A.M. Shaaban
10.1 Introduction
The concept of pre-malignancy in the development of breast
cancer has evolved over the years. Certain lesions that are
regarded as benign per se but that show epithelial atypia in
the female breast confer an increased risk for subsequently
developing breast cancer. Furthermore, these same lesions
may also contemporaneously coexist adjacent to more estab-
lished malignancy (i.e. ductal carcinoma in situ or invasive
carcinoma) and therefore highlight the need for examination
of additional tissue; this «upgrade» of different epithelial
atypical lesions varies according to the nature of the lesion
and the size of the pathological specimen provided to the
pathologist (i.e. 14-gauge cores vs. 11-, 8- or 7-gauge sam-
ples). Here, we cover the common breast lesions associated
with a risk of upgrade and/or increased future breast cancer
risk. The histological and molecular features, clinical signifi-
cance and management of these lesions are discussed.
10.2 Flat Epithelial Atypia (FEA)
10 Columnar cell lesions encompass a spectrum of changes
involving dilated TDLUs. They include non-atypical lesions
a b
..      Fig. 10.1  Columnar cell lesions. a Benign columnar cell change.
The mildly dilated acini are lined by bland cells with columnar-shaped
nuclei bearing apical snouts and with focal intraluminal microcalcifica-
tion in secretions. b Flat epithelial atypia. Dilated acini lined by small,
regular, uniform epithelial cells with round nuclei and nuclear
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such as columnar cell change (. Fig. 10.1a) and columnar cell
hyperplasia and lesions with atypia, such as flat epithelial
atypia (FEA), which may coexist with atypical ductal hyper-
plasia (ADH). These lesions are often diagnosed on mam-
mographic screening due to the presence of luminal
calcifications, and the diagnosis of columnar cell lesions has
increased since the introduction of digital mammography
[1]. Columnar cell change and columnar cell hyperplasia are
benign processes not associated with either an increased risk
of subsequent breast cancer development or upgrade to
malignancy. In the absence of other atypical lesions, these
should be categorised as B2 on core biopsy and require no
additional mammographic surveillance or follow-up. Here,
we focus on the atypical lesions, namely FEA, and FEA with
ADH.
Various terminologies have been used to define columnar
cell lesions with atypia; FEA has also been called, amongst
others, columnar cell change with atypia, atypical cystic lob-
ules, atypical cystic duct, atypical lobule type A, hypersecre-
tory hyperplasia with atypia, columnar cell metaplasia with
atypia, ductal intraepithelial neoplasia (DIN)1a, clinging
carcinoma monomorphic type and small ectatic ducts lined
by atypical ductal cells with apocrine snouts (for review, see
Schnitt 2003) [2].
stratification. Apical snouts and luminal calcifications are also noted in
this case. c Flat high-grade DCIS. Dilated acinus lined by a flattened
layer but this is formed from large pleomorphic cells (some more than
3× the diameter of adjacent red blood cells) with necrosis in the lumen.
This represents flat high-grade DCIS rather than FEA, which is low grade
Pathology of High-Risk Breast Lesions
10.2.1 Histology
FEA is seen as dilatation of terminal duct lobular units (TDLUs)
by one or more layers of mildly cytologically atypical cells
resembling those of low-grade ductal carcinoma in situ (DCIS)
(. Fig. 10.1b). By definition, FEA does not comprise high-grade
nuclei. Those very uncommon, high nuclear grade lesions that
are believed to share the same pathway as the other columnar
cell processes are classified as flat high-­grade DCIS (. Fig. 10.1c).
Multilayering of nuclei is allowed but not a complex architec-
ture in FEA; if this is seen, the diagnosis is of ADH or low-grade
DCIS depending on the size and extent of the abnormality.
The acini in FEA are often of rounded internal contour
and typically lined by cuboidal epithelium showing apocrine
snouts, indicative of the columnar phenotype. Mild nuclear
hyperchromasia, a high nuclear/cytoplasmic ratio and incon-
spicuous nucleoli are features of the lesion. An adjacent stro-
mal lymphocytic infiltrate may be identified. These lesions
are commonly associated with luminal calcifications.
The diagnosis of FEA is morphological.
Immunohistochemistry is unhelpful as the lesion shares the same
immunohistochemical profile (oestrogen receptor (ER) positive
and Ck5/6 and Ck14 negative) as the non-atypical columnar
lesions and as ADH and low-grade DCIS. In some studies it has
been shown that these lesions suffer from poor interobserver
reproducibility of diagnosis amongst general pathologists [3], but
excellent concordance has been reported amongst breast pathol-
ogy specialists following training, for example, with teaching sets
of images [4]. However, concordance is generally better for exclu-
sion of the diagnosis of atypia than its diagnosis [4].
10.2.2 Significance of FEA
FEA is currently regarded as precursor of low-grade in situ
and/or invasive carcinoma, albeit with a low risk of progres-
sion. It commonly coexists with other lesions of the low
nuclear grade neoplasia family [5] and shares common genetic
..      Table 10.1  Relative risk for subsequent breast cancer development and upgrade rate following the diagnosis of high-risk lesions
Lesion Relative risk of subsequent
carcinoma
Flat epithelial atypia (FEA) ×2
Atypical intraductal epithelial proliferation ×4.4–5
(AIDEP)/atypical ductal hyperplasia ×8 if associated family history
Atypical lobular hyperplasia (ALH) ×4–5
Classical lobular carcinoma in situ (LCIS) ×8–10
Pleomorphic lobular carcinoma in situ (PLCIS) Not known
Radial scar (RS)/complex sclerosing lesion (CSL) ×2
Intraductal papilloma ×2
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105 10
alterations with those lesions, namely, deletion of chromo-
some 16q and gain of 1p. The changes are similar to those of
associated DCIS or invasive carcinoma, if present [6, 7].
Relatively few studies, however, have looked at the long-­
term follow-up of those lesions. Eusebi and colleagues [8]
reported one recurrence of 25 low-grade clinging carcinomas
(FEA) over a period of 17.5  years. The recurrence was of
essentially similar disease with no invasive component iden-
tified. Similarly, within the EORTC 10853 DCIS trial, 4 of the
58 low-grade clinging lesions showed local recurrence (but
no invasive element) after a median follow-up of 10.5 years
[9]. Another study showed no subsequent cancer following
the diagnosis of FEA (n = 101) over a 10-year follow-up [10].
A Dutch series of 259 patients with 8-year follow-up reported
development of cancer in 3.5% (nine invasive cancers, three
of which were contralateral) [1]. A matched case control
study showed a higher relative risk (2.32) for breast cancer
development in patients with FEA [11].
However, another, more recent, analysis of the 282 women
(2.4%) with FEA (from 11,591 women with benign biopsy)
found a similar standardised incidence rate, at median follow-
up of 16.8  years, for women with atypical hyperplasia with
and without FEA (4.74 and 4.23, respectively) and for those
with usual epithelial hyperplasia with and without FEA (2.04
and 1.90, respectively), indicating that FEA has a much lower
risk of progression than ADH or DCIS and is probably more
equivalent to the minimal risk seen with florid usual epithelial
hyperplasia [12].
Although the long-term risk of development of breast
carcinoma is very low, FEA may coexist contemporaneously
with other lesions in the low-grade neoplasia family group.
The upgrade rates following the diagnosis of FEA are approx-
imately 15% [13–15], but are higher if ADH is also present
(average 29%) [14] (. Table 10.1). A recent systematic review
reported a pooled DCIS underestimation rate of 9% for FEA
(confidence intervals (CI) 5–14%) and 20% (CI 13–28%)
when ADH was present, compared with only 1.5% (CI 0.6–
4%) for non-atypical lesions [16].
Upgrade risk of contemporaneous carcinoma
13–21%, average 15% (in pure form); if coexistent
with AIDEP, then higher risk (pooled 29%)
18–87% with 14-gauge core biopsy;
pooled value 21% after vacuum-­assisted biopsy
0–43%; pooled data 19%
0–60%; pooled value 27%
30–60%; pooled value 40%
4–9% (if no epithelial atypia), 28–44% (if epithelial
atypia); pooled value 25%
3–13% (if no epithelial atypia);
33–37% (if epithelial atypia)
 106 S.E. Pinder and A.M. Shaaban

10.3 Atypical Ductal Hyperplasia (ADH)
The term refers to an intraductal proliferation with both
architectural and cytological atypia. It shares some histologi-
cal features with DCIS but does not fulfil the quantitative and
qualitative criteria for a DCIS diagnosis. ADH is an uncom-
mon lesion diagnosed mainly in association with screen-­
detected calcification and may be an incidental finding [17].
The diagnostic criteria of ADH are not perfect, and the
diagnosis suffers from lack of consistency amongst patholo-
gists in some series. Complete concordance amongst 6
pathologists was achieved in 58% of 24 cases [18]. Data from
the UK Breast External Quality Assurance Scheme [19] show
low consistency in reporting ADH, albeit a large number of
histological sections cut from any one block for circulation
are unlikely to show the same representative features of this
lesion that is, by definition, small and microfocal.
10.3.1 Histology
ADH diagnosis is quantitative. It is diagnosed where DCIS
has been considered, but the lesion has not fulfilled the quan-
titative criteria for diagnosing DCIS (i.e. two membrane-­
bound spaces fully involved by the low-grade atypical
intraductal epithelial proliferation, or at least 2 mm in size)
(. Fig. 10.2a). ADH is therefore only diagnosed when there is

a b

10

c d

..      Fig. 10.2  Atypical ductal hyperplasia and DCIS. a Low-grade
cribriform DCIS. Ducts expanded by a population of small, uniform
evenly spaced epithelial cells with a cribriform architecture. There is
microcalcification within secretions. As this involved more than two
spaces, this was classified as DCIS rather than atypical ductal hyperpla-
sia. b ADH. This small atypical epithelial proliferation has a focal
micropapillary architecture with bridges. This does not involve two
complete spaces and represents ADH rather than DCIS. c Oestrogen
receptor immunoreactivity in ADH/DCIS. Uniform and strong nuclear
reactivity is seen in all lesional cells, assisting in confirmation of
clonality. d Atypical intraductal epithelial proliferation (AIDEP) in core
biopsy. This biopsy shows a duct space with an architecturally atypical
proliferation on a background of FEA. It is not possible to assess true
extent and this is regarded as AIDEP

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Pathology of High-Risk Breast Lesions
partial involvement of ducts by a monomorphic ­population of
atypical cells that also shows architectural atypia, such as rigid
bars or bridges or a micropapillary pattern (. Fig. 10.2b). The
 
nuclei are similar to those of low-grade DCIS. The low-­grade
nuclei of both low-grade DCIS and ADH show a uniform pat-
tern of immunoreactivity with ER (. Fig.  10.2c), Ck5/6 and
 
Ck14. Cases with high-grade nuclei are not designated as ADH,
but rather as high-grade DCIS, regardless of the lesional size.
Given the quantitative/extent criteria for diagnosis of
ADH, it is not possible to definitively diagnose this entity on
core biopsy specimens, as it is impossible to ascertain if there
is additional disease in the adjacent breast and therefore
whether the focus seen is actually a small portion of a larger
area of low-grade DCIS. Whilst this may seem like semantics,
in order to maintain the specific implications of the diagnosis
(i.e. as a lesion of increased risk of subsequent carcinoma), it
is recommended that the term ADH is only used for lesions
which have been adequately sampled and that the term atyp-
ical intraductal epithelial proliferation (AIDEP) is used for
core biopsy samples [20] (. Fig. 10.2d).
 
10.3.2 Significance of ADH
Patients with atypical hyperplasia have a 4.3 times higher risk
of subsequently developing breast cancer than patients with-
out proliferative lesions. A family history of breast cancer
(FH) increases breast cancer risk 2.4 times (95% CI, 1.4–4.3)
[21, 22] in some, but not all, series. ADH is believed to be
precursor for low-grade DCIS [23].
It is reported that 37–53% of cases will be upgraded to in
situ or invasive carcinoma on subsequent tissue examination
following an ADH diagnosis [13–15, 24], at least partly
depending on the size of the core biopsy sampling used
(. Table 10.1).
10.4 Lobular Neoplasia
This refers to a spectrum of lesions characterised by solid
proliferation of small non-cohesive cells within the terminal
duct lobular units. The term was originally coined by
Haagensen in 1978 [25] to refer to lobular carcinoma in situ
(LCIS) lesions and subsequently to encompass both atypical
lobular hyperplasia (ALH) and LCIS. In addition to classical
LCIS, other rare variants of lobular neoplasia include pleo-
morphic LCIS (PLCIS), pleomorphic apocrine LCIS
(PALCIS) and LCIS with central comedo-type necrosis.
Lobular neoplasia (classical and variants) shows inactiva-
tion of the e-cadherin gene, hence the loss of cellular cohe-
sion. Polymorphism and mutation of the e-cadherin gene
have been identified in these lesions [26]. A useful diagnostic
test is, therefore, e-cadherin immunohistochemical staining,
with absent or weak e-cadherin immunohistochemical stain-
ing typical in lobular lesions.
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107 10
LCIS is a disease of premenopausal women with an aver-
age age of 49 years [27]. Lesions are often identified inciden-
tally, and the true incidence is difficult to ascertain. However,
it is reported to be identified in 0.5–3.6% of all breast biopsy
specimens. Lobular neoplasia can be multifocal/multicentric
in up to 85% of cases and bilateral in approximately 30%. The
earliest report suggested that LCIS was always multifocal and
recommended simple mastectomy for treatment [28], but
this was a lesion largely identified in association with invasive
lobular carcinoma. More recently, it has been recognised that
the invasive carcinoma developing following a diagnosis of
LCIS is three times more likely to be ipsilateral than contra-
lateral [29] indicating some precursor behaviour, at least in
some cases. Importantly, clinically, however, the presence of
LCIS at the margins of surgical specimens has been shown
not to affect the excellent local control after breast conserva-
tion and radiotherapy for lobular cancer [30].
10.5 Histology
10.5.1 ALH and Classical LCIS
As the name suggests, this lesion typically involves the lobu-
lar units, rather than ducts (. Fig. 10.3a,b). The characteristic
lobular cells are generally small and uniform and show loss of
cellular cohesion (. Fig.  10.3c). Intracytoplasmic vacuoles
(. Fig.  10.3d) are often conspicuous, and pagetoid involve-
ment of terminal ducts can be prominent (. Fig. 10.3e). The
latter is diagnosed when lobular carcinoma cells infiltrate
under the normal residual duct epithelium. Lobular cells can
be divided into type A: small uniform nuclei, indistinct
nucleoli and minimal cytoplasm and type B: larger cells with
more abundant cytoplasm and variation in nuclear size and
morphology. Neither of these types has high-grade features.
The distinction between ALH and LCIS is quantitative.
LCIS (. Fig. 10.3c) is diagnosed when more than half the acini
are filled and distended (more than 8 cells across) by the charac-
teristic lobular cells, whilst lesser degrees are regarded as ALH
(. Fig. 10.3d). Lobular neoplasia is often ER positive and HER2
negative and, as noted above, typically e-cadherin negative.
10.5.2 Pleomorphic LCIS
Pleomorphic LCIS is diagnosed when there is distension of
the TDLUs by discohesive lobular cells showing large pleo-
morphic (cytonuclear grade 3) nuclei (. Fig. 10.3f). It is a rela-
tively recently described variant of lobular neoplasia which is
often associated with comedo necrosis and microcalcification
and is therefore most commonly identified through mammo-
graphic screening. As with classical LCIS, PLCIS shows inac-
tivation of the e-cadherin gene and is typified by an absence of
staining by e-cadherin immunohistochemistry. It is more
likely to be ER negative and HER2 positive than classical
LCIS, but the two lesions often coexist [31] (. Fig. 10.3f).
 108 S.E. Pinder and A.M. Shaaban

a b

c d

e f

10

..      Fig. 10.3  Lobular carcinoma in situ and variants. a LCIS. The
lobular geography of this epithelial proliferation can be seen at low
power, as can the expansion of the acinar spaces. b Expanded acinar
spaces are seen in this case of LCIS. Although there is some increased
cellularity around ducts, these are not expanded by cells, and this
represents pagetoid spread by the neoplastic cells (see also e).
c LCIS. Lobular unit with expansion of acini by discohesive epithelial
cells (see as spaces around cells) with moderately sized nuclei. d
ALH. Acini are not expanded, but are filled by a population of cells with
prominent intracytoplasmic vacuoles. Luminal spaces are not evident
and there is discohesion of cells. e Lobular neoplasia pagetoid spread:
Duct space with normal ductal epithelium undermined by a popula-
tion of moderately sized, discohesive forms, present between the
myoepithelial layer and innermost ductal cells. In such circumstances
the degree of acinar expansion cannot be assessed, and thus the
process cannot be accurately assigned to either ALH or LCIS, although
this tends to be more conspicuous in the latter. f Pleomorphic and
classical LCIS. The acinar space on the left is expanded by a population
of large, pleomorphic epithelial cells with large nuclei (cytonuclear
grade 3) along with prominent discohesion and intracytoplasmic
vacuoles; this represents PLCIS. The acinar space on the right bears
more regular, moderately sized but discohesive cells which are those
of LCIS. g Pleomorphic apocrine LCIS (PALCIS). Several ducts contain a
solid proliferation of large, pleomorphic and discohesive cells. The cells
have abundant eosinophilic cytoplasm and prominent nucleoli. Mitotic
figures are also noted

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Pathology of High-Risk Breast Lesions
Pleomorphic lobular carcinoma in situ can rarely com-
prise a proliferation of pleomorphic but overtly apocrine
cells when it is classified as being pleomorphic apocrine type/
pleomorphic apocrine LCIS (PALCIS) [32] (. Fig.  10.3g).
 
The lesional cells have abundant eosinophilic, granular
eosinophilic cytoplasm and conspicuous nucleoli but also
lobular features, such as discohesion and a lack of e-cadherin
expression. Whilst this entity shares the loss of 16p and gain
of 1q seen in other forms of LCIS, it shows more genetic
alterations compared to classical LCIS and more usual types
of PLCIS. Historically PLCIS lesions are likely to have been
diagnosed as high-grade DCIS. This, along with limited clin-
ical evidence, supports the view that PLCIS should be catego-
rised and treated as per high-grade DCIS and pure PLCIS
lesions on core biopsy should be coded as B5a [33–36].
10.5.3 LCIS with Necrosis
This is a very rare variant characterised by prominent disten-
sion of lobules by classical LCIS but with conspicuous com-
edo necrosis. The lobular proliferation in those cases is
usually florid, and mitoses may be seen, unlike more usual
forms in which they are infrequent. Although data in the lit-
erature regarding clinical behaviour is very limited, this vari-
ant is thought to be more aggressive than classical LCIS [37].
Therefore, in its pure form, the lesion should best be catego-
rised as B4. Subsequent management, i.e. whether this
requires complete/wide local excision, is unclear.
10.6 I n Situ Carcinoma with Mixed Ductal
and Lobular Features
In occasional cases, despite thorough morphological and
immunohistochemical assessment, it can be difficult to cate-
gorise an in situ lesion as being of pure ductal or lobular
nature. Those lesions that genuinely show features of both
phenotypes (typically supported by a mixed e-cadherin
immunophenotype) should be classified as mixed, as per the
WHO classification of tumours of the breast [27].
10.7 Significance of LCIS
Lobular neoplasia has been, for a long time, regarded as a
marker of increased breast cancer risk. The relative risk for
subsequently developing breast cancer was four- to fivefold
for ALH and 8–10 for LCIS [38, 39]. This view was supported
by observations that the disease can be multifocal and bilat-
eral. More recent data, however, supports the concept that, in
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109 10
at least some cases, the lesion is likely to be a precursor of
breast cancer [29]. It is commonly associated and shares the
same genetic alterations, as invasive lobular carcinoma; both
show loss of chromosome 16p and gain of 1q [40]. It repre-
sents one of the lesions encountered within the spectrum of
the low nuclear grade neoplasia family [5].
Both classical ALH and LCIS should be coded as B3, of
uncertain malignant potential, when identified on core
biopsy [20]. The upgrade rate to DCIS or invasive carcinoma
following the diagnosis of LCIS ranges from 2 to 25% in one
systematic review [41], although another suggests an aver-
age upgrade of 27% [42], more equivalent to the data
reported in UK practice where 30.3% of cases with lobular
neoplasia were upgraded to DCIS or invasive carcinoma
[43] (. Table  10.1). The upgrade rate for PLCIS is higher
(30–60%, average 40%) [37], supporting the view that this is
a more aggressive precursor lesion. A review of the studies
published in the English literature that included 1229 lobu-
lar neoplasia patients [42] similarly reported an upgrade rate
on excision of 42% for PLCIS. Of note, however, in many of
the series, there is marked bias in the data, in that in many
series by no means, all of the patients have undergone surgi-
cal excision. The upgrade rate in many series is, however,
surprisingly high, even for cases of incidental lesions and for
ALH, and some authors have therefore recommended surgi-
cal excision following a lobular neoplasia diagnosis [42].
Several issues have led to this wide variation in upgrade
rate reported in the literature and to the differences in man-
agement that various authors have recommended when
lobular neoplasia is diagnosed on core biopsy. First, many of
the report series include a heterogeneous group of lesions
and include screen-detected and symptomatic cases, women
undergoing sporadic/population-based and family history/
high-risk screening, isolated lesions and those presenting as
mass lesions. Second, radiological-pathological correlation
is not reported in many series. Finally, some studies have
included both classical and PLCIS, which have different
upgrade rates.
Follow-up data on the clinical behaviour of PLCIS is lim-
ited. Of 47 PLCIS cases followed up for 12 years, six patients
developed ipsilateral local recurrences of invasive carcinoma
(n  =  4) or PLCIS (n  =  2) [36]. Data on the significance of
LCIS with necrosis is even patchier. The lesion is however
thought to be more aggressive than classical LCIS [33].
Sapino and colleagues reported an association with malig-
nancy in 4 of 10 lesions [44]. Fadare and colleagues reported
a higher rate (67%) of association with cancer in 18 cases
identified [37]. Our own data of 17 cases showed an associa-
tion with DCIS or invasive carcinoma in 9 (52.9%). In its
pure form on core biopsy, the upgrade rate (to DCIS) is 20%
(Shaaban et  al., Pathological Society of Great Britain and
Ireland 2016).
 110 S.E. Pinder and A.M. Shaaban
10.8  adial Scar/Complex Sclerosing
R can be helpful in highlighting the myoepithelial layer con-
Lesions
Those lesions are often diagnosed on mammographic screen-
ing, either as incidental lesions or as a stromal deformity and
thus mimicking cancer. They rarely present as symptomatic
lesions. In a series of 85 unselected autopsies from women
diagnosed with breast cancer, radial scars were identified in
28% of cases [45] and thus can be regarded as common.
Lesions are designated as complex sclerosing lesions if they
have the same morphological features of radial scars but
measure more than 10 mm in size.
10.9 Histology
Radial scars typically exhibit a stellate appearance with cen-
tral keloid-like fibroelastosis (. Fig.  10.4a). This contains
compressed, sometimes distorted, ductal structures sur-
rounded by a layer of myoepithelium. The cells lining the
ducts show no cytological atypia and do not typically show
apical snouts (. Fig. 10.4b). The periphery of the lesions may
10
contain usual epithelial hyperplasia, which can be florid, and
foci of sclerosing adenosis are not uncommon.
The ductal distortion can make the identification of a sur-
rounding myoepithelial layer morphologically difficult, and
hence these lesions can occasionally be diagnostically chal-
lenging, particularly on core biopsy. Immunohistochemistry
for myoepithelium, such as p63 and smooth muscle myosin
a b
..      Fig. 10.4  Radial scar. a Lower-power view shows central scarring
and elastosis with scanty entrapped tubules typical of a radial scar.
Peripherally, there are foci of sclerosing adenosis. b Central portion of a
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firming the benign diagnosis and excluding invasive carci-
noma.
10.10  ignificance of Radial Scars/Complex
S
Sclerosing Lesions
These lesions are associated with approximately a twofold
increase in breast cancer risk compared to women of the gen-
eral population [46–48], i.e. equivalent to florid usual epithe-
lial hyperplasia.
However, radial scars may harbour atypical hyperplasia,
LCIS, DCIS or invasive carcinoma, particularly at the periphery
of the lesions (. Fig. 10.5). The risk of associated malignancy is
higher in women aged over 50 years and with mammographi-
cally detected larger lesions (>1 cm in size) in some series [49].
As well as older age, postmenopausal status was also associated
with higher risk of radial scar upgrade in one series [50]. The
risk of upgrade following a diagnosis of radial scar without
atypia is low (4–9%), but this increases to more than 25% for
those lesions showing atypia [51, 52] (. Table 10.1).
For those reasons, further tissue examination is warranted
following the histological confirmation of a radial scar with or
without atypia. This has historically been done by diagnostic
surgical excision but is increasingly being performed by vac-
uum-assisted biopsy. On diagnostic (as opposed to excisional)
core biopsy, radial scars/complex sclerosing lesions are cate-
gorised as B3.
radial scar with fibrosis bearing entrapped tubules. The myoepithelial
layer between the bland and benign epithelium, and the stroma can
be seen even on haematoxylin- and eosin-stained section in this case
Pathology of High-Risk Breast Lesions
a b
..      Fig. 10.5  Intraductal papilloma. a Lower-power view shows a
dilated duct space bearing a papillary lesion formed of fibrovascular
cores with overlying epithelium. b Higher-power view of an intraductal
papilloma. The fibrovascular cores are broad, and the epithelium is
polymorphous rather than either uniform or markedly pleomorphic
(features of low-grade and high-grade neoplasia, respectively). There is
associated epithelial hyperplasia (top). The edge of the duct can be
seen as a flattened layer of benign epithelium. c Encysted papillary
10.11 Intraductal Papilloma
Papillomas may be solitary or multiple, central (within the
subareolar area) or peripheral in the breast. The lesions, par-
ticularly if small, may be mammographically occult. Other
lesions especially central papillomas may present with bloody
nipple discharge or as a well-circumscribed mass that can be
seen on ultrasonography.
10.12 Histology
Intraductal papilloma (. Fig. 10.5a) is characterised by prolif-
eration of papillary fronds with, usually broad, fibrovascular
cores (. Fig. 10.5b) with an overlying myoepithelial layer cov-
rares1geo@gmail.com
111 10
carcinoma. In contrast to the clear intraductal location of the lesion in a
and b, there is a surrounding thick fibrous pseudocapsule around this
papillary lesion. The lesion itself is formed from thin fibrovascular cores
with central dilated vessels and with overlying columnar-shaped
neoplastic cells. d Sclerosed papilloma. Several islands of intact
papilloma are seen (left), whilst that on the right is almost completely
sclerosed, with only scanty peripheral epithelial elements and
entrapped glands remaining within dense hyalinised fibrosis
ered by a layer of luminal epithelial cells. The lesion lies within
a dilated benign duct, which also bears surrounding myoepi-
thelium in contrast to encysted papillary carcinoma where
there is surrounding fibrosis and capsule (. Fig. 10.5c). The
myoepithelial cells can be inconspicuous and can be high-
lighted by smooth muscle immunohistochemistry. However,
myoepithelial hyperplasia can also be seen. Apocrine meta-
plasia within benign papillomas is common and may be a
useful feature to signpost the benign nature of the lesion.
Papillomas may sometimes become markedly sclerosed
(. Fig.  10.5d) with distortion and ductal entrapment and
mimic invasive disease. Careful attention to the morphologi-
cal features and myoepithelial marker immunohistochemis-
try (to confirm the presence of the myoepithelial layer) is
helpful to arrive at the correct benign diagnosis.
 112 S.E. Pinder and A.M. Shaaban
Papillomas can show superimposed epithelial hyperpla-
sia or atypia. Usual epithelial hyperplasia is common and
can, in problematic cases, be characterised with the typical
mosaic pattern of immunoreactivity with ER, CK5 and Ck15
as when seen in simple ducts. However, architectural and/or
cytological atypia may also be seen. Although some have
used the term «atypical papilloma», this is not helpful clini-
cally; it is better to record either atypia or DCIS within a
lesion within the underlying structure of a papilloma. These,
as in non-papillomatous ducts, are largely defined by the
extent of the atypical epithelial process; if the extent of a low-­
grade atypia is more than 3 mm, the diagnosis of DCIS with
a papilloma (B5a on core biopsy) is made. If less than 3 mm
in continuity, the diagnosis is of low-grade atypia within a
papilloma [53]. Due to inherent heterogeneity within intra-
ductal papillomas, any lesion, with or without atypia, which
is not completely excised within the width of a core biopsy
sample (i.e. other than very small lesions) is classified as B3,
i.e. of uncertain malignant potential.
10.13 Significance of Intraductal Papilloma
10
The upgrade rate of papilloma on surgical excision ranges
from 3 to 12.9% for lesions without associated epithelial
atypia, but this rate increases significantly to 33–36.7%, for
lesions harbouring atypia [15, 43, 54, 55] (. Table  10.1).
There is some evidence that the risk of upgrade may be higher
in older patients (above 50 years), in larger lesions (>1 cm)
and in papillomas lying more than 3 cm from the nipple [56].
10.14 Management of High-Risk Lesions
As described above, high-risk lesions in the breast when
diagnosed on core biopsy specimens are best categorised as
B3, of uncertain malignant potential, although conversely it
should be noted that not all B3 lesions are high-risk pro-
cesses. However, the upgrade risk, as well as the risk of devel-
opment of any subsequent invasive carcinoma, is not uniform
for the different patterns of high-risk disease. None, however,
has what might be considered a negligible upgrade risk, as
even papillomas or radial scars without epithelial atypia have
a 5–10% risk of associated DCIS or invasive carcinoma in the
adjacent breast tissue. The risk of upgrade is significantly
higher in the presence of epithelial atypia compared with
non-atypical lesions and is generally higher if the diagnosis is
made on a smaller (e.g. 14-gauge) core biopsy compared to
vacuum-assisted (i.e. larger) samples. Again, however, even
with the latter, there remains a risk of upgrade of more than
10% for epithelial atypia in most series.
Traditionally, these borderline or high-risk lesions have
been managed by diagnostic surgical excision. However, the
majority (70–80%) are confirmed to be benign on excision.
With this approach, therefore, it must be recognised that most
patients will undergo «unnecessary» surgery with the anaes-
thetic, psychological and surgical complications, including
rares1geo@gmail.com
scarring with its subsequent adverse implications on follow-
up mammography. Even if the lesion is surgically proven to be
DCIS or invasive carcinoma, then those patients require a
second, therapeutic, surgical procedure to obtain complete
excision of the malignancy (+/− sentinel lymph node biopsy).
Sampling a large volume/excision of such lesions is now gen-
erally straightforward (depending on the site of the abnor-
mality in the breast) with modern vacuum-­ assisted
techniques, and this is now the method of choice for provid-
ing further tissue for examination following a B3 core biopsy
or first-line vacuum-assisted biopsy diagnosis [24]. The pro-
cedure is fast, performed in the outpatient setting, and is well
tolerated by patients. Significantly, the introduction of this
management pathway has been shown to reduce the fre-
quency of benign surgical biopsy without affecting the cancer
detection rate [57].
The UK has recently developed guidance on the manage-
ment of B3 lesions, of uncertain malignant potential, recom-
mending that vacuum-assisted thorough sampling/excision
be the gold standard for sampling for the vast majority of
such lesions including FEA, radial scars with and without
atypia, papillomas and atypical intraductal proliferations. It
is still, however, presently recommended that papillomas
with associated epithelial atypia undergo diagnostic surgical
excision, since (as described above) the distinction between
ADH and low-grade DCIS in a papilloma relies on quantita-
tive assessment of the extent of atypia and thus examination
of the intact lesion. Other lesions are classified as B3 (not
described here as not regarded as high-risk per se); these
include some cellular fibroepithelial lesions where phyllodes
tumour cannot be excluded, a range of spindle cell lesions,
vascular lesions and uncommon lesions such as adenomyo-
epithelioma and microglandular adenosis. In general these
benefit from assessment as one whole piece histologically,
and diagnostic surgical excision of these is still standard of
care.
Multidisciplinary team (MDT) discussion for all these
lesions is essential as radiological-pathological correlation is
required. Whilst the approach described above is anticipated
to be the optimum for most of the high-risk lesions, these
need case-by-case review of all imaging, all histological sam-
ples (e.g. 14-gauge and subsequent vacuum-assisted speci-
mens) and clinical findings in the triple approach; any
discrepancies should be accounted for. Continuous auditing
of their diagnosis and management, including, but not exclu-
sive to, the benign diagnostic rate and cancer detection rate is
required.
The most appropriate follow-up and surveillance for
patients with lesions that confer a subsequent increased risk
of development of DCIS and invasive carcinoma are contro-
versial with various protocols applied. There is little data on
the most appropriate frequency of mammographic screening
in these women, nor for how long this should be undertaken.
Similarly the value of MRI in this setting is not clear. Present
guidelines mostly recommend annual mammography, but
more research is urgently required to assess whether this is
the optimum. What is clear is that women with atypical epi-
Pathology of High-Risk Breast Lesions
113 10
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16. Verschuur-Maes AH, van Deurzen CH, Monninkhof EM, van Diest
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grade and histological subtypes of breast cancer [56, 57]. sion necessary? A systematic review. Ann Surg. 2012;255(2):259–65.
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gen receptor positive, raising the possibility of value from TN. Atypical hyperplasia: frequency and mammographic and patho-
preventative therapy [58], this has not been shown in other logic relationships in excisional biopsies guided with mammogra-
phy and clinical examination. Radiology. 1993;189(3):667–71.
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 115 11

Ductal Carcinoma in Situ

Stacey A. Carter, Sarah E. Pinder, and Alastair M. Thompson

11.1 Introduction – 116

11.2 Epidemiology – 116

11.3 Natural History – 116

11.4 Diagnosis – 116

11.4.1 Mammogram – 116
11.4.2 Ultrasound – 117
11.4.3 MRI – 117
11.4.4 Biopsy – 117
11.4.5 Pathology – 118

11.5 Differential Diagnosis – 118

11.5.1 Receptor Status – 119

11.6 Treatment – 119

11.6.1 Overdiagnosis and Overtreatment – 120
11.6.2 Surgery – 120
11.6.3 Margins – 121
11.6.4 Lymph Nodes – 121
11.6.5 Radiation – 121
11.6.6 Endocrine Therapy – 122
11.6.7 Neoadjuvant-Targeted Therapy – 122

11.7 Recurrence – 123

11.7.1 Clinical Factors – 123
11.7.2 Pathology Factors – 123

11.8 Prognostic Scores – 123

11.9 Survival – 124

11.10 Future Perspectives – 124

11.11 Conclusions – 124

References – 124

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_11

rares1geo@gmail.com
 116 S.A. Carter et al.
11.1 Introduction
Ductal carcinoma in situ (DCIS) of the breast represents an
intraductal lesion of the breast characterised by increased
epithelial proliferation with cellular atypia not invading the
basement membrane of the ductal lobular unit. Microinvasion
of the local tissues (up to 1 mm) may be permitted as part of
the DCIS process, but extension beyond 1  mm constitutes
invasive breast cancer. DCIS reflects a spectrum of molecular
changes and is a non-obligate precursor to invasive disease
which may or may not have a stepwise progression from pre-
ceding DCIS; further, the time lines of, and any progression
to, invasive disease are highly variable. Indeed, it is reported
that some 15% of women at post-mortem have evidence of
DCIS undetected during their lifetime [1]. Although the
development of invasive breast cancer following DCIS may
be fatal, the risk of dying of breast cancer after a diagnosis of
DCIS is less than 3% after two decades [2]. This recognised
heterogeneity of DCIS has prompted prospective trials to
consider the need for radiotherapy and for endocrine therapy
and to examine clinical, pathological and molecular predic-
tors of recurrence and progression to invasive breast cancer
to delineate appropriate management of this condition.
11 11.2 Epidemiology
In general, the factors associated with invasive cancer are
similar to the factors associated with intraductal prolifera-
tive lesions such as DCIS.  Age remains an important risk
factor for DCIS. Women 70–84 are found to have DCIS with
a rate of 1.3 per 1000 screening mammograms, twice the
incidence in women aged 40–49 years. However, «overdiag-
nosis» has been used to characterise conditions, including
DCIS, which have the microscopic appearances of cancer
but are not destined to cause symptoms or death during a
patient’s lifetime [3].
The widespread adoption of screening mammography
has changed the way DCIS is detected and has contributed to
the increase in new cases of DCIS. In the past, most patients
presented with clinical symptoms such as a mass (91%),
bloody nipple discharge (7%), both (<1%) or Paget’s disease
[4]. Symptomatic DCIS is more commonly of high cytonu-
clear grade, larger in size, ER negative and HER2 positive [4].
Indeed, symptomatic DCIS more often bears an occult inva-
sive focus, and when this is present, there is more often nodal
involvement than when occult invasive cancer is identified in
screen-detected DCIS [5].
DCIS identified on screening mammography is typically
asymptomatic and non-palpable, with approximately 60% of
detected lesions being of intermediate or low nuclear grade
compared to 55% of symptomatic DCIS in some series, [4]
although in other series over half of screen-detected DCIS is
of high grade. [6] The detection rate of DCIS has dramati-
cally increased globally since the advent of breast screening.
rares1geo@gmail.com
The average frequency of DCIS detected at screening in
84  units in the UK was 1·60 per 1000 women screened
(median 1·50 [unit range 0·54–3·56] per 1000) [7]. Reflecting
this, in the USA, the incidence of DCIS has risen from 5.8 per
100,000 in the 1970s to 32.5 in 2004 with over 60,000 women
there diagnosed with DCIS annually, almost all in asymp-
tomatic individuals [8]. In the UK in 2013, there were 7288
new cases of in situ breast carcinoma, with most women
diagnosed at 60  years or older. This represents a 534%
increase in incidence of in situ breast cancer (females only)
since the late 1970s [9]. Indeed, DCIS now represents some
25% of all breast cancer diagnoses [10].
11.3 Natural History
Most data on the natural history of patients diagnosed with
DCIS refers to retrospective reviews of missed diagnoses.
They often relate to an era of lower-quality imaging, biopsy
and pathology and do not include active monitoring by mam-
mography, with almost all patients presenting symptomati-
cally. Without treatment, it is estimated that 20–30% of DCIS
overall will progress to invasive cancer [11, 12]. In keeping
with this, recent evidence from the UK Breast Screening
Programme has considered the effects of a diagnosis of DCIS
on the incidence of subsequent invasive breast cancer [7]. For
every three women with screen-detected DCIS, there was one
fewer invasive interval cancer over the next 3 years, suggest-
ing there may be benefits on a population level to detecting
DCIS through breast screening [7].
11.4 Diagnosis
11.4.1 Mammogram
The majority of DCIS is detected with imaging and often
appears as microcalcifications or less commonly as a mass or
area of architectural distortion. The minority of DCIS is
today detected by clinical symptoms (palpable abnormality,
nipple discharge or nipple alterations associated with Paget’s
disease) or incidentally in a surgical specimen obtained for
other reasons. An important factor in the management of
DCIS is to determine the extent of the disease as this may
influence surgical decision-making.
Different patterns of calcifications have been identified
which may be suggestive of DCIS [13]. Multiple clusters of
fine microcalcifications are typically seen in low-grade DCIS,
while linear, continuous, often branching, coarse calcifica-
tions are seen with high-grade disease. Microcalcifications
may thus be visible both at the imaging (usually mammogra-
phy) and microscopic level (. Figs. 11.1 and 11.2). Patients
found to have an abnormal screening mammogram should
undergo diagnostic bilateral mammography with magnifica-
tion views to assess the extent of disease. Mammograms have
Ductal Carcinoma in Situ
..      Fig. 11.1  Radiographic microcalcifications from DCIS on mammog-
raphy in a patient with a prior implant
..      Fig. 11.2  Microcalcifications (irregular purple staining) in
secretions (pink staining) in low grade DCIS
rares1geo@gmail.com
117 11
been noted to underestimate the extent of DCIS, especially
with increasing tumour size, and the comparison of mam-
mographic versus final pathology size may coincide within a
centimetre in only a third of patients [14].
11.4.2 Ultrasound
Some academic centres routinely employ ultrasound on all
women with an abnormal mammogram or a palpable mass.
In the USA, the National Comprehensive Cancer Network
(NCCN) guidelines [15] recommend that ultrasound evalua-
tion is an optional part of the work-up for patients with early-
stage breast disease. By contrast, the UK National Institute
for Health and Care Excellence (NICE) guidelines [16] rec-
ommend ultrasound evaluation of the axilla as well as the
breast for all patients with early invasive disease, but not per
se for DCIS.  Although not specifically designed to detect
microcalcifications (unlike mammography), approximately
5–15% of patients with microcalcification will have a mass
detectable on ultrasound.
11.4.3 MRI
A recent meta-analysis conducted to examine the effects of
MRI on the surgical treatment of DCIS concluded that MRI
in women with DCIS is not associated with an improvement
in surgical outcomes [17]. In this analysis, there was no dif-
ference in the proportion of women with positive margins
following breast conserving surgery (BCS) or in the reopera-
tion rate for positive margins between patients having MRI
and no MRI. Conversely, MRI was found to increase the odds
of having mastectomy rather than an initial conservation
approach. MRI use in women with DCIS does not appear to
confer an oncological advantage [18] and has a lower sensi-
tivity for DCIS compared with invasive cancer. The UK NICE
guidelines caution against routine use of MRI in patients with
DCIS and guides clinical teams to use this modality if there is
a discrepancy regarding the extent of disease between clinical
examination and other imaging modalities or if breast den-
sity precludes accurate mammographic assessment.
11.4.4 Biopsy
Any radiographically suspicious abnormality warrants biopsy.
One option is fine needle aspiration (FNA) cytology. FNA
offers the convenience of being a simple procedure with stan-
dard equipment (syringe and needle) for palpable lesions;
however, cytological examination cannot distinguish in situ
from invasive disease, and definitive preoperative diagnosis
rates for screen-detected DCIS are poor (73% sensitivity com-
pared with 94% sensitivity with core biopsy) [19]. At least

118 S.A. Carter et al.

partly for this reason, FNA alone is not recommended for likely clinical behaviour as well as the presentation on mam-
screen-detected abnormalities in the UK National Health mography. There is interobserver variability when assigning
Service Breast Screening Programme (NHS BSP). a final pathologic diagnosis of ADH versus low-grade DCIS
Core needle biopsy provides a more accurate assessment in some series (see 7 Chap. 10) [22]. To avoid overtreatment,
 

because the tissue architecture is retained and definitive diag-
nosis of DCIS, i.e. compared to invasive disease, can be made
(with the proviso that only a small portion of the lesion is
sampled and a small invasive focus may have been missed).
Additionally, core needle biopsy may provide sufficient tissue
for examination of hormone receptor status, which can have
important implications for treatment. A core needle biopsy
can be done as a stereotactic procedure for calcifications seen
on mammogram or with ultrasound guidance in patients
with a lesion seen on ultrasound. An MRI-guided core biopsy
can be used in situations where the lesion is occult on mam-
mogram and ultrasound. Among women who are diagnosed
with DCIS without invasive cancer on core biopsy, the esti-
a more appropriate nomenclature may be to reclassify DCIS
as ductal intraepithelial neoplasia (DIN) as was the idea of
reclassifying lobular carcinoma in situ (LCIS) to lobular
intraepithelial lesion (LIN) [23, 24]. However, this system has
not achieved widespread acceptance, and cytonuclear grad-
ing is the system recommended in the USA and the UK,
among others [25].
11.5 Differential Diagnosis
The pathological features of ADH and low-, intermediate-
and high-grade DCIS are presented in . Table 11.1. The rela-

mate of upstaging to invasive cancer upon surgical excision
ranges from 0% to 20% [20]. This upstaging will clearly
depend on the amount of tissue provided to the pathologist
and the accuracy of radiological sampling any areas of par-
ticular concern; the use of larger bore vacuum-assisted biopsy
tionship of DCIS to atypical ductal hyperplasia (ADH),
lobular neoplasia and invasive disease deserves attention.
Usually, diffuse-positive nuclear ER expression with contigu-
ous reactivity throughout the entire population of atypical
cells is seen in both ADH and low-grade DCIS (. Fig. 11.3)

(VAB) needles accurately delineated the presence of DCIS
alone in one small series [21], but in most, even with VAB,
occult invasive disease will be missed on biopsy in approxi-
11 mately 5%–10% of women with a biopsy diagnosis of DCIS.
11.4.5 Pathology
The pathology of DCIS can be considered as a spectrum
ranging between atypical ductal hyperplasia and invasive dis-
ease with features such as grade and necrosis reflecting the
both of which are almost always ER positive. In addition,
homogeneous absence of staining for basal cytokeratin
markers such as cytokeratins 5 and 14 is also a common find-
ing for ADH and low-grade DCIS. Thus, the distinguishing
feature discriminating ADH from DCIS is that the cellular
and architectural changes of low-grade DCIS occupy two or
more complete membrane-bound spaces, those of ADH only
one. The low-grade, solid variant of DCIS may be misinter-
preted as lobular neoplasia but can almost always be distin-
guished definitely with E-cadherin (staining indicates ductal
pathology).

..      Table 11.1  Features of DCIS by grade and in comparison to atypical ductal hyperplasia

Feature Atypical ductal Low grade Intermediate grade High grade

hyperplasia

Pleomorphism Monotonous Monotonous Intermediate Markedly pleomorphic

Cell size 1.5 × to 2 × RBCs or 1.5 × to 2 × RBCs or Intermediate >2.5 RBCs or normal
normal duct epithelial normal duct epithelial epithelial nucleus
nucleus nucleus

Chromatin Usually diffuse, finely Usually diffuse, finely Intermediate Usually vesicular,
dispersed dispersed regular chromatin
distribution

Nucleoli Only occasional Only occasional Intermediate Prominent, often

multiple

Mitoses Only occasional Only occasional Intermediate May be frequent

Orientation Polarised Polarised Intermediate Usually not polarised

Extent of lesion Less than two complete Two complete

membrane-bound membrane-bound
spaces (or less than spaces involved
2 mm in size)

RBC red blood cell

rares1geo@gmail.com
Ductal Carcinoma in Situ
..      Fig. 11.3  Estrogen receptor (ER) staining of nuclei on a histological
section of DCIS
..      Fig. 11.4  Intermediate grade DCIS
..      Fig. 11.5  High-grade DCIS with central necrosis
Low-grade (. Fig. 11.2) and intermediate-grade (. Fig. 11.4)
   
(«low risk») DCIS may have a more indolent course than high-
grade DCIS (. Fig. 11.5) with regard to its potential to develop
 
invasive disease [23]. The cytomorphological appearances, the
grade of the DCIS and the presence or absence of comedo
necrosis (necrosis in the centre of the ducts) (. Fig. 11.5) are
 
reflected in both the mammographic appearances and the sub-
sequent disease behaviour. In addition, the presence of ER, PR
and HER2 expression on immunohistological staining of the
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119 11
..      Fig. 11.6  High-grade DCIS
DCIS may have implications for the future likelihood of recur-
rence; however, the evidence is far from clear. While the micro-
scopic appearances may vary, ultimately the behaviour of DCIS
that is high grade (. Fig. 11.6) and ER negative and/or HER2
positive may be more aggressive when compared with that of
low-risk DCIS. This is considered further below in the section
on recurrence.
11.5.1 Receptor Status
The oestrogen receptor (ER), progesterone receptor (PR) and
HER2 protein status of DCIS is not routinely performed for
DCIS in some European countries such as the UK where it is
not included in national minimum datasets, although ER is
considered a routine part of assessment in the US NCCN
guidelines. Increasing DCIS grade correlates with a decrease
in hormone receptor positivity; comedo necrosis is also more
frequently seen in ER-negative tumours. The availability of
ER, in particular, may determine the use of adjuvant endo-
crine therapy following a diagnosis of DCIS (see below),
although the influence of this treatment is largely on the con-
tralateral breast, and the relevance of the ER status of the
index disease is not clear.
11.6 Treatment
Current treatment options routinely offered for DCIS include
surgery (lumpectomy/wide excision/«segmental mastec-
tomy» or mastectomy), radiation (radiation or none) and
endocrine therapy. These options constitute guideline con-
cordant care (GCC) according to the NCCN treatment rec-
ommendations [15]. Between 1991 and 2010, 23.8% of
women diagnosed with DCIS in the USA underwent mastec-
tomy, 43% lumpectomy with radiation and 26.5% lumpec-
tomy without radiation, based on data from the Surveillance,
Epidemiology, and End Points Registry [26]. Among the 97%
of women with DCIS treated with guideline concordant care,
neither randomised trials nor retrospective studies to date
have shown a survival advantage of any treatment option
over another [26].
 120 S.A. Carter et al.
11.6.1 Overdiagnosis and Overtreatment
Overdiagnosis (detection of a condition not causing symp-
toms or death if left undetected) and overtreatment (treat-
ment without benefit) resulting from mammographic
screening have been estimated to be as high as one in four
patients diagnosed with breast cancer. [27] The absence of
standard definitions for assessing overdiagnosis has led to
uncertainty and controversy around this estimate. The
national health-care expenditure resulting from false-positive
mammograms as well as breast cancer overdiagnosis has
been estimated in the USA to approach $4 billion annually
[28], and there is general consensus that much of this burden
derives from the treatment of DCIS. However, many fail to
recognise that DCIS is not a single disease process (clinically,
radiologically, biologically, histopathologically or genetically)
and that low-grade DCIS and high-grade DCIS cannot be
considered equivalent in terms of likelihood of progression to
invasive disease or subsequent behaviour. Nevertheless, for
those women whose DCIS may never progress even without
treatment, medical intervention can only do harm. In addi-
tion, the potential for overtreatment and overdiagnosis must
be balanced against the consequences of missed diagnosis
and undertreatment [7]. Thus, at present, most women who
receive a diagnosis of DCIS undergo surgical resection with
11 consideration of adjuvant radiotherapy and/or endocrine
therapy.
11.6.2 Surgery
With regard to surgical treatment for DCIS, the options com-
prise breast conserving surgery (BCS), with or without radia-
tion, versus mastectomy (with or without breast reconstruction).
There is no single approach that is best for every patient given
the heterogeneity of disease, variation in extent, age, genetic
carrier status, breast size (compared with the size of the DCIS)
and the patient’s desire for breast conservation, mastectomy
and/or reconstruction. Breast conservation surgery with adju-
vant radiotherapy has been accepted as a treatment option for
invasive disease with equivalent survival to mastectomy; this
principle in surgical management has been extended to include
DCIS. Since most DCIS is identified as a non-palpable lesion,
BCS usually requires the radiographic abnormality to be local-
ised by, for example, wire localisation or iodine-125-labelled
seed, for resection (. Fig. 11.7). Determining the extent of dis-
 
ease is important, as large lesions may need to be bracketed
with wires or seeds to ensure removal of the involved area.
Assessment of the specimen radiograph helps confirm that the
entire targeted lesion was removed.
DCIS is most commonly unifocal. Segmental, multifocal
or multicentric disease is the exception; only one of 119
mastectomies was multicentric in the series examined by
Holland and Hendriks [29]. However, while multifocal or
multicentric lesions are traditionally considered to be a con-
traindication to BCS, many groups have reported success
rares1geo@gmail.com
..      Fig. 11.7  Specimen radiography of DCIS demonstrating clip
(smaller opaque marker) and I125-labelled marker (larger opaque
marker); specimen orientated using sutures not visible to radiography
incorporating oncoplastic reconstruction, as for invasive
disease [30]. Oncoplasty has gained momentum in recent
years as it may allow for wider, negative margin resection
while achieving a good cosmetic result for the patient by
reshaping the breast. For larger resections, this procedure
can be done with a contralateral mastopexy for symmetry.
Mastectomy options include a total mastectomy, skin spar-
ing mastectomy (SSM) or nipple sparing mastectomy
(NSM). Mastectomy may be the only surgical option for a
woman with a small breast and large extent of DCIS.  For
SSM, a circumareolar incision can be modified if the patient
has a scar from a previous biopsy that needs to be incorpo-
rated with the mastectomy. For NSM, an inframammary
incision provides good access, although patients with docu-
mented retroareolar DCIS are not suitable for this approach.
Coring out the duct tissue behind the nipple, submitted
separately for pathology, can occasionally demonstrate DCIS
and necessitate a return to the operating room for excision
of the nipple. For DCIS, prophylactic contralateral mastec-
tomy does not hold a survival benefit in women that do not
have a defined genetic predisposition for breast cancer [31].
In those women who undergo surgical management of
DCIS, there is a risk of developing persistent pain at the sur-
gical sites [32]. Importantly, persistent pain after lumpec-
tomy may be as prevalent as pain after total mastectomy,
leading to disability and psychological distress, which is often
resistant to management. Prospective population-based data
have demonstrated significant patient and surgical influences
on pain, with remarkably high levels of chronic pain 4 and
9 months after breast surgery [33]. Many of these data have
been collected in women with invasive cancer, not purely
DCIS, and so the incidence of post-operative symptoms after
resection of DCIS alone is uncertain but unlikely to be very
different from that of other breast surgery.
Ductal Carcinoma in Situ
11.6.3 Margins
The goal in margin-negative resection is to remove the tar-
geted lesion with a margin of normal breast tissue. The opti-
mal margin width remains unclear and an area of controversy.
The margin of resection required has long been debated, with
the UK NICE guidelines published in 2009 [16], which rec-
ommend a minimum 2 mm radial margin for patients under-
going BCS for DCIS, concordant with meta-analysis evidence
[34]. Recently, US guidelines have changed from the tradi-
tional, wider, margins to a consensus that a 2 mm margin is
sufficient for DCIS [35]. Re-excision should be considered if
the margin is less than 2  mm after a discussion with the
patient. The British Association of Surgical Oncology recom-
mends that units develop local guidelines. Of note, not all of
the extent of DCIS necessarily bears histological (and radio-
logical) calcification, and imaging techniques tend to under-
estimate disease extent in at least a substantial proportion of
patients [13, 14]. Nevertheless, even with multiple bracketed
localisation techniques, disease may be present beyond that
anticipated. For this reason, surgical re-excision is more fre-
quently required than for invasive disease; a retrospective
study of hospital statistics in the English NHS reports 29.5%
of patients with DCIS had at least one reoperation [36].
Unfortunately, most of the evidence for optimum margin
width comes from observational studies. In the literature,
positive margins are well accepted to increase local recur-
rence. The importance of positive anatomically non-breast
margins (anterior/skin and posterior/pectoral fascia) remains
a point of debate. If a wide local excision incorporates full
thickness breast parenchyma, the only tissue anterior to the
excision cavity is subcutaneous tissue and skin, which, by
definition, does not contain breast parenchyma. One poll
showed the variability in margin widths for surgeons in the
UK and explored the different techniques surgeons use for
re-excision of a positive anterior margin (scar + skin, anterior
margin + skin, anterior margin + skin + adjacent tissue, all
margins including skin) [37].
Importantly, it appears that margins greater than 2 mm in
women treated by breast conservation and external beam
radiotherapy do not confer an advantage in terms of reduced
risk of recurrence. Previously, a meta-analysis of trials for the
effect of margin status on local recurrence after breast con-
servation and radiotherapy for DCIS [34] demonstrated that
negative margins significantly reduced the risk of ipsilateral
recurrence when compared with a close or unknown margin
(OR 0.59 and 0.56 respectively). Where margins were spe-
cifically measured, a 2 mm margin was superior to a margin
of less than 2 mm (OR 0.53) but not significantly different to
a margin >5 mm [34].
11.6.4 Lymph Nodes
In the UK, NICE guidelines recommend that sentinel lymph
node should be considered for patients undergoing mastec-
tomy, as this procedure cannot be undertaken subsequently if
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121 11
unanticipated invasive disease is detected histologically [16].
Some also consider sentinel lymph node evaluation in
patients undergoing oncoplastic reconstruction where exten-
sive tissue mobilisation is planned. If an occult invasive
malignancy is found, the tissue mobilisation can interfere
with the lymphatic drainage of the breast and may result in
inability to accurately stage the axilla.
When local excision is performed for DCIS, SLN biopsy
is possible as a subsequent procedure if invasion is identified
on final pathology. In a meta-analysis [38], Ansari and col-
leagues reported an overall 3.7% nodal positivity rate for
patients with a definitive postoperative diagnosis of pure
DCIS, although a large retrospective review in the UK identi-
fied node positivity in only 0.2% of cases of screen-detected
DCIS [39]. While the routine use of sentinel lymph node
biopsy in DCIS has been debated, in patients with pure DCIS,
lymph node status has failed to predict inferior outcomes and
hence should not change subsequent management.
11.6.5 Radiation
Unlike invasive breast cancer, radiation therapy is very rarely
used following mastectomy for DCIS with a rate of less than
1% [40]. The indications appear to be close margins and large
tumour size, in a large national UK survey of nearly 10,000
cases of DCIS, with no recurrences at 5 years follow-up.
In contrast, the majority of women with DCIS undergo
breast conserving surgery, for whom radiotherapy is offered
as adjuvant therapy in 1/3–2/3 of patients, although there is
low consensus as to how best to select women for adjuvant
radiotherapy. Whole breast radiotherapy following breast
conserving surgery (. Table  11.2) reduces the local recur-
rence by more than half from 28.1% to 12.9% and reduces the
incidence of invasive disease from 11.0% to 5.0% at 10 years
in meta-analysis [41] based on key randomised prospective
trials [2, 42–44]. More recently, other retrospective cohort
studies [45] or randomised trials of radiotherapy or not after
surgery [46] of low-risk DCIS have suggested lower levels of
recurrence than with surgery alone, but still a marked effect
of radiotherapy (. Table 11.2).
However, while radiotherapy halves breast recurrence, it
does not appear to alter long-term breast cancer-specific sur-
vival [47]. The benefits of radiotherapy may be offset by the
increased risks of lung, oesophageal and contralateral breast
cancers, cardiovascular risks and, rarely, (0.1%) angiosar-
coma based on historical studies of radiotherapy and DCIS
[41]. While there may be no demonstrable survival advantage
of breast radiotherapy, conversely there is no excess mortality
from the use of radiotherapy in the setting of DCIS [41].
The survival advantages and cosmetic benefits seen for
hypofractionation of radiotherapy for invasive breast cancer
in large Canadian, UK and US trials may be expected to per-
tain to adjuvant radiotherapy for DCIS.  The potential for
partial breast radiotherapy (whether external beam, brachy-
therapy or intraoperative radiotherapy) for DCIS has not
been fully explored.
 122 S.A. Carter et al.
..      Table 11.2  Recurrence of breast neoplasia with or without adjuvant radiotherapy
Study
Wong [45] Retrospective cohort
McCormick [46] RTOG 9804
Correa [41] Meta-analysis
Stuart [49] Meta-analysis
11.6.6 Endocrine Therapy
There is evidence from one placebo-controlled trial, NSABP
B-24, in the USA, that in pre- and postmenopausal patients
treated for DCIS with lumpectomy and adjuvant radiother-
apy, the addition of tamoxifen reduces the risk of ipsilateral
local recurrence by 30% and of contralateral breast cancer by
11 50% [48]. The absolute risk at 5 years of any (invasive or non-
invasive) breast cancer event was small (tamoxifen arm 8%
and placebo arm 13%). Survival was not influenced by treat-
ment. Another complex trial design examined the use of
tamoxifen versus no adjuvant therapy following complete
local excision of DCIS in the absence or presence of radio-
therapy [42]. In the absence of radiotherapy, tamoxifen was,
again, associated with a 30% overall reduction in breast
events through reduction in DCIS recurrence as well as con-
tralateral DCIS and invasive disease events. Tamoxifen was,
however, ineffective in preventing ipsilateral invasive recur-
rence, and in the presence of radiotherapy, tamoxifen also
appeared ineffective. Survival was not improved by the addi-
tion of radiotherapy or tamoxifen on top of surgery alone in
this trial, with breast cancer accounting for only 20% of all
deaths (2% breast deaths and 11% overall deaths) [42].
Overall, meta-analysis including these trials suggests a mod-
est additional benefit of tamoxifen over a combination of
breast conservation and breast radiotherapy for local recur-
rence with a reduction from 14.1% to 9.7% [49].
Recently, anastrozole, an aromatase inhibitor (AI), has
been compared to tamoxifen in postmenopausal women
with DCIS. In NSABP B-35 which enrolled 3104 postmeno-
pausal women who had undergone lumpectomy with con-
firmed clear margins and subsequent adjuvant radiation for
DCIS, anastrozole treatment was associated with a small but
statistically significant improvement in breast cancer-free
interval compared to tamoxifen (HR 0.73 [95% CI 0.56–
0.96], p = 0.023), although disease-free survival was the same
at 120 months (HR 0.89 [95% CI 0.75–1.07], p = 0.21) [50].
Among women <60 in this study (n = 1447), anastrozole was
associated with significant improvements in breast cancer-
rares1geo@gmail.com
DCIS features Locoregional recurrence Locoregional recurrence
no radiotherapy with radiotherapy
≤1 cm size 15.6% at10 years
>1 cm margin
Grade I, II
≤2.5 cm size ≥3 mm 6.7% 0.9%
margin
Grade I, II
18% at 5 years 8% at 5 years
28.1% at 10 years 12.9% at 10 years
24.7% at 10 years with 14.4% at10 years
tamoxifen
free interval and disease-free survival compared to tamoxi-
fen, with hazard ratios (HR) of 0.53 (95%CI 0.35–0.80) and
0.69 (95% CI 0.51–0.93), respectively. However, the
International Breast Intervention Study (IBIS) II trial, which
enrolled 2980 postmenopausal women with DCIS who had
undergone lumpectomy to achieve clear margins +/− radia-
tion, failed to demonstrate an improvement with the AI com-
pared with tamoxifen/placebo (HR 0.89 [95% CI 0.64–1.23],
p = 0.49) [51].
The reduction in contralateral disease and potentially of
local recurrence of DCIS with endocrine therapy needs to be
weighed against the relatively common side effects of tamox-
ifen (hot flashes, DVT and endometrial cancer) or aromatase
inhibition (hot flashes, arthralgia). The quality of life impacts
of symptoms secondary to endocrine therapy and the other
diseases associated with these agents give pause for thought.
As a result of the side effects, adherence to endocrine therapy
is poor; only 70% of women in the IBIS II trial were still tak-
ing their endocrine agent at 5  years [51]. Data from a
Canadian cohort [52] suggest that as few as 26% of women
will take tamoxifen as adjuvant therapy which, if extended to
the wider community, would diminish the value of adjuvant
endocrine therapy for DCIS.  However, for one woman to
benefit, 15 women with breast cancer need to be treated with
endocrine therapy [53].
Overall, by meta-analysis of 10-year event rates in 9404
women with DCIS, the event rate was 14.4% following breast
conserving therapy + radiotherapy but nearly twice that at
24.7% after breast conserving therapy + tamoxifen [49].
11.6.7 Neoadjuvant-Targeted Therapy
Neoadjuvant therapy has become standard of care for down-
staging both the primary and nodal disease for selected
patients with invasive breast cancer, but there is little evi-
dence for its use in DCIS. Although the issue of nodal disease
is not relevant for DCIS, theoretically reducing the size of
DCIS could allow the option of conservation rather than
Ductal Carcinoma in Situ
mastectomy as for invasive breast cancer. For DCIS, targeting
the oestrogen receptor or HER2 receptor preoperatively may
have theoretical appeal. The CALGB 40903 trial whereby
6  months of neoadjuvant letrozole has tested the potential
benefits of this AI to downstage DCIS in selected postmeno-
pausal women. However, given the time frames for DCIS to
recur or develop invasive disease, this currently experimental
approach will take some time to report outcomes.
11.7 Recurrence
11.7.1 Clinical Factors
Symptomatic presentation of DCIS is associated with higher
local recurrence rates [2, 43], with a relative risk on meta-
analysis of 1.35 (95% CIs 1.12–1.62) [54]. The risk of recur-
rence of DCIS decreases with age, independent of other
clinical and pathological factors; young women have a higher
overall risk and particularly a higher subsequent invasive
recurrence rate [55], although the cut-off varies within indi-
vidual studies. Given the predominance of DCIS in a screen-
detected population (usually >50  years historically), it is
largely from retrospective data sets that a higher-risk age cut-
off of 35 is apparent [47]. While family history may be associ-
ated with a higher risk of local recurrence, socioeconomic
status and ethnicity do not appear to be associated (unlike for
several forms of invasive breast cancer) [47].
11.7.2 Pathology Factors
Extent (size) of DCIS has been associated with an increased
risk of DCIS recurrence in both the randomised controlled
trial (RCT) and cohort study setting. Tumour size greater
than 2 cm compared to <0.9 cm was associated with increased
risk of local recurrence (HR 2.67, 1.66–4.30) in the UK/
Australia and New Zealand 2 × 2 design RCT of tamoxifen
and radiotherapy [44]. Similarly, extent >1.5 cm was shown
to be a risk for local recurrence in a large case series (2037) of
women treated at a single cancer centre [56].
The presence of DCIS at the resection margin in breast
conservation specimens increases the risk of local recur-
rence, whether or not radiotherapy is administered. In a
meta-analysis of 4660 women treated with breast conserva-
tion and radiotherapy from 22 trials [34], there was a two
thirds reduction in risk of local recurrence for negative com-
pared with positive margin involvement (OR 0.36, 0.27–
0.47). While no tumour on ink is acceptable at least in some
countries for invasive breast cancer margins, a margin of
2 mm between the DCIS and resection appears to be superior
to 1 mm or no tumour (DCIS) on ink in reducing the odds of
recurrence (OR 0.53, 0.26–0.96) [34], although margins up
to 10 mm do not confer additional benefits.
Grade of DCIS is difficult to assess consistently between
even experienced pathologists; the UK NHS BSP pathology
EQA scheme showed moderate reproducibility in DCIS
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123 11
when assessed on slides from a single block [57], but data in
the «real-life» setting are less consistent. The issue is compli-
cated further with different systems to grade DCIS, albeit
that DCIS grade is not typically variable within an individual
lesion [58]. The solid histological subtype of DCIS appears to
carry an increased risk of local recurrence over papillary and
micropapillary subtypes [35]. Indeed, comedo necrosis is
often a feature associated with high-grade DCIS, and at least
in some older clinical trials, the presence of comedo necrosis
has been associated with increased risk of DCIS recurrence
(HR 2.21, 1.52–3.20) [2].
Multifocality (using a definition of 5 mm separating two
foci of DCIS) has been associated with local recurrence,
independent of other pathology features both in the clinical
trial setting (HR 2.62) [59] and cohort series (HR 1.97, 1.27–
3.02) [60]; the risk, however, appears to be abrogated in part
by use of radiotherapy [41] such that breast conservation can
still be considered appropriate for such patients.
11.8 Prognostic Scores
Following the subtyping of invasive disease, it now appears
that similar molecular subtyping may be achievable and
clinically meaningful for DCIS.  Progression from DCIS to
invasive disease seems to be related to the intrinsic subtype of
the DCIS, reflecting distinct evolutionary pathways. A small
proportion of preinvasive expression profiles appear to
resemble those of invasive breast cancer with the DCIS
microenvironment potentially also involved. This raises the
possibility that such subtype-specific molecular markers
could predict risk of progression [61].
In practical terms, integrating clinical and pathological
factors is desirable to predict which DCIS may or may not
recur or which patients may develop invasive disease.
However, in the breast-screening era, such a prognostic scor-
ing system has not been achieved, and thus consideration has
been given to molecular markers including oestrogen recep-
tor (ER) progesterone receptor (PR), HER2 and markers of
proliferation. Based on retrospective series, ER-negative DCIS
has a higher rate of recurrence (12.2%) than ER-positive DCIS
(3.7%) at 5 years [62]. HER2-positive DCIS is associated with
an increased risk of recurrence of the DCIS even when cor-
rected for use of radiotherapy [63, 64]. The NSABP B-43 trial
examining the effect of two doses of adjuvant trastuzumab
concomitant with radiotherapy for HER2+ DCIS is of interest
in this regard (clearly trastuzumab as therapy for DCIS is not
considered a standard of care). High proliferation as assessed
by Ki67 expression has been linked to an increased risk of
local recurrence even adjusting for radiotherapy [64]. All
these trials suffer somewhat from short length of follow-up,
given that DCIS progression to invasive disease is recognised
to take more than 40 years in some cases [65].
Following on from the invasive breast cancer revolution in
molecular phenotyping, integrating molecular markers and
multigene expression scoring have become possible even from
formalin-fixed paraffin-embedded clinical material. From the
 124 S.A. Carter et al.
biomarker point of view, it has been proposed that expression
of p16, cox2 and Ki67 (with a cut off of 10%) is associated with
a higher (19.6% vs 4.1%) risk of subsequent recurrence as
invasive disease in a retrospective cohort of some 1162 women
treated by lumpectomy alone [66]. However, more recent
interest has focused on the Oncotype DCIS score (Genomic
Health, CA, USA) derived from the invasive breast cancer
scoring system of examining proliferation markers, ER and
HER2. The Oncotype DCIS 12 gene score, like the invasive
breast cancer score from which it was derived, generates a low
risk (<39), intermediate risk (39–54), or high risk (>55) score
on a scale of 0–100. It has been applied to two data sets of
patients treated with breast conservation alone, the ECOG
E5194 trial [67] and an Ontario cohort [68], respectively,
totalling 898 patients. Within these data sets, the DCIS gene
score has been reported to be an independent predictor of
local recurrence going beyond conventional predictive factors
such as age, size, subtype and multifocality. However, while
clear margins were required for the data analyses, the histori-
cal nature of the data sets and the relatively high local recur-
rence rates have hindered widespread adoption.
For 689 women treated with breast conservation and
radiotherapy (median follow-up of 9.2 years), the Oncotype
DCIS score was significantly associated with risk of local
recurrence (HR 2.42) although there was no interaction
11 between the DCIS score and radiotherapy [68]. Age < 50 years,
tumour size >1 cm and multifocality were independent risk
factors for local recurrence. Use of a DCIS risk score, which
could help quantify the risk of recurrence, may contribute to
individual patient decision making in the future.
Given that the recurrence rate is only 0.9% 7 years after
radiotherapy for low-risk patients with DCIS based on grade
and size [46], the true value of any genomic test may be to
distinguish which patients will benefit from radiotherapy or
even which patients benefit from any intervention at all.
11.9 Survival
Death from breast cancer after a diagnosis of DCIS is rare:
1.1% at 10 years and 3.3% at 20 years in one large US popula-
tion-based study. Young-age women (with a diagnosis of
DCIS before the age of 35) and black women had a worse
prognosis [47]. ER negativity, high grade, comedo necrosis
and larger tumour size were associated with increased risk of
death from breast cancer [47]. Surgery is associated with
improved survival for intermediate and high-grade DCIS,
but not for low-grade DCIS [69]. However, mastectomy ver-
sus breast conservation was not associated with a significant
difference in survival [47]. Despite the reduction in  local
recurrence, there is data indicating that use of radiotherapy is
not associated with a survival advantage [47], at least with the
current duration of follow-up available from most studies.
However, many still consider the prevention of invasive dis-
ease after treatment for DCIS a key issue as the minority of
women who do develop invasive disease have relatively poor
survival from the invasive breast cancer [2, 43].
rares1geo@gmail.com
11.10 Future Perspectives
Along with tailoring future treatment and selection of those
patients that may benefit from less intervention (active sur-
veillance rather than surgery, omitting radiotherapy and/or
avoiding endocrine therapy), other options may emerge. For
example, the concept of vaccine trials against HER2 for DCIS
is attractive [70] and may further change the outlook for
women with this diagnosis.
11.11 Conclusions
DCIS is currently a catch-all diagnosis for a form of non-
invasive breast neoplasia with particular histological features
but which represents a wide spectrum of conditions with
potential for overdiagnosis and overtreatment in some.
Despite concerns about overdiagnosis and overtreatment,
surgery remains the mainstay of treatment with adjuvant
radiotherapy reducing by half local recurrence of DCIS or
the development of invasive disease for breast conservation
patients and endocrine therapy also protective. The tailoring
of treatment on an individual patient basis is less certain than
for invasive breast cancer, but prognostic and predictive bio-
markers may improve therapy selection for women in the
future.
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 127 12

Imaging of the Breast
Petra Steyerova

12.1 Mammography – 128

12.1.1 Indications for Mammography – 128
12.1.2 Image Acquisition – 128
12.1.3 Breast Density – 128
12.1.4 Evaluation of the Image – 129
12.1.5 Abnormal Findings on Mammography – 130
12.1.6 Evaluation of a Previously Treated Breast – 131
12.1.7 Future Perspectives – 131

12.2 Breast Ultrasound – 133

12.2.1 Indications for Breast Ultrasound – 133
12.2.2 Ultrasound Examination of the Breast – 133
12.2.3 Abnormal Findings on Ultrasound – 134
12.2.4 Evaluation of the Axilla – 135

12.3 Breast MRI – 136

12.3.1 Indications for Breast MRI – 136
12.3.2 Technical Considerations and Protocol – 136
12.3.3 Evaluation of an MRI Study – 137
12.3.4 Limiting Factors – 137
12.3.5 Abnormal Findings on MRI – 137

12.4 Clinical Considerations – 138

12.4.1 Diagnostic Performance of Breast Imaging Modalities – 138
12.4.2 Multimodality Approach – 138
12.4.3 Preoperative Evaluation – 139

12.5 Reporting System – 141

12.6 Interventional Techniques – 141
12.6.1 Tissue Biopsy – 141
12.6.2 Imaging Guidance – 141
12.6.3 Types of Procedures – 142

12.7 Preoperative Marking – 143

12.8 Summary – 143

References – 143

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_12

rares1geo@gmail.com
 128 P. Steyerova
12.1 Mammography
Mammography is the primary imaging modality for the breast.
The technique differentiates tissues based on their density
using low-energy ionising radiation. The radiation dose from
mammography is very low (maximum 3  mGy) [1]. Digital
processing of full-field digital mammography improves image
quality; enables better visualisation of the breast parenchyma,
skin and subcutaneous tissue [2, 3]; facilitates image viewing
and archiving; and further reduces the radiation dose [4].
12.1.1 Indications for Mammography
Mammography is used for both screening and symptomatic
diagnosis. Indications for mammography include:
55 Breast cancer screening
55 Assessment of patients with clinical symptoms
55 Image-guidance for biopsy
55 Preoperative staging
55 Preoperative localisation
55 Therapy monitoring and follow-up
12.1.2 Image Acquisition
For standard examination of the breast, two views of each
12 side are obtained  – craniocaudal (CC) and medio-lateral
oblique (MLO at a 45° angle). Compression of the breast pro-
vides an even distribution of the tissue, improves contrast of
the image and reduces radiation dose, movement artefact
and summation of parenchyma (overlapping or superimpo-
sition of breast architecture). Good positioning is vital to
A B
..      Fig. 12.1  Categories of breast by density. A Breasts are almost
entirely fatty. B There are scattered areas of fibroglandular density.
C The breasts are heterogeneously dense, which may obscure small
rares1geo@gmail.com
ensure that all breast tissue is included in the image, from
nipple to chest wall together with part of axilla. More specific
views (spot compression, magnification views, lateral views,
extended and targeted views) can be used to provide more
information and to eliminate artefacts caused by superimpo-
sition of the tissue.
12.1.3 Breast Density
Breasts are composed of fibroglandular tissue and fatty tissue;
the proportion of these two determines the density of the
breast. The more fibroglandular tissue the breast consists of,
the higher the density is and the more likely small lesions may
be obscured by the background and the sensitivity reduced [5].
Breast density is classified into four categories according
to the BI-RADS® (Breast Imaging Reporting and Data
System) [6] (. Fig. 12.1):
A. Breasts are almost entirely fatty.
B. There are scattered areas of fibroglandular density.
C. The breasts are heterogeneously dense, which may
obscure small masses.
D. The breasts are extremely dense, which lowers the
sensitivity of mammography.
Approximately 10% of women have entirely fatty breasts (cat-
egory A), 40% of women have scattered densities (category
B), 40% have heterogeneously dense breasts (category C) and
10% of breasts are extremely dense (category D) [7]. Density
tends to decrease with age, therefore mammography is more
sensitive in women over 40 years of age, but there are women
with dense breasts even at an advanced age as well as young
women with fatty breasts [8].
C D
masses. D The breasts are extremely dense, which lowers the sensitivity
of mammography
Imaging of the Breast
129 12

..      Table 12.1  Proportion of women with different breast density categories according to age and age/patient group-related sensitivity
and specificity [8, 9]

Age A (%) B (%) C (%) D (%) Sensitivity (%) Specificity (%)

40–49 3 23 57 17 65.6–69.7 90.7–90.9

50–59 6 37 49 8 72.9–73.8 91.6–92.3

60–69 12 43 41 4 73.3 93

70–79 13 51 32 4 81.4 94.1

≥80 13 46 34 7 86.1 94.3

Breast implants 45 97.7

The proportion of women with different breast densities
in different age groups and sensitivity and specificity of mam-
mography in various patient groups is summarised in
. Table 12.1 [9].
 
12.1.4 Evaluation of the Image
Evaluation of a mammography study includes assessment
views are vital for differentiation of summation artefacts
from true lesions. If an asymmetric density is visible only
in one view, it is most likely caused by superimposition of
normal breast tissue; real lesions typically appear in both
views.
Comparison of new and previous images is essential for
detecting pathology, especially in the screening setting,
where a subtle change of focal breast density may be the
first and only sign of malignancy [10] (. Fig.  12.2). In

of both views of both breasts to detect possible abnormali- benign changes, comparison with previous images con-
ties; special attention is paid to the axilla and skin. Two firms the stable character and size of masses, distortions or

..      Fig. 12.2 Detecting
a b
malignancy. A developing density
as the only sign of pathology,
visible only in comparison of
current b to prior a image

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 130 P. Steyerova
microcalcifications especially if they are of not-typically
benign morphology. In such cases, the patient can be
spared unnecessary additional imaging or biopsy [11] (See
. Table 12.2).
The position of the lesion in the breast is determined
using two views. As the MLO view is obtained at a 45°
angle, the apparent position of the lesion in the MLO view
can appear to be shifted from the actual position in the
breast. Lesions located laterally are seen more cranially in
the MLO image, and lesions with a medial location in the
breast are projected more caudally as demonstrated in
. Fig. 12.3.
..      Table 12.2  Factors improving mammography performance
Full-field digital mammography
Correct positioning of the breast
Lower breast density
Comparison with previous images
12
..      Fig. 12.3  Shift in the apparent position of the lesion. The lesion
located laterally is seen more cranial in the image, lesion in medial part
of the breast is projected more caudally
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12.1.5 Abnormal Findings
on Mammography
Abnormal findings on mammography may include:
55 Masses (characterised by shape, margins and density)
55 Architectural distortions
55 Asymmetries
55 Microcalcifications (evaluated by their morphology and
distribution)
Associated features such as skin and nipple changes (thicken-
ing, retraction), chest wall invasion or axillary lymphade-
nopathy may also be seen.
Typical Imaging Findings
Typical malignant lesions appear on mammography as irreg-
ular masses with spiculated or indistinct margins and a den-
sity equal to or higher than the breast parenchyma; see
. Fig. 12.4. Distortion of the parenchyma or retraction may
be a sign of malignancy even if a distinct mass is not visible.
Mammography shows higher sensitivity for ductal carci-
noma (79.1–80%) than for lobular carcinoma (67.2–72.1%)
[12, 13]. In BRCA mutation carriers, the tumours manifest
less frequently as spiculated masses or distortions, and the
lesions are frequently well circumscribed mimicking benign
disease which results in lower sensitivity of mammography
in high-risk women [14].
Some malignant lesions manifest mainly as microcalcifi-
cations. They may or may not be associated with masses.
Microcalcifications are highly suggestive of malignancy if
they are amorphous, fine pleomorphic, fine linear with/with-
out branching or coarse and heterogeneous. Distribution fol-
lowing ductal anatomy (linear, segmental or regional) is a
suspicious feature (. Fig. 12.5) [15].
Benign lesions are usually oval or round with smooth
margins and variable density. Lesions of very low density con-
taining fat are almost always benign. Mammography alone
cannot differentiate between solid and cystic lesions as they
appear similar; consequently, additional evaluation by ultra-
sound is usually needed.
Benign microcalcification in the breast is a frequent find-
ing. Benign features include a cutaneous or vascular location,
a round shape or rim appearance, large coarse «popcorn-­
like» morphology typical for calcifying fibroadenomas, a
large rod-like shape and a peri-, intraductal or diffusely
homogeneous punctate pattern. Amorphous dystrophic cal-
cification after trauma or surgery and milk-of-calcium sedi-
ment calcifications in microcysts also have a typical
appearance and are of benign origin (. Fig. 12.6).
Imaging of the Breast
..      Fig. 12.4  Breast cancer in mammography. Typical appearance of a
malignant lesion (arrow) with indistinct margins and higher density
than normal parenchyma
12.1.6 Evaluation of a Previously Treated
Breast
During the follow-up period after locoregional treatment
(surgery and radiotherapy), mammography is an essential
part of evaluation of the breast to rule out local recurrence
[16]. Evaluation of the treated breast can sometimes be chal-
lenging due to the presence of post-treatment changes which
may make interpretation difficult (. Fig. 12.7). It is therefore
vital that the request for post-operative imaging also gives
details of the treatment.
Postsurgical and postirradiation changes include:
55 Scarring – deformity of the breast, distortion of the
parenchymal pattern.
55 Skin thickening.
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131 12
..      Fig. 12.5  Suspicious microcalcifications in magnification view.
Coarse heterogeneous morphology with ductal distribution, histol-
ogy – ductal carcinoma in situ
55 Radiation fibrosis and lymphoedema giving rise to a
reticulated pattern which may increase the density of the
breast parenchyma diffusely.
55 Postsurgical fluid collections (seromas) and hemato-
mas – may mimic masses and may persist for many
months or even years after surgery.
55 Fat necrosis – especially in cases of conservation where
extensive oncoplastic parenchymal mobilisation was
performed. Locating the site of the primary tumour
may be challenging and scarring within the breast wide-
spread.
55 Calcification – dystrophic calcification must be
­differentiated from residual calcifications (not removed
by surgery) or recurrent disease.
55 Artificial material – surgical clips, sutures, implants and
autologous flaps.
55 Lipomodelling – may have been performed which may
result in scarring, fat necrosis and calcification.
12.1.7 Future Perspectives
Several new methods based on mammography are being
developed and researched to improve diagnostic perfor-
mance of the modality.
 132 P. Steyerova

a b

c d

12

..      Fig. 12.6  Benign microcalcifications. a coarse «popcorn-like» in a benign mass representing fibroadenoma, b homogeneous punctate
microcalcifications, c large rod-like calcifications, d amorphous dystrophic calcifications in fat necrosis after surgery

Digital breast tomosynthesis (DBT) is a relatively
recent advance providing a 3D picture of the breast.
Multiple low-­dose images are taken during movement of
the x-ray tube in an arc around the breast. A 3D image of
the breast is reconstructed from the acquired images and
viewed in multiple parallel sections (slices) 1  mm thick.
This enables better visualisation of distortions and masses
as shown in . Fig. 12.8. DBT has demonstrated increased
 
sensitivity (90.7% vs. 85.2%) in comparison to digital
mammography [17] and reduced false positives caused by
summation of normal breast structures, asymmetries and
distortions [18]. However, evaluation of microcalcification
may be limited. Due to the increased number of images,
the reading time for a DBT study is longer than for mam-
mography. The radiation dose from DBT (when used as
standalone method) is not higher than that of digital mam-
mography [19].
Contrast-enhanced spectral mammography (CESM) is a
novel approach using a pair of low-energy and high-energy
images and intravenously administered iodine-based con-
trast media to improve detection of pathology. Its use is cur-
rently being studied.

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Imaging of the Breast
133 12
12.2 Breast Ultrasound

Ultrasound (or ultrasonography) is a method using high-­

frequency acoustic waves; the image is composed in real time
based on different reflective characteristics of the tissues. For
breast imaging, linear transducers with a minimum frequency
of 10–12  MHz are recommended [20]. The method carries
practically no risk to the tissue and can be safely used in all
groups of patients, also during pregnancy and breastfeeding.

12.2.1 Indications for Breast Ultrasound

Breast ultrasound is used as a standalone diagnostic technique

or in combination with other imaging modalities. Indications
for breast ultrasound include:
55 Adjunct method to screening mammography [21, 22]
55 Confirmation and characterisation of abnormalities
found in other modalities
55 Evaluation of palpable masses and other breast-related
symptoms
55 Axillary staging in women with breast cancer
55 Evaluation of breast implants
55 Guidance of interventional procedures in the breast and
axilla
55 Evaluation of young, pregnant and breastfeeding
patients with clinical symptoms [23]

12.2.2 Ultrasound Examination of the Breast

..      Fig. 12.7  Breast after surgery and radiotherapy. A marked skin Ultrasound examination is performed in the supine position
thickening and multiple distortions are seen; the recurrence (arrow) is with the arms elevated to permit examination of all parts of
difficult to detect in the altered background

..      Fig. 12.8  Tomosynthesis vs. a b

digital mammography. Carci-
noma presenting as spiculated
mass (arrow) is more clearly seen
in tomosynthesis study b in
comparison to digital mammog-
raphy a

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 134 P. Steyerova
..      Table 12.3  Factors improving ultrasound performance
Technical parameters of the machine, optimal setting of the
image, high-frequency transducer
Systematic examination of the breast (in preventive setting)
Targeted examination (with correlation to mammography, MRI or
clinical finding)
Experience of the user
the breast. Ultrasound gel enables good contact between the
transducer and the skin surface. Evaluation of the image is
done in real time; still images are recorded for future refer-
ence for all abnormalities as well as representative documen-
tation of normal finding.
The quality of the examination is variable and is affected
by a number of factors  – the technical parameters of the
machine, setting of the image and the experience of the
user. Visibility of the lesion on ultrasound depends on its
biological nature and size. Some lesions might have a very
distinctive morphology on ultrasound, such as cysts, and
some lesions might have a very subtle appearance (fibroad-
enomas or some malignant lesions). The majority of micro-
calcifications are not visible on ultrasound at all (see
. Table 12.3).
12
While handheld ultrasound is already widely available,
automated breast ultrasound (ABUS) is currently being
introduced to provide less operator dependence, higher con-
sistency and reproducibility and less physician time for image
acquisition. The image is acquired by a wide field-of-view
high-frequency transducer placed on the breast with mini-
mum compression. The images are subsequently evaluated
on a workstation; viewing in multiple anatomical planes is
a b
..      Fig. 12.9  Mass lesions in ultrasound; a malignant tumour with indistinct margins, markedly hypoechoic, with bright dots representing
microcalcifications; b benign lesion – fibroadenoma – with smooth contours, parallel orientation, homogeneous structure
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possible to detect mass lesions as well as distortions. ABUS
can be valuable especially in the preventive setting, as an
additional screening tool for high-density breasts, where it
improves cancer detection [24].
12.2.3 Abnormal Findings on Ultrasound
Breast lesions typically appear as space occupying masses
within the tissue. Lesions are assessed by their features
(shape, margins, orientation, the internal echo pattern, pos-
terior enhancement or shadowing, the presence or absence of
calcification) to estimate their biological character [25, 26].
Typical Imaging Findings
Malignant lesions typically appear as hypoechoic masses
with an irregular shape, and they have poorly circumscribed
(spiculated or lobulated) margins, orientation non-parallel to
the chest wall/skin (taller-than-wide), with posterior shad-
owing; see . Fig. 12.9a. Malignancy can sometimes be seen
as an area of decreased echogenicity possibly with posterior
shadowing.
Benign lesions are usually oval, circumscribed, with a par-
allel orientation and homogeneous echo pattern with no pos-
terior features (. Fig. 12.9b). If all the morphologic criteria of
a benign lesion are met, the lesion does not require biopsy and
undergoes follow-up within a short time interval for assur-
ance of stability over time especially in younger women and
lesions smaller than 2 cm [27]. However, whenever there is a
marked increase in size or any of the descriptive characteris-
tics is not typically benign, biopsy should be performed as
some malignant tumours (especially in young women) may
mimic benign lesions. These may include medullary ­cancers,
high-grade cancers or mucinous cancers which can have
appearance similar to cysts or fibroadenomas. The finding on
Imaging of the Breast
..      Fig. 12.10  Evaluation of a patient with nipple discharge. Dilated
duct with intraluminal proliferation representing a papilloma (arrow) is
clearly seen
ultrasound should be also always correlated with other imag-
ing methods, clinical findings, age and risk factors. Attention
is needed to make sure that no malignant morphological sign
is missed in any of the imaging methods. In BRCA mutation
carriers, any new focal lesion should be biopsied despite its
benign appearance in ultrasound.
Cysts and fluid collections can be reliably differentiated
from other lesions due to the typical feature of liquid content
appearing black (anechoic). If in doubt, fine needle aspira-
tion can be performed to confirm the cystic character of the
lesion.
Ducts are often evaluated in patients with nipple dis-
charge [28]. Focused ultrasound examination can sometimes
a b
..      Fig. 12.11  Lymph nodes in ultrasound. Normal lymph node a and pathological b lymph nodes with marked thickening of cortex and
displaced hilum
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135 12
reveal changes in the ducts, usually as echogenic lesions in
the lumen indicating intraductal proliferation (typically pap-
illoma), as shown in . Fig. 12.10.
12.2.4 Evaluation of the Axilla
Assessment of the axilla is an integral part of imaging
evaluation of the breast especially when a malignancy is
suspected. Ultrasound is a useful tool to predict lymph
node involvement and to guide tissue sampling of the
nodes [29].
To predict metastatic involvement of lymph nodes, vari-
ous aspects of the node are assessed – size, shape, margins,
cortical thickening, hilar compression or displacement.
Normal lymph nodes typically have a thin cortex
(. Fig. 12.11a). Metastatic involvement of the lymph node is
suspected if cortical thickening (more than 2.5–3  mm) is
present especially with compression or displacement of the
hilum [30] (. Fig. 12.11b). Uniform cortical thickening may
be suggestive of a range of different pathologies: reactive
changes, immunological/systemic inflammatory disease or
haematological malignancy such as lymphoma or chronic
lymphocytic leukaemia (CLL) [31].
Ultrasound is also used for guidance of lymph node
biopsy to confirm or rule out metastatic involvement. The
diagnostic performance of ultrasound, fine needle aspira-
tion biopsy and core biopsy of lymph nodes are shown in
. Table 12.4 [32, 33].
For evaluation of the axilla and nodal staging, more
advanced imaging methods have been studied such as MRI
(superparamagnetic iron oxide (SPIO) tracer-enhanced) or
PET/CT, but their use is not yet part of routine practice.
 136 P. Steyerova
..      Table 12.4  Diagnostic performance of methods of axillary
staging [32, 33]
Ultrasound (%) FNAB (%) Core biopsy (%)
Sensitivity 61.4 72.2 83.3
Specificity 82 100 100
12.3 Breast MRI
Magnetic resonance imaging of the breast (MRI, MR
mammography, MRM) is increasingly used in the charac-
terisation and diagnosis of breast pathology. The method
characterises tissues based on their morphology and tissue
composition which result in variable signals on different
MRI sequences. Breast MRI uses application of contrast
media to detect pathology and assesses the biological features
of the lesions. Interpretation is complex and requires skill,
experience and time.
12.3.1 Indications for Breast MRI
The indications include both screening and diagnostic use [34]:
55 High-risk screening – population of women with high
12 lifetime risk of breast cancer [35–37].
55 Preoperative staging – evaluation of the extent of disease
and detection of possible multifocality or multicentricity or
contralateral cancer in patients with proven breast cancer.
55 Pretreatment evaluation of local disease extent – evalu-
ation of the possible involvement of chest wall, vascular
or nerve bundles to assess operability.
55 Monitoring of primary systemic therapy – MRI can
evaluate early changes in the tumour caused by che-
motherapy to demonstrate the effect of therapy. It is
also valuable at baseline in establishing the pattern of
disease in the breast and whether it is likely to undergo
concentric or fragmented shrinkage and hence help to
select women who may be unlikely to achieve BCS after
primary systemic therapy [38].
55 Assessment of residual disease after primary systemic
treatment [39].
55 Unclear findings from conventional methods – equivo-
cal findings on mammography or ultrasound, discor-
dance with clinical findings or differentiation of scar
from recurrence; MRI is recommended only in cases
when biopsy is not possible.
55 Detection of an occult primary tumour in patients with
metastatic involvement of axillary lymph nodes (of
mammary subtype on pathology) and negative mam-
mography and ultrasound.
55 Assessment of breast implants – a non-contrast protocol
with sequences specific to silicone and fluid is used
(. Fig. 12.12).
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..      Fig. 12.12  Evaluation of implant by MRI. Sequence with silicon
suppression. The patient’s left implant (seen right on the image) is
normal, while right implant is ruptured. Pathological content of mixed
signal between capsules of the implant (asterisk) can be seen
indicating leak of silicone, and the inner capsule is markedly folded
12.3.2 Technical Considerations
and Protocol
For breast imaging, a minimum 1.5 Tesla device is used with
a dedicated breast coil providing sufficient quality images
with high spatial resolution. During the examination, the
patient lies prone on the MRI table with her breasts loosely
placed inside the coil. Gadolinium-based contrast media at a
dose of 0.1 mmol/kg body weight is given intravenously by
an automatic injection device to ensure constant flow.
Contraindications to MRI examination include implanted
pacemakers (with the exception of MRI-compatible devices),
implanted metallic material (e.g. cochlear implants, vascular
stents and clips) or metallic foreign bodies, in any anatomic
location. Claustrophobia may be a limiting factor. Allergies
to MRI contrast media and impaired renal function must be
noted [40].
Although MRI as a method is considered safe in preg-
nancy, its use for breast cancer detection requires adminis-
tration of gadolinium contrast media which crosses the
placental barrier. The gadolinium-based contrast media
seems not to have teratogenic or mutagenic effects, but long-­
term adverse effects on the foetus and child development are
possible and are still being studied, and therefore gadolinium
administration in pregnancy should not be considered risk-­
free, and the risk-benefit ratio should always be carefully
evaluated [41]. The value of MRI during breastfeeding may
be limited due to the physiological changes in the lactating
breast tissue, but can still provide important information.
Gadolinium contrast media can be used safely as it is excreted
to the breast milk; however, the amount received by the child
is very low. All of the gadolinium administered to the mother
is eliminated within 24  hours so if preferred breastfeeding
can simply be interrupted for a day.
Imaging of the Breast
Examination protocols may vary between institutions.
Scanning time using the full protocol ranges between 15 and
30 minutes and usually includes:
55 T2-weighted images (T2WI) with/without fat suppression.
55 T1-weighted images (T1WI) without contrast.
55 Dynamic T1WI after contrast media administration –
series of scans with duration of 40–60s, 5–8 repetitions,
images with/without fat suppression. Image subtraction
supports visualisation of areas of contrast uptake.
55 Diffusion-weighted sequence (DWI) or MR spectros-
copy (MRS) may be added to the protocol.
Orientation of the scans is variable; the typical orientations
are axial (horizontal), coronal or sagittal slices, which can be
used to provide better anatomical orientation.
12.3.3 Evaluation of an MRI Study
The images are reviewed to detect areas of enhancement (sig-
nal increase after contrast media administration). Malignant
lesions tend to enhance early; they are typically seen in the
early dynamic T1WI with contrast. Morphology of the lesions
is assessed together with kinetic analysis of the contrast con-
tent in the lesion using data from the dynamic sequence [42].
A signal intensity curve is constructed; two phases of contrast
media dynamics are evaluated as shown in . Fig. 12.13:  
55 Initial – lesion uptake of contrast in the early phase (fast,
medium, slow)
55 Delayed – behaviour of contrast media in the later phase
(persistent uptake, plateau, washout)
The signal in other sequences can be helpful for characterisa-
tion of the lesion:
55 T2WI enhances the signal of fluid; oedema, fluid collec-
tions and liquid content of the lesions are easily visible.
In T2WI malignant tumours are typically darker, while
benign lesions appear brighter.
Signal intensity
Initial phase Delayed phase
..      Fig. 12.13  Evaluation of contrast media dynamics in the lesion.
Red curve – rapid uptake of contrast with washout in delayed phase,
typical for malignant lesions. Blue curve – slow uptake initially,
persistent uptake in delayed phase, typical for benign lesions
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137 12
55 DWI evaluates movement (diffusion) of water molecules
through tissue. Diffusion is restricted in malignant
lesions due to their high cellularity. The restriction is
quantified by the apparent diffusion coefficient (ADC).
ADC values can be helpful in differentiation of benign
(higher values) and malignant (lower values) lesions and
can reduce the number of false positives and unneces-
sary biopsies [43].
55 Magnetic resonance spectroscopy (MRS) analyses
the chemical content of the lesions. Studies have demon-
strated elevated choline content in malignant tumours
[44].
Both advanced sequences (DWI and MRS) are not a manda-
tory part of most MRI protocols, but they can provide useful
additional information and increase the diagnostic accuracy
of the examination.
12.3.4 Limiting Factors
Background parenchymal enhancement (BPE) may limit
the efficacy of MRI. It is characterised by early symmetric
diffuse enhancement of the whole parenchyma presum-
ably based on hormonal changes [45]. Small lesions can be
masked by the enhancing background or mimic pathol-
ogy. The timing of examination during the menstrual cycle
(days 7–14) and elimination of external hormonal influ-
ence are recommended to limit BPE.  Additionally back-
ground parenchymal enhancement seems to be a risk
factor for developing subsequent breast cancer [46] (See
. Table 12.5).
12.3.5 Abnormal Findings on MRI
Pathological findings appear as:
55 Masses – characterised by their morphology (shape,
margins, internal enhancement characteristics), kinetics
of contrast media and signal characteristics in various
sequences.
55 Non-mass-like enhancement (NMLE) areas – assessed
by their distribution and internal enhancement patterns.
..      Table 12.5  Factors improving MRI performance
MRI protocol, sequences with high spatial resolution
Elimination of influence of hormonal changes to reduce
background parenchymal enhancement
Correlation of MRI with other modalities
Transfer of MRI information to clinical practice (preoperative
bracketing, clip placement)
 138 P. Steyerova

Typical Imaging Findings To differentiate benign and malignant lesions that have a
A malignant mass is usually of irregular shape with non-­ similar morphology, combined use of the sequences and con-
circumscribed (lobulated or spiculated) margins and hetero- trast dynamics may be helpful as demonstrated in . Figs. 12.15  

geneous internal enhancement (. Fig. 12.14a). After contrast

  and 12.16 .
media administration, there is a rapid inflow in the early
phase followed by washout in the delayed phase forming a
typical curve. In T2WI the mass has a decreased signal, appar- 12.4 Clinical Considerations
ent diffusion coefficient (ADC) values are low and the choline
peak is elevated. 12.4.1 Diagnostic Performance of Breast
Some malignancies (especially ductal carcinoma in situ) Imaging Modalities
appear as non-mass-like enhancement areas (NMLE)
(. Fig. 12.14b). These areas have a linear, segmental or regional The diagnostic performance of each method is shown in
 

distribution following ductal and lobar anatomy. . Table  12.6 [47]. In mammography, sensitivity greatly
 

Benign lesions are typically oval or round in shape, with depends on mammographic density; sensitivity is very high in
circumscribed margins and homogeneous enhancement. fatty breasts and lower in dense breasts. In the group of high-
The uptake of contrast media is slow initially and persistent risk women (BRCA carriers, e.g. who are usually young),
in the delayed phase. Fibroadenomas can have dark inter- detection of lesions on mammography and ultrasound is more
nal septations which are considered characteristic. In T2WI difficult than in normal women. For this reason, MRI, with its
benign lesions are usually brighter, and ADC values are sensitivity reaching almost 100%, is used for early detection in
higher due to nonrestricted diffusion; no elevated choline this population [48].
peak is observed.

12.4.2 Multimodality Approach

a Breast imaging modalities are sometimes reported separately,
sometimes as a combined examination report. When a find-
ing is unclear from one modality, the other methods can pro-
12 vide complementary additional information.
The most frequent combination is adding ultrasound to
mammography for further assessment of a finding suggested
by the images or in patients with clinical findings where
mammography is inconclusive or when a pathological find-
ing might be obscured or not captured in the image (dense
area of the breast, clinical finding in a peripheral area of the
breast or in the axilla, etc.). If an abnormity is found on mam-
mography or ultrasound that is suggestive of malignancy,
tissue biopsy is preferred to further use of advanced imaging
modalities (MRI).
b Especially in dense breasts, additional modalities are
used to increase the sensitivity of the examination and find
pathologies that might be obscured in mammography by
dense parenchyma. The value of different methods when
combined with mammography is summarised in . Table 12.7.
 

Microcalcifications are mainly assessed by mammogra-

..      Fig. 12.14  Breast cancer in MRI. Malignant lesions (arrows) appearing
as mass lesion a and extensive non-mass-like enhancement (NMLE) b
phy based on their morphology and dynamics over time (in
comparison to previous images). Negative ultrasound find-
ings for mammographic microcalcification do not rule out
malignancy, and tissue sampling is recommended based on
mammography alone. However, an associated finding on
ultrasound may increase the level of suspicion for a malig-
nant lesion [49]. MRI might be suggestive of malignancy if an
enhancing area is co-localised with an area of microcalcifica-
tion, but lower-grade pathologies such as ductal carcinoma in
situ (DCIS) might be underestimated if MRI is negative [50].

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Imaging of the Breast
..      Fig. 12.15  Characterisation of the lesion using multiple sequences.
Malignant tumour (arrows) with inhomogeneous internal enhance-
ment with slightly indistinct margins in T1WI (T1-weighted images)
12.4.3 Preoperative Evaluation
When malignancy is found, the results of all imaging modal-
ities should be correlated together and reviewed in a multi-
disciplinary meeting alongside clinical and pathology results
to give a clear conclusion and to support proper further man-
agement. Clinical considerations should be presented
(. Fig. 12.17), and all important findings must be identified
and reported.
Special attention must be paid to:
55 The presence or absence of multifocality/multicentricity
or bilateral pathology – and a detailed search for addi-
tional lesions should always follow identification of a
single lesion. MRI with its high sensitivity is sometimes
used for assessment if there are uncertainties about the
extent of the disease from conventional imaging, a dis-
crepancy between clinical finding and imaging or when
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139 12
Kinetic analysis
with contrast, lower signal and perifocal oedema in T2WI (T2-weighted
images) with fat suppression, low ADC (apparent diffusion coefficient)
values and dynamic curve with rapid uptake and washout
the histology is suggestive of possible multifocality/
multicentricity (e.g. lobular cancer subtype). MRI can
bring more information (finding more lesions in 16% of
patients, identifying contralateral disease in 3–4%) but
can also cause changes in the surgical approach (con-
version to more extensive surgery in 11% of patients;
conversion from local excision to mastectomy in 8%)
or a delay in surgical management when additional
procedures (such as biopsy of a newly found lesion) are
required [51–53]. Despite the changes in the surgical
plan induced by the use of MRI preoperatively, there
seems to be no improvement in surgical outcomes
(re-excision rate) nor long-term outcomes (ipsilateral
recurrence rate, survival rate) for most histology types
including DCIS [54]. More clinically beneficial impact
of MRI can be seen in invasive lobular carcinoma where
additional lesions are seen in 32% including 7% of
 140
P. Steyerova

Kinetic analysis

12 ..      Fig. 12.16  Characterisation of the lesion using multiple sequences. in T2WI (T2-weighted images) with fat suppression, ADC (apparent
Benign mass with lobulated margins and slightly inhomogeneous diffusion coefficient) values are high, and dynamic curve shows slow
enhancement in T1WI (T1-weighted images) with contrast, high signal persistent uptake

..      Table 12.6  Diagnostic performance of breast imaging ..      Table 12.7  Performance of imaging methods as adjunct to
modalities [21, 37, 47, 48] mammography in dense breasts (women with negative
mammography) [9, 17]
Mammography Ultrasound (%) MRI (%)
(%) +DBT + Hand-held +ABUS +MRI (%)
(%) ultrasound (%)
Sensitivity 47.8–98a 75.3–83 75–100 (%)
32.6–50 39.5–50
high-risk women high-risk women Sensitivity 91–93 80–83 67.6 75–100

Specificity 83.8–93.8 86–96.7 78–97.2 Specificity 69–71 86.4–94.5 91.6 78.1–93.2

aNote: Sensitivity of mammography depends on density – 98%

for category A, 82.9% for category B, 64.4% for category C and

47.8% for category D
patients identified as having contralateral lesions result-
ing in a change of surgical plan in 28.3% [55]. Therefore,
the use of MRI in preoperative planning should be
always discussed by the multidisciplinary team, and the
benefits to risk ratio should always be considered.
If a suspicious lesion is found on MRI which would alter
the planned treatment, histological verification is
required. Correlation with conventional methods can be
helpful as some of the lesions can be found retrospec-
(targeted ultrasound examination in correlation with
MRI images) [56] and biopsied more easily under the
guidance of conventional imaging modalities. If a
suspicious lesion can only be seen in MRI, MRI-guided
biopsy is indicated, although is only available in a
limited number of centres.
55 Skin and chest wall involvement – detailed assessment
of the skin or chest wall involvement can be difficult
to identify by mammography, but ultrasound can be
very helpful in showing thickened skin and infiltration
of the cutaneous layer by a pathologic mass, as seen
in . Fig. 12.18. Invasion of the chest wall can be more

tively on mammography or by second-look ultrasound challenging for ultrasound to identify due to the depth

rares1geo@gmail.com
Imaging of the Breast
..      Fig. 12.17  Identification of various pathological features in
mammography. Pathological mass in the breast (circle), enlarged lymph
nodes in axilla (upper arrow) and thickening of the skin (lower arrow)
..      Fig. 12.18  Skin involvement by tumour in ultrasound. Malignant
tumour with clearly visible infiltration of skin (arrow)
rares1geo@gmail.com
141 12
limitations of the probe. MRI provides the most accurate
information regarding skin or chest wall invasion.
55 Nipple involvement and tumour distance from the
nipple should also be assessed as this will help when
planning the surgical approach.
12.5 Reporting System
Breast imaging requires standardised and structured report-
ing. The report includes information regarding breast com-
position/density (which indicates the likely sensitivity of the
examination), the presence or absence of any lesions, their
size and location. The BI-RADS® assessment categories sys-
tem is used to conclude breast imaging reports. Categories
(0–6) express the likelihood of malignancy of the lesion.
For further clinical consideration, each category is associ-
ated with recommendation for the patient’s management
[57]. A summary of the BI-RADS® categories is shown in
. Table 12.8.
12.6 Interventional Techniques
12.6.1 Tissue Biopsy
If a lesion is found in any imaging modality that is classified
BI-RADS 4 or 5 indicating suspected malignancy, tissue sam-
pling is mandatory to evaluate the biology of the lesion prior
to clinical management. Indeterminate or likely benign
lesions are usually biopsied as well to determine their bio-
logical nature with the exception of young women (under 25)
with clearly benign lesions on imaging where biopsy may be
avoided.
12.6.2 Imaging Guidance
The guidance method for an intervention is chosen by the
radiologist to ensure the easiest and safest navigation of the
needle and the most reliable result of the biopsy.
55 Ultrasound guidance – If the lesion is seen on ultra-
sound, ultrasound-guided biopsy is the fastest and easiest
way of obtaining a tissue sample. Real-time navigation
of the needle ensures constant control of its position and
maximum precision of sampling. Ultrasound-guided
biopsy can also be safely used in the axilla.
55 Mammographic (stereotactic) guidance – This is mostly
performed for microcalcifications or distortions that
are not seen by ultrasound. An upright sitting or prone
table are used to position the patient and the breast. The
location of the lesion in the breast is calculated from two
15°-angle views or from the position on tomosynthesis.
The position of the needle is adjusted intermittently by
 142 P. Steyerova
..      Table 12.8  Breast imaging Reporting and Data System (BI-RADS®) categories
Category Assessment
0 Incomplete – need
additional information
1 Negative
2 Benign
3 Probably benign
4 a Suspicious
b b > 10% but
c c > 50% but <95%
5 Highly suggestive of
malignancy
6 Known biopsy-proven
malignancy
Note: Dividing category 4 into a, b, c applies only to mammography and ultrasound; MRI uses category 4 for lesions with likelihood of
malignancy >2% and <95%
mammographic monitoring. A marker clip should be left
12 at the biopsy site, both to facilitate rebiopsy or surgical
excision and also to confirm that the biopsy was taken
from the target area. Specimen radiography is performed
to confirm the presence of microcalcifications in the
samples, which must also be confirmed histologically.
55 MRI guidance – If a suspicious lesion is only seen by
MRI, MRI is used for navigation of the needle. The
position of the lesion is determined from the images
relative to a marker of known location. Insertion of the
needle into the breast requires a positioning grid or pil-
lar accommodated within the breast coil. The position
of the needle during navigation and biopsy is verified by
further MRI sequences.
12.6.3 Types of Procedures
Tissue biopsy is done by needles of various diameters.
55 FNAB (FNA) – fine needle aspiration biopsy – uses a
fine gauge (22G) needle and obtains clusters of cells.
Cooperation with an experienced cytopathologist is nec-
essary to provide a reliable diagnosis. The technique is
mainly used for assessment of lymph node involvement.
It is relatively painless, quick and cheap but has a high
rate of inadequate biopsies and is not able to discrimi-
nate between invasive and in situ disease. It is more reli-
able in the assessment of axillary nodes as normal nodes
should never contain epithelial cells so their presence in
a node FNA is abnormal by definition.
rares1geo@gmail.com
Recommended management Likelihood of malignancy
Recall for additional imaging/compari- N/A
son with prior examination/correlation
with other information
Routine preventive interval 0%
Routine preventive interval 0%
Short-interval follow-up >0% but 2%≤
(6 months)
Tissue diagnosis >2% but <95% a > 2% but ≤10%
≤50%
Tissue diagnosis ≥95%
Further management as indicated Known malignancy
clinically
55 Core needle biopsy – uses a 12–18G needle (most
commonly 14G) providing a larger tissue sample
which enables a more specific tissue diagnosis includ-
ing determination of the tumour’s biological features
and predictive markers such as ER and Her-2 status
and proliferation markers (e.g. Ki67). Core needle
biopsy is the standard method for sampling suspicious
lesions [58].
55 Vacuum-assisted biopsy (VAB) – uses a special 6G–11G
needle, modified by the application of a rotating blade in
the needle head connected to negative pressure suction
which draws the tissue into the hollow needle sample
notch. This method obtains more tissue and is mainly
used for microcalcifications, atypical lesions or sus-
pected high-risk lesions [59].
55 Breast lesion excision system (BLES, Intact®) – is an
advanced modality which acquires one large tissue
sample via a capture basket. Radiofrequency waves
are used to delineate and excise the lesion. The system
enables removal of a tissue sample in one piece and
may have both diagnostic (larger sample for tissue
diagnosis) and therapeutic roles. The system can be
safely used for removal of indeterminate or high-risk
lesions, and surgery can be avoided in these cases
[60, 61].
The diagnostic performance of interventional methods is
summarised in . Table 12.9. All methods of tissue biopsy are
very reliable in diagnosing pathology; the risk of underesti-
mation of the lesion decreases with the increased size of the
needle/sample.
Imaging of the Breast
..      Table 12.9  Performance of interventional methods [58–60]
False Underestimation Underestimation
negatives rate of high-risk risk for DCIS (%)
(%) lesions (%)
Core 1–2 16–36 26–51
biopsy
(14/16G)
VABB 1–2 13–24 8–14
BLES 0 0 10–21.4
VABB vacuum-assisted breast biopsy, BLES breast lesion excision
system, DCIS ductal carcinoma in situ
55 Interventional procedures are done under sterile condi-
tions. Local anaesthesia is used for larger-needle interven-
tions. For insertion of needles of greater diameter, a skin
incision is needed. Tissue clips are applied to the biopsy
site for further reference. Interventional methods in the
breast have a very low complication rate (approx. 1%), with
bleeding or hematoma formation being the most common.
12.7 Preoperative Marking
References
The efficacy of imaging methods in the preoperative setting
depends greatly on how the information about the pathological
process is translated from the images to surgery. Close coop-
eration between the surgeon and the radiologist is essential.
Multiple methods of preoperative marking are possible [62]:
55 Wire guidance
55 Carbon marking
55 Radioactive marking (e.g. iodine seeds)
55 Clip placement
55 Skin marking or others
Single (for solitary lesion) or multiple (for more extensive
disease) localisation markers can be used. The modality
where the extent of the pathology is most reliably seen is used
to guide the placement of markers. Ultrasound-guided mark-
ing can be used for most of mass lesions; stereotactic naviga-
tion is usually necessary for areas of microcalcifications. For
MRI-only lesions, MRI-guided marking is required to ensure
delineation of the whole affected area. A marking protocol
containing schemes or images is useful to inform the surgeon
about the localisation of the markers in relation to the lesion
and the lesion’s extent.
12.8 Summary
As can be seen from the above, the role of the breast imaging
team is integral to both the diagnosis and management of
breast cancer. Advanced techniques with increased sensitiv-
ity are now available and have been a major contributing fac-
tor to improved outcomes for women with breast cancer.
rares1geo@gmail.com
143 12
Key Points
55 The choice of breast imaging modality depends
on the age of the patient, the purpose of the
examination, prior imaging findings and the
clinical context.
55 Maximum diagnostic efficacy is achieved by
combined use of imaging methods.
55 Optimised application of each technique com-
bined with an experienced radiologist to interpret
the findings is vital for the best result.
55 A BI-RADS® category should be included in every
breast imaging report; each category is associated
with a recommendation for further management
and helps to ensure concordance between
diagnostic modalities.
55 If a suspicious lesion is found on mammography
or ultrasound, tissue biopsy should be preferred
rather than further advanced imaging for
evaluation of the lesion.
55 The method where the lesion and its extent are
best seen is used for biopsy and preoperative
marking.
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 147 13

Breast Cancer Screening

John Mathew and Mark Sibbering

13.1 Introduction – 148

13.2 Principles of Screening – 148

13.2.1  The Condition Being Screened for Should Be an Important
Health Problem – 148
13.2.2  The Natural History of the Disease Should Be Well Understood – 148
13.2.3  There Should Be a Detectable Early Stage – 148
13.2.4  Treatment at an Early Stage Should Be of More Benefit than
at a Later Stage – 148
13.2.5  A Suitable Test Should Be Devised for the Early Stage – 149
13.2.6  The Test Should Be Acceptable – 149
13.2.7  Intervals for Repeating the Test Should Be Determined – 149
13.2.8  Adequate Health Service Provision Should Be Made for the Extra
Clinical Workload Resulting from Screening – 149
13.2.9  The Risks, Both Physical and 
Psychological, Should Be Less than the Benefits – 149
13.2.10  The Costs Should Be Balanced Against the Benefits – 150

13.3 Breast Cancer Screening Modalities – 150

13.4 Evidence from Breast Cancer Screening Trials – 152

13.5 Overdiagnosis Due to Mammographic Screening – 152

13.6 Age Range of Mammographic Screening – 153

13.7 Screening for Breast Cancer in Europe – 154

13.8 Organisation and Quality Assurance of Breast Screening

Programmes – 154

13.9 Surgical Considerations in Breast Screening – 154

13.10 Conclusion – 155

References – 155

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_13

rares1geo@gmail.com
 148 J. Mathew and M. Sibbering
13.1 Introduction
The World Health Organisation (Wilson and Jungner in 1968
[1]) have described criteria for assessing health screening
programmes (see . Table 13.1). These criteria generally apply
well to breast cancer and have formed the basis for the subse-
quent introduction of population-­ based screening pro-
grammes, predominantly using mammography.
13.2 Principles of Screening
13.2.1  The Condition Being Screened for
Should Be an Important Health Problem
Breast cancer is the most frequent cancer in Europe and the
second leading cause of death from cancer in developed
countries [2, 3]. Demographic trends indicate a continuing
increase in this substantial public health problem [3].
13.2.2  The Natural History of the Disease
Should Be Well Understood
The natural history of breast cancer is not completely under-
stood. Many appear to originate at a preinvasive stage, ductal
carcinoma in situ (DCIS), which may subsequently progress
to invasive breast cancer. Evidence for this includes:
55 A significant proportion of invasive breast cancers
having associated DCIS
13 55 Autopsy studies estimating that approximately one-third
of DCIS progresses to invasive cancer [4]
55 Studies where DCIS was initially misdiagnosed as a
benign lesion and later recognised to be DCIS and
where invasive cancer subsequently developed in a
significant proportion of women (15–75%) [5, 6]
55 In patients with DCIS treated by breast-conserving
surgery, approximately 50% of the local recurrences
following surgery are invasive cancers [7–9]
..      Table 13.1  Principles of screening (World Health Organization)
The condition should be a significant health problem
The natural history should be understood
There should be an early or latent stage
Treatment at an early stage should be of more benefit than
started at a later stage
There should be a suitable test
Test should be acceptable to the population
Screening should be repeated at intervals
Facilities available for diagnosis and treatment
Chance of harm should be less than chance of benefit
Cost effective
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However, it is unclear why some, but not all, DCIS progresses
to invasive cancer and why some invasive breast cancers arise
de novo with no DCIS.
13.2.3  There Should Be a Detectable
Early Stage
Cancer screening aims to detect cancer before symptoms
appear. Screening is not useful for all cancers, and for the dis-
ease to be amenable to screening, there must be a latent
period during which it would be possible to detect the dis-
ease before it reaches an advanced stage.
Breast cancer is a heterogeneous disease both with regard
to variation among tumours and also the cellular composi-
tion within individual tumours. Two events are thought to
occur in its natural history and progression: early dissemina-
tion and phenotypic progression [10]. If one or both events
are related to the size of the breast tumour, then early detec-
tion of the tumour may prevent dissemination of tumour
cells or the development of a more aggressive tumour that
may lead to improved prognosis.
For breast cancer, there is a detectable preclinical phase
where tumours are visible on mammograms before they
become palpable. Tumours detected are more likely to be
non-invasive, and if already invasive less likely to have
regional or distant spread.
13.2.4  Treatment at an Early Stage
Should Be of More Benefit than
at a Later Stage
Screening aims to identify asymptomatic individuals at an
early point in their natural history when delivery of early
treatment could potentially reduce mortality. Direct com-
parison of outcomes in women presenting with symptomatic
breast cancer is not valid without taking into account three
potential biases:
1. Lead time bias – the apparent improvement in survival
that is seen when screening advances the time of diagno-
sis to time of death without any change in the actual time
of death, merely reflecting a greater period of time that
the individual is aware of the presence of cancer due to
earlier detection.
2. Length-time bias – screening has the potential to pick up
more cancers that are less aggressive and slow growing as
opposed to rapidly growing aggressive cancers which are
more likely to present symptomatically in-­between screens.
3. Selection bias – women who attend for screening are more
likely to be heath aware than those who decline and will
probably have a better prognosis regardless of the offer of
screening.
These biases can potentially be removed in randomised trials
of population-based screening as described later.
Breast Cancer Screening
13.2.5  A Suitable Test Should Be Devised
for the Early Stage
A screening test should detect the majority of women who
have cancer (high sensitivity) while eliminating most women
who do not have cancer (high specificity). Sensitivity is defined
as the proportion of all women with breast cancer who test
positive. Specificity is defined as the proportion of all those
without breast cancer that test negative. An ideal screening test
should have 100% sensitivity and specificity, but in reality no
screening test will achieve this. Different modalities for breast
cancer screening are described later, but mammography has
been the commonly used modality for general population-
based screening programmes due to its combined high sensi-
tivity and specificity compared to other screening modalities.
13.2.6  The Test Should Be Acceptable
The success of any screening programme will be dependent
on the acceptability of the screening test to the population
being screened. This will be reflected by the rate of uptake
following an invitation to attend for screening. In an over-
view of mammographic screening programmes operating in
Europe for the period 2005–2007 [11], 13 of the 26 pro-
grammes achieved the European Union benchmark of
acceptable participation (>70%), and 9 achieved the desirable
level (>75%) [12]. In England in 2014–2015, 2.11 million
women aged 45 and over were screened by the NHS Breast
Screening Programme, with an overall uptake of 71.3% [13].
13.2.7  Intervals for Repeating the Test
Should Be Determined
In order to be effective, screening should be repeated at regu-
lar intervals. This is a balance between the cost and practical-
ity of screening too frequently and minimising the number of
interval cancers that present between screens.
There is variation with regard to the time interval between
mammographic screens across EU states, most adopting a
policy of biennial mammograms [14], while in the UK
women are invited every 3 years.
Growth time or lead time is an important factor with regard to
deciding on frequency of screening [15]. Younger women are
more likely to have cancers with a shorter growth time poten-
tially increasing interval cancers as opposed to an increased
likelihood of slower growing cancers in older women. So theo-
retically younger women should have a shorter interval
between screens compared to their older counterparts. The
UK breast cancer frequency trial showed no benefit for women
aged 50–62 years of annual mammograms over 3 yearly mam-
mograms [16]. The study did show that tumours diagnosed in
women in the study arm were significantly smaller, but there
was no significant difference in terms of nodal status, histo-
logical grade and predicted mortality between the two groups.
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149 13
13.2.8  Adequate Health Service Provision
Should Be Made for the Extra Clinical
Workload Resulting from Screening
The impact of the introduction of breast screening pro-
grammes across Europe has been the development of breast
multidisciplinary teams both for the diagnosis and treatment
of breast cancer. The use of triple assessment for diagnosis in
breast care originated in breast screening practice and has
subsequently been widely adopted in symptomatic practice.
13.2.9  The Risks, Both Physical and 
Psychological, Should Be Less than
the Benefits
Potential physical and psychological hazards of screening
using mammography include:
1. Radiation exposure – use of x-rays for mammography
exposes women to low doses of ionising radiation that
could cause breast cancers. The actual dose of radiation
depends on several factors including the number of
views of each breast and whether film or digital mam-
mography is used.
It has been estimated that screening women every
3 years from age 47–73 in the UK breast screening pro-
gramme may cause 3–6 cancers per 10,000 women
screened [17]. Digital mammography, which uses a lower
radiation dose, is now more commonly used in screening
programmes, and it is likely that this risk is now reduced.
2. Overtreatment – unnecessary treatment following the
diagnosis of tumours that would never have been of
clinical significance in a woman’s lifetime. This is
discussed in more detail later.
3. Pain – the breast is compressed and flattened when
carrying out mammography in order to improve the
image quality and reduce the radiation dose. A substan-
tial proportion of women find this painful, and there is
evidence that painful mammography contributes to
non-re-attendance for breast screening [18].
4. False-positive results – a proportion of women are recalled
following mammography and found not to have cancer.
This is called a false-positive result. Recall rates vary
between different screening programmes and will be higher
at the first prevalent screen than subsequent incident round
screens. In England in 2014–2015, for women aged 45 and
over screened by the NHS Breast Screening Programme,
7.8% were recalled at their prevalent screen and 3.0%
following an incident round screen [13] .
Of the women recalled and found not to have cancer,
the majority will only have further imaging (ultrasound,
further mammography). Some will have a breast biopsy,
usually a core biopsy under local anaesthetic but occasion-
ally a formal open surgical biopsy under general anaes-
thetic. Numerous studies have assessed the psychological
impact of a false-­positive result on women with conflicting
 150 J. Mathew and M. Sibbering

results. A recent systematic review [19] concluded that, in
the population at general risk of breast cancer, a false-pos-
itive result can cause breast cancer-specific psychological
distress, lasting for up to 3 years.
5. False-negative results – no screening test is completely
accurate, and sometimes mammographic screening will
not detect a breast cancer. This can give a false sense of
reassurance and potentially lead to delays in treatment.
This may occur because the cancer is mammographi-
cally occult or develops as an interval cancer between
screening rounds. Women should be warned of this
possibility in literature given prior to breast screening.
13.2.10  The Costs Should Be Balanced
Against the Benefits
It is important to continually compare the cost-effectiveness of
health screening programmes against other healthcare provi-
sions. This can be expressed as cost per quality-adjusted life
year (QALY) gained. This has proved difficult to accurately
achieve for breast screening due to ongoing uncertainty regard-
ing the overall benefits and the development of breast screening
over time (e.g. one- to two-view mammography, age extension,
film to digital conversion, etc.). An assessment of the cost-effec-
tiveness of the UK NHS Breast Screening Programme con-
cluded that there was a moderate probability of breast screening
being cost-effective at a willingness-to-­pay threshold of £20,000
per QALY [20] but that further research was required.
13 In summary, breast cancer is a significant health problem,
application of mammographic screening with the aim of
early detection and treatment of cancer so as to improve out-
come. Mammography as a population-based screening
modality is well accepted in Europe and the UK as evidenced
by the relatively high participation rate as previously depicted.
Mammography is a reliable test (high sensitivity and specific-
ity) in the group undertaking screening, and the subjects are
relatively unharmed with the minimal radiation exposure
especially with the widespread adoption of digital mammog-
raphy across Europe.
13.3 Breast Cancer Screening Modalities
Three main screening methods have been assessed in
population-­based breast screening trials:
1. Clinical breast examination (CBE) – this has not been
tested in isolation but in conjunction with mammography
in randomised trials carried out in Edinburgh [21] and
Canada [22, 23]. There is no conclusive evidence showing
that CBE is effective in reducing breast cancer mortality.
2. Breast self-examination (BSE) – this has been evaluated in
population-based studies in Russia [24] and China [25].
The Shanghai study detected a significantly higher number
of breast cancers through BSE, but no significant effect on
breast cancer mortality was demonstrated in either study.
3. Mammography – this has been used as the main
screening modality for breast cancer since the 1970s. To
date there have been eight randomised trials (3 of them
reported in two parts) of mammographic screening [26],
which are summarised in . Table 13.2 and discussed in

the natural history of which is sufficiently understood for the the next section.

..      Table 13.2  Randomised trials of breast cancer screening

Start date Number of Age group Invited group Control Attendance

women (years) group
Method Interval
(months)

New York HIP 1963 62,000 40–64 M 12 nil 65%

CE

Malmo I and II 1976 60,076 45–69 M 18–24 nil 74%

Swedish Two County 1977 133,065 40–74 M 24–33 nil 85%

SE

Canada I and II 1980 89,835 40–49 and 50–59 M 12 CE and SE 88%

CE and SE

Stockholm 1981 60,800 40–64 M 24–28 nil 82%

Gothenburg 1982 52,222 40–59 M 18 nil 84%

UK Age Trial 1991 160,921 39–41 M 12 nil 81%

Edinburgh 1978 54,654 45–64 M 24 nil 65%

CE

M mammography, CE clinical examination, SE self-examination

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Breast Cancer Screening
A study of one- versus two-view mammography has shown
that the addition of a second craniocaudal view increases both
the sensitivity of screening during the prevalent round as well
as reducing recall rates [27].
More recently there has been a shift to full-field digital
mammography (FFDM) rather than analogue (film) mam-
mography for breast screening. The prospective OSLO II
Study demonstrated that FFDM resulted in a significantly
higher cancer detection rate than film mammography in a
151 13
transferred and stored providing more efficient screening
services.
A newer development in breast cancer screening is the
use of digital breast tomosynthesis (DBT) which is a three-­
dimensional mammography technique. The STORM Study
demonstrated that the addition of DBT to mammography
increases rates of detection of both in situ and invasive can-
cers and may reduce recall rates [29]. DBT is being increas-
ingly used for breast screening assessment (see . Fig. 13.1).

population-based screening programme [28]. All services
in the UK NHS Breast Screening Programme now use digi-
tal mammography, and this is also the case in a large num-
ber of diagnostic centres across Europe. Images are shown
on high-­resolution monitors and are able to be digitally
No reduction in breast cancer mortality has been demon-
strated to date using DBT, but further trials are planned.
Ultrasound has been shown to be a useful adjunct to
mammography in increasing sensitivity and detection rate of
early cancers in younger women [30].

..      Fig. 13.1  Use of digital breast

a b c
tomosynthesis in breast
screening assessment. a Screen-
ing mammogram (oblique view)
showing possible parenchymal
deformity. b Mammogram
compression view where
deformity is subjectively less
obvious (falsely reassuring).
c Digital tomosynthesis slice
image clearly showing the
deformity giving diagnostic
confidence. d Ultrasound scan
confirming abnormality (invasive
lobular carcinoma on biopsy)
(Courtesy of Dr. M Bagnall)

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 152 J. Mathew and M. Sibbering

While there is no evidence for the use of MRI in general review by Olsen and Gøtzsche failed to show a survival ben-
population screening, there is good evidence for its use as an efit for mammographic breast screening [34]. Although they
adjunct to mammography for screening women at high reported the relative risk for breast cancer mortality after
familial risk (BRCA1 or BCRA2 mutation) [31], which is dis- 13  years of follow-up as 0.80 (95% CI 0.71–0.89), in their
cussed in 7 Chap. 6.
  conclusion, they did not recognise this as a benefit suggesting
that breast cancer mortality is an unreliable measure of out-
come which is biased in favour of screening.
13.4 Evidence from Breast Cancer A more recent review by Olsen and colleagues [34] con-
Screening Trials sidered that only 3 of the 8 RCTs had adequate randomisa-
tion and that these trials did not show a statistically significant
Evidence from randomised controlled trials (RCTs) is impor- reduction in breast cancer mortality at 13 years (relative risk
tant in assessing the efficacy of breast screening in terms of (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02). They
mortality reduction from breast cancer. concluded that if it is assumed that screening reduces breast
The Health Insurance Plan study in 1963 was the first cancer mortality by 15% and overdiagnosis and overtreat-
breast cancer screening trial randomising women aged ment by 30%, it means that for every 2000 women invited for
40–64 years that were enrolees in the Health Insurance Plan screening throughout 10 years, one will avoid dying of breast
of Greater New York to either study (annual mammography cancer, and ten healthy women, who would not have been
screening and clinical breast examination for four consecu- diagnosed if there had not been screening, will be treated
tive years) or control groups [32]. At 18 years after entry, the unnecessarily.
study group had about a 25% lower breast cancer mortality As a result of this controversy, an independent review
among women aged 40–49 and 50–59 at time of entry than [26] was undertaken in the UK in 2012, where women aged
the control group. However, to a large extent, the difference 50–70 years are invited for mammographic screening every
among the 40–49-year-olds occurred in the subgroup diag- 3  years. The review panel considered the internal biases in
nosed with breast cancer after age 50 years. the trials and whether these trials, which were done a long
One of the most significant RCTs began in Sweden in time ago, were still relevant. They concluded that 20% was
1977  in the counties of Kopparberg and Ostergotland, com- still a reasonable estimate of the relative risk reduction on
monly known as the «two county trial». Women were ran- breast cancer mortality of the well run current screening pro-
domised to be invited or not invited for single-view grammes.
mammography, with women aged 50–74 years invited every In 2015, the International Agency for Research on Cancer
13 33 months and those aged 40–49 years invited every 24 months (IARC) convened a group of 29 independent international
[33]. At a mean follow-up of 10 years, there was a 31% reduc- experts from 16 countries, to evaluate the effectiveness of
tion in breast cancer mortality in the invited group. mammographic screening [35]. An evaluation of data from
Two trials were conducted in Canada, one with women about 20 cohort and 20 case–control studies conducted in
aged 40–49 years and the other with women aged 50–59 years high-income countries (in Australia, Europe and North
[22, 23]. Women randomised to screening in both age groups America) concluded that women aged 50–69 years who were
were offered annual clinical breast examination and mam- invited to attend had on average a 23% reduction in breast
mography and were taught how to practice breast self-­ cancer mortality and those who attended for mammographic
examination. In the 40–49-year age group, screening with screening a reduction of around 40%.
yearly mammography and physical examination of the A recent systematic evidence review by the American
breasts detected considerably more node-negative, small Cancer Society suggests that screening women aged
tumours than usual care, but it had no impact on death rates 40–69  years is associated with a reduction in breast cancer
from breast cancer at up to 7 years of follow-up from entry deaths across a range of study designs. Their recommenda-
[22]. In the 50–59-year age group, while screening had tion is that women with an average risk of breast cancer
detected significantly more breast cancers, at 13 years of fol- should undergo regular screening mammography starting at
low-­up, it had no impact on breast cancer mortality [23]. age 45  years, women aged 45–54  years should be screened
An update of the overview of the Swedish RCTs of mam- annually and women 55 years and older should transition to
mographic screening [23] reported a significant 21% reduc- biennial screening or have the opportunity to continue
tion in breast cancer mortality. The mortality reduction screening annually [36].
increased with age and was greatest in the 60–69-year age
group at entry (33%). The benefit in terms of cumulative
breast cancer mortality started to emerge at about 4  years 13.5 Overdiagnosis Due to Mammographic
after randomisation and continued to increase to about Screening
10 years.
There has been considerable debate regarding the inter- Overdiagnosis is a potential harm from breast screening, but
pretation of the results of mammographic screening trials. as discussed there are variable estimates of its magnitude.
The 2001 publication of a Cochrane database systematic Ductal carcinoma in situ which now constitutes 20–25% of

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Breast Cancer Screening
screen-detected disease [37] was an uncommon diagnosis
before the introduction of mammographic screening, and
there has been a further increase following the introduction
of digital screening. A significant proportion of this preinva-
sive disease may never transform into invasive cancer. The
grade of DCIS is correlated with the risk of progression, as
well as with the grade of concurrent invasive carcinoma [38,
39]. The transition from low-grade DCIS to high-grade DCIS
or to high-grade invasive carcinoma is deemed unlikely [39–
41]. A recent large modelling study to assess the overdiagno-
sis rate showed the distribution of different grades in DCIS is
dependent on age (more low-grade DCIS in older women
and vice versa) and overdiagnosis as a proportion of all can-
cers in women of screening age was 61% for low-grade, 57%
for intermediate-grade and 45% for high-grade DCIS [42].
Trials to compare treatment of DCIS to active surveillance
are open at present and should in time give us a definitive
answer [43, 44].
The best evidence of the risk of overdiagnosis came from
the three RCTs that did not systematically screen the control
group at the end of the screening period and followed these
women for several more years as well as observational studies
[26, 45]. The analysis of data by an independent panel of
experts in the UK [26] concluded that for every 10 000 UK
women aged 50  years invited to screening for the next
20 years, 43 deaths from breast cancer would be prevented.
Of the estimated 681 cancers diagnosed, 129 cases of breast
cancer would be overdiagnosed. In other words, one breast
cancer death can be prevented for about every three overdi-
agnosed cases identified and treated. Of the roughly 307 000
women aged 50–52 years who are invited to begin screening
every year in the UK, just over 1% would have an overdiag-
nosed cancer in the next 20 years.
However, following a recent systematic review of the
existing literature by the Swiss Medical Board [46], they have
taken a different view. They have concluded that the effective-
ness of mammography is still uncertain, that overdiagnosis
and false-positive tests cause harm and that the screening
programmes have an unfavourable cost-effectiveness ratio.
As a result they suggested that it is no longer reasonable for
women to attend the breast screening programme. In
Switzerland, systematic screening programmes and opportu-
nistic screening coexist in different regions of the country,
and it is therefore useful to compare mortality rates and to
estimate overdiagnosis and false positivity between regions
with different screening approaches. The analysis of the data
provided by the Swiss Federal Statistical Office shows that
there is no difference in mortality between the two major
regions of Switzerland, one with a systematic screening pro-
gramme and the other with opportunistic screening available
on request. Moreover, the introduction of the mammography
screening programme in 1999 does not seem to modify the
mortality rate, which had been progressively declining since
1990. It is thought that systemic therapies and changes in
cause of death coding could have contributed as confounders
when evaluating screening benefits [47].
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153 13
13.6  ge Range of Mammographic
A
Screening
Younger women are thought to be less likely to benefit from
population breast screening with mammography for a num-
ber of reasons:
1. Reduced sensitivity: the sensitivity of mammography is
inversely proportional to breast density. In women under
50 years of age, almost half have dense breast mammo-
graphic background patterns [48]; this results in reduced
sensitivity where the mammographic signs of malig-
nancy may be obscured. Studies have shown that in
women over 60 years of age, the sensitivity of mammog-
raphy for detecting breast cancer approaches 95%,
compared to less than 50% in women under 40 years of
age [49].
2. Lower incidence: although breast cancer is the leading
cause of death in younger women below the age of
50 years [50], women aged 40–49 years represent only
16% of all breast cancers with the incidence increasing as
age advances. For a population-screening programme to
be effective, it needs to be a significant health problem.
Screening populations of women at younger age but who
are at increased risk of breast cancer (due to hereditary
or other risk markers) where there is also an increased
incidence is discussed in 7 Chap. 6.
3. Shorter sojourn time: cancers arising in younger women
are more likely to be faster growing leading to poorer
prognosis [51]. This also leads to a shorter time interval
for cancers to be detected by mammography before
symptoms and signs of breast cancer become apparent,
increasing the proportion of interval cancers and
reducing the effectiveness of breast screening.
In 2010, an RCT extending the age range of mammographic
screening started in England including the 47–49-year age
group, and the results of this trial are awaited [52]. Previously
the UK «Age Trial» [53] compared the effect of invitation to
annual mammographic screening from age 40  years with
commencement of screening at age 50 years on breast cancer
mortality. Women were randomised 1:2 to the intervention
group (annual mammography 40–48 years) or to usual med-
ical care. At a median follow-up of 17  years, a significant
reduction in breast cancer mortality was noted in the inter-
vention group compared to the control group in the first
10 years after diagnosis but not thereafter. The overall breast
cancer incidence during the 17  year follow-up was similar
between the intervention group and the control group. The
authors concluded that the results support an early reduction
in mortality from breast cancer with annual mammography
screening in women aged 40–49 years but that further data
was needed to fully understand the long-term effects.
In younger women, there are more concerns relating to
ionising radiation which may shift the balance towards the
number of cancers induced by screening using mammogra-
phy when compared to the breast cancer deaths prevented by
 154 J. Mathew and M. Sibbering
screening [54]. However, screening women using mammog-
raphy from age 40  years is an acceptable practice in some
countries including the USA.
Only one of the historical RCTs of mammographic
screening included women over age 70 years, and data is lim-
ited in this age group. In the UK, NHS Breast Screening
Programme women over the age of 70 years are able to self-
refer for three yearly mammography, but there is a relatively
low uptake due to a perception that they are no longer at risk
and poor awareness of the option to self-refer. The RCT of
age extension in the UK is also evaluating breast screening
for women aged 71–73 years [52].
13.7 Screening for Breast Cancer in Europe
Although Europe has led the world in implementing breast
screening programmes, there is considerable variability
across different European Union member states and even
within some of the member states themselves [2, 14].
In 1974, Austria was the first European member state to
implement a breast screening programme with mammogra-
phy offered to all women over 40 years of age (34). Sweden
was one of the early adopters of breast screening, but exhib-
its considerable organisational variability [14]. Biannual
mammograms are generally offered to women aged
50–69  years. However, in more than 60% of the country,
women aged 40–49 years are invited every 18 months, and
approximately half of 70–74-year-olds are offered a biannual
13 mammogram.
In the Netherlands, screening began in 1989; women
aged 50–69 years are screened at 2-year intervals, and those
aged ≤74 years were added in 1998 [14]. In Italy, breast can-
cer screening began in 1990, with nationwide coverage being
attained in 2007 [14]. In 2010, almost 2.5 million women
aged 50–69 years were invited to have a screening mammo-
gram, and more than 1,382,000 were screened [55].
In Denmark, screening programmes have been in place
for many years especially in Copenhagen and Fyn, and
nationwide coverage was achieved in 2010 where mammo-
grams were offered to women aged 50–69  years [56]. In
France women aged 50–74 are offered mammograms every
2 years by invitation, and digital mammography was intro-
duced in 2008 [57].
In Germany there have been many pilot projects on
screening, and at present the national centre invites women
aged 50–69 years to screen every 2 years [58]. Bulgaria and
Romania have no active national programme [14]. In
England and Wales, based on recommendations of the
Forrest Committee, the breast cancer screening programme
was introduced in 1988 for women aged 50–64 years [59]. In
the UK, screening is offered at 3-year intervals, and the target
population has now been extended to 50–70-year-olds. The
RCT of age extension in England is evaluating breast screen-
ing for women aged 47–49 years and 71–73 years [52].
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13.8  rganisation and Quality Assurance
O
of Breast Screening Programmes
There are a number of essential components for population-­
based screening programmes:
55 Adequate resources: staff, facilities, equipment and
finance.
55 Protocols for the screening process underpinned by staff
training and quality assurance.
55 Programme evaluation: both short term of the screening
process (uptake, cancer detection rate, recall rate, etc.)
and long term of the outcome of screening (effect on the
mortality rate of breast cancer).
55 Information systems/population database: essential to
facilitate the process of sending invitations for screening
to the appropriate population and to collect data
regarding the personal screening histories of women
invited/attending.
55 Public information: essential both to promote general
awareness of the breast screening programme and to
give women appropriate information to allow them to
make an informed choice regarding attendance for
screening. It is also important that a variety of strategies
are utilised to disseminate this information to women
who are more difficult to reach with invitations and
information, e.g. women without a fixed address, ethnic
minorities, women with learning disabilities, etc.
Breast screening takes place within a range of different health-
care systems across Europe. European Guidelines for Quality
Assurance in Breast Cancer Screening and Diagnosis [12] have
aimed to provide an overview of the fundamental points and
principles that should support any quality screening or diagnos-
tic service including publication of key performance indicators.
These are periodically updated and are currently under review.
13.9  urgical Considerations in Breast
S
Screening
In modern breast screening practice, high nonoperative diag-
nosis rates for breast cancer are achieved using predominantly
percutaneous image-guided core biopsy or vacuum-­assisted
core biopsy. In the UK NHS Breast Screening Programme in
2014/2015, the overall nonoperative diagnosis rate was 97%
(99% for invasive cancers, 87% for non-invasive cancers) [60].
A total of 20,613 cancers were detected in women of all ages
with only 1945 diagnostic open biopsies being required. Of
these 71% were benign, giving a benign open biopsy rate of
0.6 per 1000 women screened, and 29% were malignant giving
a malignant open biopsy rate of 0.23 per 1000.
Open diagnostic surgical biopsy is now only required in a
small proportion of cases. The purpose is to remove the mam-
mographic lesion for diagnosis leaving the smallest possible
breast deformity. The European surgical quality assurance
Breast Cancer Screening
guidelines suggest the weight of the specimen should be less
than 30 grams [2]. Guidelines for UK surgeons in breast screen-
ing suggest that the weight of the specimen should be less than
20 grams in more than 90% of open surgical biopsies [61].
The majority of screen-detected abnormalities are impal-
pable and require radiological localisation to facilitate sur-
gery, and the methods used to localise these lesions may vary
between institutions. Radiological localisation may be
achieved by insertion of a marker wire(s) guided by stereo-
tactic mammography or ultrasound scan. In superficial
lesions, skin markers are often sufficient to localise the lesion.
Other localisation options include the ROLL (radioguided
occult lesions localisation) technique where a radioactive
tracer is injected into the mammographic lesion, use of
radioactive seeds or iron oxide magnetic particles and intra-
operative use of ultrasound to facilitate its localisation.
Intraoperative specimen x-ray is essential to check that
the mammographic lesion has been removed. In the case of
wide local excision, it also gives a guide to the adequacy of
the margins of excision. It is essential to orientate the speci-
men correctly to facilitate this and subsequent pathological
examination, and this is usually achieved by placement of
10. Holmberg LEA, Zack M. Do screen-detected invasive breast cancers
sutures or metal clips.
Due to earlier detection, screen-detected breast cancers
are more likely to be suitable for breast-conserving surgery
than those presenting symptomatically [62]. Modern onco-
plastic techniques also allow larger lesions in moderate to
large breasts to be excised using volume displacement (thera-
peutic mammoplasty) or volume replacement (perforator
flaps, lateral intercostal artery perforator or thoracodorsal
artery perforator flap) techniques. Where patients have
extensive disease necessitating mastectomy, this is more likely
to be for DCIS or invasive cancer with better prognostic fea-
tures where adjuvant radiotherapy or chemotherapy is less
likely. As a result, a significant proportion of these patients
are good candidates to consider immediate reconstruction.
13.10 Conclusion
Breast cancer screening is effective in reducing mortality in
certain age groups (50–69 years) through early detection and
treatment. There may be benefit from screening women
­outside this age group, although this remains unproven and
needs further evaluation. Apart from the benefits, patients
undertaking screening should also be made aware of the
potential harms of breast screening, including overdiagnosis,
to enable them to make an informed decision.
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 157 III

Early Breast Cancer:

Diagnosis and
­Management
Contents

Chapter 14 Clinical Presentation, Diagnosis and Staging

of Breast Cancer – 159
Janez Zgajnar

Chapter 15 Pathology of Breast Cancer – 177

Frederique Penault-Llorca and Nina Radosevic-Robin

Chapter 16 The Breast and Oncoplastic Multidisciplinary Team – 193

Fiona MacNeill, Marios Tasoulis, and Melissa Ley Hui Tan

Chapter 17 Surgery to the Breast: Mastectomy – 203

Petros Charalampoudis and Tibor Kovacs

Chapter 18 Surgery to the Breast: Breast Conservation

Techniques – 213
Marjut Leidenius

Chapter 19 Oncoplastic Breast-Conserving Therapy – 229

Elias E. Sanidas and Florian Fitzal

Chapter 20 Fat Transfer in Oncoplastic and Reconstructive

Breast Surgery – 245
Riccardo Bonomi, I. Fabio Rapisarda,
Gilles Toussoun, and Loraine Kalra

Chapter 21 Breast Surgery after Primary Systemic Treatment – 255

Thorsten Kuehn

Chapter 22 Surgery for Locally Recurrent Breast Cancer – 263

Roberto Agresti, Andrea Spano, Giulia Bianchi,
and Giovanna Trecate

Chapter 23 Management of the Axilla: Sentinel Lymph

Node Biopsy – 275
Leif Bergkvist and Jan Frisell

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Chapter 24 Axillary Node Clearance – 285
Tuomo J. Meretoja

Chapter 25 Axillary Management in the Neoadjuvant Setting – 291

K. Wimmer, F. Fitzal, R. Exner, and Gnant Michael

Chapter 26 Axillary Reverse Mapping: ARM – 303

Isabel T. Rubio, Ernest J.T. Luiten, and V. Suzanne Klimberg

rares1geo@gmail.com
 159 14

Clinical Presentation, Diagnosis

and Staging of Breast Cancer
Janez Zgajnar

14.1 Introduction – 160

14.2 Symptoms and Signs of Clinically Detectable Breast

Cancer – 160

14.3 Diagnosis of Breast Cancer – 163

14.4 Staging – 167

References – 174

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_14

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 160 J. Zgajnar

14.1 Introduction

Breast cancer is a heterogeneous disease which reflects in dif-

ferent clinical manifestations. A growing proportion of breast
cancers are diagnosed in a preclinical phase via screening, i.e.
prior to the development of any clinical manifestations [1].
The proportion of breast cancers diagnosed in a preclinical
stage varies considerably between countries and depends on
the presence, quality and frequency of organised mammo-
graphic screening, access to diagnostic imaging outside of
the screening programme, the age of the patient and the level
of breast cancer awareness in the population [2, 3]. In this
chapter, the symptoms and signs of different breast cancer
presentations, the diagnostic workup and finally the staging
of the disease will be reviewed.

14.2  ymptoms and Signs of Clinically

S
Detectable Breast Cancer

As mentioned above, the symptoms and signs of breast can-

cer vary. It may be difficult to clinically distinguish between
malignant and benign breast lesions in some cases; hence,
clinical assessment alone is never adequate. A «triple assess-
ment» needs to be performed: clinical evaluation, imaging of
the breast and a biopsy. Breast cancer is definitively diag-
nosed by the biopsy, but concordance of all three modalities
is a quality measure to avoid incorrect diagnosis [4, 5].
..      Fig. 14.1  Breast cancer presented with visible skin retraction
1. Common Clinical Manifestations of Breast Cancer
Breast cancer clinically presents most often as a breast
mass; however, skin retraction, nipple inversion, changes
..      Table 14.1  The level of suspicion for malignancy on clinical
in the size and shape of the breast, discoloration of the
14 skin, breast pain, oedema and redness of the skin and a
examination scale

regional nodal mass are common signs of the disease. P1 Normal

1. Breast Mass
The most common finding is a unifocal, hard painless P2 Benign
breast mass which may or may not be linked to skin P3 Uncertain
or nipple retraction (. Fig. 14.1). In a series prior to
 

the advent of mass mammographic screening, 65%
of breast cancers presented with a breast mass [6].
However, the clinical findings may be atypical and/
or lacking some of the above characteristics. For
example, invasive lobular carcinoma may present as
a subtle breast thickening with a diffuse margin, and
a triple negative cancer may feel clinically very much
like a fibroadenoma (often in the same age range
in BRCA1 carriers). In contrast some cysts and fat
necrosis may clinically appear malignant. Therefore,
even for an experienced clinician, it is often difficult
to distinguish between malignant and benign breast
lesions. In one series of those women categorised as
having clinically «definite breast cancer (P5)», breast
cancer was subsequently confirmed in only 93%
(. Table 14.1). In patients with a clinically suspicious
 
presentation (P4), only 50% of patients had a malig-
nant diagnosis [7]. In another series of 234 patients
with a breast mass of whom only 110 had a final diag-
P4 Suspicious
P5 Malignant
nosis of breast cancer, the sensitivity and specificity of
clinical examination were 89% and 60%, respectively
[8]. In a recent study, clinical breast examination had
a specificity of only 68.7% for average-risk women
[9]. Several factors influence the sensitivity of clinical
breast examination such as tumour size, age, breast
density, body mass index and hormone replacement
therapy use [10].
2. Locally Advanced Breast Cancer (LABC)
LABC is defined as any breast cancer that has the
following cTNM characteristics: T3–T4, or N2–3,
no metastases (M0) [11]. It may be operable at pre-
sentation when Stage IIIA. As an advanced form of
disease, it usually has a prolonged clinical course;
nevertheless, LABC represents a relatively common

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Clinical Presentation, Diagnosis and Staging of Breast Cancer
..      Fig. 14.2  Locally advanced breast cancer with necrosis, bleeding
and secondary bacterial infection
presentation (~5–10% in high-income countries)
even in countries with an organised screening
programme. In developing countries it accounts
for more than half of all breast cancers [2, 12].
There are several reasons to this: patients’ fear of a
cancer diagnosis, denial of the disease, psychiatric
comorbidity, limited access to the healthcare service
and even patient use of alternative medicine before
seeking help. The clinical presentation of T4 disease
is variable ranging from a minor degree of skin
involvement to a huge ulcerating mass or cancer «en
cuirasse» encasing the chest wall (. Fig. 14.2).
 
3. Inflammatory Breast Cancer
Inflammatory breast cancer is a distinct subtype of
LABC [13, 14]. The incidence is 2.5% in the USA and
is more common in black women compared to white
women. It also tends to appear at a younger age [15,
16]. The clinical signs develop relatively rapidly over
a few weeks or months. It typically presents symp-
tomatically as a rapidly growing mass or with a swol-
len, red or tender breast . In most cases, the axillary
lymph nodes are involved, and approximately 30% of
patients have distant metastases at diagnosis [14]. The
breast skin is thickened and warm and shows varying
degrees of redness. If the nipple is involved, it is usu-
ally flattened, showing varying degrees of redness; nip-
ple inversion and crusts are also common. The typical
skin appearance resembles the skin of an orange (peau
d’orange). Due to the clinical presentation, it is often
initially misdiagnosed as mastitis, and many women
are initially treated with antibiotics (. Fig. 14.3).
 
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161 14
..      Fig. 14.3  Inflammatory breast cancer; note redness and oedema of
the skin (peau d’orange) and nipple retraction
2. Less Common Breast Cancer Presentations
1. Occult Breast Cancer
This rare clinical presentation is of axillary lymph-
adenopathy with no evidence of the primary tumour
in the breast. The incidence is low, at up to 1% [17,
18]. After biopsy confirms the diagnosis of axillary
metastases (histologically consistent with a breast
primary), imaging investigations of the breast includ-
ing mammography, ultrasound and MRI should
be performed [19]. If these are negative, thorough
staging should be performed following the algorithm
for cancer of unknown primary. The most common
origins besides breast cancer of adenocarcinoma
metastases in the axillary lymph nodes are thyroid,
lung, gastric, pancreatic and colorectal cancer [20].
2. Male Breast Cancer
Male breast cancer is a rare disease and accounts for
about 1% of all breast cancers and is more common
in BRCA 2 mutation carriers [21]. Clinically it pres-
ents similarly to female breast cancer with a lump,
nipple inversion, nipple discharge and enlarged axil-
lary lymph nodes. The average duration of symptoms
before diagnosis is prolonged compared to women.
3. Paget’s Disease
Paget’s disease is a rare form of breast cancer (usually
preinvasive but occasionally invasive) with a range
from 0.5 to 5% in different series [22]. It was first
linked to breast cancer by James Paget [23] and is due
to migration of ductal carcinoma in situ through the
lactiferous ducts into the nipple-­areolar epidermis.
It is considered a variant of ductal carcinoma in situ
 162 J. Zgajnar
disease because the cells are confined within the basal
membrane of the epidermis. Clinically it has vari-
ous presentations, starting from erythema and mild
eczematous scaling which progresses to crusting,
skin erosion and ulcerations. Exudate and discharge
is also possible. While Paget’s disease of the nipple
areola complex is due to noninvasive breast cancer,
in half of affected women it is accompanied by an
underlying invasive cancer. The prognosis of Paget’s
disease therefore depends on the characteristics of
the underlying breast cancer if one is present [24–26].
4. Phyllodes Tumour
Phyllodes tumours are a group of rare fibroepithelial
lesions with a range of different malignant potentials,
representing 0.3 to 0.5% of all breast tumours [27].
The majority present as benign-feeling lumps often
thought to be fibroadenomas clinically or on imaging
but may be larger or grow more rapidly. The majority
of them are diagnosed in the fourth and fifth decade
of life although they can appear at almost any age.
Usually they are clinically detected as a single, firm,
well-rounded unilateral breast mass. Diagnostic imag-
ing procedures and fine needle aspiration (FNA) often
do not give conclusive results (being unable to differ-
entiate between fibroadenomas, benign or malignant
phyllodes tumours), and in most cases a definitive
diagnosis is established only after core needle biopsy
and in some cases surgical excision [28].
5. Non-epithelial Malignancies of the Breast
The breast is infrequently the site of non-epithelial
malignant tumours [29]. They can be primary
tumours, mostly sarcomas and lymphomas or meta-
14 static tumours. There are several different types of
primary sarcomas of the breast: the most common is
the malignant phyllodes tumour (see above), less fre-
quent angiosarcoma, osteogenic sarcoma, embryonal
rhabdomyosarcoma, lymphoedema-associated lym-
phangiosarcoma and miscellaneous breast sarcomas.
Breast sarcomas share some mutual clinical charac-
teristics including a rapid rate of growth later stage
at diagnosis, and unlike epithelial malignancies, they
rarely metastasise to regional nodes. Further details
on breast sarcomas are given in 7 Chap. 46. Primary
 
breast lymphomas clinically present as a painless
palpable mass and may be associated with enlarged
axillary lymph nodes. Imaging findings for primary
breast lymphomas are non-specific. Core biopsy and
sometimes surgical biopsy are warranted to obtain
material for diagnosis which may require specialist
interpretation due to the complexity of lymphoma
classification [30].
Finally, a variety of different tumours may metas-
tasise to the breast, the most common of which is
melanoma [31, 32] although contralateral breast can-
cer may also be the source, which may only become
apparent on phenotyping [33].
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3. Locoregional Recurrence
Locoregional recurrence after the treatment of primary
breast cancer is often detected on clinical examination.
In a recent study 50% of local recurrences after breast-
conserving treatment were detected by physical exami-
nation [34]. The presenting symptoms in the breast are
similar to primary cancer; however, the finding tends to
be more subtle predominantly because of the presence
of surgical scarring and radiation fibrosis. Local recur-
rences after mastectomy usually occur earlier compared
to recurrences after breast-­conserving surgery. Local
recurrence after mastectomy usually presents as a pain-
less nodule in the scar or on the chest wall. Frequently
the local recurrence presents as a diffuse infiltration of
the soft tissues, with skin colour changes, multiple nod-
ules and ulceration extending from the boundaries of
the primary surgical or radiotherapy treatment area. A
large proportion of patients with locoregional recurrence
will be diagnosed with distant metastases shortly before
or after the appearance of locoregional recurrence, and
for this reason, local recurrence is an indication for
full staging. In a large study 24% of patients with local
recurrence after breast-­conserving surgery and 33% after
mastectomy were diagnosed with simultaneous meta-
static disease [35].
4. Metastatic Breast Cancer
Clinical manifestation of metastatic breast cancer depends
on the site and size of metastases [36]. The most common
organs that breast cancer metastasises to are the bone,
lung, liver and brain. Each has their own specific symptom
complex, and in addition there may be non-specific symp-
toms such as fatigue and weight loss, although the latter is
less marked than with many other malignancies.
1. Metastases to bone usually manifest with progressive
pain which is usually a dull ache, often worse at night
and often affects the back, pelvis and hips. Pathologi-
cal fracture is a relatively common occurrence and
may be the first presentation. More serious is impend-
ing or actual spinal cord compression due to spinal
metastases, and suspicion of this (back pain, loss of
bladder or bowel control, perineal numbness) is a
medical emergency. Hypercalcaemia may also cause
symptoms including polyuria, polydipsia, abdominal
pain, constipation, drowsiness and confusion. Occa-
sionally swelling over the metastatic site is observed.
2. Metastasis to the lung is associated with chronic non-
productive cough, breathlessness or chest pain due to
pleural involvement.
3. Metastasis to the liver is associated with abdominal
pain, abdominal swelling, anorexia, nausea, vomiting,
jaundice and pruritus.
4. Metastasis to the brain may have several neurological
consequences including progressive headache (typi-
cally worse in the morning), vomiting, visual distur-
bance, loss of balance, seizures, personality change
and focal symptoms.
Clinical Presentation, Diagnosis and Staging of Breast Cancer
Whenever the above-mentioned manifestations are noted,
the corresponding diagnostics should be performed prior to
further treatment [37].
14.3 Diagnosis of Breast Cancer
The ultimate diagnosis of breast cancer is histopathological,
but the diagnostic process and treatment planning require
that all patients undergo triple assessment. This consists of
clinical examination, imaging investigations and a biopsy.
The EUSOMA quality indicators specify that physical exami-
nation and imaging of the breast should be performed in at
least 90% of breast cancer patients and definitive diagnosis
made prior to first treatment in at least 80% of patients [38].
In palpable breast cancer, triple assessment should be per-
formed in 95% of patients [5]. These steps are described in
detail below:
1. Clinical Examination
All women should have a detailed medical history and
physical examination performed.
1. Medical History
A detailed history of previous and current diseases,
surgical or other interventions and medications
should be recorded. A family history of cancer should
be recorded to assess the risk of a familial tendency
which may affect risk and management. A systematic
gynaecological history should be recorded to include
the age at menarche, a number of completed preg-
nancies and the age at first childbirth and history of
breast-feeding. In premenopausal women, the date of
the last period and the use and duration of hormonal
contraception should be recorded. In postmeno-
pausal women the age at menopause, the cause of
menopause and the use and duration of hormonal
replacement therapy should be recorded. Of particu-
..      Fig. 14.4  Patient and arm positions during inspection
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163 14
lar interest is a history of previous breast complaints
or surgeries, especially previous breast biopsies or
breast augmentation or reduction.
2. History of the Presenting Complaint
The duration of symptoms and whether they are
stable, resolving or worsening and whether the symp-
toms are cyclical or not. The latter is more in keeping
with a benign diagnosis.
3. Physical Examination
Physical examination should include examination of
the breasts, chest region and the regional lymph node
basins in the axilla and infra- and supraclavicular
fossae.
55 Inspection
A chaperone should always be present. Inspec-
tion starts in the upright position with the
patient unclothed to the waist. The patient is
asked to elevate her arms above her head and
finally to put them onto the hips and contract
the pectoral muscles. During all three phases
of inspection, the clinician should observe for
breast asymmetry (size, shape or distortion), skin
changes (skin retraction, erythema, ulceration,
oedema or eczematous changes) and changes
to the nipple (symmetry, retraction, inversion,
nipple discharge or crusting). In cases of nipple
discharge, it is very important to record whether
the discharge is unilateral or bilateral, uniduct
or multiduct and spontaneous or induced and
the colour of the discharge (especially if blood
stained) (. Fig. 14.4).
55 Palpation
Inspection is followed by thorough palpation of
the breast, axilla and lymph nodes in the supra-
and infraclavicular fossae (. Figs. 14.5, 14.6, and
14.7). If a lump is found, its size, mobility, position
 164 J. Zgajnar

separated by less than 4 cm, or multicentricity, two

or more lesions in different quadrants or separated
by more than 4 cm) and bilaterality of suspicious
lesions. All these data are of paramount importance
for determining whether breast-conserving surgery is
possible. These imaging investigations are described
in details in 7 Chap. 12, including the BIRADS clas-
 

sification system. This chapter will focus on the use

of these methods during the diagnostic workup of a
clinically suspicious breast lesion.
55 Mammography
Diagnostic bilateral two-view mammography is
..      Fig. 14.5  Breast palpation in the upright position of the patient
14
..      Fig. 14.6  Palpation of the axillary lymph nodes
(in the breast and relative to the nipple) and con-
sistency should be assessed. If the lump is fixed, it
should be noted whether to the chest wall, to the
skin or to both.
4. Imaging of Early Breast Cancer
Clinical examination is followed by imaging inves-
tigations of the breasts: mammography, ultrasound
and in some cases MRI. The goal is to further charac-
terise breast lesions and to assess the number (multi-
focality, two or more lesions in the same quadrant or
usually performed in any woman over the age of
35. The only two exceptions are pregnancy and
young age (see below).The standard views are
the craniocaudal (CC) and mediolateral oblique
(MLO); however, additional mammography
techniques may be indicated to further evaluate
the breast lesion, like magnification views of sus-
picious areas with focal compression. Whenever
possible it should be performed before needle
biopsies as they may produce changes (i.e. hema-
toma) which may reduce the diagnostic value of
the mammogram. It is also advisable to obtain
any previous mammograms of the patient for
comparison. Diagnostic mammography is known
to be more sensitive but less specific compared to
screening mammography due to the likely more
advanced stage of symptomatic disease [39].
Mammography sensitivity is diminished by high
breast density, young age, hormone replacement
therapy, some biological subtypes (i.e. invasive
lobular carcinoma) and the presence of breast
implants. If implants are present, special views
may be taken to «see around» the implant, but
these do not fully compensate for the loss of sensi-
tivity in these women.
There are several mammographic abnor-
malities which are suspicious for breast cancer:
masses, architectural distortions and microcal-
cification. Microcalcifications are particularly
important in diagnosing ductal carcinoma in situ
(DCIS) [40].
In young patients less than 30–35 years of age,
ultrasound is the modality of choice for breast
imaging [41], but US should ideally be used on
older women as an adjunct to mammography
and to undertake a guided biopsy (which has a
lower false-negative rate than a clinically guided
biopsy). In young women, high breast density lim-
its the value of mammography. However, if breast
cancer is subsequently diagnosed, then bilateral
mammography should be performed as in older
women.
Diagnostic evaluation of a newly discovered
breast mass in a pregnant woman is challenging.
Physiological changes during pregnancy make

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Clinical Presentation, Diagnosis and Staging of Breast Cancer
..      Fig. 14.7  Breast palpation in
supine position
physical examination difficult due to increased
density and nodularity, and for the same reasons
mammographic sensitivity is low. The imaging
method of choice is therefore ultrasound although
mammography with proper shielding is safe for
the foetus [42]. Any clinically or ultrasonically
discrete or suspicious lesion should be subjected
to core biopsy, and it is important to notify the
pathologist of the pregnancy as otherwise the
highly proliferative state of the pregnant breast
epithelium might cause undue concern. If breast
cancer is discovered, then mammography with
foetal shielding may be performed.
55 Ultrasound
Ultrasound is an important diagnostic investiga-
tion to further characterise a clinically and/or
mammographically suspicious breast lesion. It
is also now routinely used to stage the regional
lymph nodes (see below). It has a very high sen-
sitivity and specificity in experienced hands [43].
There are several indications to perform a breast
ultrasound:
55To characterise a solid mass or architectural
distortion present on mammogram. A benign
US result should not deter biopsy of a lesion. In
a Dutch study the added value of ultrasound to
clinical examination and mammography was
reported: the sensitivity, specificity and positive
and negative predictive values for clinical
examination plus mammography plus US were
96.9, 94.8, 39.2 and 99.9 per cent, while the
corresponding values for clinical examination
plus mammography were 91.5, 87, 19.7 and
99.7 per cent, respectively [44].
55To further characterise a palpable lesion not
clearly seen on mammogram. This is particu-
larly the case when a lump is discovered by
self-examination, and the breasts are dense
on mammography giving the latter a lower
sensitivity. In order to distinguish an area of
low suspicion nodularity of the breast from a
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165 14
discrete breast mass, an ultrasound is of great
value. The negative predictive value for
malignancy after both a normal mammogram
and ultrasound is 99. 8% [44, 45]. Therefore,
a biopsy may be avoided in some cases,
although all clinically discrete, asymmetric
lesions should be biopsied in women over the
age of 25.
55To identify cystic lesion of the breast and to
distinguish simple cysts from a complex cysts.
Simple cysts can be aspirated or left untreated;
however, a complex cyst may require a formal
biopsy [46].
55In young women age < 30, ultrasound is the
primary imaging investigation [47]. In most
cases an ultrasonically benign lesion is found
and can be needle biopsied or simply followed
up a few months later. In clinically and
ultrasonically suspicious lesions, a needle
biopsy and mammogram should be per-
formed.
55In pregnant and lactating women, ultrasound is
the primary imaging modality, followed by
mammography with shielding only in suspi-
cious cases.
55In patients with uniduct nipple discharge that is
milky, serous, bloody or serosanguineous, an
ultrasound examination may reveal a papillo-
matous lesion (or several papillomas) which
may be biopsied under US guidance.
55Breast inflammation/abscesses are another
indication for ultrasound as it may facilitate
drainage of pus, especially in complex multi-
loculated sepsis, or reveal an underlying
malignancy in breast inflammation that does
not respond to antibiotic treatment.
55Second-look ultrasound after an MRI investiga-
tion of the breast. MRI has a low specificity and
is not generally used to undertake an image-
guided biopsy (unless special equipment is
available). Ultrasound is a useful tool to
 166 J. Zgajnar
reassess the MRI result and biopsy the lesion.
However, only about half of MRI visible lesions
are visible on ultrasound.
55To search for multifocality/multicentricity or
bilaterality in already proven breast cancer
patients prior to treatment, particularly women
with lobular cancer who have a preference for
breast-conserving surgery. MRI would be the
preferred modality in this setting if available
however.
55Ultrasound is an excellent tool to guide needle
biopsies of suspicious lesions and to guide the
marking of a tumour with a clip prior to
neoadjuvant systemic therapies.
55 MRI
The use of MRI in the diagnostic evaluation of
breast lesions has increased significantly in the last
two decades. MRI is highly sensitive but less spe-
cific than other imaging methods [19]. Therefore,
the indications for the use of MRI are in many
scenarios still a matter of controversy as it may
delay the diagnostic process, lead to unnecessary
biopsies and result in overtreatment (elevated
ipsilateral and bilateral mastectomy rates) with-
out any proof of survival benefit for the patients.
Thus, MRI should not be routinely used in every
breast cancer patient. When used, the MRI find-
ing alone without biopsy of the suspicious lesions
should not be used to divert patients from breast-
conserving surgery to mastectomy.
There are several clinical situations where
MRI is of undisputed value in breast lesion diag-
14 nostics. The use of MRI as a screening method
in high-risk women is discussed elsewhere in
7 Chap. 6.
 
55In patients with an equivocal or discordant
physical examination, mammography and
ultrasound results to enhance the diagnosis and
staging of breast cancer.
55In occult breast cancer with axillary adenopa-
thy or Paget’s disease of the nipple with no
mammographic, sonographic or physical
evidence of the primary cancer.
55For patient with planned neoadjuvant systemic
treatment to assess the initial extent of the
disease and to follow up the effect of the
systemic therapy. Interpretation of the effect of
treatment should be done with caution as MRI
can overestimate the extend of the disease after
neoadjuvant systemic treatment.
55Patients with invasive lobular cancer.
55Patients with breast implants.
55For patients with chest wall involvement to
accurately determine the feasibility of surgery.
55In high-risk women where the probability of
contralateral breast cancer is elevated (i.e. family
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history, prior radiotherapy to the chest wall, e.g.
mantle radiotherapy for Hodgkin’s lymphoma).
5. Biopsies
Percutaneous biopsy of every suspicious palpable
lesion or imaging identified breast abnormality is
obligatory European quality indicators mandate
at least 80% (desirable target 90%) of women with
breast cancer (invasive or in situ) should have a pre-
operative definitive diagnosis of breast cancer [38].
Diagnostic surgical biopsy should only be performed
when percutaneous biopsy is not technically feasible.
There are several methods of breast biopsy in use
today: fine needle aspiration (FNA) biopsy, core
biopsy (CB), vacuum-­assisted biopsy, punch biopsy
and incisional and excisional biopsy. They can be per-
formed free-hand or image-guided, depending on the
clinical situation. In all cases, the biopsy result should
be compared with the imaging results to ensure
concordance at the MDT. In all cases with discordant
results, further diagnostics are indicated. All these
methods are briefly reviewed below:
55 FNA
Despite the steady decline in the use of the FNA in
the diagnosis of a breast lesion, it is still a valuable
method in experienced hands and some clinical sit-
uation. It also allows hormonal receptor status and
Her-2 status to be evaluated in some cases, although
less reliably than core biopsy. The advantages of
FNA are as follows: it is quick to perform, requires
less patient preparation, provides rapid results and
is low cost. The disadvantages are as follows: it
provides less material for diagnosis and lower and
variable sensitivity and specificity, ranging from
65–98% to 34–100%, respectively [48]. It also does
not give full histological information (invasiveness,
grade, tumour architecture). Lastly, clip placement
into the biopsy site is not possible. Nevertheless, it
is very useful in palpable lesions, particularly clini-
cally suspicious cysts; when a cyst is fully drained
and the aspirate is non-blood stained, it can be dis-
carded. The FNA is also an alternative approach in
patients taking antithrombotic treatments as there
is less risk of bleeding. Because of the lower sensi-
tivity of FNA, when its results are inconclusive, CB
should be performed. In non-palpable lesions FNA
is not an appropriate biopsy method as it is – for
various reasons – non-diagnostic in a much higher
proportion of patients [49].
US-guided FNA is a popular method also to
stage the axillary lymph nodes [50]. The indica-
tions to perform FNA of the lymph nodes are
based on established US criteria [51]. In the set-
ting of FNA of lymph nodes, it is more discrimi-
nant than FNA of the breast, as any epithelial cells
are regarded as abnormal because a node should
just contain lymphoid cells.
Clinical Presentation, Diagnosis and Staging of Breast Cancer
55 Core biopsy
As mentioned above, CB is the gold standard
of percutaneous biopsy techniques. In contrast
to FNA it has higher sensitivity and specificity, it
allows full histopathological diagnosis of the lesion
including all important biological features of the
tumour and it allows positioning of clips into the
biopsy site which is extremely important when
further surgery is needed and/or when neoadju-
vant systemic therapies are planned [49]. It is more
time-­consuming and painful and is performed
under local anaesthesia. It requires a small skin
incision, and patients on antithrombotic treat-
ments should have these stopped to allow clotting
to nearly normalise before biopsy. The final diag-
nosis takes longer and it is more costly. Despite
these disadvantages CB is the only appropriate
method in non-palpable lesions. A variant of the
CB is the vacuum-­assisted core biopsy (VACB)
which allows harvesting of more material for diag-
nostic tests. It is most often used in patients with
microcalcification or where a previous CB has
yielded inadequate or discordant results.
After VACB or core biopsy for microcalcifica-
tion, the specimen should be radiographically
checked for the presence of the biopsied lesion,
thus confirming that a representative sample has
been acquired.
In non-palpable lesions, an image-guided
biopsy is performed, using the imaging method
which allows visualisation of the lesion. However,
many lesions can be visualised by several imag-
ing techniques, and in this case the easiest one is
chosen. For instance, when small mammographic
stellate lesions are also clearly seen on ultrasound,
most radiologist would perform CB under US
guidance. Or when a second-look US reveals an
MRI-­detected lesion, US will be used to guide the
biopsy. In cases of microcalcification however the
usual way to guide the biopsy is by stereotactic
(mammography) guidance. The most demanding
way to guide the biopsy is by MRI guidance which
is only performed when the lesion cannot be visu-
alised by other methods. This is only available in
certain specialised centres.
55 Punch biopsy
With a punch biopsy a sample of a skin lesion
is obtained in order to differentiate between
benign and malignant skin lesions such as Paget’s
disease and skin recurrence.
55 Galactography and ductoscopy
In patients with nipple discharge, several
diagnostic options are available. As cytological
examination of nipple discharge is relatively insen-
sitive for detecting an underlying malignancy
and a negative result should not prevent surgical
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167 14
excision of the duct, galactography may be used
to show filling defects in the ductal tree. In a large
series the sensitivity for detecting breast cancer
was 54% and the specificity 98%, respectively [52].
A recent meta-analysis showed that ductoscopy
detects about 94% of all underlying malignancies
in patients with pathological nipple discharge but
does not permit reliable discrimination between
malignant and benign findings [53]. It is not in
widespread use clinically.
55 Surgical biopsy
Excision biopsy
As stated before, surgical excision biopsy
should be performed only in selected situations.
First, when the percutaneous biopsy did not
definitively diagnose the lesion, especially if VACB
is not available.
Second, when the result of the percutaneous
biopsy showed a lesion which might be associ-
ated with an underlying breast cancer so a larger
volume sample is mandated (i.e. radial scar, papil-
loma, atypical ductal hyperplasia, lobular carci-
noma in situ).
Third, when the biopsy result and the imaging
features are discordant.
Finally, when a percutaneous biopsy is not
technically feasible (i.e. the position of the lesion).
Surgical biopsy is usually associated with general
anaesthesia and is linked to more complications
compared to percutaneous biopsies, like hema-
toma or infection. For non-palpable lesions, a
variety of localisation methods are in use and are
discussed in more detail in 7 Chap. 18.
Incisional biopsy
Incisional biopsy is rarely performed, usually
in cases when the excision of the entire lesion
would compromise the aesthetic appearance of the
breast, for example, in cases with extensive micro-
calcification or a large mass on which percutane-
ous biopsy has been non-diagnostic.
14.4 Staging
Patients can be staged clinically or pathologically, the latter
being considered more accurate. Clinical staging can be used
initially to guide treatment and subsequently changed
accordingly by histopathological results. Today the seventh
version of the TNM system is used to stage patients by the T
(tumour), N (nodes) and M (metastasis) characteristics of
the disease [11]. Patients are further grouped into stages
from Stage 0 to Stage IV. The TNM system is based on retro-
spective survival data (. Table 14.2).
In order to stage a breast cancer patient, several investiga-
tion methods are indicated, depending on the clinical stage
of the disease [41, 54].

168 J. Zgajnar

..      Table 14.2  Tumour node metastases (TNM) staging system for carcinoma of the breast

Primary tumour (T)a, b, c

TX Primary tumour cannot be assessed

T0 No evidence of primary tumour

Tis Carcinoma in situ

Tis (DCIS) Ductal carcinoma in situ

Tis (LCIS) Lobular carcinoma in situ

Tis (Paget’s) Paget’s disease (Paget disease) of the nipple not associated with invasive carcinoma and/or carcinoma in situ (DCIS and/
or LCIS) in the underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget’s disease are
categorised based on the size and characteristics of the parenchymal disease, although the presence of Paget’s disease
should still be noted

T1 Tumour ≤20 mm in greatest dimension

  T1mi Tumour ≤1 mm in greatest dimension

  T1a Tumour >1 mm but ≤5 mm in greatest dimension

  T1b Tumour >5 mm but ≤10 mm in greatest dimension

  T1c Tumour >10 mm but ≤20 mm in greatest dimension

T2 Tumour >20 mm but ≤50 mm in greatest dimension

T3 Tumour >50 mm in greatest dimension

T4d Tumour of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)

  T4a Extension to the chest wall, not including only pectoralis muscle adherence/invasion

  T4b Ulceration and/or ipsilateral satellite nodules and/or oedema (including peau d’orange) of the skin, which do not meet the
criteria for inflammatory carcinoma

  T4c Both T4a and T4b

  T4d Inflammatory carcinomae

14 Posttreatment ypT.f The use of neoadjuvant therapy does not change the clinical (pretreatment) stage. Clinical (pretreatment) T will be
defined by clinical and radiographic findings, while y pathologic (posttreatment) T will be determined by pathologic size and extension.
The ypT will be measured as the largest single focus of invasive tumour, with the modifier «m» indicating multiple foci. The measurement of
the largest tumour focus should not include areas of fibrosis within the tumour bed

Regional lymph nodes (N)

Clinical

NX Regional lymph nodes cannot be assessed (e.g. previously removed)

N0 No regional lymph node metastases

N1 Metastases to movable ipsilateral level I, II axillary lymph node(s)

N2 Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in clinically detectedg ipsilateral
internal mammary nodes in the absence of clinically evident axillary lymph node metastases

  N2a Metastases in ipsilateral level I, II axillary lymph nodes fixed to one another (matted) or to other structures

  N2b Metastases only in clinically detectedg ipsilateral internal mammary nodes and in the absence of clinically evident level I, II
axillary lymph node metastases

N3 Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node
involvement; or in clinically detectedg ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary
lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal
mammary lymph node involvement

  N3a Metastases in ipsilateral infraclavicular lymph node(s)

  N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)

  N3c Metastases in ipsilateral supraclavicular lymph node(s)

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Clinical Presentation, Diagnosis and Staging of Breast Cancer
169 14

..      Table 14.2 (continued)

Pathologic (pN)h, i

pNX Regional lymph nodes cannot be assessed (e.g. previously removed, or not removed for pathologic study)

pN0 No regional lymph node metastasis identified histologically

pN0(i-) No regional lymph node metastases histologically, negative immunohistochemistry (IHC)

pN0(i+) Malignant cells in regional lymph node(s) no greater than 0.2 mm (detected by H&E or IHC including isolated tumour cell
clusters (ITC))

pN0(mol-) No regional lymph node metastases histologically, negative molecular findings (RT-PCR)j

pN0(mol+) Positive molecular findings (RT-PCR)j, but no regional lymph node metastases detected by histology or IHC

pN1 Micrometastases; or metastases in 1–3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected
by sentinel lymph node biopsy but not clinically detectedk

  pN1mi Micrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than 2.0 mm)

  pN1a Metastases in 1–3 axillary lymph nodes, at least one metastasis greater than 2 mm

  pN1b Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node
biopsy but not clinically detectedk

  pN1c Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases
detected by sentinel lymph node biopsy but not clinically detected

pN2 Metastases in 4–9 axillary lymph nodes; or in clinically detectedl internal mammary lymph nodes in the absence of axillary
lymph node metastases

  pN2a Metastases in 4–9 axillary lymph nodes (at least one tumour deposit greater than 2.0 mm)

  pN2b Metastases in clinically detectedl internal mammary lymph nodes in the absence of axillary lymph node metastases

pN3 Metastases in ten or more axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in clinically detectedl
ipsilateral internal mammary lymph nodes in the presence of one or more positive level I, II axillary lymph nodes; or in
more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases
detected by sentinel lymph node biopsy but not clinically detectedk; or in ipsilateral supraclavicular lymph nodes

  pN3a Metastases in ten or more axillary lymph nodes (at least one tumour deposit greater than 2.0 mm) or metastases to the
infraclavicular (level III axillary lymph) nodes

  pN3b Metastases in clinically detectedl ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary
lymph nodes; or in more than three axillary lymph nodes and in internal mammary lymph nodes with micrometastases or
macrometastases detected by sentinel lymph node biopsy but not clinically detectedk

  pN3c Metastases in ipsilateral supraclavicular lymph nodes

Posttreatment ypN

   osttreatment yp «N» should be evaluated as for clinical (pretreatment) «N» methods above. The modifier «sn» is used only if a sentinel
P
node evaluation was performed after treatment. If no subscript is attached, it is assumed that the axillary nodal evaluation was by axillary
node dissection (AND)

  The X classification will be used (ypNX) if no yp posttreatment SN or AND was performed

  N categories are the same as those for pN

Distant metastasis (M)

M0 No clinical or radiographic evidence of distant metastases

cM0(i+) No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumour
cells in circulating blood, bone marrow or other nonregional nodal tissue that are no larger than 0.2 mm in a patient with-
out symptoms or signs of metastases

M1 Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven larger
than 0.2 mm

(continued)

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170 J. Zgajnar

..      Table 14.2 (continued)

Posttreatment yp M classification. The M category for patients treated with neoadjuvant therapy is the category assigned in the clinical
stage, prior to initiation of neoadjuvant therapy. Identification of distant metastases after the start of therapy in cases where pretherapy
evaluation showed no metastases is considered progression of disease. If a patient was designated to have detectable distant metastases
(M1) before chemotherapy, the patient will be designated as M1 throughout.

Anatomic stage/prognostic groupsm

0 Tis N0 M0

IA T1n N0 M0

IB T0 N1mi M0

T1n N1mi M0

IIA T0 N1o M0

T1n N1o M0

T2 N0 M0

IIB T2 N1 M0

T3 N0 M0

IIIA T0 N2 M0
n N2 M0
T1

T2 N2 M0

T3 N1 M0

T3 N2 M0

IIIB T4 N0 M0

T4 N1 M0

T4 N2 M0

IIIC Any T N3 M0
14 IV Any T Any N M1

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the
AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer New York, Inc.
(Reprinted from [11] with permission from Springer Healthcare)
aThe T classification of the primary tumour is the same regardless of whether it is based on clinical or pathologic criteria, or both. Designa-

tion should be made with the subscript «c» or «p» modifier to indicate whether the T classification was determined by clinical (physical
examination or radiologic) or pathologic measurements, respectively. In general, pathologic determination should take precedence over
clinical determination of T size
bSize should be measured to the nearest millimetre. If the tumour size is slightly less than or greater than a cut-off for a given T classifica-

tion, it is recommended that the size be rounded to the millimetre reading that is closest to the cut-off
cMultiple simultaneous ipsilateral primary carcinomas are defined as infiltrating carcinomas in the same breast, which are grossly or macro-

scopically distinct and measurable. T stage is based only on the largest tumour. The presence and sizes of the smaller tumour(s) should be
recorded using the «(m)» modifier
d Invasion of the dermis alone does not qualify as T4; dimpling of the skin, nipple retraction or any other skin change except those

described under T4b and T4d may occur in T1, T2 or T3 without changing the classification. The chest wall includes ribs, intercostal muscles
and serratus anterior muscle but not the pectoralis muscles
eInflammatory carcinoma is a clinical-pathologic entity characterised by diffuse erythema and oedema (peau d’orange) involving a third or

more of the skin of the breast. These skin changes are due to lymphoedema caused by tumour emboli within dermal lymphatics. Although
dermal lymphatic involvement supports the diagnosis of inflammatory breast cancer, it is neither necessary nor sufficient, in the absence
of classical clinical findings, for the diagnosis of inflammatory breast cancer
fIf a cancer was designated as inflammatory before neoadjuvant chemotherapy, the patient will be designated to have inflammatory

breast cancer throughout, even if the patient has complete resolution of inflammatory findings
gClinically detected is defined as detecting by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having

characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with
cytologic examination. Confirmation of clinically detected metastatic disease by fine needle aspiration without excision biopsy is

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Clinical Presentation, Diagnosis and Staging of Breast Cancer
171 14

..      Table 14.2 (continued)

designated with an (f ) suffix, for example, cN3a(f ). Excisional biopsy of a lymph node or biopsy of a sentinel node, in the absence of
assignment of a pT, is classified as a clinical N, for example, cN1. Information regarding the confirmation of the nodal status will be
designated in site-specific factors as clinical, fine needle aspiration, core biopsy or sentinel lymph node biopsy. Pathologic classification
(pN) is used for excision or sentinel lymph node biopsy only in conjunction with a pathologic T assignment
hClassification is based on axillary lymph node dissection with or without sentinel lymph node biopsy. Classification based solely on

sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (sn) for «sentinel node», for example,
pN0(sn)
iIsolated tumour cell clusters (ITC) are defined as small clusters of cells not greater than 0.2 mm, or single tumour cells, or a cluster of fewer

than 200 cells in a single histologic cross-­section. ITCs may be detected by routine histology or by immunohistochemical (IHC) methods.
Nodes containing only ITCs are excluded from the total positive node count for purposes of N classification but should be included in the
total number of nodes evaluated
jRT-PCR reverse transcriptase/polymerase chain reaction
k«Not clinically detected» is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical

examination
l«Clinically detected» is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having

characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis based on fine needle aspiration biopsy with
cytologic examination
mAnatomic stage

  M0 includes M0(i+)
  The designation pM0 is not valid; any M0 should be clinical
  If a patient presents with M1 prior to neoadjuvant systemic therapy, the stage is considered Stage IV and remains Stage IV regardless of
response to neoadjuvant therapy
  Stage designation may be changed if postsurgical imaging studies reveal the presence of distant metastases, provided that the studies
are carried out within 4 months of diagnosis in the absence of disease progression and provided that the patient has not received
neoadjuvant therapy
  Postneoadjuvant therapy is designated with the «y» prefix. For patients with a pathologic complete response (pCR) to neoadjuvant
therapy, no stage group is assigned (i.e. yT0N0M0)
nT1 includes T1mi
oT0 and T1 tumours with nodal micrometastases only are excluded from Stage IIA and are classified Stage IB

1. Staging of the primary tumour
All patients should undergo a full clinical examination.
A bilateral mammogram is mandated in all patients,
followed by other imaging investigations of the breast if
needed.
2. Staging of regional lymph nodes
Imaging of the axillary lymph nodes with US mostly
combined with image-guided FNA/CB is the norm
as clinical examination of axillary lymph nodes is
notoriously inaccurate [55]. Of note, in approximately
40% of patients with clinically negative axillary lymph
nodes, metastatic deposits to the lymph nodes are
found after sentinel node biopsy [56]. Furthermore,
even clinically positive axillary lymph nodes are often
negative for metastasis on final histopathological
result; in the MSKCC series, 25% of clinically suspi-
cious cases were actually benign on pathology [57]
showing how unreliable clinical assessment can be.
The most widely used imaging method is ultrasound,
and several morphologic features of suspicious lymph
nodes are used: thickening of the lymph node cortex
(above 2–3 mm), cortex shape (eccentric or irregular),
and the absence of a central fatty hilum and rounded
shape (ratio of the longitudinal and transverse dimen-
sion) [58]. Ultrasound alone has a median sensitivity of
61.1% and a median specificity of 82% [59]. Performing
needle biopsy in suspicious axillary nodes results in
an improved median sensitivity of 79.4% and median
specificity of 100% as reviewed by Houssami and col-
leagues [58]. It seems that CB has a slightly higher
sensitivity compared to FNA; however, both methods
are clinically valuable [60]. Using US combined with
needle biopsy identifies approximately 50% of patients
with axillary metastases prior to surgery, and a median
of 19.8% of patients can be converted to an upfront
ALND. However, this approach is being questioned
after the results of the ACOSOG Z11 trial were pub-
lished, as in patients with up to two positive sentinel
nodes in breast-conserving surgery ALND might not
be necessary [61], although further research is needed
to clarify this such as the Sentinel Node vs Observation
After Axillary Ultrasound (SOUND) trial [62].
FDG-PET was also tested in assessing lymph node
­metastases. However, due to its spatial resolution being
limited to 5–6 mm, it cannot replace other established
methods like SLNB and ALND in axillary lymph node
staging [63]. The sensitivity of PDG-PET/CT varies from
37 to 77% and its specificity from 92 to 100% [64]. PDG-
PET is comparable to US in sensitivity and specificity;
therefore, due to its high radiation dose and cost, it has
no advantage over US. It can add however additional
information in cases with inconclusive US results.
Furthermore, it also reveals suspicious nodes outside of
axilla and potential other disease sites [65].

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 172 J. Zgajnar

3. Search for distant metastases

1. Stages I and II
The prevalence of asymptomatic metastatic disease
in early breast cancer patients is low (below 2%),
and therefore, routine-intensive laboratory staging
and imaging diagnostics is not indicated [19, 54].
Blood test including full blood count, liver and
renal function tests and alkaline phosphatase and
calcium levels should be obtained prior to surgery
or neoadjuvant systemic therapy. Further investi-
gations like chest computed tomography (CT) or
MRI, abdominal CT, US or MRI and bone scan
should be considered in case of pathological labora-
tory tests, T3 tumours, clinically palpable regional
lymph nodes or clinical signs of metastatic disease
(. Figs. 14.8, 14.9, 14.10, and 14.11). Performing a
 

PDG-­PET/CT is to be considered in cases of incon-

clusive conventional diagnostics [19, 54]. PDG-
PET/CT detects approximately 25% additional ..      Fig. 14.8  Pulmonary metastases diagnosed by the chest CT

..      Fig. 14.9  Liver metastases

diagnosed by the liver ultrasound

14

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Clinical Presentation, Diagnosis and Staging of Breast Cancer
173 14
metastases in asymptomatic patients compared to
conventional imaging [66] (. Fig. 14.12). The sen-
 

sitivity and specificity of the imaging methods are

listed in . Table 14.3.
 

2. In Stage IIIA (T3 N1 M0) disease, all the above-listed

additional investigations can be considered [19].
3. All Stage III (except T3 N1 M0) and Stage IV
patients’ complete diagnostic workup is necessary.
The same intensive diagnostic workup should be
performed in cases of local or regional recurrence
of the disease.

..      Fig. 14.10  Liver metastases diagnosed by the abdominal CT

..      Fig. 14.11  Bone metastases diagnosed by the bone scintigraphy

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174 J. Zgajnar

..      Fig. 14.12  Metastases to the internal mammary lymph nodes diagnosed by the PET/CT

14
..      Table 14.3  Median sensitivity and specificity of imaging
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 177 15

Pathology of Breast Cancer

Frederique Penault-Llorca and Nina Radosevic-Robin

15.1 Fundamentals of Breast Cancer Histopathology – 178

15.2 Pathology Input and Role in the Diagnosis

of Breast Cancer – 179

15.3 «What is new»: Evolution of Practices in Pathology – 179

15.3.1 Micro- and Macrobiopsies – 179
15.3.2 Communication Between Radiologists and Pathologists – 179

15.4 Pathology Report of Invasive Breast Cancer – 180

15.4.1 General Information: Identification – 180
15.4.2 Gross Examination (Specimen Orientation, Frozen Section
Examination, Surgical Margin Status and SLN Examination) – 180
15.4.3 Description of Microscopic Findings – 181

15.5 Molecular Biology Assays – 187

15.5.1 Molecular or Intrinsic Subtypes of Breast Cancer – 187
15.5.2 Multigene Signatures for Breast Cancer – 188

15.6 Conclusion – 189

References – 189

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_15

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 178 F. Penault-Llorca and N. Radosevic-Robin
15.1  undamentals of Breast Cancer
F
Histopathology
Histopathological (microscopic) analysis of breast tumour
tissue samples is the primary modality for establishing a
breast cancer diagnosis. According to the latest, fourth World
Health Organisation (WHO) classification of breast tumours,
[1] the majority (70–80%) of breast cancers (BCs) are classi-
fied as invasive carcinoma of no special type (NST), so this is
the diagnosis by default (invasive breast carcinoma NST, for-
merly termed invasive ductal carcinoma, IDC) (. Fig. 15.1).  
Breast cancers, other than invasive carcinomas NST, may
belong to one of a number of major categories as follows:
special types of invasive breast carcinoma, epithelial-­
myoepithelial tumours, fibroepithelial tumours, mesenchy-
mal tumours and lymphomas. In this review, these BC
subtypes will be described as they are important for under-
standing both clinical behaviour and in directing treatment.
Some of the rarer subtypes will not be addressed here in
detail. Several good articles have recently been published
which cover these subtypes in more detail for the interested
reader [2, 3], and several are also covered in other chapters
in this book (7 Chaps. 46 and 47).
The second most frequent histological subtype of BC,
and the most frequent special type of BC, is invasive lobular
carcinoma (ILC, 10–12% of all BCs) (. Fig.  15.2). It has a
particular clinical behaviour pattern which corresponds to
its particular genotype: mutation or loss of the gene for
E-cadherin, a cellular adhesion molecule (CDH1) [4].
Lobular carcinomas tend to have a more diffuse pattern of
spread within the breast making them difficult to clinically
and radiologically characterise (tumour size often underesti-
mated both clinically and on imaging). They also may be
mammographically occult so magnetic resonance imaging
15 (MRI) is often advocated to fully characterize these lesions
before offering conservation surgery. They are also more
likely to be multifocal [5] which again justifies the use of pre-
operative MRI [6]. Lobular breast cancers tend to be histo-
..      Fig. 15.1  Invasive breast cancer of no special type
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..      Fig. 15.2  Invasive lobular cancer
logical grade 2, to be oestrogen receptor (ER) positive, to be
HER-2 negative and to have an unusual pattern of metastatic
spread where they are more likely to infiltrate the viscera
(stomach, bladder, bowel, etc.) than other breast tumour
subtypes [7].
Among the BC types other than invasive ductal or lobular
carcinoma, some are characterized by a particularly good or
poor prognosis. Tubular, colloid (mucinous), adenoid cystic
or secretory breast carcinomas, in general, have a good prog-
nosis, so most of them can be effectively controlled by first-
line surgery and anti-oestrogens (+/− adjuvant radiotherapy
if appropriate), without the need for systemic chemotherapy
[2, 3, 8]. For example, tubular carcinomas are usually small,
node negative, low grade and ER+ and have an excellent
prognosis compared to other invasive carcinomas of NST [9].
In contrast, micropapillary, metaplastic and pleomorphic
lobular breast carcinoma has an intrinsically aggressive
behaviour pattern and poor prognosis [10–12].
Medullary breast carcinoma is a very rare BC subtype but
deserves special attention as it was the first type of BC which
demonstrated that a dense lymphocytic infiltration in a high-­
grade cancer can be associated with a favourable prognosis. It
was first described almost 60 years ago [13] and named med-
ullary because of its close resemblance to a lymph node.
However, besides its high-grade and dense lymphocytic infil-
trate, this BC subtype is also characterized also by syncytial
architecture and circumscribed margin. This combination is
now considered classically to denote a «true» medullary BC,
whereas other BCs rich in tumour-infiltrating lymphocytes
(TILs) belong mostly to two other categories, atypical
­medullary BC and BC with medullary features. «True» med-
ullary BC is a rare tumour (comprising less than 0.5% of all
BCs), has the «triple-negative» phenotype (ER-, PR-, HER2-)
and is TP53-mutated. It has been demonstrated, during the
past 10 years, that most medullary BCs or BCs with medul-
lary features are triple negative or HER2+. The triple negative
ones frequently arise in patients having a germline BRCA1
mutation [14]. If this mutation is not present, other heredi-
tary mutations may be found, mostly in genes involved in
Pathology of Breast Cancer
DNA damage repair (DDR) [15]. In addition, such tumours
may have numerous other anomalies in the DDR pathway
and are said to have «BRCAness», i.e. pathobiological fea-
tures typical of BCs associated with BRCA1 mutation [16].
The presence of BRCAness is usually assessed by several
molecular assays and is demonstrated to be associated with
increased tumour sensitivity to DNA-damaging agents like
platinum salts and/or to the inhibitors of poly (ADP-ribose)
polymerase (PARP) [17–19]. These molecular features influ-
ence the therapeutic approach to BC, as tumours with
BRCAness can often be successfully treated by neoadjuvant
therapies containing DNA-damaging agents, which allows
for a reduction tumour burden («downstaging») and subse-
quent breast conservative surgery. A high number of tumour-­
infiltrating lymphocytes (TILs) in a BC, the most striking
«medullary feature», have been demonstrated in several
recent studies to be a powerful prognostic and predictive bio-
marker in BC [20]; however, at the time of writing this chap-
ter, no clinical decisions regarding BC can be made on the
basis of TIL level  – they can only be used for selection of
patients for clinical studies of neoadjuvant chemo- or immu-
notherapies.
Inflammatory breast cancer is characterized by tumour
infiltration into the dermal lymphatic vessels causing oedema
of the skin overlying the breast. This diagnosis is principally
clinical, as the «orange peel» breast skin texture (peau
d’orange) is observed clinically and can be documented by a
skin biopsy [1]. This subtype of BC has a very unfavourable
prognosis and is treated initially by neoadjuvant systemic
chemotherapy [21] (see 7 Chap. 48, locally advanced breast
cancer).
Other rare tumour types include desmoid tumours,
phyllodes tumour, primary sarcoma and lymphoma (most
of which are dealt with elsewhere in this book (7 Chaps. 46
and 47).
15.2  athology Input and Role
P board meetings, through clinical-pathological and radiologi-
in the Diagnosis of Breast Cancer
The daily practice of the breast pathologist has changed sub-
stantially over the last 30 years. Mass screening has pro-
foundly modified the natural history of BC, its clinical
presentation and, consequently, its management. The BC
samples submitted for pathological analysis are smaller
(obtained by diagnostic core biopsies or conservative sur-
gery), as indeed is the average tumour size (remarkably
decreased due to mass screening and early detection); para-
doxically, the number of samples that need to be examined by
the pathologist is growing (exhaustive management of prein-
vasive lesions, microcalcifications, surgical margins).
Nowadays, the diagnosis of BC is established before surgery
in the vast majority of cases by diagnostic percutaneous
biopsy. The global number of frozen section analyses remains
stable as the role of this procedure has switched from surgical
BC diagnosis to sentinel lymph node (SLN) assessment in
some but not all countries/centres. The wider implementa-
rares1geo@gmail.com
179 15
tion of intraoperative SLN assessment is associated with a
new specific workflow in some pathology labs, dedicated to
the search for macro- and micrometastases either by classical
histopathological techniques or by newer molecular biology
methods. Intraoperative assessment of margins is also some-
times undertaken.
The era of targeted therapies has modified the pathologi-
cal evaluation of BC, which has moved from the purely mor-
phological, on microscopically identified lesions (diagnosis
of malignancy, tumour histopathological grade, lymph node
(LN) involvement) to the phenotypical, using IHC (tumour
proliferation degree, presence of LN micrometastases and of
therapeutic targets such as HER2 and hormone receptors
(HR)) and evaluation based on molecular biology methods
(in situ hybridization (ISH), molecular profiling via gene
expression analysis, search for LN micrometastases).
15.3 « What is new»: Evolution of Practices
in Pathology (. Box 15.1)
15.3.1 Micro- and Macrobiopsies
The pathological diagnostics of BC are usually performed on
small specimens in modern practice (i.e. core needle biopsies)
in cases of frankly malignant lesions, or on macrobiopsies, in
some cases of microcalcifications detected in the breast tissue
by radiological examination (e.g. vacuum-­assisted biopsies,
excision biopsies).
15.3.2 Communication Between
Radiologists and Pathologists
The modern breast pathologist works in close communica-
tion with other physicians involved in patient care. Discussion
of individual clinical cases at the multidisciplinary tumour
cal consensus and discussion, is of particular importance and
should be the standard of care in all institutions involved in
BC diagnostics and/or treatment.
Box 15.1  «What is new»: changes in  the  practice of
breast cancer diagnostics
Mass screening: smaller tumours at diagnosis
Pre-surgery «strategic biopsy»: less frozen sections for
breast cancer diagnosis
Therapeutic de-escalation in surgery: sentinel lymph node
assessment
Personalized medicine:
55 Treatment driven by tumour biology («intrinsic»
classification) rather than by stage
55 Reflex testing of predictive factors (hormonal receptors,
HER2)
Therapeutic de-escalation in oncology: prognostic and
predictive molecular signatures
 180 F. Penault-Llorca and N. Radosevic-Robin

the specimen, which, regrettably, also represents the surgical

..      Table 15.1  Difficulties of diagnostics on biopsies
margins. These artefacts can alter morphology to the extent
Correct identification of pre-invasive lesions implying surgical
that distinction between benign and malignant lesions is
verification (atypical ductal hyperplasia, lobular neoplasia, etc. ...) impossible. When the surgical specimen (lumpectomy, partial
mastectomy or mastectomy) is removed, specimen orienta-
Diagnosis of microinvasion
tion must be performed in the operating room by the surgeon
Establishment of the grade and of other histoprognostic and or a trained nurse. The type and number of orientation marks
predictive parameters on small samples (in case of pre-operative have to be discussed and agreed between the breast surgeons
or neoadjuvant treatments)
and pathologists and ideally should be to a standardized pro-
tocol. One such protocol is to use a short suture for superior,
long for lateral, medium for medial and others as appropriate.
Use of radio-opaque markers such as metal clips may be help-
The communication between radiologists and patholo-
ful if specimen X-ray is to be performed but are not adequate
gists is indispensable in the initial phase of breast lesion
alone as they need to be removed by the pathologist before
diagnostics: even before the gross (macroscopic) analysis of
specimen processing which may damage the tissues. The spec-
a breast tissue specimen, the pathologist needs to know the
imen should be sent unsliced to the pathology department.
degree of radiological suspicion (ACR classification) and the
When handling an image-guided excision (that is an
type of ­ mammographic abnormality. This information
impalpable lesion marked using a guide wire, ROLL or a
determines the type and extent of breast specimen sampling.
radioactive seed), the first step is to obtain a digital or X-ray
In particular, if microcalcifications in the breast are radio-
image of the specimen, in order to be sure that the intended
logically detected, their presence and localization in macro-
radiographic abnormalities have been totally excised. The
biopsy samples should be verified and precisely reported by
specimen radiography can be performed either in the oper-
the radiologist. The radiological findings should be com-
ating room, the radiology department or the pathology
pared to the pathological assessment of the sample, and in
laboratory. The images are essential to the pathologist to
case of significant discordance, additional biopsies should
guide sampling of specimens with impalpable lesions
be considered [22]. The diagnosis of BC on biopsies does
(. Fig. 15.3).
have certain limitations (. Table  15.1), and the ones pro-
 

The specimens are then inked to mark the surgical mar-

 

voked by inadequate sample size and/or quality can and

gins, eventually with each colour corresponding to a specific
must be overcome by adequate communication between the
orientation (. Fig. 15.4).
sample providers (usually radiologists) and the pathologists.
 

15.4  athology Report of Invasive

P
Breast Cancer
15 The first mission of the pathologist is to provide an accurate
diagnosis of malignancy [23].

15.4.1 General Information: Identification

Detailed information must be provided to ensure the correct

identification of the sample and correct orientation of a sur- ..      Fig. 15.3  X-ray image of a breast specimen containing a metal clip
gical specimen. Besides demographic data and clinical his-
tory, it is essential to specify the side and the exact location of
the lesion(s) within the breast, as well as to provide details of
any prior treatment, i.e. neoadjuvant chemo- or hormone
therapy, or re-excision for unsatisfactory margins.

15.4.2  ross Examination (Specimen

G
Orientation, Frozen Section
Examination, Surgical Margin Status
and SLN Examination)

Electrocautery introduces artefacts into histologic evaluation

of breast specimens. The maximal effects are on the surface of ..      Fig. 15.4  Inking of a breast surgical specimen

rares1geo@gmail.com
Pathology of Breast Cancer
Before fixation, the pathologist will macroscopically
examine the specimen and decide whether or not to perform
a frozen section on an area of the specimen. This procedure
is indicated as an intraoperative assessment when the preop-
erative diagnosis is uncertain, when an unexpected lesion is
seen and in cases where the surgeon is concerned about
grossly suspicious surgical margins. There is no indication to
perform frozen sections in cases of microcalcifications
extending to the surgical margin in the absence of a mass
lesion however. In such cases the frozen section procedure
could impair the morphology and waste tissues and eventu-
ally diminish the capacity of the pathologist to make the right
diagnosis, for example, between a proliferative lesion and an
in situ carcinoma.
If the surgical procedure involved taking intraoperative
margin shaves or in case of re-excision for positive margins
(biopsy cavity margins, shaved margins), the new cut surface
will also be inked specifically. The specimen should be seri-
ally sectioned, perpendicularly to the inked surface to permit
analysis of the widest extent of the new surgical margin.
Before fixation, the pathologist will describe the gross
anatomy of the surgical specimen and measure the tumour(s)
in three dimensions and its distance to the margins. Specimen
weight should also be recorded before fixation either in the
operating room or in the pathology department. In the final
pathological report, this macroscopic description and the
results from the frozen sections (if performed) are reported
for medicolegal reasons.
Ideally the oriented breast specimens should be sliced
prior to fixation to ensure more rapid and thorough fixation
(. Fig. 15.5). If this is not possible, the sample has to at least be
 
incised centrally to help penetration of the fixative. The fixa-
tive should be 10% buffered formalin and the fixation dura-
tion between 6 and 72  h [24, 25]. If fixation is significantly
delayed, it may permit tissue degradation which may render it
impossible to adequately grade the tumour. Ideally therefore
fixation should be carried out within 1 hour of surgery.
..      Fig. 15.5  Slicing of a breast specimen
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181 15
In case of SLN biopsy, the node is first examined macro-
scopically by the pathologist. A touch preparation or frozen
sections of a slice can be performed intraoperatively if
required. Intraoperative diagnosis can also be established
by a molecular biology method (such as the one-step
nucleic acid technique, OSNA) [26]. However, this practice
is not standard in the majority of European Units for a
number of reasons including cost, interpretation of whether
positive results equate to micro- or macrometastases com-
pared to standard validated node assessment methodology
and the increasing trend for more selective ANC in patients
with low-volume nodal disease based on MDT review of
full histology. For the same reason, frozen section examina-
tion is usually performed only in cases of highly suspicious
SLN macrometastasis so that the surgeon can decide on
further axillary management and whether it is appropriate
to complete an axillary clearance or not (see algorithm on
7 Chap. 24). The LNs obtained by axillary dissection are
processed by complete inclusion of each node after slicing,
usually at 2  mm intervals, except for the obviously meta-
static ones (which will have only one slice per node).
15.4.3 Description of Microscopic Findings
The pathology report should provide the following: diagno-
sis of the lesion, surgical margin status (free or involved and
specifying whether it is in situ or invasive disease at the mar-
gin as well as the distance from the lesion to each specified
surgical margin), a report of lymph node involvement
(number uninvolved and number involved, subclassified
according to macrometastases, micrometastases or isolated
tumour cells) and the presence of lymphovascular invasion
(emboli). In addition, a detailed description of the cancer
biotype (grade, hormone receptor status, HER-2 status) is
mandatory. All those data are indispensable for adjuvant
therapy decision-making at the MDT and whether further
surgery is indicated [1, 22, 23]. The use of a standardized
synoptic pathology report with a check list is highly recom-
mended [27, 28].
Surgical Margins
This has been a subject of intense debate in recent years with
a general downwards trend towards narrower acceptable
margins based on several papers showing that on detailed
sectioning of mastectomy specimens, breast cancer often has
small satellite lesions such that to achieve 100% clear mar-
gins, a 10 cm margin is required [29, 30]. The only margin
proven to confer a significant impact on local recurrence after
conservation surgery is a positive margin (0 mm, tumour at
ink) [31, 32]. The adequacy of a «no tumour at ink» margin
was recently endorsed by several national and international
bodies [33–35]. However, there are concerns that whilst this
may be adequate for invasive disease, there is less certainty for
DCIS, and indeed the most recent ASCO guidelines have
advocated a 2 mm margin for DCIS. In many MDTs a margin
 182 F. Penault-Llorca and N. Radosevic-Robin

of less than 1 mm will be reviewed to look at disease pattern
and other risk factors to decide if this is acceptable and mini-
mal acceptable margins may vary by country and by unit.
Elements of the TNM Stage (. Table 15.2)  
The TNM staging was revisited in 2002 (version VI); impor-
tant changes were made in terms of the introduction of LN
metastasis classification and in integration of IHC and
molecular biology parameters related to the wide implemen-
tation of SLN examination. The 2010 version of TNM has
only slight variations [36], compared to the 2002 version.
Below is a description of the pTNM staging system (p stands
for pathologic), which is determined by the microscopic
evaluation of the samples (as opposed to clinical TNM).
Tumour Size (pT)
It is recommended to perform the following:
55 Measure at least two tumour dimensions; however,
indicate only the size of the invasive lesion, at its greatest
dimension.
55 Always verify the tumour size under the microscope; in
case of difference between the tumour sizes determined
during the gross and at the microscopic examination, the
size determined by microscopy will be taken into account
for staging (pT).
55 In case of multiple tumours, the tumour size should not
be determined as the sum of individual tumour sizes; the
individual tumour sizes should be reported, and the most
voluminous tumour will be taken into account for
staging (pT). The issue of T staging in multifocal disease
is somewhat controversial, and using such a system it is
recognized that prognosis may be less accurate as this
system underestimates tumour volume [37].
Lymph Node Status (pN)
The strong prognostic impact of LN involvement and of the
number of involved LNs is well known. In the new TNM
classification, involvement of the subclavicular LN corre-
sponds to N3 status (instead of being categorized as M1, as
in the previous classification). The pathology report should
contain the number of involved nodes among all the excised
nodes and, eventually, the size of the largest metastasis. In
case of SLN excision, the node is cut at three levels at least.
The use of IHC to detect micrometastases or isolated
tumour cells is not standardized and depends upon local
guidelines.

..      Table 15.2  Pathologic TNM or pTNM classification for breast cancer staging, 7th edition (2010), as measured on surgical specimens

Pathologic TNM staging of the primary tumour (pT)

pTX Primary tumour cannot be assessed

pT0 No evidence of primary tumour

pTis Carcinoma in situ

  pTis (DCIS) Ductal carcinoma in situ

15   pTis (LCIS) Lobular carcinoma in situ

  pTis (Paget) Paget disease of the nipple not associated with invasive carcinoma and/or carcinoma in situ (DCIS and/or LCIS) in the
underlying breast parenchyma. Carcinomas in the breast parenchyma associated with Paget disease are categorized
based on the size and characteristics of the parenchymal disease, although the presence of Paget disease should still
be noted

pT1 Tumour ≤20 mm in greatest dimension

  pT1mi Tumour ≤1 mm in greatest dimension

  pT1a Tumour >1 mm but ≤5 mm in greatest dimension

  pT1b Tumour >5 mm but ≤10 mm in greatest dimension

  pT1c Tumour >10 mm but ≤20 mm in greatest dimension

pT2 Tumour >20 mm but ≤50 mm in greatest dimension

pT3 Tumour >50 mm in greatest dimension

pT4 Tumour of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)

  pT4a Extension to the chest wall, not including only pectoralis muscle adherence/invasion

  pT4b Ulceration and/or ipsilateral satellite nodules and/or oedema of the skin (including the «peau d’orange»/«orange
peel» aspect), which do not meet the criteria for inflammatory carcinoma

  pT4c Both T4a and T4b

  pT4d Inflammatory carcinoma

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Pathology of Breast Cancer
183 15

..      Table 15.2 (continued)

Pathologic staging of regional lymph nodes (pN)a

pNX Regional lymph nodes cannot be assessed (e.g. previously removed, or not removed for pathologic study)

pN0 No regional lymph node metastasis identified histologically. Note: Isolated tumour cell clusters (ITCs) are defined as
small clusters of cells ≤0.2 mm, or single tumour cells, or a cluster of <200 cells in a single histologic cross-section;
ITCs may be detected by routine histology or by IHC methods; nodes containing only ITCs are excluded from the total
positive node count for purposes of N classification but should be included in the total number of nodes evaluated

  pN0(i-) No regional lymph node metastases histologically, negative IHC

  pN0(i+) Malignant cells in regional lymph node(s) ≤ 0.2 mm (detected by haematoxylin-eosin stain or Iby HC, including ITCs)

  pN0(mol-) No regional lymph node metastases histologically, negative molecular findings (reverse transcriptase-­polymerase
chain reaction, RT-PCR)

  pN0(mol+) Positive molecular findings (RT-PCR) but no regional lymph node metastases detected by histology or IHC

pN1 Micrometastases or metastases in 1–3 axillary lymph nodes and/or in internal mammary nodes, with metastases
detected by sentinel lymph node biopsy but not clinically detectedb

  pN1mi Micrometastases (> 0.2 mm and/or > 200 cells, but none > 2.0 mm)

  pN1a Metastases in 1–3 axillary lymph nodes (at least 1 metastasis >2.0 mm)

  pN1b Metastases in internal mammary nodes, with micrometastases or macrometastases detected by sentinel lymph node
biopsy but not clinically detectedb

  pN1c Metastases in 1–3 axillary lymph nodes and in internal mammary lymph nodes, with micrometastases or macrome-
tastases detected by sentinel lymph node biopsy but not clinically detectedb

pN2 Metastases in 4–9 axillary lymph nodes or in clinically detectedc internal mammary lymph nodes in the absence of
axillary lymph node metastases

  pN2a Metastases in 4–9 axillary lymph nodes (at least 1 tumour deposit >2.0 mm)

  pN2b Metastases in clinically detectedc internal mammary lymph nodes in the absence of axillary lymph node metastases

pN3 Metastases in ≥10 axillary lymph nodes; or in infraclavicular (level III axillary) lymph nodes; or in clinically detectedc
ipsilateral internal mammary lymph nodes in the presence of ≥1 positive level I, II axillary lymph nodes; or in >3
axillary lymph nodes and in internal mammary lymph nodes, with micrometastases or macrometastases detected by
sentinel lymph node biopsy but not clinically detectedb; or in ipsilateral supraclavicular lymph nodes

  pN3a Metastases in ≥10 axillary lymph nodes (at least 1 tumour deposit >2.0 mm); or metastases to the infraclavicular
(level III axillary) nodes

  pN3b Metastases in clinically detectedc ipsilateral internal mammary lymph nodes in the presence of ≥1 positive axillary
lymph nodes; or in >3 axillary lymph nodes and in internal mammary lymph nodes, with micrometastases or
macrometastases detected by sentinel lymph node biopsy but not clinically detectedb

  pN3c Metastases in ipsilateral supraclavicular lymph nodes

Histologic grade (G)

GX Grade cannot be assessed

G1 Low combined histologic grade (favourable)

G2 Intermediate combined histologic grade (moderately favourable)

G3 High combined histologic grade (unfavourable)

aClassification is based on axillary lymph node dissection, with or without sentinel lymph node biopsy. Classification based solely on

sentinel lymph node biopsy without subsequent axillary lymph node dissection is designated (sn) for «sentinel node», for example,
pN0(sn).
b«Not clinically detected» is defined as not detected by imaging studies (excluding lymphoscintigraphy) or not detected by clinical

examination.
c«Clinically detected» is defined as detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having

characteristics highly suspicious for malignancy or a presumed pathologic macrometastasis on the basis of fine-needle aspiration biopsy
with cytologic examination.

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 184 F. Penault-Llorca and N. Radosevic-Robin
a b
..      Fig. 15.6  a Micrometastasis in a lymph node, H&E staining. b Micrometastasis in a lymph node, immunohistochemistry for pan-cytokeratin
In the new TNM classification, a LN micrometastasis is
defined as the presence of a metastatic deposit of 0.2–2.0 mm
size at its greatest dimension (. Figs.  15.6a and 15.6b).
 
Smaller metastatic foci (less than 0.2 mm) or single cancer
cells are classified as pN0(i+) if they are confirmed by IHC
or (mol+) if the evaluation of LN involvement is made by
the molecular biology method OSNA® (one-step nucleic
acid amplification, Sysmex, Japan) [26]. The new TNM sys-
tem thus provides a classification of LN micrometastases,
which have been increasingly detected since the SLN tech-
nique was implemented. However, the prognostic impact of
metastatic microfoci, detected by IHC only, remains contro-
versial.
Tumour Histopathological Subtype
15 Breast cancer histological subtype is determined according to
the fourth WHO classification of breast tumours [1], details
of which are presented in . Table 15.3.
 
Tumour Histological Grade
Histological grade of BC is an important element of pathol-
ogy reporting as it allows for a precise prognostic classifica-
tion into three categories. The Scarff-Bloom-Richardson
(SBR) grade, modified by Elston and Ellis («the Nottingham
grade») [38], is currently recommended as this system is
more easily standardized than the previous grading schemes.
To establish the grade, three parameters are taken into
account, each graded using a scale from 1 to 3: differentia-
tion, anisokaryosis (cellular variability) and mitoses. Among
other precautions, it is important to determine the absolute
value of the mitotic count.
Hormone Receptor and HER2 Status
Hormone receptor (HR, oestrogen (ER) and progesterone
receptor (PR)) and HER2 status of the invasive BC cells are
recognized by European recommendations (St Gallen [39],
ESMO [40], ASCO [24, 41]) as predictive factors indispens-
able for BC therapy decision-making. They are assessed by
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immunohistochemistry (IHC) on formalin-fixed, paraffin-­
embedded breast cancer tissue sampled at diagnosis. The
assessment of HR and HER2 status is obligatory for all inva-
sive BCs.
Pathology laboratories assessing the HR or HER2 status
in BC should participate in regular quality assurance, in col-
laboration with regional or national specialized centres.
Hormone Receptors
The cut-off for HR-positive status in BC, for clinical deci-
sions, recommended by the American Society of Clinical
Oncology and College of American Pathologists (ASCO/
CAP), is 1% of immunostained cells, irrespective of the sig-
nal intensity [24]. Only nuclear staining is significant. Breast
cancer is considered «receptor positive» when it expresses
the ER and/or PR. It is recommended to report the percent-
age of stained cells and the staining intensity (weak or +,
moderate or ++, strong or +++). The two most widely
known methods for quantifying ER expression which use
these two criteria are the Allred score [42, 43] and the H
score [44]. The Allred score recognizes six categories of the
percentage of positive cells: 0 (score 1), <1% (score 2),
1–10% (score 3), 11–33% (score 4), 34–66% (score 5) and
≥67% (score 6). The intensity of staining is graded into four
scores: 0 (no staining), 1 (weak staining), 2 (intermediate
staining) and 3 (strong staining). The final Allred score is
obtained by multiplying the proportion score by the inten-
sity score. According to ASCO/CAP, a total Allred score of
0–2 is considered negative, whereas a total score of 3–8 is
considered positive.
The H score is determined by multiplying the percentage
of positive cells by the staining intensity score (from 0 to 3, for
no staining, weak, intermediate and strong staining, respec-
tively). Thus, according to ASCO/CAP, an H score of 0 is con-
sidered to be a negative result (<1% positive cells, irrespectively
of the staining intensity). Some would further state that a score
of 50 or less is weakly positive. The maximal H score is 300 and
tumours scoring over 250 are regarded as strongly positive.
Pathology of Breast Cancer
185 15

..      Table 15.3  2012 WHO classification of tumours of the ..      Table 15.3 (continued)

breast
Secretory carcinoma
Invasive breast carcinoma
Invasive papillary carcinoma
Invasive carcinoma of no special type (NST) (formal ductal
Acinic cell carcinoma
carcinoma and rare variants, pleomorphic carcinoma, carcinoma
with osteoclast-like stromal giant cells, carcinoma with Mucoepidermoid carcinoma
choriocarcinomatous features, carcinoma with melanotic
features) Polymorphous carcinoma

Special types Oncocytic carcinoma

Invasive lobular carcinoma Lipid-rich carcinoma

    Classic lobular carcinoma Glycogen-rich clear cell carcinoma

    Solid lobular carcinoma Sebaceous carcinoma

    Alveolar lobular carcinoma Salivary gland/skin adnexal type tumours

    Pleomorphic lobular carcinoma     Cylindroma

    Tubulo-lobular carcinoma     Clear cell hidradenoma

    Mixed lobular carcinoma

Tubular carcinoma
HER2
Cribriform carcinoma Recent guidelines from ASCO/CAP have stated that HER2
Mucinous carcinoma status has to be determined in all patients with invasive BC
on the basis of one or more HER2 test results (negative,
Carcinoma with medullary features
equivocal or positive) [41, 45]. Three methods are currently
    Medullary carcinoma recommended for the assessment of HER2 status in routine
    Atypical medullary carcinoma practice: IHC, fluorescent in situ hybridization (FISH) or
chromogenic ISH. IHC is most frequently considered as the
    Invasive carcinoma NST with medullary features
first option for HER2 status assessment. Positive HER2 status
Carcinoma with apocrine differentiation by IHC is defined as more than 10% of invasive cells showing
Carcinoma with signet-ring differentiation
intense, complete membranous staining and is given the 3+
score. Testing criteria define HER2 status as positive when
Invasive micropapillary carcinoma there is evidence of protein overexpression (by IHC) or gene
Metaplastic carcinoma of no special type amplification (HER2 copy number or HER2/CEP17 ratio by
ISH), in more than 10% of contiguous and homogeneous
    Low-grade adenosquamous carcinoma
invasive tumour cells. If results are equivocal (on revised cri-
    Fibromatosis-like metaplastic carcinoma teria) [41] on IHC or ISH, testing should be performed using
    Squamous cell carcinoma the alternative assay. Approximatively 10–15% of breast can-
cers are HER2 positive. If the result is still equivocal after the
    Spindle cell carcinoma
second test, the patient may be considered as «eligible» for
    Metaplastic carcinoma with mesenchymal differentiation anti-HER2 targeted therapy. Repeat testing should be consid-
 Chondroid
     differentiation
ered if results appear discordant with other histopathologic
findings. In cases with a negative HR or HER2 status on the
 Osseous
     differentiation preoperative core needle biopsy or fine-needle aspiration
 Other
     types of mesenchymal differentiation sample, reassessment on the surgical specimen (excised
breast tumour) is recommended because of possible intra-­
Mixed metaplastic carcinoma
tumour heterogeneity.
Myoepithelial carcinoma There is an increasing awareness of tumour evolution,
Rare types and those changes in immunophenotype may occur between
primary presentation and local, regional or metastatic recur-
Carcinoma with neuroendocrine features
rence, as well as between the tumours before and after neoad-
    Neuroendocrine tumour, well differentiated juvant therapy [46, 47]. Consequently, retesting for both HR
 Neuroendocrine
    carcinoma, poorly differentiated (small cell
and HER2 status is usually requested on local recurrences
carcinoma) and biopsy accessible metastases [48]. Retesting after neoad-
juvant therapy is not mandatory but is advised as it can help
    Carcinoma with neuroendocrine differentiation
better tailoring the adjuvant therapy [47].

rares1geo@gmail.com
 186 F. Penault-Llorca and N. Radosevic-Robin
Proliferation
Breast cancer proliferation is an important parameter to take
into account in the evaluation of disease aggressiveness and
thus in therapeutic decision-making, especially in the decision
about chemotherapy. This is currently valid only for HR+
breast cancers, since chemotherapy is given to practically all
patients (unless the primary is less than 5 mm and node nega-
tive) with HER2+ (chemotherapy and anti-HER2 agents) or
with triple-negative tumours (ER-, PR-, HER2-) regardless of
histological subtype [49]. In many centres, there has been
widespread adoption of a nuclear marker of proliferation, the
Ki67 labelling index (MIB-1). This determines the proliferating
fraction of the tumour. A fraction of <15% is low risk, 16–30%
intermediate and over 30% high risk. It is not universally used
or officially recommended due to the absence of international
consensus about the scoring and cut-off values [50]. It is recog-
nized to be of clinical value if available in predicting prognosis
and chemotherapy benefit [51]. In some health economies, its
use has been superseded to some extent by gene arrays many of
which incorporate a Ki67 measurement.
Lymphovascular Invasion
The presence of lymphovascular invasion (LVI, tumour
emboli in blood or lymphatic peritumoural vessels) should
be noted as it is also a confirmed prognostic factor, especially
for node-negative patients [52]. Another marker of tumour
invasiveness, uPA-PAI1 (urokinase-type plasminogen activa-
tor and plasminogen-activator inhibitor-1), measured by
ELISA, has been validated in prospective clinical trials as a
prognostic marker for both N- and N+ breast cancers (level
of evidence IA). Fresh tissue is required for uPA-PAI1 assess-
ment, which limits its use [53].
Ductal Carcinoma in Situ
15 If a component of ductal in situ carcinoma (DCIS) is present,
it has to be described and quantified. The presence of DCIS at
the periphery of the tumour is a prognostic factor for local
recurrence. A 2 mm clear margin is usually sufficient to avoid
re-excision [54] although as with invasive margins it is a sub-
ject of recent debate.
Evaluation of Response to Therapy
In cases of neoadjuvant treatment (NAT), the evaluation of
pathological response to therapy (chemo- or hormonal ther-
apy) is performed on breast and LN specimens obtained at sur-
gery after completion of treatment. There is great diversity in
the classifications of BC response to NAT among pathologists
around the world. Given the lack of consensus regarding the
pathological assessment of post-NAT BC specimens, an inter-
national multidisciplinary working group produced guidelines
covering various aspects of post-NAT BC evaluation [55].
rares1geo@gmail.com
Communication between pathologists and the multidisci-
plinary clinical team (surgeons, radiologists, oncologists) is
mandatory for optimal handling of the post-NAT breast can-
cer surgical specimens. The pathological evaluation request
form must at least indicate that NAT has been administered, as
well as to stipulate the tumour location and its pretreatment
size. The pathologists should be provided with information
about the degree and type of clinical BC response to NAT, as
that is of paramount importance for tumour bed sampling.
Clinical examination, US or MRI can reveal several patterns of
response which are classified as: complete response, concen-
tric shrinkage or scattered foci of residual tumour on imaging.
Gross examination of the post-NAT breast surgical speci-
men is probably the most challenging part of assessment,
since the treatment-induced tissue changes like fibrosis can
make localizing the tumour bed difficult. If the residual
tumour (RT) is macroscopically visible (partial or no response
in the breast), the pathologist examines the slices and per-
forms gross evaluation of the residual tumour size and mar-
gin status. Insertion of metallic clips into tumour bed before
NAT is strongly recommended, since it can guide the surgical
excision and the gross pathological examination in case of a
significant or complete response to NAT. The sampling must
be systematic and exhaustive in order to ensure the correct
histopathological evaluation; in case of a clinically non-palpa-
ble breast mass (clinical complete response) in general, at
least 10–15 tumour bed samples are taken and subsequently
examined for the presence of microscopic residual disease.
Small breast resection specimens (4–5 cm) should be submit-
ted entirely.
The surgically removed axillary LNs are processed the
same way as in cases without NAT.
After fixing in formalin and embedding in paraffin, sec-
tions of the suspicious areas and margins are evaluated on
haematoxylin and eosin staining. The post-NAT breast speci-
men evaluation follows the same rules as for the regular
specimens: the parameters which should be assessed are
tumour size, type and grade, the presence of LVI and carci-
noma in situ, lymph node and surgical margin status.
Post-neoadjuvant tumour residue is evaluated using his-
topathological classifications which describe and quantify
the treatment effect (complete or incomplete response; ypT).
Achieving complete pathological response (pCR) after NAT
is strongly associated with favourable outcome in the HER2+
and TN breast cancer. The Residual Cancer Burden (RCB)
score [56] should be used to standardize quantification of
residual disease. The post-NAT TNM is specified as ypTNM.
The indispensable elements of a breast cancer pathology
report are summarized in . Table 15.4. The criteria necessary
for therapeutic decision in breast cancer are presented in
. Box 15.2.
Pathology of Breast Cancer
187 15

..      Table 15.4  Pathology report for invasivea breast cancer:

15.5 Molecular Biology Assays
check list
15.5.1  olecular or Intrinsic Subtypes
M
General information of Breast Cancer
    Identification of the patient
The technological progress made during last 20  years, and,
    Clinical information especially, the development of high-throughput technologies
    Type of specimen (biopsy, surgical specimen, etc.) for gene expression (GE) analysis, has seen the development
of a new taxonomy for BC, the so-called intrinsic classifica-
    Localization (right or left breast, quadrant)
tion of Perou and Sorlie [57]. Those molecular biology tech-
Macroscopic description (specify if inking of the limits, specimen niques were also exploited in the conception of prognostic
radiography, measurements) and predictive gene signatures [53].
Frozen section On the basis of the oestrogen receptor gene (ESR1)
expression, the intrinsic classification distinguishes four sub-
Microscopic description (can be short)
types of BC: luminal A and B (expressing ESR1), basal (with-
Conclusion (+/− recall the clinical context) out ESR1 expression) and HER2-enriched. Those subtypes
    Histopathological type represent gene expression (GE) profiles, which may be char-
acterized using multigene array technologies such as the
    Tumour size
50-gene signature (PAM50) or may be approximated more
    Grade SBR easily and cheaply by using previously described IHC-based
    Peritumoral emboli (seen/not seen) tests [58] (. Box 15.3). These subtypes are described below:
 

55 Luminal subtypes: Luminal A and B breast cancers display

    DCIS component strong positivity for HR and express luminal differentiation
    Lymph node status cytokeratins: 8, 18 and 19. Luminal B tumours show a
higher expression of proliferation-­related genes and may
    Sentinel lymph node
also show overexpression of the HER2 gene (ERBB2). Those
    Number of the involved among the total excised lymph nodes tumours also have some genetic instability. Luminal A
 Margins
    (free or positive (invasive or in situ cancer) + distance tumours are very sensitive to hormonal therapies, whereas
from the tumour edge) luminal B benefit more from chemotherapy, associated with
    Hormone receptor status
anti-HER2 agents in case of positive HER2 status.
55 Basal subtypes: Breast cancers of this subtype do not
    HER2 status express either the ER or the PR and do not demonstrate
    +/− Proliferation by Ki67 HER2 gene amplification («triple negative» BC). Therefore
hormonal or anti-HER2 therapies, indicated for the HR+
    +/− Molecular signature
or HER2+ breast cancers, are not efficacious in these
aForductal in situ carcinoma: grade, differentiation, necrosis, size cancers of basal molecular subtype. Expression of basal
or number of positive blocks, margins, oestrogen receptor status differentiation cytokeratins (5/6) and/or of EGFR can
confirm the basal subtype GE profile [59]. Several studies

Box 15.2  What to remember: criteria necessary for ther- Box 15.3  Intrinsic breast cancer classification by immu-
apeutic decision in breast cancer nohistochemical «surrogate» markers, currently in  use
55 Histological type (WHO 2012 classification)
55 Histological grade Scarff-Bloom-Richardson (SBR) for routine patient management (Adapted from Coates,
modified by Elston and Ellis [38] St Gallen 2015 [39])
55 Tumour size, single or multiple tumours Luminal subtype: ER+
55 Excision margins (mm) 55 Luminal A: ER+ and PR+, low grade, HER2-, non-proliferative
55 Vascular invasion/emboli 55 Luminal B: ER+ and PR- or PR -ow, or high grade, or
55 Hormone receptor status: ER and PR proliferative, or HER2+
55 HER2 status
55 Lymph node status HER2: HER2+, ER-
55 Stage pT/pN (UICC TNM 2010) Triple negative: ER-, PR-, HER2-

rares1geo@gmail.com
 188 F. Penault-Llorca and N. Radosevic-Robin

a Survival by molecular classes b Survival by molecular classes in LN–

(P = 0.0003) (P = 0.09)
1.00 1.00
Survival probability

Survival probability
0.75 0.75
0.50 0.50
0.25 0.25
0.00 0.00
0 5 10 15 20 25 0 5 10 15 20 25
Follow-up (years) Follow-up (years)

c Survival by molecular classes in LN+

(P = 0.2)
1.00
Survival probability

0.75
0.50
0.25
0.00
0 5 10 15 20 25
Follow-up (years)
Luminal A Luminal B
HER- 2+ Triple negative

..      Fig. 15.7  Kaplan-Meier survival curves with respect to molecular Serena Bonin, Renzo Barbazza, et al., «Are Breast Cancer Molecular
classes of breast cancer a the cohort of breast cancer patients Classes Predictive of Survival in Patients with Long Follow-Up?»,
(N = 304,128, BC-specific mortality), b lymph node-negative tumours Disease Markers, vol. 35, no. 6, Article ID 347073, 11 pages, 2013.
(N = 15,039, BC-specific mortality) and c classes in lymph node-nega- 7 https://doi.org/10.1155/2013/347073 [66] (Published under a
 

tive tumours (N = 15,489, BC-specific mortality) (From Danae Pracella, Creative Commons Attribution License)

have reported that the basal subtype encompasses most of reported [63–65]. None of them has been introduced into the
the BCs associated with BRCA1 mutations, as well as med- routine clinical management of BC at present; however, they
15 ullary and metaplastic cancers (ex-­carcinosarcomas). are recommended for use in selection of patients for clinical
trials.
The importance of recognition of basal molecular subtype lies 55 HER2-enriched subtype: These breast cancers overex-
in the fact that such BC is characterized by defects in the press HER2, have inactive HRs, frequently are very
double-strand DNA repair (DDR) pathway as well as by proliferative and show a degree of genomic instability.
increased genomic instability [60]. This renders them more
sensitive to DNA-damaging agents, such as platinum salts Prognosis varies markedly between these subtypes as does
and anthracyclines, so the basal molecular subtype is consid- biological behaviour and response to treatments (. Fig. 15.7).  

ered to carry a positive predictive value for response to neo-

adjuvant therapies based on the agents interfering with the
DDR pathway. However, recent genomic studies have revealed 15.5.2  ultigene Signatures for
M
significant heterogeneity among basal-like and triple-­negative Breast Cancer
BCs. One of those classifications, made at Vanderbilt
University in Nashville, TN, USA, distinguishes two basal- In the early 2000s, several multigene signatures were devel-
like BC molecular subtypes, which have significantly different oped (MammaPrint®, Agendia, the Netherlands), 76-gene
genomic profiles and, consequently, differing sensitivities to signature (Veridex, USA), Oncotype DX® (Genomic Health,
DNA damage-inducing chemotherapy [61]. Besides those USA)) by searching, without a priori biologic assumption,
two basal-like subtypes, there are five more subtypes of triple- for GE profiles associated with the clinical outcome of breast
negative BC, based on genomic profiling, and those subtypes cancer (reviewed in Wirapati et al., 2008, and in Harris et al.,
have also been demonstrated to respond differently to various 2016) [53, 67]. Although all multigene signatures have dem-
therapeutic agents [61, 62]. A few other genomic classifica- onstrated additional prognostic value, they did not have
tions of triple-negative BC or BC in general have been many genes in common. The genes selected are involved in

rares1geo@gmail.com
Pathology of Breast Cancer
different biologic processes of BC carcinogenesis, e.g. cell
cycle regulation, invasion, metastasis, angiogenesis, immune
response and, for some of them, in ER-, PR- and HER2-­
related pathways.
Then a second generation of GE signatures was devel-
oped, with Endopredict® (Myriad Genetics, USA) and
Prosigna® (NanoString Technologies, USA) signatures.
Like Oncotype DX®, these commercially available tests are
dedicated to ER-positive, HER2-negative breast cancers,
node negative or node positive for up to three nodes.
Endopredict® is a RT PCR-based test of 12 genes, with
three proliferation-­ related genes, five ER-related genes,
three normalization genes and one DNA control gene. The
results are given in a binary fashion (high risk vs low risk)
with the EndoPredict score (EP) or the EndoPredict clini-
cal score (EP Clin) by adding tumour size and nodal status.
The proliferation gene module predicts for early distant
recurrence and the oestrogen-­related gene module for late
(>5  years) recurrence. The Prosigna® test provides the
PAM50 profile (50 target genes plus eight normalization
genes) of the intrinsic classification plus a 19 proliferation-
associated gene expression module) along with tumour
size. The test gives a risk of recurrence (ROR) score (with
two different scales depending upon the nodal status), risk
category (low, intermediate and high) and intrinsic sub-
type (luminal A/B, HER2-enriched, basal-like).
The capacity of gene signatures to predict late relapse in
ER-positive breast cancer has been evaluated prospectively
for Oncotype DX® and MammaPrint® [68] and retrospec-
tively for Prosigna® and EndoPredict®, and all of them dem-
onstrated independent correlation with late relapses, but the
association was weaker than with early relapses. Thus, if
proliferation-based GE signatures are strongly prognostic
for early relapses, in ER-positive, HER2-negative breast
cancers, they are suboptimal to predict late relapses,
although that capacity is strong for PAM50 and encourag-
ing data have been published for EndoPredict® and
Oncotype DX® in post-­menopausal women treated by hor-
monal treatment [69, 70]. These arrays are discussed more
fully in 7 Chap. 9.
 
15.6 Conclusion
The pathologist is a key player in the multidisciplinary treat-
ment of a modern breast cancer patient. However, the role of
the pathologist in this domain has been underestimated for
many years. Even the mere histological evaluation of a breast
tumour must be performed with strict respect of well-­
established rules which ensure that the breast cancer histology
report provides most of the elements necessary for disease
prognostication. The pathologist also has a significant role in
the choice of adjuvant therapies by providing prognostic and
predictive parameters assessed by immunohistochemistry
and molecular biology, like hormone receptor and HER2 sta-
tus. These parameters are highly important in the current era
rares1geo@gmail.com
189 15
where patients are increasingly treated according to intrinsic
tumour biology and not solely according to tumour stage.
The fast pace of personalized medicine development
mandates that the pathologist keep adapting and updating
his/her knowledge, technologies and experience in order to
provide the most accurate and up-to-date service to the
patient and the other members of the multidisciplinary
team.
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Pathology of Breast Cancer
53. Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-­
Angulo AM, et al. Use of biomarkers to guide decisions on adjuvant
systemic therapy for women with early-stage invasive breast can-
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line. J Clin Oncol. 2016;34(10):1134–50.
54. Morrow M, Van Zee KJ, Solin LJ, Houssami N, Chavez-MacGregor M,
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Radiation Oncology-American Society of Clinical Oncology consen-
sus guideline on margins for breast-conserving surgery with
whole-breast irradiation in ductal carcinoma in situ. Ann Surg
Oncol. 2016;23(12):3801–10.
55. Provenzano E, Bossuyt V, Viale G, Cameron D, Badve S, Denkert C,
et  al. Standardization of pathologic evaluation and reporting of
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ommendations from an international working group. Mod Pathol.
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The genomic and transcriptomic architecture of 2,000 breast
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 193 16

The Breast and Oncoplastic

Multidisciplinary Team
Fiona MacNeill, Marios Konstantinos Tasoulis, Melissa Ley Hui Tan,
and Andreas Karakatsanis

16.1 Introduction– 195

16.2 Definitions– 195

16.3 Specialist Cancer MDTs and Services: The History– 195

16.4 Specialist Cancer MDTs and Services: The Future– 196

16.5 The Breast MDT– 196
16.5.1 Core Breast MDT– 196
16.5.2 Affiliated Breast MDT Members– 196

16.6 Multidisciplinary Meetings– 197

16.7 Organization and Format of MDMs– 197

16.8 Requirements for a High-Quality, Effective MDM– 197

16.8.1 The Team– 197
16.8.2 Personalized, Patient-Centred Treatment Planning– 197
16.8.3 MDM Infrastructure, Organization and Governance– 197

16.9 Benefits of MDT Working– 198

16.9.1 MDT Benefits– 198

16.10 Barriers and Challenges to MDT Working– 198

16.11 The Future of MDT Working– 199

16.12 Oncoplastic MDT– 200
16.12.1 Introduction– 200

16.13 Definition– 200

16.13.1 Oncoplastic Breast Surgery– 200
16.13.2 Education and Training in Oncoplastic Breast Surgery– 200
16.13.3 Improved Alignment and Closer Collaboration Within a MDT– 200
16.13.4 Setting Up Oncoplastic MDMs– 200

The original version of this chapter was revised.

An erratum to this chapter can be found at https://doi.org/10.1007/978-3-319-56673-3_65

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_16

rares1geo@gmail.com
16.14 Limitations of Oncoplastic MDMs– 201

16.15 Benefits of Oncoplastic MDMs– 201

16.15.1 Patient– 201
16.15.2 Surgeon– 201
16.15.3 Institution– 201
16.15.4 Academic– 201

16.16 Essential Skills for Members of the Oncoplastic Team– 201

16.16.1 Attitudes– 201
16.16.2 Skills– 201

References – 201

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The Breast and Oncoplastic Multidisciplinary Team
16.1 Introduction
Cancer-specific multidisciplinary team (MDT) working is
now well established in many countries worldwide. The
objective of MDT working is to optimize breast cancer out-
comes using effective evidence-based treatments, reduce
cancer mortality and morbidity as well as provide a high-
quality and seamless patient experience.
Whilst MDT working is regarded as the ideal model of
cancer care and is evidence of a specialist cancer service,
direct improvements in cancer survival outcomes have been
difficult to prove [1–3], but other benefits such as more breast
conservation and immediate reconstruction and standard-
ized access to systemic therapies and other indicators of qual-
ity care are well evidenced.
However, as the complexity of breast cancer management
rapidly increases, the need for MDT working to ensure opti-
mal treatment has never been more important. Our better
understanding of the biological heterogeneity of breast can-
cer [4] combined with the advent of biologically targeted
systemic therapies offers evermore treatment options, requir-
ing sophisticated personalized treatment planning. In view of
this, the MDT remains pivotal to the delivery of optimal
cancer care.
Effective, integrated multidisciplinary working is not
easy to achieve within highly complex and often fragmented
healthcare environments – MDT core personnel, organiza-
tion and processes will vary from hospital to hospital and
country to country, but the underlying principle remains
the same: patient-focused interdisciplinary communication
and working aimed at delivering a high-quality patient
experience and optimizing treatment and cancer outcomes.
Patient participation in treatment planning should be
encouraged and supported as their values and preferences
will refine and personalize the final treatment plan.
Although direct patient involvement in the MDT is not a
current practice it seems to be to be effective and well
received when implemented [5].
16.2 Definitions
A breast multidisciplinary team (MDT) can be defined as a
group of specialists in breast care who can make a unique
contribution to the treatment plan and management of an
individual patient. The multidisciplinary meeting (MDM)
is the forum in which these individual contributions can
be formulated into a coherent documented plan. The
United Kingdom (UK) Department of Health defines the
MDT and MDM as «a group of people from different
healthcare disciplines who meet to discuss individual
patients and who are each able to contribute independently
to the diagnostic and treatment decisions about the
patient» and provide detailed quality standards for MDT
provision in the UK [6].
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195 16
16.3  pecialist Cancer MDTs and Services:
S
The History
Before the early 1990s, only a small proportion of women
benefited from specialist breast MDT working in a handful of
dedicated breast centres. Diagnostic assessments and cancer
treatments were usually performed by generalists who did not
have breast-specific knowledge and skills. There was little
interaction between surgeons (who were usually the first and
main caregivers) and the other disciplines of radiology,
pathology and oncology. Consequently important factors rel-
evant to best treatment planning were missed or not discussed,
and patients were not always offered all potentially beneficial
treatments such as endocrine therapy, chemotherapy and
radiotherapy resulting in suboptimal care and outcomes.
In addition, data was not collected to support research,
audit and service improvement, and patients had little access
to high-quality information, or specialist nurse support and
their care was fragmented between community, hospital and
other services. In England in 2000, only 20% of cancer
patients were managed by a specialist team, increasing to
80% in the mid-2000s [2, 7].
To address these challenges, specialist cancer teams and
services were developed evolving to the current well-known
model of MDT working. In the UK, MDT working was
regarded as integral to the successful delivery of the National
Health Service (NHS) breast screening programme (NHSBSP),
established in 1987, and MDT discussion became an important
quality metric, regarded as essential for the delivery of high-
quality breast care [8]. Breast surgeons working within the
NHSBSP were at the forefront of improvements in UK breast
cancer care, publishing guidelines on MDT management of
breast cancer in 1992 and 1995. In 1996 (updated in 2001), the
UK NHS executive published the Improving Outcomes in Breast
Cancer [4, 5] manual mandating that all new cancers should be
managed to agreed protocols by MDTs and discussed at MDMs.
In addition the UK National Institute for Health and Care
Excellence (NICE) has consistently highlighted MDT working
as integral to the delivery of good cancer services (NICE 2002,
2006, 2009). In Sweden, MDT working for breast care has a 25
year history, and the national guidelines clearly state that all
patients with a diagnosis of breast cancer have to be discussed
in an MDM preoperatively and postoperatively.
Apart from national policies, the essential role of MDT
working as a quality indicator for breast cancer care has been
repeatedly emphasised in European Society of Breast Cancer
Specialists (EUSOMA) statements since 2000 [9, 10].
In Australia, the National Multidisciplinary Care
Demonstration Project was undertaken in the early 2000s to
incorporate MDT working in breast cancer treatment, aim-
ing to improve cancer care outcomes. A survey in 2006
showed that 85% of breast surgeons were regularly involved
in an MDM; however, there was considerable variance
depending on healthcare setting (private or public) as well as
location (metropolitan or rural) [11].
 196 F. MacNeill et al.
Despite the fact that multidisciplinary care is regarded as
essential for high-quality cancer care and MDT working has
been promoted around the world including the USA [12] and
member states of the European Union(s), MDT working is
not universal. Specifically for breast cancer, MDT working is
mandatory in approximately two-thirds of centres in Eastern/
Western Europe and only a quarter of centres in South
America and a third in Asia [13]. In the USA the efficacy of
MDT working was demonstrated as early as 1997 [14], but
recent data suggest that only 3% of Medicare patients with
non-metastatic breast cancer will undergo a multidisci-
plinary clinic before surgery [15].
Access to and delivery of highly specialized breast ser-
vices (e.g. breast reconstruction) can be problematic in
sparsely populated regions: innovative models of MDT
working are required such as the creation of «virtual» MDTs
using modern telecommunications or establishing an onco-
plastic surgery network to allow access to a range of specialist
surgical procedures beyond the local hospital.
16.4  pecialist Cancer MDTs and Services:
S to the local cancer (breast) unit.
The Future
MDT working is now regarded as fundamental to cancer ser-
vice delivery and is increasingly embedded in cancer care. In
the early years, the focus in most countries was on establish-
ing MDTs, defining roles and responsibilities and setting up
the processes and infrastructure to support MDT working.
More recently as MDT working has become well established,
the impact of MDT working on improving outcomes is being
examined.
16.5 The Breast MDT
16 Breast cancer care should be provided by breast specialists in
each discipline. They should work as a team and should be
proficient in the diagnosis, management and follow-up care of
all cancer patients from early detection through to advanced
disease. The exact composition of the MDT and individual
roles may vary from breast unit to breast unit depending on
local circumstances, needs and skill mix but the team should
consist of two main groups: the core members and the affili-
ated members. Each team member should have undergone
specialist training according to national recommendations,
understand their specialist roles and responsibilities both to
the patient and team and have clearly defined job plans,
opportunities for professional development and regular
appraisals. The skills and qualifications required by breast care
specialists have been extensively described for EUSOMA [16].
To deliver high-quality breast diagnosis and treatment,
core members are required to have the necessary breadth and
depth of specialist knowledge, skills and expertise.
Increasingly, to meet the demands of providing an expert
service for such a high-volume disease, core personnel have
to focus solely on breast care with less involvement in the
non-breast services of their parent discipline. This has train-
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ing implications requiring a balance between the needs to
acquire specialist skills with generalist training as well as
careful workface planning at a national level.
16.5.1 Core Breast MDT
Core breast MDT members include:
55 Oncoplastic breast surgery team: oncoplastic breast
surgeons and plastic surgeons. The oncoplastic surgery
team should be able to provide the wide range of oncoplas-
tic conservation procedures and breast reconstructions.
55 Radiology team: radiologists with expertise in screening
and symptomatic mammography, ultrasonography and
magnetic resonance imaging as well as in image-guided
biopsies.
55 Histopathologist (+/- cytologist) specialized and ideally
exclusively involved in breast disease/cancer.
55 Oncologist(s) specialized in the management of breast
cancer. Whilst they may be based at a regional/city
cancer centre, they should have dedicated time allocated
55 Nurse specialists: each breast unit should have at least one
full-time breast nurse specialist trained in the management
of breast cancer, providing information and offering
psychological support. In addition, some units now employ
nurse practitioners as breast diagnosticians to coordinate
and to run nurse-led diagnostic and review clinics.
55 MDT coordinator/administrator: their role is to facilitate
the patient pathway and organize the weekly MDMs,
prepare the agenda, ensure accurate data collection and
record treatment plans and decisions.
55 Trainees: MDMs have an important teaching and
training role, so it is essential that trainees (in any of the
breast disciplines such as surgery, pathology, radiology,
oncology, nursing, etc.) are supported in regular atten-
dance as part of their specialist training.
16.5.2 Affiliated Breast MDT Members
The core group is complimented by affiliated personnel who
will offer specialist care to a wide range of cancer patients.
Only in very large units or centres would affiliated personnel
solely practise in breast care. Affiliated specialists do not nec-
essarily form part of the core team. Members of this group
may include the following:
55 Geriatrician to facilitate optimal cancer care in older
patients
55 Psychiatrist and/or a clinical psychologist
55 Palliative care specialists
55 Orthopaedics and/or neurosurgeons with a declared
interest in surgical oncology
55 Lymphoedema specialist
55 Physiotherapists/occupational therapists/prosthetic fitter
55 Clinical geneticist
55 Pharmacist
55 Research nurses
The Breast and Oncoplastic Multidisciplinary Team
Core and affiliated members have two main aspects to their
MDT role:
55 Diagnostic/assessment team (surgeons, radiologists,
pathologists, nurses, affiliated members)
55 Treatment team (surgeons, oncologists, nurses and
affiliated members)
55 Survivorship and recovery team (family physicians,
nurses, psychologists, therapists, dieticians etc)
16.6 Multidisciplinary Meetings
Multidisciplinary meetings (MDMs) are an important aspect
of MDT working and should be held regularly to promote
involvement of all core personnel in breast (cancer) case
review and treatment planning. The frequency and format of
MDMs may vary but EUSOMA recommends weekly MDM
as a prerequisite for a specialist breast centre [17].
16.7 Organization and Format of MDMs
The number, organization and format of MDMs will vary
according to local needs and patient population, but meet-
ings should last no longer than 1.5 h: concentration and com-
plex decision-making deteriorate with time.
Larger units may have a number of MDMs with selected
attendance of core MDT members.
For example:
55 Diagnostic/assessment MDM: to review non-­concordant/
indeterminate imaging, review triple assessment findings
(examination, imaging and biopsy) and establish a
management plan. Participants are mainly surgeons, radi-
ologists, pathologists and advanced nurse practitioners.
55 New cancer MDM: review cancer extent and pathology/
biology to establish primary treatment plan. Participants
are mainly surgeons, oncologists and nurse specialists.
55 Oncoplastic MDM: optimize maintenance of breast
aesthetics/reconstruction. Participants are breast and
plastic surgeons and nurse specialists.
55 Adjuvant therapy MDM: review surgical pathology and
establish adjuvant treatment plan. Participants include
surgeons, pathologists, oncologists and nurse specialists.
55 Advanced breast cancer MDM: review all new recur-
rences (local/systemic) with full staging and pathology.
Participants are mainly oncologists, radiologists, nurse
specialists and affiliated personnel.
16.8 Requirements for a High-Quality,
Effective MDM
There are many factors that contribute to high-quality, effec-
tive MDT working in MDMs. These could be classified as:
55 The quality of the team and its leadership
55 Focus on patient-centred treatment planning
55 MDM infrastructure, organization and governance [18]
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197 16
16.8.1 The Team
An MDT chairperson is essential to lead the meeting, initi-
ate discussions and secure a true consensus in difficult case
reviews. The quality of the chairpersons’ leadership is cru-
cial to the functionality of the MDT and MDM. Often com-
plex human dynamics and hierarchies must be
acknowledged and managed to prevent dysfunctional
working and encourage effective team communication and
decision-making. It is of paramount importance to cultivate
an environment of inter-­professional respect, open non-
judgemental discussion and good communication between
MDT members.
All core MDT members must have contractual time for
MDM attendance which is mandatory, recorded and moni-
tored for regulatory appraisals and employer job planning.
To provide continuity of care, there should ideally be a mini-
mum of two core members for each discipline.
16.8.2 Personalized, Patient-Centred
Treatment Planning
The MDT must consider the whole patient, not just the can-
cer, so MDM recommendations must be discussed with the
patient so the final treatment plan is only formulated after
the patient has expressed their views, preferences and cir-
cumstances. Discussions and recommendations must be
clearly recorded in patient records and a copy provided to
the patient and primary care doctor. Any significant changes
to the MDT recommendations with the reasons should be
clearly documented, so the MDT has the opportunity to
review and learn.
16.8.3  DM Infrastructure, Organization
M
and Governance
Team meetings should take place in rooms of appropriate
size and layout equipped with all the necessary technology
for radiology and pathology review, access to databases and
video conferencing.
The MDM should be held during working hours at a
regular fixed time, chosen to maximize attendance. The
agenda must be circulated in advance. The type of cases to
be reviewed should be predetermined by the MDT and
names/clinical details submitted to the MDM co-coordina-
tor with sufficient time to allow participants the opportunity
of a pre-meeting case review and revision. Sufficient clinical
information, up-­to-­date imaging, pathology reports, etc.
must be provided to allow a full and meaningful discussion
at the MDM.  Finally, it is important that there are agreed
policies and protocols that define the function of the MDM
with clear quality standards and mechanisms for regular
quality review. These mechanisms also use the collected data
for research and audit aiming to continuously improve
patient care.
 198 F. MacNeill et al.
16.9 Benefits of MDT Working
The predicted primary benefits of MDT working are improve-
ments in cancer outcomes and patient experiences with sec-
ondary benefits in cost reductions for healthcare providers
and improvements in the working environment of healthcare
professionals.
In countries such as the UK, breast cancer mortality has
declined by 30% over the last three decades, paralleling the
introduction of modern breast services including MDT
working and MDMs. However, it is difficult to prove that
MDT working and MDM recommendations for systemic
therapies where indicated are responsible for this impressive
decline in breast cancer mortality [19].
However, there is much indirect evidence that suggests
MDT working and MDMs are valuable: for example, diag-
nostic workup and pretreatment staging are standardized so
limiting duplicate investigations and improving accuracy,
resulting in more specific and targeted MDM treatment rec-
ommendations [20]. In one of the first reports [20], MDT
working resulted in the change of recommendation in 43% of
breast cancer patients that had previously been assessed by
outside physicians. A recent systematic review revealed a
35% uplift in diagnostic and staging workup recommenda-
tions and cancer diagnosis after the MDM so that more accu-
rate staging at diagnosis was more frequent [21].
It has also been shown that MDT working (combined with
high-volume case load) results in a higher probability of breast
conservation as well as more appropriate adjuvant treatment
resulting in improved survival [22]. Interestingly, this was a
common finding in studies conducted in the UK, Australia
and the USA, suggesting that this particular benefit of MDT
working is independent from the healthcare setting [22, 23].
The presence of MDMs/tumour boards has been associ-
ated with the appropriate use of neoadjuvant treatment,
resulting in more preoperative downstaging and more cura-
16 tive rather than palliative surgery in other cancer primaries
[21].
MDT working has simplified and sped up the interdisci-
plinary referral process and avoidance of duplicate examina-
tions and investigations [24]. This results in shorter time
between first diagnosis and complete diagnostic assessment
[25, 26] as well as shorter interval from initial diagnosis to
first treatment.
Furthermore, MDT working has been associated with
enhanced patient satisfaction. Use of a «rapid» MDM path-
way resulted in improved patient experience in a study on
non-small cell lung cancer [27]. Additional reports point out
the importance of this fact in the multidisciplinary setting
since «the tumour is not the target», and it seems that MDT
working can facilitate direct and continuous contact with the
cancer patients, allowing for the improvement of patient
experience [28].
MDT working also ensures adherence to guidelines, pro-
viding evidence-based care with tailored individualized
treatment; minimizes deviations originating from strongly
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held personal views or isolated institutional practice; facili-
tates communication between primary, secondary and ter-
tiary clinical care; and allows for continuity of care and
follow-up, even when different aspects of care are delivered
by different providers. This policy consequently allows for
higher-quality national registries, strengthens the quality of
data for audit and research and facilitates the recruitment of
patients in clinical trials [29].
The secondary benefits of MDT working on enhanced
working experience for healthcare professionals are equally
important. It allows time for exchange of ideas and peer sup-
port especially for difficult clinical problems, helping indi-
vidual members with the presumed «burden of responsibility».
Moreover, it is an opportunity for education and learning for
all team members including trainees and, finally, to promote
good personal and professional relationships. Literature sug-
gests that it also contributes to the enhancement of quality of
life of participants and reduces work environment-related
stress [2].
16.9.1 MDT Benefits
Primary
Adherence to protocols and development of guidelines
55 Standardized, accurate and timely assessment
55 Minimizes time from first symptom to first treatment
55 Robust evidence-based treatment decisions
55 Improved clinical outcomes (more breast conservation,
probable reduction in mortality)
55 Improved patient experience
55 High-quality data collection
55 Improved patient selection and recruitment for investiga-
tional trials
Secondary
55 Streamlined high-quality care reduces healthcare costs.
55 Less healthcare worker stress.
55 Opportunities for ongoing education.
55 Team building and socializing improve professional
communication.
16.10  arriers and Challenges to MDT
B
Working
MDT working requires commitment and continuity to
MDMs, and one of the main reported barriers to implement-
ing MDT working is lack of time for MDMs. In the UK,
where MDT working has been encouraged since the mid-­
1990s, data from 2006 revealed that only 28% of MDMs were
held in «protected» sessions [30]. The 2011 MDT systematic
review also identified lack of protected time to prepare for
the MDM, as well as excessive workload and other time pres-
sures as factors leading to time wasting during MDMs with
rushed clinical decision-making [19].
The Breast and Oncoplastic Multidisciplinary Team
Another challenge to MDT working is regularity and
duration of MDM attendance by core members, with sig-
nificant variance according to discipline. Breast surgeons,
radiologists, pathologists and breast nurses are regular
attendees, present for the duration of the MDM, but the
participation of oncologists is less frequent. The probability
of attending the entire MDM is related with the session
being protected [30].
Plastic surgeons are core MDT members crucial to the
delivery of oncoplastic surgery but they rarely attend the
main cancer MDM with less than 10% of MDTs having a
plastic surgeon present in the majority of MDMs (more than
75%) [31].
The MDT leader/MDM chairperson are crucial in pro-
moting good communication between the MDTs, an impor-
tant factor in ensuring effective MDT performance, as is
active participation of specialist nurses. Conflict and lack of
clarity over leadership are negative predictors of effective
internal communication [32]. Additionally, decision-making
is improved when issues such as the clear role and task of
each member, the standardization of «check lists» so that
nothing is forgotten and the limitation of hierarchy impact
are addressed. Disagreement in clinical decision-­ making
should not only be acceptable, but should also be recorded in
the MDM notes [33].
Lack of administrative and technical assistance has also
been identified as a confounding factor for MDT working
provision. The presence of coordinators or designated per-
sonnel to document the decisions of the MDM is considered
to be important for the function of MDMs [30]. On the other
hand, telemedicine services are generally thought to elimi-
nate distance and are not costly when used regularly (20–30
sessions/year) [34], but they have not been associated with
significant differences regarding change in treatment recom-
mendations or time to treatment [19].
Patient centeredness is an issue of paramount impor-
tance in MDT working which has not been addressed
appropriately. It has been shown that physicians partaking
in the MDM decide based almost exclusively on biomedi-
cal parameters, neglecting or being unaware of patients’
views. It is generally accepted that nurses represent the
patient at the MDM. However, nurses have a peripheral
role in clinical decision-making, which means that the
patient may not be adequately represented. This is a fact of
which MDT members are aware of, according to a study
from the UK, in which self-assessments of MDM members
were cross-­validated with assessments of expert external
observers [35]. MDMs may discuss cases referred from pri-
mary care or screening. These patients may have not met
any member of the MDT before their case is discussed at
the MDM. This may result in inadequate knowledge of
patient’s views, wishes, opinions and incorrect information
concerning clinical status and comorbidities. However all
MDT recommendations must be discussed with the patient
in the clinic and the recommendations/plan adjusted to
take account of the patients views and preferences. The
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199 16
most appropriate healthcare professional for this clinic dis-
cussion is generally considered to be the treating physician
or the contact nurse [33].
16.11 The Future of MDT Working
MDT working and in particular the MDM have evolved
organically, layer on layer over the last few decades, and
so are at risk of becoming unwieldy, bureaucratic and
focused on process and proof (ticking boxes), ironically
hindering the quality care they were designed to encour-
age.
There has been little examination of MDM cost-effective-
ness, and with scarce resources MDMs have to justify their
cost. A recent study in a large tertiary cancer centre in
London established [36] that over 54% of new cancer patients
were referred by surgeons and the weekly breast MDM was
attended by 14 senior clinicians, discussing 45–73 patients
per session, costing approximately £105–116/patient with a
monthly MDM cost of over £38,000 pounds (or just under
£500,000/year). Other cancer site MDMs were costed up to
£516/patient.
The study confirms that the majority of clinicians
adhered to MDM recommendations. Deviation from the
treatment pathway agreed upon at the MDM was often a
consequence of patient preference, a change in the patient’s
general health or patient’s comorbidities not highlighted at
the MDM and occasionally the final decision of the treating
consultant.
Interestingly however the consultant treatment plan,
taken from the pre-MDM clinic, was agreed by the MDM in
over 87% of cases. This fact, combined with the costly nature
of MDMs, could put the necessity of MDMs into challenge
at least for the simple cases. There should be a discussion
within oncology as to how MDM processes and practices
are reformed trying to cut down expenses and staff work-
load without compromising quality of care. To this direc-
tion, there could be a system where complex and difficult
cases are flagged for MDM discussion, whilst routine treat-
ment decisions are overseen by strict protocols and regular
audits [24].
On the other hand, despite the financial challenges, the
benefits to individual MDM members in terms of improving
working relationships and sharing of coordination and
responsibility for patient care cannot be understated [37].
Additionally, MDMs play a pivotal role as an educational
forum, especially for young clinicians, and provide an envi-
ronment that can act as a catalyst for ideas for research and
audit, also encouraging recruitment of patients in clinical tri-
als [38].
The challenge is how in these times of shrinking health-
care resources we can streamline the MDM processes and
improve efficiency without losing the considerable benefits
associated with regular MDMs.
 200 F. MacNeill et al.
16.12 Oncoplastic MDT
16.12.1 Introduction
There is a continuing desire within the breast cancer surgical
community to improve patient outcomes by incorporating
oncoplastic breast surgery (OPBS) procedures into the treat-
ment pathways for breast cancer [39, 40]. Oncoplastic breast
surgery should be available to all patients, within the context
of MDTs that include accredited surgeons who consult with
each other early in the treatment pathway [39]. These onco-
plastic MDTs should focus on achieving not just positive
oncologic outcomes but also aesthetic outcomes in line with
patient wishes, to achieve optimal quality of life. In the UK,
the Association of Breast Surgery (ABS) and the British
Association of Plastic, Reconstructive and Aesthetic Surgeons
(BAPRAS) produced oncoplastic breast reconstruction best
practice document in 2007 and guidelines in 2012 [40]. These
documents focused on delivering oncoplastic breast surgery
services with emphasis on building a MDT with common
goals in patient education, oncologic and aesthetic outcomes
and patient satisfaction.
16.13 Definition
16.13.1 Oncoplastic Breast Surgery
The surgical options for breast cancer fall into two main cat-
egories – mastectomy and breast conservation surgery (BCS).
The evolving OPBS techniques have extended the role of BCS
and enabled better aesthetic outcomes from both BCS and
mastectomy [41]. OPBS may be defined as breast surgery
focusing on optimizing both oncologic and aesthetic out-
comes, irrespective of the type(s) of surgery performed. All
breast cancer surgery should be performed with the princi-
16 ples of OPBS in mind.
16.13.2 Education and Training
in Oncoplastic Breast Surgery
Whilst a multidisciplinary collaborative approach is impor-
tant in optimizing outcomes, it is also essential that recon-
structive surgeons (irrespective of their surgical specialty)
are specialized and formally trained in the full range of OPBS
techniques. Unfortunately, the availability of training in
OPBS and the techniques that are used vary widely between
countries and institutions [42]. Training in oncoplastic sur-
gery in Portugal, Spain, Brazil and the UK reported signifi-
cant variations in the levels of oncoplastic services in different
countries and highlighted a lack of available skills, variable
patient information and differences in levels of access to pro-
cedures [43]. Progress is hindered by a lack of training,
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under-education of patients regarding treatment choices, an
absence of clearly defined surgical practice standards and dif-
ficulties in forming multidisciplinary treatment teams.
Formalizing oncoplastic training programme that integrates
training an breast oncology surgery and breast plastic sur-
gery and improving training among surgeons performing
reconstructive surgery would ensure that patients are offered
all available options for which they are suitable.
16.13.3 I mproved Alignment and Closer
Collaboration Within a MDT
Surgical teamwork is an integral part of the total treatment
plan for any breast cancer treatment. Collaborative working
between oncological breast and plastic surgeons is essential if
patient are to have access to a full range of OPBS techniques.
This approach can be achieved by a well-defined MDT
including the relevant expertise to offer all surgical options,
incorporating all relevant oncoplastic surgical expertise and
the patient within the decision-making process. No single
surgeon will be able to offer all oncoplastic treatment options
as it is not possible for any one surgeon or discipline to
acquire and maintain all the skills and expertise. Hence, an
MDT from the outset should manage a patient. A closer col-
laboration can be achieved through oncoplastic MDMs,
maximizing utilization of available expertise, strengthening
team working and facilitating progression towards high-
quality seamless oncoplastic care.
16.13.4 Setting Up Oncoplastic MDMs
There is paucity of data on improved outcomes to support the
MDMs at the expense of increasing financial constraints in
any cancer specialty. However, MDMs are now regarded as
best practice. Whilst breast cancer MDMs are now part of a
standard breast cancer service, an additional oncoplastic
MDMs seems like an idealized position that may not be eas-
ily feasible in all institutions and in all countries at the pres-
ent time. Particularly as there is a lack of data to support the
evidence of added value of having an oncoplastic MDM. The
UK Royal Marsden Hospital set up its first oncoplastic MDM
in 2007 [43]. It is a fortnightly 1-hour meeting with video
linking across two sites. It is believed that this might drive
oncoplastic surgery to an evidence-based position from
which oncoplastic excellence can be achieved.
The core members of the oncoplastic MDT can com-
prise of:
55 Oncoplastic breast and reconstructive breast surgeons
55 Plastic, reconstructive and aesthetic surgeons
55 Breast care nurses
55 Surgical trainees and fellows
55 MDT co-coordinator
The Breast and Oncoplastic Multidisciplinary Team
This additional oncoplastic MDM provides a forum to pres-
ent patient’s clinical pathology and comorbidities, examina-
tion findings and standardized photographic views followed
by open discussion on proposed OPBS and reconstructive
options to achieve the desired outcomes in line with patient
wishes. This MDM consolidates the oncoplastic MDT work-
ing and allows transparent decision-­making, standardization
of care and recording of the oncoplastic MDT recommenda-
tions.
16.14 Limitations of Oncoplastic MDMs
55 Financial constraint
55 Scant evidence to support the value of MDMs
55 Not feasible in all institutions or in all countries
16.15 Benefits of Oncoplastic MDMs
16.15.1 Patient
55 Streamline patient pathway
55 Improve patients’ education and outcome
16.15.2 Surgeon
55 Improve multidisciplinary working and morale
55 Cross-fertilization of knowledge
55 Dissemination of skills
55 Opportunities for education/professional development of
team members
55 Open discussion
55 Consensus decision making
16.15.3 Institution
55 Development of patient- and procedure – specific
consent forms
55 Standardized photographic views secured in web-based
archives
55 Stronger team identity useful in operational and strategic
meetings with the hospital executives
16.15.4 Academic
55 Strengthen the ethos of good clinical governance
55 Increase trial recruitment
55 Enhance oncoplastic breast surgery development
55 Rigorous outcome measures and recognized standards
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201 16
16.16  ssential Skills for Members
E
of the Oncoplastic Team
16.16.1 Attitudes
55 Exhibit a compassionate, empathetic and non-­
judgemental approach to women with breast disease and
their families
55 Respect and value other team members
55 Desire to provide the best possible outcomes to women
seeking surgery
16.16.2 Skills
55 Effective communication with patients and colleagues
55 Ability to work as part of a MDT
55 Organizational skills as appropriate to their role
55 Any surgeon performing surgery on the breast must
understand the principles and concepts of oncoplastic
surgery and be able to offer core oncoplastic surgery skills. A
modern breast surgeon must be able to place scars that will
not compromise future oncoplastic procedures and
understand what can be done to achieve the optimal balance
between minimum defect in the breast and maximal
oncological safety at the time of the primary procedure
55 Not every breast surgeon will want or be able to offer the
full range of oncoplastic surgery (especially reconstruc-
tive or free flap surgery) but the patient must have access
to a comprehensive range of oncoplastic skills and
expertise through the oncoplastic breast team
55 The oncoplastic team requires surgeons from different
surgical specialities to collaborate and cooperate for the
benefit of the patient, rather than compete, across
traditional professional boundaries. This sharing of skills
and knowledge will ensure the highest quality of care and
optimal outcomes.
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 203 17

Surgery to the Breast:
Mastectomy
Petros Charalampoudis and Tibor Kovacs

17.1 Introduction – 204

17.1.1 Historical Overview – 204
17.1.2 Mastectomy: Global Trends and Indications – 204
17.1.3 Non-conservative Mastectomy: Marking, Technique
and Complications – 205
17.1.4 Conservative Mastectomies: Marking, Incisions and Technique – 206
17.1.5 Conservative Mastectomies: Oncological Safety – 206
17.1.6 Nipple Involvement and Tumour to Nipple Distance (TND) – 209
17.1.7 Skin Flap Necrosis, Nipple Loss and Free Nipple Grafting – 209

References – 210

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_17

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 204 P. Charalampoudis and T. Kovacs

17.1 Introduction ..      Table 17.1  Important definitions pertaining to mastectomy

17.1.1 Historical Overview Mastectomy Removal of the totality of the glandular

breast tissue (as opposed to breast-
The pre-Halsted era witnessed brutal treatments for breast conserving surgery)
cancer such as cauterization or amputation of the breast. Radical mastec- Removal of the totality of the glandular
Surgery before the nineteenth century did not involve any tomy (Halsted) breast tissue, overlying skin, nipple-
anaesthesia, and according to historical reports, mastecto- areola complex, pectoralis major and
mies were as radical and locally aggressive as possible, mak- minor muscles and ipsilateral axillary
lymph nodes
ing sure «every atom of morbid mischief in the lump’s
vicinity» was excised [1]. The first report of a radical mastec- Modified radical Removal of the totality of the glandular
tomy is attributed to Bernard Peyrilhe (1737–1804), a French mastectomy (mus- breast tissue, overlying skin, nipple-
cle-sparing radical areola complex and concurrent level I–II
surgeon. However, it was William Stewart Halsted who per-
mastectomy) axillary lymph node dissection
formed the first clearly documented radical mastectomy in
the United States at Johns Hopkins Hospital (1882), and it Simple mastec- Removal of the totality of the glandular
was he who popularized and described the technique in tomy breast tissue with overlying skin ellipse
and nipple-areola complex (no axillary
detail. Until the mid-1970s, the Halsted mastectomy was the surgery)
standard of care for the surgical treatment of breast cancer.
Moreover, as the Halstedian approach to the natural history Skin-sparing mas- Removal of the totality of the glandular
tectomy (SSM) breast tissue, removal of the nipple-
of the disease was well accepted during this era, radical mas- areola complex, preservation of the skin
tectomy was believed to serve its purpose well, aiming to halt envelope overlying the breast (followed
the centrifugal spread of breast cancer from its primary by immediate reconstruction)
source (the breast), towards the lymph nodes and further to
Nipple-sparing Removal of the totality of the glandular
distant organs [2]. mastectomy (NSM) breast tissue, preservation of nipple-are-
From 1969 to 1976, Turner and colleagues randomized or total skin-spar- ola complex and skin envelope (followed
574 patients with clinical stage I–II breast cancer to either ing mastectomy by immediate reconstruction)
radical or modified radical mastectomy and compared over- (TSSM)
all survival, local recurrence, distant relapse and disease-free Skin-reducing Removal of the totality of the glandular
survival, showing no statistically significant difference in any (+/−nipple-spar- breast tissue, reduction of the skin envelope
of the four outcome variables between the two groups [3]. ing) mastectomy (followed by immediate reconstruction)
Fisher and colleagues launched the seminal NSABP B-04
randomized clinical trial (1971), to determine whether
patients who received procedures less than a radical mastec-
..      Table 17.2 Abbreviations
tomy would have outcomes similar to those achieved with a
radical mastectomy. A total of 1079 women with clinically SSM Skin-sparing mastectomy
node-negative breast cancers underwent radical mastectomy,
total mastectomy without axillary dissection but with post- NSM Nipple-sparing mastectomy
operative irradiation or total mastectomy plus axillary dis- IMF Inframammary fold
section only if their nodes became positive. Furthermore, a
17 total of 586 women with clinically node-positive disease
NAC Nipple-areola complex

either underwent radical mastectomy or total mastectomy TSSM Total skin-sparing mastectomy
without axillary dissection but with postoperative irradia- MRM Modified radical mastectomy
tion. A 25-year follow-up to the trial was published in 2002
BCS Breast-conserving surgery
and corroborated earlier findings showing that there was no
survival advantage conferred by radical mastectomy, when
compared to modified radical mastectomy either for clini-
cally node-negative or node-positive breast cancer [4]. The 17.1.2 Mastectomy: Global Trends
high-quality evidence emanating from this trial has been and Indications
practice-changing, and radical mastectomy has been aban-
doned for operable, non-locoregionally advanced disease. Although breast-conserving surgery (BCS) with whole breast
Other trials comparing radical to non-radical mastectomy irradiation has emerged as a safe approach to treat early
independently confirmed the NSABP B-04 results [5, 6] breast cancer, removal of the totality of the breast tissue
(. Tables 17.1 and 17.2).
  (mastectomy) is still appropriate in many cases. Interestingly,

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Surgery to the Breast: Mastectomy
..      Table 17.3  Indications for mastectomy
(a) Extensive, multisite invasive or in situ disease not ame-
nable to breast-conserving surgery
(b) Second ipsilateral in-breast event (recurrence or second
primary cancer) following previous breast-conserving
surgery and radiotherapy
(c) Patient choice (instead of breast-conserving surgery)
(d) Prophylactic (risk-reduction) surgery in patients with
high family risk of breast cancer (i.e. BRCA or p53 muta-
tion carriers, or non-carriers with >30% overall lifetime
risk of breast cancer)
(e) Locally advanced non-inflammatory breast cancer (rela-
tive indication)
(f ) Inflammatory breast cancer (absolute indication)
(e) Previous mantle radiotherapy for Hodgkin’s disease
several single-institutional studies have reported that mas-
tectomy rates have markedly increased with a corresponding
decrease in BCS rates. However, national and international
trends do not necessarily reflect single-centre reports. In the
United States, a total of 233,754 patients with DCIS or stage
I–III breast cancer were identified in the Surveillance,
Epidemiology and End Results (SEER) programme database
from 2000 to 2006. The proportion of women treated with
mastectomy significantly decreased from 41% in 2000 to 37%
in 2006 [7]. A multi-institutional database in Europe recently
reported a significant decline in mastectomy rates from a
peak in 2006 [8]. Indications for mastectomy are depicted in
. Table 17.3.
 
17.1.3 Non-conservative Mastectomy:
Marking, Technique
and Complications
The patient is marked in the standing position, with her
hands against her thighs. The sternal notch, midline and
breast contour are drawn and the IMF is marked. The medial
and lateral edges of the mastectomy incision are then marked
and connected by a continuous line to form the final elliptic
shape of the mastectomy incision (which can be transverse or
oblique at the discretion of the operating surgeon and taking
into account the position of the tumour and possible scar
encroachment into the cleavage area). The vertical elasticity
of the skin envelope determines how wide the elliptical inci-
sion will be. A small firm breast will require a smaller ellipse
than a large ptotic breast. When marking for non-­conservative
mastectomy, the surgeon has to bear in mind that the skin
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205 17
flaps should close comfortably without tension, being neither
too loose (risk of redundant post-mastectomy skin) nor too
tight (risk of skin flap necrosis and wound dehiscence).
Previous BCS scars should ideally be encompassed within
the ellipse, unless they are located in a very remote position
from the mastectomy incision. Coombs and Royle suggested
an easily reproducible formula for estimating the width of the
breast ellipse when designing a non-conservative mastec-
tomy incision. According to this formula, the required inci-
sion width (W) can be calculated as W = C − L, where C is
the total length of skin following the breast curvature from
the midclavicular point to the IMF and L is the straight line
distance from the midclavicular point to the IMF [9]. Several
authors have advocated a «teardrop» ellipse with lateral tri-
angular de-epithelialization in an attempt to minimize
redundant skin and lateral dog-ear formation, especially in
obese patients [10]. Other techniques to minimize lateral
skinfolds in obese patients include a lateral «fishtail» incision
pattern.
Following incision, the mastectomy flaps are dissected
aiming to remove the totality of the glandular breast tissue
and achieve well-vascularized skin flaps which come together
at closure with no tension and no redundant skin. Dissection
along the flaps follows the oncoplastic plane defined by the
suspensory ligaments of Cooper, between the limits of the
glandular tissue and subcutaneous fat. Flap thickness will
therefore vary according to the thickness of the subcutis in an
individual woman. Dissection is carried out up to the level of
the clavicle superiorly, down to the IMF and rectus sheath
inferiorly, lateral to the sternum medially and up to the ante-
rior border of the latissimus dorsi laterally. Complete removal
of the IMF leads to a flatter, aesthetically comfortable post-­
mastectomy scar. Various techniques have been employed
with regard to dissecting the mastectomy flaps, including
scissors, scalpel, harmonic scalpel and standard diathermy.
In a meta-analysis by Huang and colleagues, harmonic scal-
pel dissection compared to standard electrocautery decreased
the rates of postoperative seroma, blood loss and wound
morbidity in modified radical mastectomy, without increas-
ing operative time [11].
Bleeding after mastectomy occurs in about 3% of cases;
heart failure, pulmonary disease, obesity and diabetes have
been recognized as risk factors [12]. Seroma occurs com-
monly after non-conservative mastectomies, particularly
when extensive axillary surgery is concurrently performed.
Steroid injections into the mastectomy wound seem to reduce
the rate and volume of immediate postoperative seroma [13].
Standard practice involves insertion of closed suction drains
deep to the mastectomy flaps and the axilla aiming to reduce
seroma formation. Despite the routine use of drains, clini-
cally significant seroma requiring aspiration still occurs in up
to 50% of patients undergoing mastectomy. Purushotham
and colleagues randomized patients undergoing non-­
 206 P. Charalampoudis and T. Kovacs

conservative mastectomy to either insertion or non-insertion
of drains. Omission of drainage after mastectomy led to a
reduced hospital stay, whereas there was no difference in
seroma formation, volume of seroma aspirated postopera-
tively or wound sepsis between the two groups [14].
incision may be used (which also facilitates exposure to the
axilla in cases of concurrent axillary surgery). Radial inci-
sions are commonly used in NSM. In case of nipple involve-
ment with cancer, the incision can be extended to remove the
NAC.  Periareolar incisions for NSM have been associated
with higher risk of nipple necrosis [15, 16] (. Figs. 17.1 and

17.2). During NSM, several surgeons advocate sharp dissec-

17.1.4 Conservative Mastectomies: Marking, tion with scissors as opposed to diathermy in order to mini-
Incisions and Technique mize thermal damage to the NAC subdermal plexus [17].
Removal of the retro-NAC breast tissue may be performed
The patient is marked in the standing position using a mea- by nipple inversion and coring. Patients with previous reduc-
suring tape and a surgical marker pen. Different colour tion or mastopexy may undergo a NSM through the vertical
markers may be useful, especially in cases where a skin-­ limb of their previous incisions with or without a lateral
reducing mastectomy (with or without a dermal sling) is extension. Skin-reducing mastectomy (with or without nip-
planned, in order to define the areas to be de-epithelialized ple preservation) is indicated for patients with ptosis, asym-
and to design the pedicle on which the nipple will be mounted metry or macromastia. This technique is frequently
in its new position (in cases where a nipple-sparing mastec- combined with an inferior dermal sling, which is created by
tomy (NSM) is being performed). The surgeon marks the de-epithelializing a pre-marked area on the inferior skin flap
sternal notch, midline, breast meridian and IMF. Furthermore, of the mastectomy. During preparation of the dermal sling,
the breast contour is drawn, including the IMF and the supe- care should be taken not to injure the subdermal plexus,
rior breast takeoff, in order to define the borders of the glan- which could lead to postoperative sling necrosis and loss of
dular resection. The following distances are calculated and the reconstruction [18–20].
marked: sternal notch to nipple, nipple to IMF, midclavicular
point to nipple and meridian to midline. It is important to
mark both breasts, even when planning for a unilateral mas- 17.1.5 Conservative Mastectomies:
tectomy, and encompass both sides when draping the surgi- Oncological Safety
cal field, to obtain the maximum information on symmetry
during reconstruction. There is an ongoing debate regarding the oncological safety
The patient is placed in the supine position with both of a conservative mastectomy compared to a total non-­
arms abducted at 90°. For skin-sparing mastectomy (SSM), conservative mastectomy. Preservation of the skin envelope
an ellipse is drawn on the breast, encompassing the nipple-­ +/− the nipple-areola complex has understandably raised
areola complex (NAC). Incision planning should, whenever concerns over the years with regard to how much, if any,
possible, take into account any previous breast-conserving breast tissue is left behind, especially adjacent to the skin
surgery scars on the ipsilateral breast; ideally, any old scars flaps and nipple-areola complex, and to what extent this
are encompassed within the mastectomy incision. reflects an oncological risk. Hicken (1940) was the first to
Furthermore, in cases where the tumour is located close to investigate how much breast tissue can be potentially left
the skin, the involved area should be excised as part of the behind after a total mastectomy. He performed mammogra-
planned incision. The skin and subcutaneous adipose tissue phy with intraductal contrast in 385 breasts and analysed
are incised and then gently lifted with skin hooks or «cat’s histologically 17 mastectomies with regard to the limits of
17 paws»; counter-traction is applied gently by the operating breast resection. Interestingly, breast tissue extended into the
surgeon, to better expose the oncoplastic plane of resection axillary fossa in 95%, into the epigastric region in 15%,
between the subcutaneous fat and upper limit of the breast beyond the lateral border of the latissimus dorsi in 2% and
tissue. During surgery, flap thickness is regularly checked by past the midsternum in 2 of the cases, respectively. Similarly,
digital palpation, and lighted retractors are employed during Temple and colleagues identified a substantial amount of
deeper dissection of the gland. When dissection between the glandular breast tissue in the IMF of 13 out of 24 mastectomy
skin and the breast is complete, the gland is dissected from specimens [21]. Rosen and Tench sectioned 101 nipples from
the chest wall. Meticulous haemostasis is maintained while mastectomy specimens in breast cancer patients. The authors
respecting the subdermal plexus of the skin flaps. identified the presence of lobules in 17% and in situ carci-
For nipple-sparing mastectomy (NSM), a variety of inci- noma in 13% of the cases, respectively. Mammary ducts have
sions have been suggested. For small volume (A or B cup) also been described even at the level of the areolar dermis
breasts, an inframammary incision may be employed as this after nipple coring [22, 23].
provides an aesthetically pleasing scar hidden within the Taking into consideration the above data, one could argue
IMF. Lateral placement of the incision avoids transection of that even the most radical mastectomy could potentially
the superficial branch of the superior epigastric artery, as it leave residual glandular breast tissue, mammary ducts or lob-
crosses the IMF to provide blood supply to the inferior aspect ules behind, let alone a skin-sparing or a nipple-sparing mas-
of the skin flap. For larger volume breasts, a lateral crease tectomy, where the skin flaps over the breast, the nipple-areola

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Surgery to the Breast: Mastectomy
207 17

..      Fig. 17.1  Conservative mastectomy incisions. From upper left to clockwise direction: NSM inframammary, SSM circumareolar, SSM circumareo-
lar with lateral extension, SSM elliptical

complex (in NSM) and the IMF are preserved with a view to
immediate reconstruction. Can any type of breast tissue trig-
ger a breast cancer or a recurrent event after a prophylactic or
therapeutic conservative mastectomy? Modern histopathol-
ogy supports the fact that breast cancer is thought to origi-
nate in the terminal ductal lobular unit (TDLU). The TDLU
consists of terminal ducts and clusters of up to 100 sac-like
acini, forming a well-recognized functional and anatomical
unit of the breast. It could therefore be more appropriate to
investigate how many TDLUs may be left behind after a con-
servative mastectomy, as opposed to scattered subunits of
glandular tissue, lobules or isolated ducts. Torresan and col-
leagues analysed 42 skin flaps from skin-sparing mastecto-
mies and found residual TDLUs in 60% of cases. Flap
thickness >5 mm was significantly associated with a higher
risk of residual TDLUs [24, 25]. Stolier and colleagues exam-
ined 32 NACs after NSM and found TDLUs within the nipple
in 3 out 32 cases. Reynolds and colleagues examined 33 NSM
specimens from BRCA carriers to find TDLUs in 24% of
cases. In one third of these cases, the TDLUs were present
within the nipple. Similarly, Kryvenko and colleagues identi-
fied residual TDLUs in 26% of cases [26–28].

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 208 P. Charalampoudis and T. Kovacs

17

..      Fig. 17.2  Conservative mastectomy incisions (continues). From upper left to clockwise direction: NSM lateral crease, NSM periareolar with
lateral extension, skin reducing +/− dermal sling, SSM transvertical

Conclusively, even the most meticulous mastectomy,
conservative or not, will probably result in some glandular
breast tissue or even TDLUs being left behind, at the level of
the skin flaps or in the nipple in cases of NSM. But in what
way is this clinically significant? Skin- and nipple-sparing
mastectomies have been widely used during the last decades,
either as prophylactic or therapeutic procedures, and their
oncological benefit in high-risk patients is well documented.
A BRCA mutation carrier, with an 85% overall lifetime risk
of breast cancer and a 60% risk of a second breast cancer, is
estimated to benefit from a 90% risk reduction following a
prophylactic conservative mastectomy [29]. Van Verschuer
and colleagues reviewed 24 studies between 1976 and 2014
where 5548 conservative prophylactic mastectomies (SSM
and NSM) were performed. The authors identified 17 pri-
mary breast cancers which occurred after mastectomy among
these cases [30]. Moreover, two retrospective studies of NSM
in 176 patients with BRCA mutations and a mean follow-up
of 4 years reported on a 2.8% rate of incidental breast cancers
and only one event of a primary breast cancer developing
after prophylactic mastectomy [31–33].
Local recurrence rates after mastectomy (any technique)
have remained unchanged over the past 50  years. Gilliland
and colleagues reviewed 3600 patients undergoing radical

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Surgery to the Breast: Mastectomy
and modified radical mastectomies from 1948 to 1978, and
although data on follow-up are not clearly documented, the
overall local recurrence rate was 4.6% [34]. Carlson looked at
565 therapeutic SSMs with a median follow-up of 5 years and
reported on a 5.5% rate of local recurrence [35]. A meta-­
analysis of observational studies comparing SSM and simple
mastectomy for breast cancer suggested that rates of local
recurrence do not differ significantly between the two tech-
niques. The local recurrence rate in comparative studies
included in the meta-analysis varied from 3.8% to 10.4%
after SSM and from 1.7% to 11.5% after simple mastectomy
[34–37].
17.1.6  ipple Involvement and Tumour
N flaps and nipple-areola complex. During a conservative mas-
to Nipple Distance (TND)
There are several widely accepted contraindications for nip-
ple and areola preservation when a conservative mastectomy
is planned. These include clinical or radiological evidence of
NAC involvement, Paget’s disease of the nipple and bloody
nipple discharge. In cases where the above clinical contrain-
dications do not apply, tumour-to-nipple distance (TND) on
MRI or other imaging is used in order to decide if the NAC
can be preserved or not (. Table 17.4). Traditionally, a TND
<2 cm on MRI has been widely accepted as a contraindication
to preserve the NAC, as a short distance between the cancer
and the NAC is believed to confer a higher risk of NAC
involvement by the adjacent breast cancer. Recently, however,
this dogma has been challenged. Coopey and colleagues per-
formed 315 therapeutic NSMs, and in 28 of these cases, the
TND was <2 cm on MRI but frozen sections from the nipple
base were negative (in all 28 cases). At a mean follow-up of
22 months, the authors reported on a local recurrence rate of
2.6%, with no recurrence in the NAC [38]. Ryu and colleagues
performed 266 therapeutic NSMs, of which 145 cases (54.5%)
presented with a TND <2 cm on MRI. Median follow-up was
25.6 months. There was no statistically significant difference
in  local recurrence rates between the patients with TND
<2  cm and those with TND >2  cm. More notably, no local
recurrence occurred in the NAC [39].
The rates of occult cancer in the NAC demonstrate a wide
variation across surgical series. In a large retrospective study,
occult nipple involvement was 10.7% in 2323 mastectomy
specimens, of which half harboured DCIS [40]. In another
..      Table 17.4  Studies on tumour to nipple distance less than
2 cm and NAC recurrence
Total Cases Follow- Local
no. of with ­up recur-
cases TND (months) rence
<2 cm (%)
Coopey [37] 315 28 22 2.6
Ryu [38] 266 145 25.6 2.2
209 17
in vivo study, 52 NSMs were evaluated. Occult NAC cancer
was reported in 25% of the cases, and 8 out of 13 nipple fro-
zen sections were false negative [41]. Alperovich and col-
leagues performed nipple frozen section in 500 mastectomies
and concluded that this practice is moderately sensitive. In
this series, the risk of unnecessary NAC resection (false-­
positive frozen section) was null [42].
17.1.7  kin Flap Necrosis, Nipple Loss
S
and Free Nipple Grafting
Apart from oncological concerns, conservative mastectomy
potentially confers a risk of vascular compromise to the skin
tectomy, the skin and NAC lose their parenchymal perfora-
tors due to total gland removal, and as a result the NAC and
skin rely solely on their subdermal plexus blood supply.
Several risk factors for skin flap and NAC ischemia have been
recognized, most importantly smoking, high BMI, hyperten-
sion, diabetes, age, type of incision and previous radiotherapy
[43–46]. Interestingly, flap thickness <5  mm is associated
with a higher risk of skin and NAC ischemia, whereas (as
already discussed above) flap thickness >5  mm confers a
higher risk of residual TDLUs in the skin flap. It is therefore
crucial that the breast surgeon maintains a fine balance
between these two factors in order to perform an aestheti-
cally and functionally sound mastectomy/reconstruction
with minimal oncological risk.
The incidence of NAC ischemia varies widely across stud-
ies (from 0% to 48%), but most series report on rates between
10% and 15% [45]. Donovan and colleagues assessed 351
NSMs for ischemic complications. NAC necrosis was
reported in 14% of cases, but NAC resection following full-­
thickness necrosis was deemed necessary in only 2% of cases.
There was no statistically significant difference in NAC
necrosis rates between cases where diathermy was used and
cases where mastectomy was performed by scissors or scal-
pel. However, a non-significant trend (p = 0.06) for a higher
risk of NAC necrosis was observed in the diathermy group.
Periareolar incisions with a lateral extension conferred the
highest rates of NAC necrosis (4%), whereas there was no
necrosis in patients where a vertical, lateral-only or crease
incision was employed [47]. Mastroianni and colleagues
looked at 775 NSMs with immediate reconstruction and
assessed ischemic complications. Fifty-one (51) nipples
(6.6%) became necrotic (all grades of necrosis), of which one
third required removal [48]. Similarly, Donovan and col-
leagues showed that a periareolar incision was a positive pre-
dictor of NAC ischemia. Conversely, the Memorial Sloan
NAC
recur-
Kettering Centre experience reports on lower rates of NAC
rence ischemia following a periareolar approach. However, this dis-
crepancy could be attributed to the fact that a two-stage
expander to fixed volume implant reconstruction is the dom-
Nil inant method of reconstruction in this institution, possibly
Nil resulting in less tension on the skin flap during the early
reconstruction phase [48, 49].
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 210 P. Charalampoudis and T. Kovacs
Recently, Doren and colleagues reported on free nipple
grafting (akin to the breast reduction technique) in cases
where NSM could portend a high risk of NAC ischemia. The
authors retrospectively looked at 36 skin-sparing mastecto-
mies with free nipple grafting and reported on an average
graft take of 93%, whereas full NAC loss was null. This
approach could represent a promising alternative to standard
NSM in patients in high risk of NAC ischemia [50].
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 213 18

Surgery to the Breast: Breast

Conservation Techniques
Marjut Leidenius

18.1 Introduction – 215

18.2 Tailoring Breast Conservation – 215

18.3 Young Age: Family History – 216

18.4 Multifocal and Multicentric Cancer – 216

18.5 The Role of Radiotherapy – 217

18.6 Previous Breast Surgery – 217

18.7 The Role of Breast MRI in Patient Selection

for Breast Conservation – 217

18.8 The Role of Oncoplastics – 218

18.9 Breast Symmetry – 218

18.10 Other Important Aesthetic Issues – 218

18.11 The Role of Neoadjuvant Systemic Treatment – 218

18.12 Technical Considerations in Breast Conservation – 219

18.12.1 Lumpectomy Only or Full-Thickness Wide Local Excision
Including Overlying Skin and Underlying Pectoral Fascia – 219

18.13 Impalpable Tumour Localization – 220

18.13.1 The Guidewire – 220
18.13.2 Roll – 220
18.13.3 Radioactive Seed Localization – 221
18.13.4 Intraoperative Ultrasound Localization – 221
18.13.5 Other Localization Methods – 221

18.14 Which Method to Choose – 222

18.15 Targeting Radiotherapy Boost – 222

18.16 Closing the Breast Parenchyma – 222

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_18

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18.17 Orienting the Specimen for the Pathologist – 222

18.18 Pseudo-Positive Margin – 223

18.19 Margins – 223

18.19.1 Patients with Neoadjuvant Systemic Treatment
and Those with Partial Breast Radiotherapy – 224

18.20 Intraoperative Margin Assessment – 224

18.21 Summary – 224

References – 224

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Surgery to the Breast: Breast Conservation Techniques
18.1 Introduction
The role of breast-conserving surgery was established during
the 1980s, thanks to the pioneering (and at the time contro-
versial) work of Umberto Veronesi in Italy and Bernard Fisher
in the USA. They published randomized trials showing that
overall survival after breast conservation plus adequate radio-
therapy was similar to that following mastectomy [1, 2].
Quality of life is better after breast conservation when
compared with mastectomy. Therefore, breast conservation
should be performed if technically possible if this is the
patient’s preference, and there are no contraindications.
Likewise a woman’s request for mastectomy must be
respected, but careful counselling should always be provided
as some women have misconceptions about the oncological
and treatment-related benefits of mastectomy.
There are only two absolute contraindications to breast-
conserving surgery: a failure to achieve negative margins
without causing breast deformity and inflammatory breast
cancer. All other contraindications are more or less relative
and often relate to an increased risk of local recurrence.
However, distant metastasis is the most common first recur-
rence event, even among patients with small primary
tumours [3]. Therefore, all the relative contraindications
should be weighed against the prognosis of the patient, their
life expectancy due to age and comorbidities and, last but not
least, the patient’s preference for breast conservation.
The most important independent risk factors for local
recurrences after breast conservation include positive mar-
gins and young patient age [4, 5]. However, local recurrence
rates are currently much lower than in the past, at approxi-
mately 0.5% per year [3, 6, 7]. The decrease in local recurrence
rates has been most significant in premenopausal patients [6].
The reason for the decreased risk of local recurrence is
multifactorial. Improved patient selection, better quality sur-
gery, better histopathological evaluation of resection mar-
gins, and use of tumour bed radiotherapy boost have all
contributed, especially in younger patients [8]. However,
perhaps the most important reason is the more extensive use
of systemic adjuvant treatment and also the use of more
effective regimens, like aromatase inhibitors instead of
tamoxifen, use of trastuzumab in patients with HER2-
positive tumours [9, 10] and better chemotherapy regimens
such as anthracycline- and taxane-based protocols.
The risk of local recurrence after breast conservation for
DCIS seems somewhat higher than that seen with invasive
cancer. The 10-year LR rate has been reported to be between
6% and 13% when radiotherapy is given and 28.1% in patients
without radiotherapy [11]. The higher local recurrence risk
in DCIS is due to the diffuse growth pattern of the disease.
Moreover, in many institutions adjuvant endocrine treat-
ment is not routinely given in DCIS patients (unless they
have ER-positive DCIS in some units). Reassuringly, recent
reports suggest that LR is falling in conservatively managed
cases of DCIS [12].
The presence of an extensive intraductal component in
association with an invasive malignancy has been reported to
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215 18
be a risk factor for local recurrences [13] However, it seems
to be a risk factor only when there are positive resection mar-
gins [14]. Local recurrences have also been more frequent in
patients with biologically aggressive tumour subtypes such as
triple negative cancers and Her2-positive disease [15]. In
women with such high-risk tumours, the risk of distant
metastases is a greater risk than local recurrence. Therefore,
effective systemic treatment, rather than mastectomy,
improves survival in these patients. Moreover, effective sys-
temic treatments also decrease the risk of local recurrences in
patients with biologically aggressive tumours [9, 10].
It is noteworthy that the risk of local recurrences may be
higher in patients who undergo breast conservation after neo-
adjuvant therapy, when compared with patients who have
upfront surgery [16]. The risk factors for local recurrence in
these patients include clinical nodal stages 2–3, histological size
of the residual primary tumour larger than 2  cm, multifocal
residual tumour and the presence of lymphovascular invasion
in the primary tumour [17]. When none of the aforementioned
four risk factors was present, the 10-year local recurrence risk
was just 5%. When all four risk factors were present, the 10-year
local recurrence rate was as high as 61% [18].
It is important to minimize the risk of local recurrence
after breast conservation. Local disease control improves sur-
vival. One breast cancer death can be avoided by preventing
four local recurrences, as reported in the EBCTCG overview
2005 [19].
18.2 Tailoring Breast Conservation
There are numerous issues to be taken into account and to be
discussed with the patient when tailoring breast conserva-
tion. The most important ones are provided in a form of a
checklist in . Table 18.1.
..      Table 18.1  The checklist for planning of breast-­conserving
surgery
The extent and the location of the primary tumour
The size of the breast
The density of the breast parenchyma and the grade of ptosis of
the breast
The BMI and the body confrontation of the patient (very skinny,
slim, normal, obese, very obese)
Previous breast surgeries
Tumour biology – especially when considering neoadjuvant
treatment
Contraindications to radiotherapy
The age and comorbidities of the patient
Family history of the patient
Patient preference
 216 M. Leidenius

18.3 Young Age: Family History

Young age is an independent risk factor for local recur-

rences [4]. According to a study conducted at the Dana-
Farber Cancer Institute/Brigham, USA, between 1997 and
2006, the 5-year local recurrence rate was 5.0% for
23–46-year-old patients, whilst it was 2.2% for 47–54-year-
old patients and just 0.6% for patients in the 55–63 years age
group [20].
However, the risk of local recurrences has decreased sig-
nificantly in recent years, and this decrease has been most
striking among younger patients. According to a study based
on the Eindhoven Cancer Registry, the 5-year local recur-
rence rates in patients 40 years or younger were 9.8% when
treated in the period between 1988 and 1998, 5.9% when
treated between 1999 and 2005 and just 3.35% when treated
between 2006 and 2010 [21].
Young age is also associated with an increased risk of
local recurrences in DCIS cases, despite the use of radiother-
apy [11]. In particular, the risk of invasive local recurrence is
higher [22]. Invasive local recurrences after breast conserva-
tion in DCIS, in turn, are associated with a poor prognosis
[23, 24]. For these reasons, mastectomy should be discussed
in young women with DCIS to minimize the risk of subse-
quent invasive local recurrence, in a similar way to discus-
sions with high familial-risk women about risk-reducing
mastectomy.
Young patients with a positive family history or even
..      Fig. 18.1  Screen detected multicentric breast cancer in a 61-year-
those with diagnosed BRCA gene mutations do not have an old woman. The small tumours were located at 3 and at 9 o’clock and
elevated risk of local recurrences, when compared with were localized with two guidewires (2 mammographic projections).
patients of a similar age [25]. Therefore, there is no reason to The 7 and 10 mm tumours represented invasive ductal cancer, and the
push these patients towards mastectomy. Instead, it is impor- resection margins were excellent. No recurrences have been observed
during 5 years of follow-up
tant to treat the cancer effectively and estimate the prognosis
of the patient based on tumour stage and biology. Both ipsi-
lateral and contralateral mastectomies are measures for sec- 5-year local recurrence rate was 4.9% in the 421 patients with
ondary prevention in these patients. The need and the timing multifocal disease and 8.0% in 55 patients with multicentric
of mastectomy and contralateral mastectomy should be tumours [26]. Smaller studies have reported 0–4.5% local
evaluated and discussed with the patient in the same way as recurrence rates during follow-up periods of between 3.5 and
with healthy high-risk women without cancer. However, 4.6 years [27, 28]. These figures seem higher when compared
unlike in healthy gene mutation carriers, the index cancer to patients with unifocal tumours, but the local recurrence
often determines the prognosis of the patient and therefore rates are also higher in patients with multifocal and multi-
18 influences the benefit of the secondary prevention measures. centric cancers even when treated with mastectomy which
However, in the case of DCIS, the prognosis is similarly may reflect disease biology rather than surgery type [29]
excellent, and so prevention assumes much greater impor- (. Fig. 18.1).
 

tance. The level of evidence behind guidelines recommending

18.4 Multifocal and Multicentric Cancer
In many guidelines, multicentric tumours and sometimes
even multifocal tumours are considered to be contraindica-
tions to breast conservation. However, there is not much
high-quality evidence underpinning the safety of breast con-
servation in patients with multifocal or multicentric tumours.
The largest series with the longest follow-up comes from
Milan. During a median follow-up of more than 6 years, the
mastectomy in patients with multifocal or even multicentric
cancers is low, largely at the level of expert opinion, the low-
est level in the hierarchy of evidence. Therefore, breast con-
servation may be considered in these patients provided they
are aware of the academic uncertainty of this treatment and
provided negative margins can be achieved without breast
deformity. The use of MRI and an oncoplastic approach is
helpful in these cases [30]. Individual decision-making is
necessary, and each case should be discussed in the multidis-
ciplinary team meeting and should also respect patient pref-
erence.

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Surgery to the Breast: Breast Conservation Techniques
217 18
18.5 The Role of Radiotherapy The risk of fat necrosis and necrosis of the nipple areolar
complex may be higher than usual, and this risk must be fully
Breast radiotherapy is an essential part of breast-conserving discussed with the patient.
treatment. According to the EBCTG meta-analysis published Patients who have undergone previous implant augmen-
in The Lancet 2005, radiotherapy after breast conservation tation may have unrealistically high expectations regarding
not only decreases the local recurrence rate but also improves the cosmetic outcome of cancer surgery. This relates to the
survival [19]. fact that they often have a limited amount of the native breast
Radiotherapy also substantially reduces the risk of local tissue which may limit the feasibility of breast conservation,
recurrences in elderly breast cancer patients; however, especially if the implant is removed. Moreover, if the implant
whilst in younger women this leads to a small survival is removed, the contralateral breast usually needs surgery for
advantage, in the elderly it does not. This difference is prob- symmetry [34]. The placement of the scar may also limit the
ably due to the shorter life expectancy of older women as use of certain oncoplastic pedicles.
the survival advantage of radiotherapy is not apparent until If the implant is not removed, there is up to a 65% risk of
15 years after treatment, by which time many older women capsular contracture after breast-conserving surgery and
will have died of other causes [31]. If an elderly patient is radiotherapy, possibly leading to further surgeries, poor cos-
too frail for radiotherapy, breast radiotherapy can be omit- mesis and pain [34]. If the implant is sub-glandular, the tissue
ted, if breast conservation is the patients’ preference. remaining after wide local excision may not be sufficient for
Endocrine therapy should be given in patients with endo- implant coverage. In these cases, the sub-glandular implant
crine-responsive tumours whether they have radiotherapy can be changed to a smaller, sub-pectorally placed implant.
or not. Also in these cases surgery to the contralateral breast is often
For some patients who live in remote areas, the require- needed, to change the size and placement of the contralateral
ment for daily travel to the radiotherapy centre for several implant. When planning breast conservation in patients with
weeks may be burdensome. For some this may steer them to a previous implant augmentation, all the aforementioned
choose mastectomy. However, intraoperative radiotherapy or issues have to be considered and discussed with the patient.
other forms of brachytherapy may be given in selected, low-­ Implant choice is also important, especially if an expander
risk cases. The short-term outcome after intraoperative implant is used as some integral ports may impact on radio-
radiotherapy in selected patients has been excellent [32, 33], therapy delivery.
but longer follow-up is needed to establish the role of the
intraoperative radiotherapy.
A history of previous radiotherapy to the thoracic area, 18.7 The Role of Breast MRI in Patient
for example, mantle radiotherapy for Hodgkin’s disease, may Selection for Breast Conservation
compromise the ability of a woman to have breast conserva-
tion as the previous radiotherapy fields may have overlapped Breast MRI may reduce the need for reoperation due to posi-
with the tangential breast fields used in whole-breast radio- tive resection margins in premenopausal patients [35] and in
therapy after conservation. The fields of previous radiother- those with invasive lobular cancer [36]. However, breast MRI
apy should be checked with a radiation oncologist before does not reduce the risk of local recurrences [37]. Moreover,
decision-making, to avoid an unnecessary mastectomy. the risk of local recurrence is similar in patients with invasive
When mastectomy is necessary, immediate breast recon- ductal carcinoma and invasive lobular carcinoma, even with-
struction should be discussed with the patient. out MRI [3].
Breast MRI may lead to unnecessary mastectomies [36].
Therefore, all additional lesions detected by MRI should be
18.6 Previous Breast Surgery biopsied before planning more extensive surgery, especially
before recommending mastectomy to the patient instead of
The patient may have undergone previous breast surgery, breast conservation. Consequently MRI may also delay sur-
such as for benign diseases or more cosmetic procedures gery [38]. MRI is not helpful when planning surgery in
such as reduction mammoplasty or implant augmentation. patients with DCIS [39].
These previous breast surgeries are not a contraindication to However, in patients undergoing neoadjuvant therapy,
breast conservation. However, individual tailoring of surgery MRI is superior to breast ultrasound, mammography or
is needed and is sometimes challenging when previous surgi- clinical evaluation when evaluating the size of the residual
cal scars interfere with surgical planning for cancer surgery. disease in the breast [40]. Therefore, MRI is recommended
Breast conservation is feasible in patients who have in patients who are candidates for breast conservation after
undergone previous reduction mammoplasty, mastopexy, or neoadjuvant treatment. A baseline scan is required, both for
breast resection of a benign breast lesion if the tumour size is comparison with post-treatment scans to assess response
not too large in relation with the size of the breast. However, but also to assess the pattern of disease before treatment to
the scars and the pedicle from a previous surgical procedure assess and likely success of NAC in facilitating conserva-
should be taken into account when planning the operation. tion.

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 218 M. Leidenius
18.8 The Role of Oncoplastics
Good cosmesis is an important goal in breast conservation.
When doing conventional wide local excision, breast defor-
mity is likely when more than 20–30% of the breast tissue is
removed [41]. Even a smaller volume excision may cause
deformity, when the tumour is located either medially or
caudally in the breast [41]. In these cases deformity can usu-
ally be avoided by using an oncoplastic approach. Oncoplastic
breast surgery allows larger excisions whilst maintaining
good cosmesis and thus also extends the indications for
breast-conserving surgery.
18.9 Breast Symmetry
To achieve symmetry after oncoplastic breast conservation,
surgery to the contralateral, healthy breast may be necessary.
The need for, and timing of, symmetrization surgery should
be discussed with the patient. Many patients are tolerant of
even major degrees of asymmetry such as several cup sizes
between the breasts, whilst minor asymmetry may annoy
others. Asymmetry is not just about volume discrepancy but
may relate to changes in the breast shape or degree of ptosis.
Again patients vary in their tolerance, and whilst some
women will be happy if they can achieve «in bra» symmetry,
for others, perfect unclothed symmetry is desired. Correcting
deformity is time consuming, and the outcome may not be as
desired, even after several sessions of autologous fat grafting
or a range of other techniques, and it is preferable to plan
primary surgery to avoid these problems in the first place.
These corrective procedures may also be more prone to mor-
bidity due to the fact that the surgeon will be operating on
irradiated tissues, leading to higher rates of wound break-
down, fat necrosis and capsule formation if implants are used.
The contralateral breast may usually be successfully corrected
for symmetry, in many cases with less risk, if the patient is
prepared to accept a change in breast shape and size.
When operating on patients with cancer who are candi-
dates for reduction mammoplasty due to macromastia,
regardless of their cancer diagnosis, it is usually advisable to
18 perform contralateral reduction at the same time as their
cancer surgery to avoid gross size asymmetry. In other cases
where breast size and/or ptosis is less marked, it is better to
postpone the contralateral symmetrization procedures for
2–3  years. By this stage the treated breast will have fully
recovered from radiotherapy and can be used as a template
for the symmetrization procedure.
18.10 Other Important Aesthetic Issues
Complex oncoplastic surgery should not be used if deformity
can be avoided without it. It is advisable to always select the
simplest surgical technique to achieve the desired aesthetic
outcome.
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Another factor to consider when planning BCS is optimal
scar placement. Scarring, especially if poorly sited, may be a
cause of patient dissatisfaction. Good quality subcuticular
suturing and a sympathetically placed scar (e.g. ideally avoid-
ing the cleavage area) are important. Scars may be «hidden»
in the inframammary fold or at the junction of the areolar
and breast skin. Radial scar placement may contract and pull
the nipple out of position and so peri-circumareolar scars
may be better. Such scars also run in Langer’s lines and will
tend to heal with less prominent scarring. Postoperative
radiotherapy will make the scars in the treated breast less vis-
ible, but will have no impact on any scars in the contralateral
breast, if symmetrization surgery is performed. This has to be
discussed with the patient.
Complications like infection and skin or fat necrosis will
destroy the aesthetic outcome of the breast after breast con-
servation, and these should be avoided, whenever possible. It
is important to take into account comorbidities and the
smoking history of the patient, which may increase the risk
of wound complications.
The selection of surgical technique should take into
account the consistency of the breast parenchyma. In dense
breasts, any technique may be chosen. However, extensive
undermining should be avoided in fatty breasts, because it
often leads to fat necrosis [41]. In a patient with very fatty
and fragile breast tissue, the classic reduction mammoplasty
techniques may lead to fat necrosis. The more fatty and frag-
ile the breast parenchyma is, the more simple and straight-
forward surgical technique should be.
It is not enough that the shape of the breasts and the sym-
metry are excellent. Also the size of the breasts after surgery
should be large enough in relation to the body habitus of the
patient. Very small breasts in an obese patient may lead to
poor body image. Efforts should be made to establish the
desired breast size of the patient and match this to the surgi-
cal outcome if possible.
18.11  he Role of Neoadjuvant
T
Systemic Treatment
The size of the tumour may be just too large to allow breast
conservation even with an oncoplastic approach. In these
cases, the tumour can often be downsized by using primary
systemic therapy, either chemotherapy or endocrine therapy.
Careful patient selection is crucial: patients with multifocal
or multicentric disease and those with extensive microcalci-
fications are not optimal candidates for this treatment
option.
Although the response rate in general is good or even
excellent (depending on the biological subtype of the dis-
ease), not all responders will achieve breast conservation.
The response can be total or partial. If partial, the response
may be concentric, but not sufficient. The response may also
be honeycomb-­like, so that the extent of the tumour is the
same as before the treatment [42] (. Fig. 18.2).
Surgery to the Breast: Breast Conservation Techniques
..      Fig. 18.2  The response to
neoadjuvant chemotherapy
may be complete, partial
but concentric or partial and
honeycomb-like. The latter case
which is breast conservation is
not feasible
CR
As regards neoadjuvant chemotherapy to facilitate breast
conservation, there should be a good oncological indication
for chemotherapy in terms of disease prognosis and sub-
type. Patient should also be a good candidate for chemo-
therapy as regards to their age and comorbidities. It is also
advisable to discuss the expected response and the prob-
ability that breast conservation will be possible after che-
motherapy. Tumour biology influences the response rate.
The response is best in triple negative and HER2-positive
tumours, when compared with luminal-type tumours [43].
Patients with invasive lobular cancer often have multicen-
tric or multifocal disease and tend to respond poorly to
neoadjuvant chemotherapy, although for some of these
patients the response may be sufficient to achieve breast
conservation [44]. In patients with ER-positive tumours,
breast conservation can also be attempted with neoadjuvant
endocrine therapy.
The clinical response to neoadjuvant treatment can be
complete tumour regression. Therefore, the tumour should
be marked with a clip before starting neoadjuvant treat-
ment. A radioactive seed may be used for this purpose or a
simple metal clip. The radioisotope in the seed is I125, which
has a half-life of 60  days. This has the advantage that the
radioactivity remains for long enough that it can be used to
permit gamma probe localization at surgery without an
extra localization method, even after neoadjuvant chemo-
therapy [45].
When the aim of neoadjuvant treatment is breast conser-
vation, the response should be monitored by breast imaging.
MRI is the most accurate method to evaluate the size and the
pattern of residual disease [40]. Breast ultrasound may also
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219 18
PR PR
be used. Ideally the same imaging method should be used
throughout when evaluating the response as switching
modalities may misinterpret response.
18.12  echnical Considerations in Breast
T
Conservation
18.12.1  umpectomy Only or Full-Thickness
L
Wide Local Excision Including
Overlying Skin and Underlying
Pectoral Fascia
It is not necessary to perform full-thickness wide local exci-
sion in all patients. Lumpectomy including overlying skin
and the underlying fascia is not necessary if the tumour is not
located close to the skin or close to the fascia (. Fig. 18.3a).
However, in these cases not only the radial margin but also
the anterior or posterior margin or both have to be evaluated,
and when positive, redo surgery should be considered. When
the skin overlying the tumour is included, the anterior mar-
gin does not matter (. Fig. 18.3b). When the underlying fas-
cia is included in the specimen, the posterior margin does
not matter, unless the tumour is infiltrating the fascia or the
underlying muscle (. Fig. 18.3c, d). The latter cases are read-
ily recognized during surgery, and it is easy just to excise a
circular piece of the underlying pectoral muscle to ensure a
negative posterior margin.
Sometimes extensive excision of the breast skin is neces-
sary for aesthetic purposes, to downsize the skin envelope
during oncoplastic surgery or correct a degree of ptosis.
 220 M. Leidenius
a b
c d
..      Fig. 18.3  a wide local excision can be either full-thickness type
including both the overlying skin and underlying fascia. When the
tumour is not located close to the skin or fascia, a full-thickness resec-
tion is not necessary, but in these case also anterior and posterior
margins matter. b When the tumour is located adjacent to the skin,
excising a slice of the overlying skin ensures anterior margin. c When
the tumour is located adjacent to the pectoral fascia, excising the
18 underlying fascia and overlying skin ensures posterior margin. d
The tumour may infiltrate the underlying pectoral fascia or even the
muscle. In this case, local excision of the underlying pectoral fascia and
underlying muscle ensures posterior margin
18.13 Impalpable Tumour Localization
With the widespread adoption of screening across Europe, a
significant proportion of breast cancers are clinically occult/
impalpable. It is technically challenging to excise impalpable
cancers with negative margins and to do this without remov-
ing too much healthy breast tissue. There are a number of
different techniques to facilitate specimen localization, and
these are reviewed below.
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18.13.1 The Guidewire
The gold standard in the localization of impalpable tumours
has been the placement of a guidewire under ultrasound, ste-
reotactic or even MRI control. Most often ultrasound guid-
ance is used, because 95% of tumours are visible on breast
ultrasound. The advantage of the guidewire is that the dis-
tance of the wire from the tumour can be readily evaluated by
confirmation mammography (unless the lesion is mammo-
graphically occult). In cases with a large area of microcalcifi-
cation, the area can be bracketed with 2–3 wires. Also
multiple lesions can be marked using two or even three wires
(. Fig. 18.1). The disadvantages include patient discomfort,
migration or loss of the wire after placement and risk of
puncture injuries to the surgical team and pathology labora-
tory staff. For technical reasons, the insertion point of the
wire is sometimes remote from the tumour site, occasionally
even in a different breast segment. This makes planning of
the incision challenging, even when the tip of the wire is
close to the tumour. Another issue is the logistics of coordi-
nating wire insertion in the imaging department before sur-
gery [46, 47].
18.13.2 Roll
Radioisotope localization of sentinel nodes led to an idea to
localize not only the sentinel node but also the impalpable
tumour with radioisotope. This technique is called radiogu-
ided occult lesion localization (ROLL) [48]. The technique
can be performed in a number of ways. Two different iso-
topes may be used, one with small particles injected superfi-
cially to localize the sentinel nodes and another isotope with
larger particles to the tumour site [48]. It is also possible to
use a single peri- or intra-tumoural injection of radioiso-
tope, both for tumour and sentinel node localization [49].
The disadvantage of the latter practice is less frequent senti-
nel node visualization, especially in elderly and obese
patients with a tumour located deep in a large, fatty breast.
The visualization of sentinel nodes is better after a superfi-
cial injection.
The advantage of ROLL over wire-guided localization is
in patient comfort. There is no need for the patient to spend
time with the discomfort and inconvenience of having a wire
in situ whilst waiting for surgery, and also the isotope injec-
tion may be more comfortable when compared with wire
placement. Also the placement of the incision is easier; it can
be directed according to the point of maximum radioactivity.
The presence of radioactivity in the resected specimen and in
the resection cavity can be checked after resection using the
handheld gamma probe to confirm localization. The logisti-
cal problems are similar as in guidewire placement due to a
short half-life of the isotope. One possible problem is the lack
of ability to confirm co-localization of the radioisotope and
the tumour on post-placement mammography. Rarely, the
Surgery to the Breast: Breast Conservation Techniques
liquid radioisotope may migrate in the breast, for example,
along the injection channel, which may cause difficulties dur-
ing surgery.
18.13.3 Radioactive Seed Localization
Localization of impalpable tumours with I125 radioactive
seeds was introduced as early as 2001 [50], but the method
did not gain popularity because of the introduction of
ROLL.  However, the method has been revisited and has
recently gained increasing popularity. This procedure com-
bines the advantages of ROLL and wire localization. The
location of the seed in relation to the tumour can be readily
evaluated by post-placement confirmation mammography
(. Fig. 18.4), but the patient has the advantage that they have
 
no need to spend time with a wire in situ before surgery. A
large area of microcalcification may also be bracketed with
2–3 seeds. Moreover, the radioactivity is very focal, and there
is minimal risk of migration after placement. Therefore, the
resection can be directed even more accurately when com-
pared with ROLL with liquid radioisotope, at least in theory.
..      Fig. 18.4  Radioactive seed localization: The seed is adjacent to the
tumour (the arrow) in position-confirmation mammography
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221 18
Also multiple lesions in the same breast can be marked sepa-
rately which can be challenging and uncomfortable with wire
placement techniques.
Another advantage of seed localization lies in the logis-
tics. The seed can be placed several days and even several
months before surgery, which is a particular advantage in
patients receiving neoadjuvant treatment [45]. No further
localization is needed when performing breast conservation
after neoadjuvant treatment. The half-life of I125 is 60 days,
which is much longer when compared with the 6 h half-life of
Tc99m.
The long half-life of I125 is not only an advantage of the
method but also a disadvantage: there are some complex
radiation safety issues. No seed must be lost during the pro-
cedure. Also local written guidelines are needed regarding
how to handle seeds that are detached from the specimen
during surgery and how to handle cases, where the seed is
placed far away from the tumour due to technical problems
[46, 47].
Another disadvantage of the seed-guided localization is
that not all gamma detectors can readily distinguish the
activity from I125 and Tc99m. There is no problem in sentinel
node harvesting, but the radioactivity from the injection site
of the Tc99m may interfere with that of the seed. However, the
interference depends on the distance between the seed and
the Tc99m injection as well as on the amount of radioactivity
used in the sentinel node localization, the amount of radioac-
tivity in the seed and also the gamma detector used.
18.13.4 Intraoperative Ultrasound
Localization
Intraoperative ultrasound has gained increasing popularity
as a method to localize impalpable tumours. No radioactivity
is needed and the method is also easy from a logistical view-
point. It is also pleasant for the patient because no extra
breast punctures are needed [47]. Also the resection margins
can be evaluated in the resected specimen [47] (. Fig. 18.5).
Intraoperative ultrasound may also facilitate excision of
palpable tumours, as it is easier to excise the tumour with
uniform margins, without removing excess healthy breast
tissue [51]. However, it is challenging to detect a very small
lesion in a dense breast with heterogeneous echogenicity.
Also there is an increased risk of margin positivity in cases of
microcalcification and in multifocal tumours. A marker vis-
ible on ultrasound can be used to facilitate the localization
procedure [47].
18.13.5 Other Localization Methods
Carbon dye injection has been used for localization pur-
poses. The method includes injection of carbon dye under
ultrasound control into the tumour site and also injecting it
along the needle channel. Surgeon is then able to follow the
needle tract to the tumour site and perform the excision.
 222 M. Leidenius
..      Fig. 18.5  The resection margins can be assessed using an intraop-
erative ultrasound
Superparamagnetic iron oxide (SPIO) has also been used
in impalpable tumour localization in conjunction with a
handheld magnetometer. The injection site of the iron parti-
cles is identified using the same equipment as used in senti-
nel node localization (the Sentimag© technique). The
disadvantage of this method is that the magnetometer head is
sensitive to metal instrument so special instrument is needed
at the time of surgery and the SPIO injectate may «stain» the
injection site causing a bruised appearance which may persist
for many months and which may interfere if subsequent MRI
18 of the breast is required.
These and some less common or experimental localiza-
tion methods are described in detail in an excellent review
article by Ahmed and colleagues [46].
18.14 Which Method to Choose
There are several studies, even randomized controlled trials,
comparing wire localization, ROLL and seed localization, in
regard to the rate of successful localization, proportion of
patients with negative margins, unnecessarily large excisions,
operation time and even patient satisfaction. Unfortunately
the majority of these studies were underpowered to detect
the often small differences between the evaluated meth-
ods. Meta-analysis of these studies concluded that there is
rares1geo@gmail.com
insufficient evidence of objective benefit of one method over
the others, and costs, access to radioactive materials and
local preference are the usual deciding factors for choice of
technique [46].
With regard to patient satisfaction, successful resection
rate and the proportion of patients with negative resection
margins, intraoperative ultrasound seems to be the best
method [47]. However, some of the studies addressing the
superiority of intraoperative ultrasound may suffer from
selection bias, because they necessarily include only lesions
visible on ultrasound [46].
Nevertheless, the most important issue in successful
occult tumour localization is the experience of the multidis-
ciplinary team and the communication between team mem-
bers. Accordingly, the team should select the method they
feel that is working best at their unit.
The advantages and disadvantages of wire-guided local-
ization, ROLL, radioguided seed localization and intraopera-
tive ultrasound are summarized in . Table 18.2.
18.15 Targeting Radiotherapy Boost
A radiotherapy boost dose to the tumour bed decreases the
risk of local recurrences [8]. To target the boost to the tumour
bed, the tumour cavity has to be marked with titanium clips.
Marking the tumour bed is of special importance in cases
where level II oncoplastic techniques have been used. It is
important that clips are used to mark the tumour bed in all
cases, and any local or national protocols for cavity marking
are adhered to.
18.16 Closing the Breast Parenchyma
Previously it was popular just to excise the tumour and close
the overlying subcutaneous tissue and skin, without mobiliz-
ing and closing the breast parenchyma. The aesthetic out-
come after this method is excellent 2–3 weeks after surgery,
with a haematoma/seroma filling the cavity. However, after
resorption of the haematoma/seroma, retraction often fol-
lows, leading to a poor aesthetic outcome. Therefore, it is
advisable to mobilize and close the breast tissue (level I onco-
plastic surgery), except in patients with very fatty breast
­tissue. Extensive mobilization and suturing the extremely
fragile breast parenchyma will lead to fat necrosis.
18.17 Orienting the Specimen
for the Pathologist
The resected specimen should be oriented to facilitate the
histopathological evaluation of the specimen and especially
margin assessment. Sutures of different lengths or sutures
with different numbers of clips have been used for this pur-
pose. Special specimen boards are available to facilitate spec-
imen marking and orientation (. Fig. 18.6).
Surgery to the Breast: Breast Conservation Techniques
223 18

..      Table 18.2  Advantages and disadvantages of wire-­guided localization (WGL), radioguided occult lesion localization (ROLL), radioac-
tive seed localization (RSL) and intraoperative ultrasound (IOUS) in the localization of impalpable breast tumours

WGL ROLL RSL IOUS

Gold standard Yes No No No

Logistics Challenging Challenging Easy Easy

Patient discomfort Major Minor Minor Nonea

Extra visit in imaging department Needed Neededb Needed Not neededc

Incision placement Challenging Optimal Optimal Optimal

Nuclear medicine facilities Not needed Needed Needed Not needed

Radiation safety issues None Like in SNB Complex None

Feasibility when multiple lesions Excellent Limited Excellent Good?

Feasibility when extensive microcalcifications Excellent Limited Excellent Limitedd

Apparel needed in OR None Gamma probe Gamma probe Ultrasound

Intraoperative margin assessment No No No Yes

aMinor,when a clip visible in ultrasound is placed before surgery

bNot,when using image-guided intra- or peritumoural isotope injection
cNeeded, when a clip visible in ultrasound is placed before surgery
dMultiple clips visible in ultrasound can be used

men request form between the surgeon and the pathologist is

required, in order to avoid misunderstanding. Otherwise, the
pathologist may stain the cleft in the specimen, and the
microscopic assessment will show «tumour at ink» leading to
unnecessary second surgery.
An alternative is to just resect more tissue as a cavity
shave. The cavity shave specimen should also be oriented for
the pathologist to show which is the new surgical margin.

18.19 Margins

According to the 2014 meta-analysis by Houssami and col-

..      Fig. 18.6  The resected specimen is placed on a plate with a draw-
ing of left breast. In addition, two orientation sutures are used. The yel-
low pins in the centre of the specimen have been placed in the imaging
department and point the location of the tumour to the pathologists
18.18 Pseudo-Positive Margin
Sometimes there are technical difficulties in tumour localiza-
tion, which may lead to cutting very close to the tumour or
even cutting into the tumour itself. In these cases the surgeon
may just correct the direction of the resection to achieve an
adequate margin and close the cleft in the specimen with
sutures. However, clear communication of this on the speci-
leagues, positive resection margins increase the risk of local
recurrence with an odds ratio of 2.44 in patients with inva-
sive breast cancer [5]. However, the risk of local recurrences
in patients with invasive cancer does not decrease with free
tissue margins larger than 1 mm [5].
In DCIS, a meta-analysis concluded that the margins
should be at least 2 mm, but wider margins do not decrease
the risk of local recurrence [52]. However, another meta-­
analysis concluded that margins at least 10  mm reduce the
local recurrence risk with an odds ratio of 0.46, when com-
pared with 2  mm [53]. Nevertheless, free tissue margins
larger than 2  mm lead to less local recurrences in DCIS
patients without radiotherapy and are recommended in
patients who want to avoid radiotherapy after breast conser-
vation for DCIS [54].
However, there is neither data nor a consensus regarding
whether negative margin (no tumour at ink) or 1 mm mar-
gins are sufficient in patients with invasive cancer and an

rares1geo@gmail.com
 224 M. Leidenius
extensive intraductal component or whether more extensive
margins are required.
It is noteworthy that even very extensive resection mar-
gins do not guarantee that there is no residual tissue in the
breast. Additional tumour foci have been detected in more
than 70% of cases, with 43% of these additional foci being
more than 2 cm away from the index tumour [55]. Indeed,
almost 80% of breast cancers may actually be multicentric
harbouring foci beyond the index quadrant [56]. Therefore,
radiotherapy is an essential part of breast conservation.
Whether just radial margins or even anterior and poste-
rior margins should be taken into account depends on the
resection technique (. Fig. 18.3 a–d). If the anterior margin
 
is positive and there is breast tissue between the skin and the
resected specimen, second surgery should be considered.
Similarly, if the posterior margin is positive, second surgery
should be considered, if there is residual breast tissue left on
the fascia, underlying the tumour.
18.19.1  atients with Neoadjuvant Systemic
P recently with the advent of neoadjuvant therapy and onco-
Treatment and Those with Partial
Breast Radiotherapy
The data from the meta-analysis [5] addressing margin width
and local recurrences are based on studies which excluded
patients receiving neoadjuvant treatment and partial breast
radiotherapy. No evidence exists about the optimal margin
width in these patient groups.
18.20 Intraoperative Margin Assessment
Reoperation rates of up to 40% due to inadequate resection
margins have been reported [46]. To avoid involved resection
margins and associated second surgeries, there are numerous
methods for intraoperative margin assessment. Many local
guidelines recommend radiography of the resected specimen
in cases with impalpable tumour localization in order to con-
firm successful resection and sufficient radiological margins.
18 Specimen radiography may be also performed in palpable
tumours, if the extent of the tumour and negative margins is
not certain during surgery.
However, specimen radiography may not always show
the tumour and margins adequately, despite successful
localization, especially when the breast tissue is dense and
the tumour is very small or if there are several foci in the
resected specimen. In these cases specimen ultrasound is
often helpful.
In some institutions frozen section or imprint cytology
from the shavings of the walls of the resection cavity is per-
formed. This method has been shown to decrease the rate of
second surgeries for positive margins. In a cohort study by
Zavagno and colleagues, the reoperation rate was 5.5% in
those with intraoperative assessment of cavity shaves versus
21% in patients without [57].
rares1geo@gmail.com
There are some novel and very promising methods for
intraoperative margin assessment applying technologies
such as radiofrequency spectroscopy, near-infrared optical
imaging and high-frequency ultrasound. For example, radio-
frequency spectroscopy seems to decrease the reoperation
rates by approximately 50% [58]. Most of these have been
shown to reduce rates of positive margins, although some are
limited by the high cost of the equipment. It is likely that
these will become more widely adopted in future as the evi-
dence for their use strengthens.
18.21 Summary
Breast conservation surgery (plus radiotherapy) is now the
most common form of surgery for early breast cancer and
has been proven to be oncologically safe and associated with
improved cosmesis and quality of life. Local recurrence rates
continue to fall as surgical techniques and adjuvant therapies
improve. The indications for BCS have been extended
plastic breast surgery techniques and a relaxation of attitudes
towards multifocal (and to a lesser extent multicentric) dis-
ease, such that few women who wish to retain their breast
must now face mastectomy.
Key Points
1. Breast conservation should always be performed when
it is the patient’s preference and in the absence of con-
traindications.
2. The absolute contraindication to breast conservation is
a failure to achieve negative resection margins without
resultant breast deformity.
3. A favourable aesthetic outcome is an important goal
of breast conservation.
4. The indications for breast conservation can be
extended and the aesthetic outcome improved with
oncoplastic techniques and primary systemic therapy.
5. Positive resection margins increase the risk of local
recurrence.
6. Local recurrences after breast conservation are cur-
rently rare and ideally less than 5% over 10 years of
follow-up.
7. Local recurrence is associated with a small but definite
survival disadvantage on long-term follow-up.
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mans WF, Tutt A, Pusztai L. Recommendations from an international
consensus conference on the current status and future of neoad-
juvant systemic therapy in primary breast cancer. Ann Surg Oncol.
2012;19(5):1508–16. doi: 10.1245/s10434-011-­2108-2. Epub 2011
Dec 23.
44. Lips EH, Mukhtar RA, Yau C, de Ronde JJ, Livasy C, Carey LA, Loo
CE, Vrancken-Peeters MJ, Sonke GS, Berry DA, Van’t Veer LJ, Esser-
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Investigators. Lobular histology and response to neoadjuvant
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WK, de Widt-Levert LM, van der Veen H, Rijna H, Bergers E, Jóźwiak
K, Meijer S, van den Tol MP.  Intraoperative ultrasound guidance
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 229 19

Oncoplastic Breast-Conserving
Therapy
Elias E. Sanidas and Florian Fitzal

19.1 Introduction – 230

19.2 Indications for Oncoplastic Surgery – 230

19.2.1 Oncological Safety of Oncoplastic Techniques – 231

19.3 Achieving Clear Resection Margins

in Oncoplastic Surgery – 231

19.4 Specimen Marking – 232

19.5 Cavity Marking – 232

19.6 Oncoplastic Techniques: Classification – 232

19.6.1 Volume Replacement, Volume Displacement, Level 1 and 2 – 232
19.6.2 Volume Displacement – 233
19.6.3 Technical Atlas of Level 1 Techniques – 233
19.6.4 The Batwing Mastopexy – 233
19.6.5 Doughnut Mastopexy – 236
19.6.6 Round Block Mastopexy – 236

19.7 Technical Atlas of Level 2 Techniques – 236

19.8 Relative Contraindications for Oncoplastic Surgery – 241

19.8.1 Contraindications – 241

19.9 Cosmetic Outcomes – 242

References – 243

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_19

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 230 E.E. Sanidas and F. Fitzal
19.1 Introduction
When the word oncoplastic was first introduced in the early
1990s, the rationale was clear. Breast conservation rates were
progressively increasing with rates as high as 90% in some
series; however, in some cases, this was at the expense of poor
cosmetic outcomes (. Figs.  19.1 and 19.2). The aim was to
improve long-term cosmetic outcomes after breast conserva-
tion and radiotherapy, facilitating conservation surgery
where more than the traditional relative volume (usually up
to 20%) needed to be excised or where the location of the
tumour was adverse (superior/medial/inferior). It was
realised that breast volume, shape and symmetry could be
maintained or even, in some cases, enhanced whilst resecting
up to 50% of breast volume without loss of oncological safety.
Since then, there has been a massive expansion in the num-
..      Fig. 19.1  Poor cosmetic outcome from conservation surgery for an
inferiorly placed cancer resulting in a typical bird’s beak deformity
19
..      Fig. 19.2  Poor cosmetic outcome from conservation surgery for a
superiorly placed tumour resulting in size and volume asymmetry and
nipple malposition
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ber of techniques available, a greater understanding of the
oncological implications of such surgery and a progressive
increase in the training of the breast workforce in these often
complex techniques. The techniques are broadly divided into
two groups: volume displacement (often also termed thera-
peutic mammoplasty techniques) and volume replacement
which may be subdivided into lipofilling and flap-based tech-
niques. More detailed discussion of lipomodelling is given in
7 Chap. 20 and flap-based techniques in 7 Chap. 31, and
these techniques will not be addressed in this chapter which
will focus on mammoplasty techniques.
There has been a rapid growth in the use of and interest in
these techniques and a proliferation of methods available [1].
Complex atlases of procedures based on the site and size of
the tumour are available to aid the surgeon in selecting the
optimal technique [2]. The techniques are complex and
require skill and training both in understanding their indica-
tion and contraindications and in their optimal performance
surgically to get good results. In some centres, these proce-
dures are performed jointly between breast oncology sur-
geons and plastic surgeons. In some centres, fully oncoplastic
trained surgeons perform both the ablative and restorative
components of surgery. Training in oncoplastic surgery is
now more widely available, and good quality training pro-
grammes and guidelines are being developed globally to
make these techniques more widely available and enhance
quality [3–5].
19.2 Indications for Oncoplastic Surgery
1. Adverse tumour volume to breast volume ratio.
Resection of more than 15–20% of breast volume is likely to
result in asymmetry and adverse cosmetic outcomes
(. Figs. 19.1 and 19.2) as was elegantly shown by the Nottingham
group [6] with patient satisfaction rates of over 90% if only 5%
or less of breast volume was excised to only 25% satisfied once
20% of breast volume is lost. Whilst this may be addressed by
the use of neoadjuvant systemic therapy in some cases, in oth-
ers, the use of oncoplastic techniques will permit higher per-
centage volume loss with good cosmesis and better patient
satisfaction by reshaping the breast to minimise indentation
and deformity.
2. Adverse tumour location (superomedial, central/sub-
areolar, inferior).
Some areas of the breast are more difficult to resect tissue
from than others whilst maintaining good cosmesis. Areas of
concern are medially located tumours where the scar or
indentation may lie in the cleavage area and where there is
less breast parenchymal volume and superiorly sited tumours
for the same reason. Both sites may also result in nipple mal-
position due to scar retraction. Resection of inferiorly sited
tumours may cause nipple malposition or a bird’s beak defor-
mity. Centrally located tumours may necessitate loss of the
nipple and, if resected as an ellipse, cause a flattened off breast
Oncoplastic Breast-Conserving Therapy
shape. Oncoplastic techniques allow better cosmesis follow-
ing resections in these areas. A disc of nipple skin may be
imported to create a base for a nipple reconstruction for cen-
trally located tumours.
3. Redo conservation surgery.
This is a more controversial indication for oncoplastic surgery
[7]. There is little good quality evidence at present in support
of this, but for some women who have a strong preference for
a conservative approach, oncoplastic operations may contrib-
ute to acceptable cosmetic results. Caution is needed in under-
taking these procedures as these women will have had breast
radiotherapy and may be at higher risk of wound healing prob-
lems and pedicle hypovascularity. The oncological safety of
these procedures is also not supported by high-level evidence.
4. Multifocal and multicentric disease.
There is emerging evidence that BCT in multifocal (MF) dis-
ease is oncologically safe [8] but may result in a slightly infe-
rior outcome compared with BCT in unifocal breast cancer.
Patients in the MF group had higher 10-year LRR however
(0.6% vs. 6.1%, p < 0.001). Oncoplastic surgery may be used
to perform segmentectomy in MF disease confined to one
segment with subsequent reshaping of the breast. In multi-
centric disease, oncoplastic techniques may also be used to
resect more than one discrete area in different breast quad-
rants whilst retaining breast shape; however, there is little
high-level evidence supporting the oncological appropriate-
ness of this approach at present although a number of case
series show acceptable oncological outcomes [9, 10].
5. Macromastia.
For women with pre-existing macromastia, oncoplastic sur-
gery offers an opportunity to simultaneously perform bilat-
eral breast reduction which may have considerable appeal for
these women. Macromastia may cause shoulder and back
pain, embarrassment, difficulty finding suitable clothes and
problems with skin infections in the inframammary fold. For
many of these women, bilateral breast reduction may have
many benefits by reducing these symptoms, but also, women
with large breasts may be technically challenging for the
radiation oncologist to administer whole breast radiotherapy
to and may also suffer more significant post-radiotherapy
complications such as breast oedema and skin reactions. The
majority of studies of therapeutic mammoplasty for macro-
mastia achieve low rates of incomplete excisions (approxi-
mately 10%) [11]. The wide local excision is usually performed
prior to, and as a separate specimen to, the reduction proce-
dure; although the tumour is in one of the primary areas
where tissue is excised as part of the reduction, the tumour
may be excised en bloc with the reduction sample, but care
must be taken with margin marking and orientation. Rates of
local recurrence with this technique are acceptable [11].
A large review including data on 276 patients [12] treated
with bilateral reduction mammaplasty concluded that women
with breast cancer and macromastia can obtain oncologically
safe and cosmetically excellent outcomes.
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231 19
A detailed review [13] of the evidence about therapeutic
mammaplasty (TM) concluded that the oncological out-
comes appear comparable to simple BCS. However, they note
that no randomised controlled trials have been performed
and the evidence in support of these techniques is all derived
from case series and cohort studies.
19.2.1  ncological Safety of Oncoplastic
O
Techniques
Due to the sometimes complex nature of such surgery, which
may make margin assessment more challenging, complicate
surgery to take cavity shaves and make breast radiotherapy
boost more difficult to localise, concerns have been raised
about whether these procedures are oncologically safe.
Whilst there have been no randomised trials to compare the
outcomes of standard BCS/mastectomy with oncoplastic sur-
gery, there have been numerous large cohort studies, often
with long follow-up reported, which show that these tech-
niques can result in acceptable local regional recurrence rates
[14–18]. Even in cases with large-sized primary tumours,
acceptable rates of recurrence are reported [15]. A recent sys-
tematic review has confirmed this general finding [16].
Based on the fact that oncoplastic techniques generally
have the flexibility to remove larger volumes of breast tissue
[14], this should give the surgeon flexibility to take wider
margins and hence enhance oncological safety. However, the
often complex pattern of tissue removal and repositioning
means great care is needed in orienting specimens and docu-
menting and marking cavities.
Early in the oncoplastic era, small, retrospective and rela-
tively short follow-up series were published presenting recur-
rence rates and/or survival rates. One such early series in
2003 presented 101 patients with a 16% re-excision or subse-
quent mastectomy rate, a LRR of 9.4% and an overall survival
rate of 95.7% after 44  months of follow-up [14]. Whilst a
9.4% LRR is high by modern standards and was relatively
high for that time subsequent series have shown much better
results. For example, Rietjans and colleagues [18] in 2007
presented 148 cases with only a 2.2% re-excision/mastectomy
rate, a 3% LRR and an overall survival rate of 92.4% after
74 months of follow-up. Numerous studies have now reported
on oncoplastic BCS, and the results are generally very good
and similar to standard oncology outcomes [14–18].
19.3  chieving Clear Resection Margins
A
in Oncoplastic Surgery
Whilst rates of local recurrence are falling steadily following
BCS, when it does occur, it is distressing and may result in the
need for mastectomy [19] and a slightly higher late mortality
disadvantage. Rates are falling due to better adjuvant radio-
therapy and systemic therapy regimes, coupled with better
surgery and margin assessment by pathologists. However,
wider margins are not the answer. Indeed recent evidence
 232 E.E. Sanidas and F. Fitzal
and consensus are that a no-tumour at the inked margin is
acceptable [20] and wider margins than necessary adversely
affect cosmesis. Reoperation for cavity re-excision also has an
adverse cosmetic impact as well as the financial costs and per-
sonal burden to the patient. There are a range of techniques to
ensure that adequate margins are achieved which have proven
efficacy in reducing rates of positive margins, but detailed
review is out of the scope of this chapter. Excellent reviews are
available [21]. Use of these techniques is very relevant in the
oncoplastic setting where it may be technically challenging to
go back to re-excise a positive margin.
The tumour cavity surgical margins after an oncoplastic
procedure may be altered or transferred from the primary
tumour location to other quadrants in the breast due to the
use of local or distant displacement/replacement flaps as it
happens in lateral or J-mammaplasty or reduction mamma-
plasty techniques such as inverted T mammoplasty. It is
therefore imperative that the surgeon keeps detailed notes
and diagrams of the operation and marks the original tumour
bed with clips and ideally, in complex cases, uses some form
of intraoperative margin assessment to minimise the need to
go back for cavity shaves. Good communication with the
radiation oncologists is essential when boost is planned as
the skin scar may be some distance from the tumour bed and
use of marker clips to the tumour bed, before rotation/trans-
location of the tissue, is essential [22, 23]. Placement of six
clips has been proposed as optimal (medial, lateral, superior
and inferior and to mark the deep fascia and subcutaneous
margins).
19.4 Specimen Marking
Specimen orientation in breast surgery is of paramount
importance. This is more so in oncoplastic surgery where the
specimens may be irregular and asymmetric due to tissue
removal for reshaping of the breast in addition to the actual
tumour specimen. In oncoplastic cases, the tumour is more
likely to be complex: large, multifocal or multicentric
tumours or a known area of impalpable DCIS adjacent to an
invasive focus, all of which must be communicated to the
pathologist. Some cases may have followed primary systemic
therapy, and only a marker clip may indicate the original pri-
mary location. The pathologist must be made aware of these
19 preoperative tumour characteristics to avoid missing known
second lesions at specimen «cut up» which is vital for margin
assessment. Specimen X-rays should be sent to the pathology
lab, especially in cases with complex tumour patterns (e.g.
DCIS extent). This may help the pathologist to locate an
impalpable tumour in the specimen. Each margin must be
specifically marked and a detailed diagram provided showing
which marker indicates which margin in the event that re-­
excision is needed. This will ensure that only the involved
margin needs to be re-excised rather than the entire cavity
re-excision [24]. Any intraoperative cavity shaves must be
similarly identified and the new cut surface marked. Despite
the importance of specimen marking and orientation, there
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is no universally accepted and implemented specimen mark-
ing system. A recent survey in the UK [25] of 117 breast
units, nearly one quarter had no specimen orientation proto-
cols. Among these, 11 were national breast screening units.
In general, the surgeon places sutures or clips during sur-
gery, and inking of the specimen margins is done later by the
pathologist in the pathology laboratory [26]. However, there
may be better re-excision rates if the orientation is done
intraoperatively with sutures and ink applied by the surgeon
in the presence of the pathologist [27]. There are also com-
mercially available orientation boards/holders to which
specimens may be pinned and orientated in some detail to
facilitate both cut up and specimen radiology [25, 28–30].
The most common protocol seems to be the method with dif-
ferent length/number of sutures or clips on three of the six
margins [25, 31]. However, the suture-only method may not
facilitate optimal specimen orientation by the pathologist,
especially in small specimens (smaller than 20 cm3), whilst
the presence of the skin or muscle on the specimen does not
contribute to better orientation [30].
19.5 Cavity Marking
Knowing the exact position of the tumour bed has always
been a great help for the radiation oncologists to deliver
boost radiotherapy to breast patients. Although there are no
data to support that more accurate tumour bed delineation
will lead to improvement of local control, it may very well
improve cosmetic outcomes [32].
Delineation of the resection cavity by seroma formation
or location of the skin incision is relatively largely inaccurate
[32]. The best marking method is the placement of metallic
clips to the tumour cavity varying from one clip (not very
accurate) to six clips for each margin of the cavity and up to
8–10 surgical clips [33] into the tumour bed after resection
and before oncoplastic reconstruction. Detailed notes should
be kept of clip placement.
19.6 Oncoplastic Techniques: Classification
19.6.1 Volume Replacement, Volume
Displacement, Level 1 and 2
There are two broad techniques in oncoplastic surgery to
reconstruct the breast parenchymal defect:
1. Volume displacement: Local breast parenchyma is
repositioned to fill the defect using either simple advance-
ment or more complex pedicles (levels 1 and 2, respec-
tively).
2. Volume replacement: Distant autologous or heterologous
material such as muscle or dermofascial flaps (see 7 Chap.
31, Autologous Flaps), silicone prostheses (7 Chap. 29,
Implants, de Boniface, and 7 Chap. 30, Implant-­Based
Techniques, Douek) or fat grafting (7 Chap. 20,
Lipomodelling) may be used.
Oncoplastic Breast-Conserving Therapy
233 19
..      Fig. 19.3  Atlas of techniques
of oncoplastic reshaping
according to the quadrant of the
breast containing the cancer

19.6.2 Volume Displacement
Local breast parenchymal rotation flaps can only be used in
breast conservation surgery. There are several options from
small parenchymal rotations after lumpectomy and semi-
circular incisions up to complex breast reduction tech-
niques, nipple transposition and local skin rotation flaps.
These techniques may be divided into level 1 and 2 depend-
ing on whether a formal pedicle is used. There are a variety
«atlases» of techniques for tumours in different breast
quadrants [2], and surgeons should be familiar with a range
of methods for each site as well as having an understanding
of how they may need to be modified in certain circum-
stances (. Fig. 19.3).
fascia as well as between the skin and breast gland to rotate
the breast parenchyma into the defect and close it) are level 1
techniques. In general, these techniques are best performed
on women with dense breasts, especially if significant paren-
chymal flap mobilisation is used. Women with fatty breast
may be at increased risk of fat necrosis.
19.6.4 The Batwing Mastopexy
The batwing technique derives its name from the shape of the
incision. In general, this technique is ideal in cases of breast
tumours close to the skin behind or just above the nipple. In
these cases, it is necessary to resect the skin together with the
tumour. The resected skin with its underlying defect may eas-

ily be filled with the tissue located caudally from the breast
tumour (Figs. . 19.4a, b, . 19.5, and . 19.6). Women with
     

19.6.3 Technical Atlas of Level 1 Techniques
All types of breast defect reconstructions using local breast
tissue without the use of breast reduction techniques or
major nipple transposition belong to level 1 techniques
(. Fig.  19.4a–f ). Typical level 1 techniques include batwing
 
flaps (. Figs. 19.5 and 19.6) and round block and doughnut
 
ptotic as well as non-ptotic and smaller breasts are ideal can-
didates for batwing procedures. The technique has a very low
morbidity as the nipple retains most of its attachments and
vascular supply with very little parenchymal undermining,
so there is little risk of fat necrosis. If the resection volume is
too large, the resultant breast shape may be somewhat flat-
tened (. Fig. 19.7). Larger defects above 20% of breast vol-

techniques (. Fig.  19.7a–f ). Also intra-parenchymal flaps

  ume are not suitable for this technique. Cosmetic outcomes
using dual-layer undermining (between the pectoralis and its are generally very positive [34].

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234 E.E. Sanidas and F. Fitzal

Batwing mastopexy

a b

a c
Cancer e
a c
f
b d
Skin + b d
breast
excision

Nipple

Pre-operative marking Post-operative scar pattern

Grissotti Mastopexy
c
d

Retroareolar d d
cancer
c
Neo-areolar
skin disk a a
c
Skin for de-
epithelialisation b
b

19
Pre-operative marking Post-operative scar pattern

..      Fig. 19.4  Batwing mastopexy. a Preoperative marking. b Post-operative scar pattern. Grisotti mastopexy. c Preoperative marking. d Post-operative
scar pattern. Doughnut mastopexy. e Preoperative marking. f Post-operative scar pattern, Sutures in parenchyma to close defect

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Oncoplastic Breast-Conserving Therapy
235 19
Donut mastopexy
e f

Sutures in
parenchyma
Cancer to close
Breast defect
parenchyma
mobilised
into defect

Nipple

Skin for de-

epithelialization

Pre-operative marking Post-operative scar pattern

..      Fig. 19.4 (continued)

..      Fig. 19.6  Post-operative outcome of a batwing mastopexy for a

tumour located in the 12.00 position

..      Fig. 19.5  Preoperative marking of a batwing mastopexy for a

tumour located in the 12.00 position

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 236 E.E. Sanidas and F. Fitzal
..      Fig. 19.7  Flattening of the
breast mound due to higher-
volume resection with a batwing
mammoplasty
19.6.5 Doughnut Mastopexy
The doughnut technique is based on a circum-areolar inci-
sion and de-epithelialisation of the epidermis around the
nipple-areola complex. The diameter of the de-epithelialised
area may be chosen based on the planned resection volume
and breast size. Breast tumours in any location, even behind
the nipple, may be resected with this technique. It is an
appropriate technique for smaller- to medium-sized breasts
and more peripherally located breast tumours. Morbidity is
low and cosmesis is usually excellent with a periareolar scar
(. Fig. 19.8a–f). The size of the areola may change after sur-
 
gery and may necessitate contralateral adjustment. The
doughnut technique is easy to learn and has a very low mor-
bidity rate.
19.6.6 Round Block Mastopexy
19 A modification of the doughnut technique is the round block
technique. Without de-epithelialisation, the nipple-areola
complex is circumcised completely, and the breast tissue is
separated from the skin above the tumour (. Fig.  19.9a–d)
 
[35]. The round block must not be used for centrally located
tumours. It gives similarly excellent results to the doughnut
technique.
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19.7 Technical Atlas of Level 2 Techniques
In cases of large or ptotic breasts with an estimated resection
volume of more than 25%, level 1 techniques will not achieve
satisfactory results. Thus, therapeutic mammoplasty tech-
niques (ThMP) with nipple-areola complex transfer and
larger scars are necessary to close the defect after lumpec-
tomy. There are a wide range of level 2 oncoplastic techniques.
These may be adapted to deal with tumours in each quadrant,
and there are now well-established protocols for how to deal
with each site as shown in . Fig. 19.3. Examples of when to
use these techniques are given below in a series of vignettes.
For many of these techniques, the nipple is repositioned
with a vascularised pedicle, which may arise either inferiorly,
superomedially, superolaterally, superiorly or even a combi-
nation of several pedicles (e.g. which may be of value in
higher-risk cases such as previous radiotherapy, diabetes,
smoking, previous scarring). The vascular robustness of
these various pedicle origins has been well described by
O’Dey and colleagues [36]. A standard mammoplasty tech-
nique may have to be modified by adjusting the pedicle posi-
tion to avoid a pre-existing scar or the tumour so it is
important that surgeons are familiar with the principles of
pedicle vascularity.
1. Inverted T inferior/central pedicle oncoplastic technique
(suitable for a superiorly sited cancer medial or lateral)
Oncoplastic Breast-Conserving Therapy
237 19

a b

e f

..      Fig. 19.8  Stages of a doughnut mastopexy procedure. a Marking up. b De-epithelialisation. c Resection of tumour. d Mobilisation of breast
parenchyma to fill defect. e Suture of the skin to tighten skin envelope. f Early post-operative result

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 238 E.E. Sanidas and F. Fitzal

a b

c d

..      Fig. 19.9  Stages of a round block technique. a Full circumcision of the areolar and access to the breast parenchyma for tumour resection. b
Parenchymal mobilisation to close the defect. c Skin closure. d Early post-operative result

. Figure 19.10a–f shows a patient with a 2 cm superomedially

  pedicle, the dermis from the lateral as well as the caudal area
sited breast cancer and large ptotic breasts, undergoing a is completely excised, and the skin is lifted from the breast
simultaneous wise pattern therapeutic mammoplasty and parenchyma. The new nipple-areola complex is left as a skin
symmetrisation to the other breast. A typical wise pattern island below the true nipple-areola complex, and after resec-
skin marking was performed preoperatively (. Fig. 19.10a).  tion of the breast cancer with the nipple, the neo-areola is
The pedicle and periareolar skin are then de-epithelialised rotated into the defect. Parenchymal sutures are used to
(. Fig. 19.10c). The superior skin flap is then elevated, and a
  improve defect closure and the skin is closed (. Fig. 19.12c,
 

tumour in any superiorly sited location can be removed and d), and . Fig.  19.12e shows the final result. This technique
 

19 the parenchyma reapposed (. Fig.  19.10d, e). The whole is

 
then closed as a standard wise pattern breast reduction
(. Fig. 19.10f). A description of standard wise pattern mark-
 
ing is given in . Fig. 19.11.
 
2. The vertical Hall Findlay oncoplastic technique with a
medial pedicle (suitable for a central breast cancer)
belongs to the vertical scar group of techniques and may not
be used in large breasts as rates of local skin morbidity such
as necrosis and infection increase with larger breast volumes.
3. Vertical scar technique with a superior pedicle (Lejour)
(suitable for an inferiorly located breast cancer medial or
lateral)

For a centrally located breast cancer, there are several options
such as the batwing, the Grisotti or the modified Hall Findlay
technique [37]. The latter may be used for medium-­sized
breasts with or without ptosis. The nipple-areola complex has
its pedicle from the central and medial part of the breast
This technique may be used in medium-sized breasts with or
without ptosis. It should be used if the breast has to be lifted
up and there is enough tissue to be rotated into the defect.
Otherwise, the doughnut technique would be adequate.
. Fig. 19.13a shows the typical indication. The breast with the

(. Fig.  19.12a, b). After de-epithelialisation of the medial

  cancer is larger and slightly lower than the other side.

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Oncoplastic Breast-Conserving Therapy
239 19

a b

c d

e f

..      Fig. 19.10  Sequence showing an inverted T mammoplasty for a tumour. c De-epithelialisation of the inferior pedicle. d Demonstration
woman with large ptotic breasts and a 2 cm tumour in the superome- of the tumour defect following excision. e Closure of the parenchymal
dial quadrant. a Preoperative marking. b Mammogram showing 2 cm defect. f Late post-operative result

rares1geo@gmail.com
 240 E.E. Sanidas and F. Fitzal

a b

a b n
i e e
i
j k c d

a/b

g k/c
h f
j\h d\f
g

Pre-operative marking Post-operative scar pattern

..      Fig. 19.11  Marking up of a standard inverted T mastopexy

a b c

d e

19

..      Fig. 19.12  Vertical Hall Findlay technique for a centrally located tumour. a Preoperative marking. b De-epithelialisation and tumour excision. c
Breast reconstitution. d Skin closure. e Long-term post-operative result

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Oncoplastic Breast-Conserving Therapy
241 19
..      Fig. 19.13  Vertical scar
a b
mastopexy with superior pedicle
(Lejour). a Preoperative markup. b
De-epithelialisation. c Tumour
resection. d Late post-operative
result

c d

However, the breast is medium sized, and the skin is firm so

..      Table 19.1  Results of voting at the 2013 St. Gallen
there is no need for a large skin resection for mastopexy. International Breast Consensus meeting regarding whether a
After the epidermis has been removed around the nipple, the range of controversial clinical scenarios would be viewed as a
dermis is incised (. Fig. 19.13b, c), and the breast cancer at
  contraindication to breast conservation surgery
the 6 o’clock position may be resected together with the over-
lying skin. After closure, the breast has been lifted upwards, Yes (%) No (%) ? (%)
and the defect is completely closed (. Fig. 19.13d). If there is
 
Extensive microcalcification 20 74 6
a large amount of skin to be resected, this technique can be
combined with an inverted T incision. Multifocality 7 89 4
There are numerous other techniques for details of which Multicentricity 30 65 5
the reader may consult any one of a number of excellent
Close to nipple-areolar complex 0 96 4
books and papers.
Goldhirsch et al. [38]

19.8 Relative Contraindications

for Oncoplastic Surgery
19.8.1 Contraindications
There are oncologic and cosmetic contraindications for
oncoplastic surgery. Oncologic contraindications are similar
to those for breast conservation and should follow interna-
tional guidelines such as the St. Gallen guidelines [38].
Whilst it is considered appropriate for multifocal and multi-
centric cancer to be treated with conservation surgery pro-
vided clear margins are possible (. Table 19.1), the evidence
 
for conservation surgery for multicentric cancers is still rela-
tively weak.
There is emerging evidence that BCT in multifocal dis-
ease is oncologically safe [39], but it may result in a slightly
inferior outcome compared with BCT in unifocal breast can-
cer, and patients in the MF group may have higher 10-year
LRR (0.6% vs. 6.1%, p < 0.001) [8]. Other authors share the
same view, stating that based on historical data, it is expected
the local recurrence rates will be somewhat higher but that
there will be little or no impact on survival [40]. However,
attention is drawn to the hypothesis that MF/MC tumours
may have a worse biological behaviour and that the presence
of multiple foci should be considered in planning adjuvant
treatments [41]. It seems that there is enough evidence to
justify a randomised trial [42].

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 242 E.E. Sanidas and F. Fitzal
..      Table 19.2  Table showing rates of morbidity following
standard breast conservation surgery (BCT), types 1 and 2
oncoplastic surgery (iTOP 1/2) and breast reconstructive surgery
(iTOP 3) (F Fitzal, unpublished data)
Seroma Bleeding Necrosis Infection
BCT (N = 71) 9(12%) 2(3%) 0 1(1.5%)
iTOP 1 or 2 6(16%) 4(11%) 4(11%) 4(11%)
(N = 37)
iTOP 3 (N = 27) 1(4%) 0 4(15%) 1(4%)
BCT breast conservation therapy, iTOP 1 or 2 oncoplastic type 1
or 2, iTOP 3 mastectomy and immediate reconstruction.
Prospective non-randomised observational study (unpublished
interim analysis)
If conservation is unlikely to result in a good cosmetic
outcome, even with the use of an oncoplastic procedure, a
recommendation for neoadjuvant therapy or immediate
mastectomy, based on the tumour biology, may be more
appropriate. Usually multicentric invasive lobular disease is
not ideal for an oncoplastic procedure due to the higher risk
of margin involvement due to the diffuse spreading nature of
this subtype. Patients with recurrent cancer following BCS
and adjuvant whole breast radiotherapy are at high risk for
complications from oncoplastic surgery due to a high risk of
fat necrosis and vascular insufficiency of the pedicle and
wound edges due to the previous radiotherapy.
There are some relative contraindications such as comor-
bidities like diabetes, heavy smoking and obesity. Patients
have to be aware that they have an increased risk of local
morbidity after oncoplastic surgery. A recent prospective
observational study of oncoplastic surgery techniques (iTOP
NCT01396993) investigated 30-day morbidity rates after sur-
gery (. Table  19.2). This has demonstrated that bleeding,
necrosis and infections are increased up to tenfold after
oncoplastic breast-conserving surgery in some cases.
19.9 Cosmetic Outcomes
The cosmetic appearance of the breast after BCT depends on
19 the relative proportion of breast volume excised and on the
location of the tumour within the breast [43]. However, assess-
ing cosmetic outcomes is complex. Initial attempts to quantify
cosmesis were entirely subjective, simply using phrases such as
«excellent» [44]. The subjective opinion of the surgeon was the
norm in early series [14] with little consideration being given
to the opinion of the patient [45]. However, it was soon realised
that the opinion of the patient and the judgement of indepen-
dent clinicians might be of more value and objectivity and be
less biased. The role of psychological factors from a patient’s
perspective was also recognised to be important.
There is no better example on the above interference than
the findings of Sackey and colleagues [46] who report that
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women with mastectomy and immediate reconstruction for
DCIS reported better physical functioning and less bodily
pain not only compared to women who had just undergone
wide local excision with or without radiotherapy but also
from age-adjusted healthy women. The authors explained
this by the so-called response shift, which is an adaptation
process whereby patients with a severe disease accommodate
their illness. During this process, internal values are chang-
ing, and conceptualisation of quality of life alters. To make
cosmetic assessment even more complex, Nahabedian and
colleagues [47], in an editorial, add the «age» parameter,
assuming that breast reconstruction is an important consid-
eration for most, if not all, patients less than or equal to
30 years of age and that it is an important aspect of their psy-
chological well-being and body image. However, it is difficult
for someone to understand why the authors’ assumption
does not equally apply to women older than 30 years.
All of the above give us insight into the difficulties of sci-
entifically addressing questions on the aesthetic result of an
operation and its advantages or disadvantage over other
operations [48]. With the introduction of objective analysis
tools, early data (e.g. using the Breast Analysing Tool (BAT®))
is that oncoplastic surgery seems to improve symmetry [49].
Other attempts which include a semiautomated breast cancer
conservative treatment.cosmetic results (BCCT.core) soft-
ware have been presented [50, 51] which agreed to the
patients’ evaluation by BCTOS (Breast Cancer Treatment
Outcomes Scale) in a range between 35% and 44%.
Interestingly the patients judged their aesthetic outcome
more positively than the software. The authors concluded
that objective measurements and patients’ perspectives eval-
uate similar dimensions differently and that it seems neces-
sary to apply both approaches in order to gain a more
comprehensive knowledge of breast aesthetics. No matter
how objectively doctors measure breast symmetry, it seems
that it is not a major factor for a patient’s quality of life and
breast ­self-­esteem. Patients consider the oncological outcome
of the disease as of primary importance [52]. That is probably
why Metcalfe and colleagues [53] found no differences in
psychosocial functioning at 1 year between women who had
undergone mastectomy alone and those undergoing mastec-
tomy and immediate or delayed reconstruction. They con-
clude that women need further support after breast cancer
diagnosis even if they have breast reconstruction.
In general, patient’s opinion and satisfaction are of most
importance and address not only the shape and feeling of the
breast (both alone and in comparison to the contralateral
breast) but also its influence on the quality of life of the
patient.
Finally, it is important to be aware that the aesthetic result
may change with time, and whilst the majority of women feel
they have acceptable results at 6  months post-operatively
[33], the impact of scarring contracture and radiotherapy
may lead to suboptimal results at 5 or even 10 years of follow-
­up [47], and these long-term evaluations should be reported
alongside oncological outcomes [33].
Oncoplastic Breast-Conserving Therapy
In summary, to date, no prospective controlled trial has
demonstrated that oncoplastic surgery may improve objective
breast cosmesis and thus long-term quality of life. The ongo-
ing iTOP trial (. Table 19.2) institute might be able to shed
some light onto this issue. Early data will be available shortly.
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 245 20

Fat Transfer in Oncoplastic and

Reconstructive Breast Surgery
Riccardo Bonomi, I. Fabio Rapisarda, Gilles Toussoun, and Loraine Kalra

20.1 Introduction – 246

20.2 The History of Autologous Fat Grafting – 246

20.3 Indications for Fat Grafting – 246

20.4 Specific Indications for Lipomodelling – 247

20.5 Complications of Fat Grafting – 249

20.5.1 Complications – 249
20.5.2 Follow-Up – 250

20.6 Technique – 250

20.7 Informed Consent – 250

20.8 Preoperative Assessment – 250

20.8.1 Specific Considerations – 251

20.9 Techniques of Fat Grafting – 251

20.9.1 Injection Technique – 251
20.9.2 Postoperative Management – 252

20.10 Conclusion – 252

References – 252

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_20

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 246 R. Bonomi et al.
20.1 Introduction
It has long been realized that the cosmetic outcome of treat-
ment for breast cancer is of great importance to many women,
and the increasing popularity of breast conservation surgery
and reconstructive surgery after mastectomy is testimony to
this. The range of surgical procedures to maintain cosmesis
has expanded rapidly in the past few decades. Lipomodelling
has a role both as a potential primary means of reconstruc-
tion and as an adjunct to other techniques. It also has an
important role in the correction of defects caused by breast
conservation surgery and radiotherapy and even in the cor-
rection of congenital deformities of the breast and chest wall.
There are numerous techniques available depending on
the local availability of expertise and equipment and depend-
ing on the volume of fat required from small volume tech-
niques transferring decilitres of fat such as the Colman
technique to high-volume techniques capable of transferring
many hundreds of millilitres of fat. Harvested fat may even
be safely frozen if required for later use, with reasonable lev-
els of tissue viability. These techniques are reviewed in this
chapter along with their advantages and disadvantages. The
techniques are not without complications, which may be
severe and include fat necrosis, infection and donor site mor-
bidity such as chronic pain, oedema and scarring. However,
there is now a considerable body of evidence to suggest that
fat grafting is not linked to adverse oncological outcomes,
even with long-term follow-up. All of these issues will be
reviewed in this chapter.
20.2 The History of Autologous Fat Grafting
Gustav Neuber in 1893 was the first to use autologous free fat
taken from the arm to correct a facial soft tissue depression
[1]. In breast surgery it was Vincenz Czerny who in 1893,
used a lipoma from the flank to fill the defect created in the
breast due to a fibroadenoma resection [2]. The fat auto graft
was successful and persisted 1 year after the surgery, with a
good cosmetic result. In 1912, Eugene Hollander described
with varying degrees of success a technique of using a «broth»
composed of human and ram fat to correct facial depressions
and adherent post-mastectomy breast scars [3].
In 1919 and 1924, Erich Lexer in his book titled «Die
freien Transplantationen» described the usefulness of har-
vesting fat from the thigh and reported long-term fat survival
20 for a variety of procedures, ranging from aesthetic facial reju-
venation to surgery for Dupuytren’s contracture [4]. In 1931,
Lexer described the use of an axillary fat graft to reconstruct
a mastectomy defect, but due to lack of nourishment from
the recipient bed, he reported significant reabsorption of the
graft.
Bircoll triggered a controversy over the safety of fat trans-
fer when he presented a case, initially in Bangkok in 1984 and
subsequently to the California Society of Plastic Surgeons in
1985, of using fat transfer for breast augmentation in a 20-year-
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old patient who had initially benefited from fat transfer for
correction of a deformity due to a dog bite and then subse-
quently requested bilateral breast augmentation using the
same technique [5].
There was a complete cessation of research on fat transfer
techniques following the ­committee on new procedures deci-
sion in 1987 that breast augmentation using autologous fat
grafting should be banned on the grounds that non-viable fat
grafts underwent necrosis and resulted in microcalcifications
that could compromise radiological surveillance of breast
cancer patients [6]. Ironically, the same journal, in the same
year, published a retrospective study that reported on calcifi-
cations being found in 50% of all mammograms more than
2 years from the time of mastopexy reduction [7]. The same
publication concluded that “confident differentiation between
benign postoperative calcifications and carcinoma” could be
made in most cases. In the modern era a competent radiolo-
gist can usually distinguish between benign, indeterminate
and malignant calcification [8–10]. Sydney Coleman in 1994
reintroduced the technique with a set protocol for harvesting
fat, with specially designed cannulae, and a process of cen-
trifugation to separate fat cells from the other components of
the lipoaspirate along with a specific technique of injection
for the placement of grafts at the recipient site [11, 12]. Since
then the technique has gained widespread popularity, and the
range of indications has expanded massively.
Despite concerns raised that adipose-derived stem cells
might contribute to an increased risk of local recurrence in
fat-grafted patients based on in  vitro data beautifully
reviewed by Gennari and colleagues [13], this concern has
never been demonstrated in clinical studies with several large
meta-analyses and case control studies not showing an
increased risk of local recurrences [14, 15].
20.3 Indications for Fat Grafting
Current evidence and guidelines [16, 17] support the use of
lipomodelling for the following indications:
55 Following breast-conserving surgery for correction of
defects and asymmetry [8, 12, 17–19].
55 To improve the pliability and elasticity of scar tissue [20].
55 In irradiated tissue to stimulate neovascularization [21, 22].
55 Correction of contour or volume defects after breast
reduction or mastopexy [23].
55 Following implant-based surgery to improve soft tissue
coverage, disguise capsular contracture and rippling and
create an aesthetically better cleavage and slope [24, 25].
55 Following LD flap reconstructions to replace implants if
there is an unsatisfactory cosmetic result in the long
term [8, 18, 19].
55 For aesthetic enhancement, alone or after removal of
implants [5, 8, 26, 27].
55 In autologous whole breast reconstruction for augmen-
tation of volume and refinement including in the
correction of congenital deformities [18, 27–29].
Fat Transfer in Oncoplastic and Reconstructive Breast Surgery
20.4  pecific Indications for
S The combination of an autologous LD flap and lipomodel-
Lipomodelling
1. Lipomodelling of Contour Defects After Breast Conserva-
tion Surgery
One of the most frequent uses of fat grafting is the correc-
tion of contour deformities after breast conservation surgery.
Scar release may be performed using a cutting cannula before
the lipoaspirate is injected to fill out the defect. Outcomes are
generally good with low rates of complications, no evidence
of oncological risks in most series [30, 31] and good patient
satisfaction [32] (. Fig. 20.1).
2. Lipomodelling of the Breast After Extended Latissimus
Dorsi Reconstruction
247 20
ling to augment the volume obviating the need for an implant
is attractive for many patients, giving good consistency and a
more natural and durable breast shape and reducing the inci-
dence of implant-related complications or recurrences in the
longer term [18, 19, 28, 33]. The latissimus dorsi flap is an
ideal recipient site for fat grafting because of its excellent vas-
cular network that can support large volumes of injected fat
[34] with up to 500 ml of purified fat in a single sitting being
possible. In a large single institution series, it was possible to
achieve symmetry with the contralateral breast in 70% of
patients. In those 30% where volume enhancement with fat
grafting was insufficient, symmetry was achieved through
contralateral mastopexy/reduction or insertion of a prosthe-
sis on the reconstructed side [18, 19, 28] (. Fig. 20.2).

a b

..      Fig. 20.1  a Patient following right wide local excision and retraction and contour deformity. b Patient following lipomodelling for
centralization of the nipple areola complex for invasive ductal symmetrization (result at 1 year after injection of 200 cc of purified fat)
carcinoma and radiotherapy. Evident lack of volume with scar

a b

..      Fig. 20.2  a Patient following right skin-sparing and left nipple- following lipomodelling for symmetrisation (6 months after lipomodel-
sparing mastectomy and immediate reconstruction with extended ling: 150 of purified fat injected in the right breast, 300 cc in the left
autologous LD flap. Evident asymmetry with left breast smaller than breast)
the contralateral one and with contour irregularities. b Patient

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 248 R. Bonomi et al.
3. Lipomodelling in Conjunction with Implant-based
Reconstruction
Breast reconstruction with implants is associated with a
number of potential problems. First, a defect in the cleavage
area resulting in a visible step in the upper pole of the
reconstructed breast and asymmetry of the cleavage area
compared with the contralateral side. A second defect is
frequently seen at the medial aspect of the breast character-
ized by a lack of filling and an excessively wide intermam-
mary space. Finally there can be a lack of filling on the
lateral aspect of the reconstructed breast immediately
beneath the anterior axillary line. In addition there may be
irregularities due to variable flap thickness and areas where
implant coverage is thinned resulting in visible and palpa-
ble wrinkling. In the delayed reconstruction setting, espe-
cially when chest wall radiotherapy has been administered,
the remaining skin may be of poor quality, scarred, lacking
in elasticity and often with a thin layer of subcutaneous fat.
Preemptive fat grafting may help to improve the quality of
the flaps before or after definitive surgery. Fat transfer can
be utilized to overcome these defects [24–26, 28, 35, 36]. In
the upper medial pole of the cleavage area, fat is transferred
mainly into the pectoralis major muscle. In the medial
aspect of the breast (the intermammary area), fat should be
transferred into the pectoralis muscle and between the skin
and the periprosthetic capsule. The lateral defect can also be
treated with an injection between the skin and the peripros-
thetic capsule. In these last two cases, an implant exchange
is strongly recommended as inadvertent implant puncture
is possible, especially in the presence of thin flaps. Smaller
amounts of fat are generally required in these circumstances
compared with autologous reconstructions, commonly
involving volumes ranging from 50 to 150 cm3 of purified
fat (. Fig. 20.3).
 
Tissue quality must be carefully assessed as it is often
inferior to autologous reconstructions. The recipient sites
should not be saturated to ensure the best possible graft sur-
vival. The aesthetic results are usually very good and improve
a b
20
..      Fig. 20.3  a Patient following bilateral nipple-sparing, skin-­
reducing and risk-reducing mastectomy and reconstruction with
expander implants. Lack of volume is visible in the cleavage bilaterally.
rares1geo@gmail.com
the cosmetic outcome compared to use of an implant alone.
In addition, pericapsular fat injection may reduce the capsu-
lar contracture rate, which has been shown in animal models
[37], but further clinical studies are needed to support this
use.
4. Breast Reconstruction with Lipomodelling Alone
The idea of reconstructing an entire breast mound with
exclusive use of fat transfer [38, 39] is surgically challenging.
This technique is only applicable to a select number of cases,
and specifically three main conditions must be met. The
patient’s contralateral breast should be of small to moderate
volume. The chest wall tissues at the mastectomy site have to
be of good quality (in terms of thickness of the subcutis and
muscle layers and their suppleness), and, finally, the patient
must possess donor sites with plentiful excess of fat to allow
for multiple harvest and transfer procedures. If all these cri-
teria are fulfilled, then the patient can be considered for this
technique and should be informed of the multiple-stage
nature of this reconstruction and the fact that the breast
mound may not be fully restored for some considerable time.
Based on these limitations, few women elect to have this type
of reconstruction when it is offered [39] (. Fig. 20.4).
The principles of fat harvesting, fat processing by cen-
trifugation and the injection technique are similar to those
described for general lipomodelling.
There are two main scenarios for an exclusive lipomodel-
ling reconstruction:
The first case is a delayed breast reconstruction where part
of the upper abdominal skin is used to perform an
abdominal advancement flap to increase the volume of
the recipient site and restore the breast footprint (the
inframammary and lateral folds in particular) (see
7 Chaps. 31 and 30, for more details).
A second, less common, scenario is the exclusive use of
lipomodelling in immediate breast reconstruction
after skin-­sparing mastectomy where the skin enve-
lope is preserved, thereby improving the shape of the
b Patient following bilateral lipomodelling (2 sessions of lipomodelling
required with a total of 380 cc of purified fat injected in the cleavage
area and around the implants each side)
Fat Transfer in Oncoplastic and Reconstructive Breast Surgery
a b
..      Fig. 20.4  a Patient awaiting right breast reconstruction exclusively
with lipomodelling. b Patient following right breast reconstruction
exclusively with lipomodelling (four sessions of lipomodelling required,
reconstructed breast. In all cases fat is transferred into
the pectoralis major muscle and the subcutis of the
cleavage area. The skin envelope or the abdominal
advancement flap is quilted onto the pectoralis muscle
to accelerate tissue adhesion. Subsequent lipomodel-
ling sessions are planned to restore the full breast
mound observing a minimum interval of 4 months
between sessions. The mean number of surgical
procedures required is three (range 1–5) and is usually
carried out in a day case setting. It is crucial to
accurately assess the potential volume of fat available
and properly manage the donor site. Overestimation
of available fat donor sites could compromise the final
reconstructed breast volume and prompt conversion
from autologous to implant reconstruction.
Retrospective analysis suggests that the transferred fat vol-
ume needs to be about twice the amount necessary when
compared with combined reconstruction with a latissimus
dorsi flap for obtaining the same degree of breast volume
enhancement. The possible explanation for this significant
difference is the lack of a mechanical and vascular scaffold,
which is conferred by the latissimus dorsi flap [39].
20.5 Complications of Fat Grafting
20.5.1 Complications
Common donor and recipient site complications include
pain bruising, haematoma and swelling, excessive loss of vol-
ume, infection, fat necrosis, calcifications and oil cyst forma-
tion [8, 25–28, 40].
rares1geo@gmail.com
249 20
with a total of 756 cc of purified fat injected) and left mastopexy
reduction for symmetrisation
Pain
Significant pain relief can be achieved in the first 10 h by using
postoperative infiltration of local anaesthetic. In the first post-
operative day pain can be managed with analgesics like
paracetamol and dihydrocodeine. Acute pain may last for about
48 h, and then only hypersensitivity or a dull ache can persist for
a period of 1–3 months. In the longer term, a small percentage
of patients may experience longer-term or even chronic pain,
and patients must be warned about this at the time of consent.
Bruising and Oedema
Bruising at the donor site may take 2–3  weeks to resolve,
while oedematous changes usually takes a month to resolve
but may persist for longer if harvesting was overly aggressive
or previous scarring and lymphatic drainage was compro-
mised or infection develops. This may benefit from compres-
sion garments which provide both symptomatic support and
reduce oedema, bruising and aid contouring [16].
Volume loss at the recipient site is an important issue.
Injectate volume generally decreases by about 30%, although
this rate can be as high as 40–50% depending on tissue qual-
ity at the recipient site, the quality of the injectate (generally
better quality fat is harvested from those who are not very
obese as the adipocytes are less fragile) and the volume of
liquid in the injectate (e.g. poor centrifugation). The rate of
reabsorption is lower for subsequent fat transfers as the qual-
ity and thickness of the tissues improve with every procedure
and stabilizes over a period of 3–4 months.
Other Complications
Rarer complications include hypertrophic scarring, altered
sensations, under- or overcorrection of the defect and contour
irregularities; very rarely damage to underlying ­structures,
 250 R. Bonomi et al.
e.g. implants, pneumothorax, peritonitis and fat embolism,
have all been reported infrequently [8, 24, 26, 28].
As a guide, in a large single centre series of 950 lipomod-
elling procedures (all eligible patients being included) the
following complications occurred [8, 19, 29, 39]:
55 A 0.7% rate of wound infection, with most cases
responding to standard oral antibiotic treatment.
55 A 3% rate of fat necrosis, presenting clinically either as a
palpable lump or an area of firmness, which slowly
resolved. It should be noted that in some cases, ultra-
sound examination of fat necrosis can mimic cancer. If
any doubt exists and particularly if any increase in size
of the necrotic area is noted, a core biopsy should be
performed to exclude tumour recurrence.
55 A 0.1% rate of intraoperative pneumothorax secondary
to perforation of the pleura by the transfer cannulas.
Multilayer parallel injections, in a tangential direction
(avoiding perpendicular trajectories) will prevent such a
rare complication.
There were no documented cases of fat embolism or perfora-
tion of any intra-abdominal viscus.
According to guidelines overall complication rates that
are acceptable are an infection rate of 0.6–1.1%, fat necrosis
3–15% and calcifications 4.9% [16, 17, 40].
20.5.2 Follow-Up
Surgical follow-up. An assessment should be planned for
3  months to evaluate the recipient and donor sites and for
planning further staged procedures. Evaluation of midterm
outcomes can be made at an interval of 1 year.
Radiological and oncological follow-up should be accord-
ing to local protocols. However, lipofilling may cause changes
on breast imaging. Mammography is best performed before
the actual procedure and deferred for at least 6 months post-
operatively. The clinician requesting the mammogram must
provide adequate information regarding the procedure and
site where lipomodelling has been performed so accurate
interpretation of imaging changes is possible. Usually an
interval of 12–18 months is required before microcalcifica-
tions associated with lipofilling become apparent on mam-
mography. An experienced radiologist aware of a past history
of lipofilling can usually easily discriminate between the
typical resulting benign calcifications and new suspicious
20 microcalcification. Biopsy may however be needed in some
cases and patients need to be made aware that this procedure
has the potential to subject them to a need for extra interven-
tional procedures and biopsies [9, 10, 41].
20.6 Technique
Joint guidelines developed by the Association of Breast
Surgery, the British Association of Plastic, Reconstructive and
Aesthetic Surgeons and the British Association of Aesthetic
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Plastic Surgery emphasize the need for detailed and informed
assessment of patients suitability and individual risk factors,
to identify those who will benefit from the technique and to
minimize the risk of adverse outcomes [16].
It is important to ensure that local governance processes
are in place and adhered to when introducing lipomodelling
as a new procedure in an institution. Patients should be given
preoperative, operative and postoperative information in
detail and explanation about short-and long-term complica-
tions. It is important that surgeons have received appropriate
training in the technique.
20.7 Informed Consent
Informed consent should be in the form of an ongoing agree-
ment with the patient about the treatment and requires a full
and detailed explanation of all risks and benefits.
Although lipomodelling is now an established procedure
and performed frequently, patients should be made aware
that they are being offered a procedure with limited knowl-
edge of longer-term outcomes.
Emphasis should be placed on patient education includ-
ing associated risks and potential complications, and given
that multiple factors may affect the final appearance of the
breast, both the surgeon and patient should have realistic
expectations from the onset. Patients should be asked to
maintain their weight and regular caloric intake before and
after the procedure as the transferred fat retains «memory» of
its original anatomical location and therefore is susceptible to
any subsequent weight loss or gain, which can affect the
results of the lipomodelling procedure. Donor site complica-
tions such as bruising, indentation and tiny scars should be
explained to the patient. Recipient site complications like
immediate bruising, fat necrosis, reabsorption rate and the
potential need for multiple procedures should be discussed
from the outset. Finally delayed complications like calcifica-
tion oil cysts, and chronic pain which may be seen on mam-
mograms should be mentioned [10, 42].
20.8 Preoperative Assessment
Patient selection should take into consideration the diagnosis
of breast cancer and so should include all the principles out-
lined in oncoplastic breast surgery – A guide to good practice
[17]. When planning the procedure, multidisciplinary team
discussion and review of clinical findings and imaging should
be up to date, and recurrent cancer should be excluded. A
general assessment should be conducted determining fitness
for surgery. The procedure may be performed under general
local anaesthesia with or without sedation. Infection and
bleeding may also be increased if there is a history of use of
medications such as aspirin, non-steroidal anti-­inflammatory
drugs, cytotoxic and immunosuppressant drugs recently.
Smoking is a relative contraindication, while bleeding disor-
ders and vasospastic conditions may increase the risk of post-
Fat Transfer in Oncoplastic and Reconstructive Breast Surgery
operative complications. Suitability of the patient in terms of
donor and recipient site should be assessed and the presence
of adequate donor sites ascertained dependant on the quan-
tity of fat transfer requirement. The clinical examination
should be supplemented with standard photographs to estab-
lish the best donor site. The most common sites for harvesting
fat are the lower abdomen and the loin areas, followed by the
regions on the outer and inner thighs and knees. While deter-
mining the amount of fat required, a predicted loss of 30%
should be considered due to centrifugation. Clinical examina-
tion should also document the presence of any abdominal
hernia or pre-existing surgical scars in order to avoid damage
to the intra-abdominal structures at the time of harvesting.
20.8.1 Specific Considerations
Diet. Patients must be advised not to actively diet around the
time of fat grafting [16].
Baseline imaging. This should include a follow-up mam-
mogram before commencing lipomodelling, although in the
absence of clinical concern, the radiological assessment of
the breast is not advocated by the Royal College of
Radiologists Breast Group [43].
Time interval for multiple procedures. It is important to
delay the fat grafting procedure for at least 4–6 months after
the first stage of surgery/reconstruction in order to avoid the
presence of any cavity or tissue undermining, as injecting fat
into dead spaces leads to fat necrosis and an unpredictable
final outcome [8, 19, 39].
Radiotherapy. When planning lipomodelling after radio-
therapy, waiting for the acute reaction to resolve is ideal,
some even recommend waiting for 1  year as a safe time
period [25, 44].
Type of anaesthesia. When a relatively large volume of
harvested fat tissue is required, the operation is performed
under general anaesthesia. Local anaesthesia may be used if
the amount of fat required is minimal (e.g. for correction of
small residual defects) [8, 28].
Technical issues. Fat grafting though appearing to be an
apparently simple procedure is highly dependent on meticu-
lous surgical technique, and a successful outcome is depen-
dent on the team having acquired the relevant knowledge,
training and experience, about the technique, instruments
and equipment.
20.9 Techniques of Fat Grafting
There are a number of techniques in clinical use for harvest-
ing and preparing fat ranging from small to higher volume
techniques. A detailed description of the various techniques
is not within the scope of this chapter (. Fig.  20.5) Which
 
ever technique is used the principle remains the same and is
depicted in . Fig. 20.5.
 
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251 20
..      Fig. 20.5  Luer lock syringes. The first syringe on the right without
the plunger contains the fat prior to centrifuging, the syringe in the
middle, after centrifuging, contains the fat separated in three layers
(top layer oil, middle layer transplantable fat, bottom layer blood and
Hartman solution) and the syringe with the plunger contains 10 ml of
purified fat ready for the graft
20.9.1 Injection Technique
Regardless of the method used to harvest fat, the injection
technique is critical to maximize fat survival. It is important
to avoid depositing particles larger than 3 mm. All tissue lay-
ers should be infiltrated with fat grafts starting from the
deepest one on the pectoralis major muscle and subsequently
infiltrating all the tissues up to the subcutaneous layer [45].
Blunt tipped cannulas (2 mm in diameter and 9 cm in length)
are usually used to perform this task, but if scarring with
resultant fibrosis is encountered within the subcutaneous tis-
sues, a cutting or sharp tip reinjection cannula can be used
with caution. It is important to avoid any inadvertent tissue
undermining with this cannula as fat would otherwise not
take in such areas. For success, the injections should follow a
three-dimensional network of microtunnels crossing each
other into the reconstructed breast. Ideally, no more than
1 ml of fat should be transferred during each pass when pull-
ing out the cannula from the microtunnels.
Once the recipient site is saturated, it is pointless to
attempt transfer of additional volume, as this will lead to for-
mation of «blobs» of fat that predispose to fat necrosis. A 30%
resorption rate is considered normal and should be antici-
pated intraoperatively with the reconstructed breast being
made larger than the contralateral side [34]. The final volume
will be attained at 3–4  months postoperatively and should
remain stable provided the patient does not undergo signifi-
cant weight loss. If the size of the contralateral breast remains
disparate, a complementary lipomodelling procedure can be
performed 4–6 months later.
There are a number of alternative commercially available
systems which contain satisfactory instrumentation for infil-
tration, harvesting and centrifuging and are equally effective
such as «jet» infiltration systems, lipodialysis systems using
 252 R. Bonomi et al.
semipermeable membranes or filters in conjunction with low
level suction. All these systems can be easily adapted for this
procedure with adequate training.
20.9.2 Postoperative Management
Infection, necrosis and haematoma should be excluded with
an early review. Immediate treatment should be started if
there are any signs of infection, and all attempts must be made
to identify early onset of sepsis. Failure of graft take may result
in fat necrosis and is usually due to injection of large volumes
of fat into poorly vascularised tissue or excessive deposit in a
single area [8, 12]. Fat necrosis can result in masses that are
difficult to differentiate form cancer and may then result in an
increasing need for interventional procedures.
20.10 Conclusion
The technique of autologous fat transfer by injection known
as lipomodelling constitutes a major advance in plastic,
reconstructive and aesthetic surgery of the breast.
It is an ideal complementary procedure for all types of
autologous breast reconstructions, which are characterized
by the presence of a robust stromal and vascular scaffold for
adipocyte grafting. Lipomodelling can also be of value in
implant reconstruction where it permits correction of sig-
nificant residual defects with almost negligible morbidity.
Use in the post-breast conservation setting to help restore
volume and fill out defects is also of value.
The capacity to restore a full breast mound exclusively
using fat injections is evidence of the efficiency, safety and
flexibility of fat transfer techniques. Several other applica-
tions of fat grafting are influencing routine practices in breast
reconstruction. Congenital breast malformations such as
Poland’s syndrome and tuberous breast deformity can benefit
from these techniques, which gives an excellent quality of
reconstruction with minimal morbidity and negligible scar-
ring. Unsightly cases of pectus excavatum can also be treated
with lipomodelling when sufficient donor sites are available.
Finally, fat transfer techniques represent a new alternative
method for correction of breast asymmetry and hypotroph-
ric conditions.
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32. Groen JW, Negenborn VL, Twisk JW, Ket JC, Mullender MG, Smit
JM.  Autologous fat grafting in cosmetic breast augmentation: a
systematic review on radiological safety, complications, volume
retention, and patient/surgeon satisfaction. Aesthet Surg J.
2016;36(9):993–1007.
33. Masia J, Bordoni D, Pons G, Liuzza C, Castagnetti F, Falco
G. Oncological safety of breast cancer patients undergoing free-flap
reconstruction and lipofilling. Eur J Surg Oncol. 2015;41(5):612–6.
34. Ho Quoc C, Taupin T, Guerin N, Delay E. Volumetric evaluation of
fat resorption after breast lipofilling. Ann Chir Plast Esthet.
2015;60(6):495–9.
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35. Delay E, Delpierre J, Sinna R, Chekaroua K. How to improve breast
implant reconstructions? Ann Chir Plast Esthet. 2005;50(5):
582–94.
36. Auclair E, Blondeel P, Del Vecchio DA. Composite breast augmen-
tation: soft-tissue planning using implants and fat. Plast Reconstr
Surg. 2013;132(3):558–68.
37. Roca GB, Graf R, da Silva FR, Salles G Jr, Francisco JC, Noronha L,
et al. Autologous fat grafting for treatment of breast implant cap-
sular contracture: a study in pigs. Aesthet Surg J. 2014;34(5):
769–75.
38.
Babovic S.  Complete breast reconstruction with autologous fat
graft - a case report. J Plast Reconstr Aesthet Surg. 2010;63(7):e561–3.
39. Delaporte T, Delay E, Toussoun G, Delbaere M, Sinna R. Breast vol-
ume reconstruction by lipomodeling technique: about 15 con-
secutive cases. Ann Chir Plast Esthet. 2009;54(4):303–16.
40. Gutowski KA, Force AFGT.  Current applications and safety of
autologous fat grafts: a report of the ASPS fat graft task force.
Plast Reconstr Surg. 2009;124(1):272–80.
41. Chan CW, McCulley SJ, Macmillan RD.  Autologous fat transfer--a
review of the literature with a focus on breast cancer surgery. J
Plast Reconstr Aesthet Surg. 2008;61(12):1438–48.
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transfer to the breast compared with changes after breast reduc-
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cal radiology. 2012.
44. Rigotti G, Marchi A, Galie M, Baroni G, Benati D, Krampera M, et al.
Clinical treatment of radiotherapy tissue damage by lipoaspirate
transplant: a healing process mediated by adipose-derived adult
stem cells. Plast Reconstr Surg. 2007;119(5):1409–22. discussion
23-4
45. Ersek RA, Chang P, Salisbury MA. Lipo layering of autologous fat:
an improved technique with promising results. Plast Reconstr
Surg. 1998;101(3):820–6.
 255 21

Breast Surgery after Primary

Systemic Treatment
Thorsten Kuehn

21.1 Introduction – 256

21.2 Therapeutic Implications of Breast Surgery

After PST (Current Status) – 256

21.3 Diagnostic Implications of Breast Surgery After PST – 256

21.4 Neoadjuvant Chemotherapy and Breast Surgery

in Suspected BRCA Carriers – 256

21.5 General Remarks: Interdisciplinary Cooperation – 256

21.6 Pre- and Post-PST Evaluation of the Tumour – 256

21.7 Breast Surgery After PST – 257

21.8 Pathologic Evaluation – 260

21.9 Timing of Surgery and Radiotherapy – 260

21.10 Recent Development of Breast Surgery After PST – 260

21.11 Complications for Breast Surgery After NACT – 260

21.12 Future Perspectives – 260

21.13 Conclusion – 260

References – 261

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_21

rares1geo@gmail.com
 256 T. Kuehn
21.1 Introduction
Primary systemic treatment (PST), most often applied as pri-
mary (neoadjuvant) chemotherapy (NACT), has primarily
been introduced to allow surgery in  locally advanced and
inoperable breast cancer patients. Today PST is an estab-
lished treatment strategy in early breast cancer with steadily
raising application. Up to 20% of patients are treated with
PST today [1]. The reason for the increasing role of PST is
twofold: Primarily systemic treatment can reduce the extent
of surgery and increase the rate of breast-conserving surgery
(BCS) [2]. In addition, tumour response is an important
prognostic factor and a surrogate marker for overall survival
at least for some intrinsic subtypes of breast cancer. Surgery
following PST is therefore a diagnostic as well as a therapeu-
tic procedure. Furthermore it may improve surgical decision
making in patients with suspected BRCA mutation carriage
where delaying definitive surgery during PST permits time
for gene testing to occur.
21.2  herapeutic Implications of Breast
T gical decision making in patients with suspected hereditary
Surgery After PST (Current Status)
Randomized trials have shown equivalency between adjuvant
and neoadjuvant systemic treatment in terms of disease-free
and overall survival [2, 3]. In the NSABP-B 18 trial, a signifi-
cantly higher rate of BCT was achieved for patients who
underwent PST without jeopardizing disease-free survival
(DFS) or overall survival at a follow-up of 15  years [2].
Downstaging of axillary lymph node status can be achieved
in more than 20% of patients according to early randomized
trials [4] and may spare these women from full axillary dis-
section (AD) (see 7 Chap. 25). Today even higher rates of
axillary downstaging are expected [5]. In summary, PST can
reduce the extent of surgery and improve quality of life due to
higher rates of breast- and axilla-conserving surgeries.
21.3  iagnostic Implications of Breast
D
Surgery After PST
Clinical response rates are achieved in up to 80% of patients
treated with NACT [6, 7]. Histopathologic complete response
(pCR) is defined as the absence of any residual cancer on
evaluation of the breast specimen and all sampled ipsilateral
lymph nodes following completion of neoadjuvant systemic
21 treatment [8]. Pathological CR is associated with improved
disease-free survival and overall survival in some intrinsic
subtypes of breast cancer [9]. Therefore pCR emerges as a new
prognostic surrogate marker with a high potential to tailor
future locoregional and systemic treatment decisions. The US
Food and Drug Administration (FDA) recently recom-
mended pCR as an endpoint for accelerated approval of new
drugs in the neoadjuvant setting [10]. NACT is therefore
increasingly used in the context of clinical trials to optimize
chemotherapy combinations and integrate targeted therapies.
rares1geo@gmail.com
Tumour biology is highly indicative of the response to
PST. In triple negative cancers (TNBC), pCR rates up to 64%
can be achieved [11]. The highest rates have been described
for ER-negative/HER2-positive tumours (up to 76%) [9, 11
12]. Much lower response rates are observed for luminal
tumours even in the presence of a positive HER2 receptor [9,
13]. For this reason the intrinsic subtype can be used as a tool
to predict response to PST. Additional use of carboplatin or
pertuzumab in combination with transtuzumab in triple
negative and HER2-positive breast cancer, respectively, has
shown improved response rates compared to the standard
regimen [13, 14]. Apart from the stage of the primary tumour
and the tumour/breast volume ratio, clinicians increasingly
employ the intrinsic subtype as a tool to select patients for
PST or primary surgery.
21.4  eoadjuvant Chemotherapy and
N
Breast Surgery in Suspected BRCA
Carriers
Another option for the use of PST is the improvement of sur-
breast cancer. Women with a family history of breast cancer
or patients with suspicious biological features (e.g. triple neg-
ative cancers, young age) may be tested for a BRCA mutation
during the time of chemotherapy. In case of a positive result,
the patient may be a candidate for bilateral mastectomy with
primary reconstruction after PST. The time of chemotherapy
can be used for counselling and to allow the patient to decide
on the surgical approach (conventional surgery vs risk-reduc-
ing surgery). Secondary operations can be avoided, and the
cosmetic outcome in patients, who primarily would have
been treated with BCT and irradiation of the breast and who
decide later to have their breast(s) removed, is improved.
21.5  eneral Remarks: Interdisciplinary
G
Cooperation
PST with subsequent breast surgery requires a close interdis-
ciplinary cooperation between radiologist, surgeon and
pathologist. This relates to the pre-PST evaluation of all clin-
ical and imaging procedures regarding the primary tumour
size and its growth pattern as well as to the tumour response
and the extent of the remission pattern during and after che-
motherapy. Regular assessment of tumour response during
PST is mandatory and can exclude the rare case of a tumour
progression under chemotherapy. In order to assure optimal
management for the patient who undergoes PST, some spe-
cific measures should be considered.
21.6  re- and Post-PST Evaluation
P
of the Tumour
Risk assessment for hereditary breast cancer and determination
of the initial tumour stage is important for patients who are
candidates for PST. Clinical examination including p ­ alpation,
Breast Surgery after Primary Systemic Treatment
mammography and ultrasound of both breasts and axillae is
mandatory for every patient who undergoes breast cancer
treatment. In the neoadjuvant setting, the additional role of
MRI is controversial at present. According to several trials and
a meta-analysis, MRI overestimates the pathologic tumour size
after PST. Ultrasound provides comparable results compared to
MR.  Agreement of palpation and mammography with the
definite pathologic findings appears to be poorer than US and
MRI. Palpation and ultrasound are therefore the most impor-
tant clinical tools to evaluate the primary extent of the tumour
and its response to PST [15–18].
Assessment of contrast enhancement in MRI may pro-
vide additional information regarding the response pattern
of the tumour. Since MRI provides a reliable comparability of
pre- and post-PST imaging, the technique is preferred by
many clinicians to assess response of the tumour under PST.
Image-guided, percutaneous core needle biopsy (CNB) is
required to determine the histologic type, tumour grade, oes-
trogen and progesterone receptor status, HER2 status and the
proliferation rate (KI 67). An adequate number of sufficiently
thick, nonfragmented cores are needed.
Pretreatment localization of the tumour is strongly rec-
ommended to ensure an adequate resection in case of com-
plete clinical response after PST. Clip placement at the time
of diagnosis or during the course of treatment represents the
standard of care to locate the original tumour bed.
Additionally photographs may be helpful to assess tumour
location and the response of the tumour to chemotherapy
in locally advanced disease.
21.7 Breast Surgery After PST
Randomized trials have shown that PST is associated with
higher rates of BCT compared to primary surgery [2, 3]. The
improvement of BCT rates does not translate into higher
recurrence rates or a higher mortality. In a meta-analysis
comparing neoadjuvant with adjuvant systemic treatment,
Mauri and colleagues confirmed equivalency between both
treatment strategies in terms of survival and overall disease
progression [19]. However, neoadjuvant therapy was associ-
ated with a higher risk of local recurrence when radiotherapy
without surgery was adopted as exclusive local treatment.
Therefore it is generally accepted today that breast surgery
after PST remains an essential part of locoregional therapy.
The target volume for breast surgery after PST is defined as
the post-PST tumourload as identified by clinical and imag-
ing techniques. Patients with locally advanced breast cancer
who are primarily candidates for mastectomy can be spared
from radical surgery when post-PST imaging suggests that
BCT is feasible within new (post-PST) margins. No data
from prospective trials are available to define the role of mar-
gin width with regard to locoregional recurrences or survival.
Smaller retrospective studies [20, 21] could not detect a
higher rate of margin involvement after PST compared to
primary surgery. There was no difference in the rate of
tumour involvement in the re-excision specimen. However
an association between lobular subtype and higher risk of
rares1geo@gmail.com
257 21
margin involvement was described. A broad consensus has
been reached in international guidelines that the target surgi-
cal resection volume is based on postoperative imaging. All
residual disease detectable by clinical or imaging techniques
should be removed with clear margins [22]. In cases of com-
plete radiologic response, the centre of the original tumour
bed should be removed including the marking clips placed
prior to or during the course of PST.
For patients who present initially with multifocal or mul-
ticentric disease, the impact of the surgical extent (BCT vs
mastectomy) after PST on local recurrence and survival has
not yet been examined in prospective trials. In a retrospective
analysis of 6134 patients from the German GeparTrio,
GeparQuattro and GeparQuinto trials with operable or locally
advanced tumours receiving anthracycline, taxane and tar-
geted neoadjuvant therapy, the lesions of the participants were
classified into unifocal (one lesion), multifocal (>1 lesion in
one quadrant) or multicentric (>1 lesion in >1 quadrant) [23].
Local recurrence-free, disease-free and overall survival
according to focality stratified by type of surgery and pCR was
examined. Patients with multicentric tumours had worse dis-
ease-free and overall survival compared to patients with mul-
tifocal or unifocal disease. When pCR was achieved, there was
no difference in all outcome parameters when breast-conserv-
ing therapy was performed. The authors concluded that BCT
is feasible in clinically multifocal or multicentric breast cancer
patients treated with PST without worsening local relapse-free
survival if tumour-free margins can be attained and/or if
patients achieved a pathologic complete response.
Close interdisciplinary cooperation between radiologist
and breast surgeon is required for patients who undergo
PST. This includes a thorough evaluation of all imaging pro-
cedures to define the target volume for surgical excision. If
this volume does not correspond to the clinical finding (pal-
pation), further measures should be taken to remove all
detectable residual disease (imaging and palpation). Wire
localization of the clip placed prior to or during the course of
PST is widely used to indicate the original tumour site in case
of a non-palpable lesion. Additional wires may be used to
define a specific target volume. Intraoperative ultrasound is
increasingly employed to guide the surgeon to locate the
tumour and resect an adequate volume. Specimen imaging
(radiography, ultrasound) is mandatory in cases of preopera-
tive image-guided localization of the non-palpable tumour
or the clip.
Clear orientation of the specimen is required (template,
sutures) (. Figs. 21.1., 21.2., 21.3., and 21.4.). This allows an
adequate histopathologic evaluation of the resection margins
and a targeted reresection in case of incomplete surgery.
Intraoperative placement of clips to the tumour bed is
strongly encouraged to allow a well-directed boost irradia-
tion for patients who undergo BCT.
In cases of an unfavourable relation between the target
resection volume and breast size, oncoplastic techniques can
be applied to ensure an adequate resection volume and a good
cosmetic outcome (see 7 Chap. 19). Surgical solutions for
eventual reresections and the necessity for unexpected, more
extensive surgery should, however, be anticipated.
 258 T. Kuehn

A close interdisciplinary cooperation between surgeon
and pathologist is required to allow a high-quality histo-
pathological evaluation. Ideally patients are discussed in a
preoperative conference/multidisciplinary tumour board.
The following information should be communicated to the
pathologist:
1. The specimen must be clearly marked as a post-PST
specimen.
2. Clear orientation of the specimen is mandatory.
3. Results of previous core biopsies should be available.
4. Clinical tumour size before and after chemotherapy
(information given in cm or mm, rather than T-stage).
5. Location of the tumour/tumour bed/after chemotherapy
(ideally by a diagram or drawing).
6. Information on close margins based on intraoperative
findings (specimen radiography).

..      Fig. 21.1  Pre- and post-NACT MRI showing a complete clinical response

a b

21

..      Fig. 21.2  a Clip placed in the centre of the original tumour bed and b needle localization of the clip

rares1geo@gmail.com
Breast Surgery after Primary Systemic Treatment
259 21

..      Fig. 21.3  Handling and orientation of the specimen – the specimen is fixed on a template and prepared for radiography in two planes to
identify the clip

..      Fig. 21.4  Specimen radiography in two planes. The clip is located in the centre of the specimen with the wire in place

rares1geo@gmail.com
 260 T. Kuehn
21.8 Pathologic Evaluation
The pathologic evaluation should include information on the
adequacy of surgery (identification of the tumour bed) (e.g.
clip) and the resection margins. Several reporting systems
have been established to allow standardized histopathologic
information on tumour response after chemotherapy [24–
26]. The residual cancer burden (RCB) that assesses tumour
extent, cellularity, size of lymph node metastases and pres-
ence of treatment effects in the breast and the lymph nodes
after PST is widely used within clinical trials today [27, 28].
The RCB provides a standardized and reproducible tool to
define tumour response after PST with a good association
with clinical outcome in terms of DFS and overall survival.
21.9 Timing of Surgery and Radiotherapy
Surgery after PST should be planned after the nadir of the
leucocyte count, in general 2–4 weeks after the last course of
chemotherapy. Radiotherapy should be planned within a
timeframe of 2–3 weeks after surgery [29].
21.10  ecent Development of Breast
R and the increasing sensitivity of imaging techniques to assess
Surgery After PST
Refinements of neoadjuvant regimen and the introduction
of targeted therapies such as trastuzumab or pertuzumab
have improved pCR rates and outcome after PST consider-
ably. Histopathologic complete response is observed in
between 20 and 40% of the patients today, and a pCR rate as
high as 74.6% has been achieved for HER-positive and
ER-negative patients [12]. Astonishingly, these constantly
improving response rates do not translate into a higher rate
of BCT which ranges between 13% and 69% [30–31]. The
reason for the persisting high mastectomy rates after PST is
still unclear. Probably the consensus with regard to the
extent of breast cancer surgery after PST is not yet widely
accepted by the majority of breast surgeons. However,
patients who are candidates for mastectomy prior to PST
and whose clinical evaluation after chemotherapy reveals a
good response to PST so that BCT appears feasible should
be spared by the mutilating procedure of mastectomy wher-
ever possible.
According to a study from the MD Anderson, four fac-
tors are associated with an increased recurrence rate in
cases of BCT after PST: N2 or 3 disease, the presence of
21 lymphovascular invasion (LVI), residual pathologic tumour
size >2 cm and a multifocal residual pattern of disease [33].
These factors were summarized in a prognostic score rang-
ing from 0 to 4 according to the number of risk factors
involved. This prognostic index for locoregional recurrence
after BCT was evaluated retrospectively in an independent
cohort of 551 patients. The 5-year LLR rate was 92%, 92%,
84% and 69% when the index was 0 (no risk factor present),
rares1geo@gmail.com
1 (1 risk factor), 2 (2 risk factors) and 3–4 (3–4 risk factors
present). When the prognostic index was 3–4, the 5-year
LRR-free survival was significantly lower for patients
treated with BCT compared with mastectomy [34].
21.11  omplications for Breast Surgery
C
After NACT
The effect of PST on postoperative complications has not yet
been investigated prospectively. In a retrospective analysis of
44,533 patients registered in the American College of
Surgeons National Surgical Quality Improvement Programme
database, the overall wound complication rate was low (3.4%
vs 3.1%) and independent from the use of neoadjuvant che-
motherapy. Smoking, functional dependence, obesity, diabe-
tes, hypertension and mastectomy were the main risk factors
for wound complications [35].
21.12 Future Perspectives
In view of the constantly improving response rates to sys-
temic treatment regimens (including new targeted drugs)
the post-PST tumourload, the issue of whether breast sur-
gery is required at all in cases of clinical complete response is
a current matter of debate. This relates to the effect of surgery
on local control but also to the diagnostic purpose of breast
surgery to assess pCR.
Clinical and imaging procedures are not associated with
an acceptable sensitivity to assess pCR.  Clinical complete
response was associated with a 25% sensitivity to predict
pCR for physical examination and mammography and 50%
for ultrasound and MRI [36]. Shin and colleagues reported
an accuracy of pCR prediction of 38% for mammography,
13% for ultrasound and 75% for MRI [37].
Heil and colleagues investigated the false-negative rates
(FNR) and the negative predictive values (NPV) (to predict
pCR after PST) for core needle biopsy (CNB) and vacuum-­
assisted biopsy (VAB) in a prospective study of 164 patients
[38]. The FNR was, however, as high as 49.3% and the NPV
71.3%. In a small cohort of 16 patients within this study in
whom VAB was performed, no FN case was observed. Future
studies are being designed to examine the role of minimally
invasive procedures to assess pCR.
21.13 Conclusion
Primary systemic treatment is becoming increasingly impor-
tant in the treatment of breast cancer and has a high potential
to tailor future systemic and locoregional treatment deci-
sions. PST allows a more individualized and risk-adapted
treatment of the patient. The treatment strategy of PST
requires a high standard regarding the radiologic diagnostic
Breast Surgery after Primary Systemic Treatment
workup, the planning of surgical strategies and the patho-
logic workup of the specimen. Close interdisciplinary coop-
eration is an important precondition to ensure that the great
potential of a primary systemic treatment strategy can suc-
cessfully be employed to improve the treatment of an indi-
vidual patient.
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breast cancer burden to predict survival after neoadjuvant chemo-
therapy. J Clin Oncol. 2007;25:4414–22.
29. Arbeitsgemeinschaft Gynäkologische Onkologie (AGO). Guidelines
of the AGO Breast Committee. http://www.ago-online.de/en/
guidelines mamma, 2016.
30. Guarneri V, Frassoldati A, Bottini A, Cagossi K, Bisagni G, Sarti S, et al.
Preoperative chemotherapy plus trastuzumab, lapatinib or both in
human epidermal growth factor receptor 2-positive operable
breastcancer: results of the randomized phase II CHER-LOB study. J
Clin Oncol. 2012;30:1989–95.
31. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin
S, et al. Neoadjuvant chemotherapy with trastuzumab followed by
adjuvant trastuzumab versus neoadjuvant chemotherapy alone in
patients with HER2-positive locally advanced breast cancer (the
NOAH trial): a randomized controlled superiority trial with a parallel
HER2-negative cohort. Lancet. 2010;375:377–84.
 262 T. Kuehn
32. Semiglazov V, Eiermann W, Zambetti M, Manikas A, Bozhok A, Lluch
A, et  al. Surgery following neoadjuvant therapy in patients with
HER2-positive locally advanced or inflammatory breast cancer par-
ticipating in the NeOadjuvant Herceptin (NOAH) study. Eur J Surg
Oncol. 2011;37:856–63.
33. Chen AM, Meric-Bernstam F, Hunt KK, et  al. Breast conservation
after neoadjuvant chemotherapy: the MD Anderson Cancer Center
Experience. J Clin Oncol. 2004;22:2303–12.
34. Chen AM, Meric Bernstam F, Hunt KK, Thames HD, Outlaw ED, Strom
EA, et  al. Breast conservation after neoadjuvant chemotherapy.
Cancer. 2005;103:689–95.
35. Decker MR, Greenplatt DY, Havlena J, Wilke LG, Greenberg CC, Neu-
man HB. Impact of neoadjuvant chemotherapy on wound compli-
cations after breast surgery. Surgery. 2012;152:382–8.
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36. Schott AF, Roubidoux MA, Helvie MA, Hayes DF, Kleer CG, Newman
LA, Pierce LJ, Griffith KA, Murray S, Hunt KA, Paramagul C, Baker
LH.  Clinical and radiologic assessments to predict breast cancer
pathologic complete response to neoadjuvant chemotherapy.
Breast Cancer Res Treat. 2005;92(3):231–8.
37. Shin HJ, Kim HH, Ahn JH, Kim SB, Jung KH, Gong G, et al. Compari-
son of mammography, sonography, MRI and clinical examination in
patients with locally advanced or inflammatory breast cancer who
underwent neoadjuvant chemotherapy. Br J Radiol. 2011;84(1003):
612–20.
38. Heil J, Kümmel S, Schaeffgen B, Paepke S, Thomssen C, Rauch G,
et al. Diagnosis of pathological complete response to neoadjuvant
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 263 22

Surgery for Locally Recurrent

Breast Cancer
Roberto Agresti, Andrea Spano, Giulia Bianchi, and Giovanna Trecate

22.1 Introduction – 264

22.2 Ipsilateral Breast Tumour Recurrence After

Breast-Conserving Surgery – 264

22.3 Ipsilateral Breast Tumour Recurrence After Mastectomy – 264

22.4 Breast Irradiation for Locally Recurrent Breast Cancer

and Second Breast-­Conserving Surgery – 267

22.5 Reconstructive Surgery for Ipsilateral Breast

Tumour Recurrence After Breast-Conserving
Surgery or Mastectomy – 267

22.6 Axillary Staging in Locally Recurrent Breast Cancer – 268

22.7 Indication and Need for Systemic Treatment After Locally

Recurrent Breast Cancer – 268

22.8 Conclusion – 271

References – 271

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_22

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 264 R. Agresti et al.
22.1 Introduction
Local recurrences in breast cancer after breast-conserving
surgery or mastectomy represent two completely different
oncological events, differing in terms of risk factors, clinical
presentation, surgical treatment and prognosis. The clinical
presentation of local recurrence following mastectomy is
generally that of dermal lymphatic and subcutaneous nod-
ules on the chest wall, usually as a local manifestation of dis-
seminated disease. In contrast local recurrence following
conservative surgery may generally be the growth of unde-
tectable microscopic multifocal or multicentric tumour foci,
not necessarily associated with distant disease. It may or may
not be linked to poor prognosis disease. As far as risk factors
are concerned, the importance of the molecular subtypes of
breast cancer and local therapy outcomes has been identified.
The risk of local recurrence following conserving surgery and
mastectomy varies with molecular subtypes [1], indicating
that biological information should be taken into account
when planning the type of and extent of surgery. In particu-
lar, there is a substantially lower risk of local recurrence in
luminal-like than in basal-like or HER2-positive breast can-
cer irrespective of the type of surgery [2–7]. However “bigger
surgery does not overcome bad biology” [8], and biological
subtype, stage and systemic and local therapies all interact to
dictate outcomes, showing the importance of multidisci-
plinary review of each case.
Treatment planning for IBTR is complex and, following
exclusion of systemic metastatic disease, must determine the
optimal surgical strategy for the recurrence, whether axillary
restaging is performed and whether further radiotherapy is
possible. Reconstructive surgery may also need to be inte-
grated into treatment planning.
22.2 I psilateral Breast Tumour Recurrence
After Breast-Conserving Surgery
Mastectomy is still considered the gold standard of treatment in
patients with ipsilateral breast tumour recurrence (IBTR) after
conservative breast surgery and postoperative standard whole
breast radiotherapy [9]. This results in a locoregional control
rate of 90% [10]. As previously shown, the yearly probability for
IBTR, after adequate breast-conserving surgery, is relatively
low, less than 1% up to the tenth year [11–14], and IBTR are
affected by young age, extensive intraductal component, peritu-
moural lymphatic invasion and radiation boost [15, 16].
Several reports have indicated that IBTR is an independent
predictor of distant metastases and poor prognosis [10, 17, 18],
but the evidence that some groups of IBTR patients have a
favourable outcome [19, 20] suggests that two distinct types of
22 local recurrence may exist, raising doubt about whether a
recurrence is a true IBTR or a new ipsilateral primary tumour
[16, 21]. It is clear that this question does not have a simple
answer. By definition, a true IBTR should arise from micro-
scopic tumour foci left behind during surgery (. Fig.  22.1):
 
although positive margins have been found to be predictive of
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IBTR after breast-conserving surgery, this relationship is
strictly linked to the extension of involved margins [22].
Tumour site (near to the previous surgery) and correspon-
dence of histologic subtypes [23], mean time to recurrence [13]
or, recently, gene-expression profiling (or its surrogate) [24]
may be suggestive but not conclusive for identifying the clinical
and biological origin of IBTR. Panet-Raymond and colleagues
developed a flowchart using these criteria and applied it to a
series of IBTR patients, classifying the cases into two groups:
one likely to represent true recurrence and the other probable
new primary cancers. The mean time to recurrence was sig-
nificantly shorter in true recurrence patients, with similar sur-
vival rates to new primary breast cancer patients [25]. The
same authors, in the same series, showed that positive lympho-
vascular invasion status, oestrogen receptor negative status,
high-grade histology and close or positive margins are inde-
pendent prognostic factors in patients with IBTR [26].
However, there are no published or pending incontro-
vertible data suggesting a real advantage in terms of overall
survival for total mastectomy versus second conservative
surgery as a surgical approach in IBTR patients [27–29]. A
recent cohort study using propensity score analysis showed
no difference in distant disease-free survival (DFS) or overall
survival between mastectomy and second breast-conserving
surgery after IBTR [30]. Further breast-conserving surgery is
the subject of intense debate at present. Gentilini and col-
leagues suggested that the subset of patients with a recurrent
tumour <2 cm in size, occurring >48 months after primary
surgery, may be suitable for breast preservation [31]. Ishitobi
and colleagues have suggested that oestrogen receptor posi-
tivity may also be considered as potential criteria for further
conservation [32]. Obviously, other general criteria for cor-
rect selection of patients for a second breast-conserving sur-
gery are the patient’s desire for a conservative approach and a
reasonable likelihood of an acceptable cosmetic result.
Ideally, to rigorously assess the oncological safety and
other outcomes of secondary conservation surgery compared
to mastectomy for surgical management of IBTR after breast-­
conserving therapy, it would be desirable to design a phase
III randomized clinical trial comparing salvage mastectomy
versus second breast-conserving surgery (probably with re-­
irradiation), although some concerns regarding trial design
are still unclear, such as the best primary endpoint (local con-
trol or disease-free and overall survival) and the number of
patients to be enrolled. Such a trial would be challenging as a
low event rate would mandate a large sample size, long fol-
low-­up would be required, and it is highly probable that
many patients would refuse randomization, due to strong
personal preferences about surgery.
22.3 I psilateral Breast Tumour Recurrence
After Mastectomy
Local recurrences after mastectomy tend to present rela-
tively early, as an asymptomatic nodule(s) in the skin near
the scar of the mastectomy (. Fig.  22.2). These are usually
Surgery for Locally Recurrent Breast Cancer
265 22
..      Fig. 22.1  Patient aged 80, Clip of previous surgery
submitted to quadrantectomy
17 years before because of an IDC,
10 mm, G2, ER+, PgR+, Her2−, a b
Ki67 15% in the left breast. Breast
cancer recurrence at MRI along the
scar and close to the clips of previ-
ous surgery, with involvement of
the nipple. Evidence of the surgical
clip a and scar b on T1-weighted
images. Several foci of suspicious
enhancement along and next to
the scar with an involvement of
the nipple after the injection of
contrast medium and subtraction
of images c–e. Histology revealed
IDC, G2 ER+, PgR−, Her 2−, Ki67
10%

Surgical scar
c

Breast Cancer
recurrence along
the scar and close
to clips of previous
surgery, with
involvement of the
nipple

d e

high-risk patients from the outset with involved axillary [33] usually in the first few years after mastectomy. The vast
nodes, lack of systemic therapy, adverse disease biology, and majority of local recurrences after mastectomy are within
advanced T stage of the primary tumour. Their onset is sig- the first 5 years from surgery, ranging from 60 to 85% within
nificantly earlier than IBTR after breast-conserving surgery the first 3 years [33, 34]. Furthermore, the outcome of these

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266 R. Agresti et al.

..      Fig. 22.2  BRCA1 mutation Post surgical granuloma Breast prosthesis after mastectomy
carrier, aged 54, submitted to
mastectomy 5 years before for a
extensive DCIS combined with
multicentric IDC, with the largest
single lesions of 20 mm, (G2, ER+,
PgR+, Her2−, Ki67 10–30%) in
the left breast and contemporary
breast reshaping on the right.
MRI evidence of breast cancer
recurrence on the left and cancer
development on the right. On
T1-weighted images, there is evi-
dence of the prosthesis on the left Signs and subtle
and several surgical granulomas intraparenchymal scar after
on the right breast a–c. Subtracted
breast reshaping
images after injection of contrast
medium. There are two suspicious c
b
new enhancing nodes on the left,
close to the prosthesis d, e and
several enhancing, irregular foci
of enhancement on the right both
along the scar of previous reshap-
ing and within the parenchyma
f. FNAB revealed IDC, ER+, PgR−,
p185+ on the left and IDC G2 on
the right

Several post surgical granulomas

Breast cancer
recurrence close
to the proshesis e
d

22

Breast cancer detected in controlateral breast after reshaping

both along the scar and within the parenchyma

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Surgery for Locally Recurrent Breast Cancer
267 22
patients is generally poor, although some subgroups of 22.5  econstructive Surgery for Ipsilateral
R
patients seem to have a more favourable prognosis. A worse Breast Tumour Recurrence After
prognosis is related to pT3–4 disease, nodal involvement, Breast-Conserving Surgery or
grade III, oestrogen receptor negative tumours and short Mastectomy
time to recurrence (<1  year) [35]. In another study at
Memorial Sloan Kettering, the major predictive factors for Reconstructive surgery for locally recurrent breast cancer is a
isolated locally recurrent breast cancer after mastectomy challenge, with significant potential problems faced and a
were young age, lymphovascular invasion and multicentric- lack of established consensus guidelines. In the overwhelm-
ity [36]. Elective post-­mastectomy radiotherapy reduces the ing majority of cases, the main problem is radiotherapy,
risk [3] in selected patients, as well as systemic adjuvant either the previous adjuvant radiotherapy after breast-­
treatment [37]. conserving surgery or mastectomy, or, in cases where this
A multidisciplinary approach is required for optimal was omitted during treatment of the primary, it is highly
management of local recurrence after mastectomy [38]. likely to be advised after surgery for recurrence [45].
Rather than systemic hormonal or chemotherapeutic In case of salvage mastectomy for locally recurrent cancer
treatment, a surgical approach may be the best choice for after breast-conserving surgery, an implant-based breast
local control of disease but can be performed only in reconstruction may be difficult with a considerably higher
favourable cases, if the size and the location of the recur- rate of complications related to the previous adjuvant radio-
rence permit this. In general, surgical excision for post- therapy. Additional trials need to be carried out to determine
mastectomy recurrence must be as wide as possible and if immediate 1-stage or 2-stage prosthetic breast reconstruc-
ideally at least two or three cm from the nodule, particu- tion can be performed successfully in selected patients [46].
larly if the area to be excised shows more than one nodule. The rate of early complications in this patient group is higher
In many cases use of a flap-based technique or even skin than in the non-irradiated cohort but remains acceptable [47,
grafting to close the defect will be required. The width of 48]. Women considered for this must have very good skin
surgical excision will depend on the local extent of the elasticity and quality and no evidence of post-radiation dam-
recurrence, whether the tissues have been previously irra- age. Smokers must be excluded and particular attention
diated which reduced tissue elasticity and will impair should be given to the use of atraumatic surgical technique,
wound healing if any tension is present in the wound clo- avoidance of tension on the wounds and excellent postopera-
sure, invasion of the chest wall and the laxity of the residualtive care. The use of biological (ADMs) and synthetic meshes
chest wall skin. When surgery is not feasible, other local for breast reconstruction has increased during the last
therapeutic options may be radiotherapy (the possibility 5 years, although caution must be exercised when using these
has to be carefully evaluated if the skin has been previously meshes in irradiated patients as no randomized trials have
irradiated) or electrochemotherapy combined with a range been conducted and their use is associated with higher rates
of systemic therapies [36, 39]. of infection in most series [49].
In many cases autologous flap reconstruction, from the
abdomen or from the back, may be the first or the only
22.4 Breast Irradiation for Locally Recurrent reconstructive option for patients who develop local recur-
Breast Cancer and Second Breast-­ rence following earlier breast-conserving surgery [50–52].
Conserving Surgery Only autologous tissue reconstruction has been shown to
have an acceptable rate of complications comparable to those
Some trials have been performed to evaluate potentially safe of primary reconstruction. Khansa and colleagues evaluating
radiotherapeutic techniques to be used after a second breast-­ 802 breast reconstructions reported that radiation in the set-
conserving surgery. Interstitial brachytherapy is the most ting of breast-conserving surgery did not increase the overall
widely applied technique, with some technical variants, rate of complications or dissatisfaction with subsequent
including low, pulsed or high dose rate [40–42]. The results breast reconstruction if autologous reconstruction was per-
of this approach seem promising with a low rate of severe formed in the majority of cases [53]. However, they found a
toxicity and good cosmetic results and appear to be compa- higher incidence of mastectomy skin flap loss, but this did
rable with salvage mastectomy in terms of oncologic out- not represent a major issue if a healthy autologous flap was
comes [40–42]. However, these techniques are highly underneath the skin (DIEP, TRAM, LD, etc.).
specialized and complicated and published experience is Patients with locally recurrent breast cancer who have
extremely limited. In addition the added value of adding previously had mastectomy and implant reconstruction are
brachytherapy to second breast-conserving surgery versus generally offered a new wide excision. The challenge is to sat-
surgery alone is not yet clear. Further early trials reporting isfy oncologic radicality and preserve the previously inserted
external beam re-irradiation with electron therapy to the implant: the closure may be too tight due to loss of the skin
tumour bed [43] or intraoperative radiation therapy (IORT) and soft tissue coverage. Alternatively, a smaller implant, able
[44] may be easier options but need to be verified in larger to achieve a moderate level of symmetry, may be considered
studies. [54]. Subsequent symmetrization may be offered if required.

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 268 R. Agresti et al.
Patients should be informed about the possible long-term
complications of postoperative radiotherapy treatment to a
reconstruction and in particular the higher rates of implant
loss, capsule formation and progressive asymmetry [55].
However, even in these cases, autologous reconstruction
may be the best option to reduce local short- and long-term
complications, which probably outweigh the disadvantage such
as more prolonged surgery and donor-site morbidity. [56]
Furthermore, in case of large excisions and those in need of
postoperative radiotherapy, the option of delayed reconstructive
flap surgery may be considered to ensure that the new autolo-
gous breast-like tissue has sufficient long-term softness [57].
Conversely, when flap reconstruction is not an option, for
example, where previous surgery has already used a particu-
lar donor site or there are other contraindications, a two-step
breast reconstruction may be the only possibility, although
multiple fat-transfer procedures become necessary to
improve tissue vitality before substituting the expander with
the implant. In these cases, radiotherapy may be performed
with the expander in situ [58].
Immediate flap reconstruction for locally recurrent breast
cancer may have two other advantages: firstly, a further local
recurrence can be easily detected and, secondly, it may be
easily managed, considering that breast mound reconstruc-
tion with autologous tissue even after wide excisions may be
effectively reshaped with a good breast contour in most cases
[59] (. Fig. 22.3).
 
22.6  xillary Staging in Locally Recurrent
A
Breast Cancer
Until 15 years ago, axillary dissection was the gold standard
in any case of primary breast cancer, although the manage-
ment of axillary nodes had progressively changed from a
therapeutic option to a largely staging procedure for plan-
ning adjuvant treatment for most women [60] as less invasive
sentinel node biopsy has superseded axillary dissection in
women with a clinically negative axilla [61–63].
Consequently, the type of axillary restaging in cases of
isolated local recurrence, with previous sentinel node biopsy
and without gross nodal metastases at the time of local recur-
rence, has been widely debated because the non-dissected
axilla leaves all possibilities open (no surgery, re-operative
sentinel node biopsy, or axillary dissection). However,
although much clinical evidence has been collected, there is
no consensus to standardize practice at present.
At the beginning of the sentinel node era, previous axil-
lary surgery was considered a strong contraindication,
although much data have been progressively reported to
refute this concept, including several large series [64–66].
22 The rate of detection and removal of re-operative sentinel
nodes is substantially lower than those of sentinel nodes for
the primary tumour in all series evaluated (likely due to a
combination of previous axillary surgery and breast radio-
therapy), even if repetition of sentinel node biopsy is tech-
nically safe, feasible and accurate [64–66]. A possible
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solution for improving the detection rate of re-operative
sentinel nodes might be injection of a larger amount of
tracer (>180  MBq) [67] or performing a dual technique
(lymphoscintigraphy and blue dye). The basic concept is
that, after a previous axillary operation, in case of partial
blockage of lymph flow, an axillary sentinel node may still
be found, consistent with the hypothesis that breast tumours
drain through common afferent lymphatic vessels from a
sub-areolar plexus; even in case of complete interruption of
lymphatic flow, this is only temporary because the lym-
phatic plexuses will have re-grown in the time between pre-
vious surgery and IBTR [68]. The issue of a possible
alteration of lymphatic drainage pathways after previous
sentinel node biopsy has been evaluated in a recent meta-
analysis, showing that only in 17.4% of cases was an aber-
rant drainage pathway observed and that the predominant
locations were in the contralateral axilla and internal mam-
mary chain (. Fig. 22.4) [69]. The same meta-analysis also
reported that the sentinel node was involved in 19.2% of
patients and that 27.5% of these metastases were in the
aberrant lymph drainage basin [69].
In a very recent report, Ugras and colleagues showed, in a
limited series of 83 patients, that re-operative sentinel node
biopsy is feasible, but the risk of axillary failure and rates of
disease-free survival or overall survival are comparable to
patients who did not receive any axillary restaging at the time
of local failure, subsequent conservative surgery or mastec-
tomy [70].
22.7 I ndication and Need for Systemic
Treatment After Locally Recurrent
Breast Cancer
Patients with locoregional failure after breast-conserving
surgery have an increased risk of distant disease and death
from cancer [71].
In a retrospective review of 10 National Surgical Adjuvant
Breast and Bowel Project (NSABP) clinical trials involving
6468 patients treated with conservative surgery, 5-year
distant-­free survival after an ipsilateral breast tumour relapse
was 67% in node negative tumour and 51% for node positive
cancers. Other locoregional recurrence such as nodal and
chest wall recurrence resulted in a DFS of 19–29% in node
positive and node negative women, respectively [71, 72].
Even if chemotherapy is largely used to decrease the risk
of recurrence after a resected locoregional recurrence in
breast cancer, few randomized trials have been conducted in
this clinical setting.
Several randomized trials have prematurely closed due to
low rate of accrual justified by the issue to randomize patients
with high risk of recurrence to the no chemotherapy arm.
The CALOR trial is the first randomized trial to confirm
evidence of chemotherapy benefit in patients with histologi-
cally proven and completely excised isolated local recurrences
(ILRR). The initial planned sample was almost 1000 patients
but was later amended to 276 and final enrolment was 162
Surgery for Locally Recurrent Breast Cancer
269 22
..      Fig. 22.3  A 35-year-old
woman had a widespread cutane-
ous LRR almost 2 years after BCS
followed by adjuvant chemother-
apy and radiotherapy. The primary
tumour was G3, oestrogen and
progesterone-receptor negative,
HER2+, ductal invasive breast
cancer associated with an exten-
sive intraductal component and
heavy axillary node involvement.
After the histological diagnosis
of LRR, the patient was treated
with further cycles of second line
chemotherapy with Herceptin, a: Preoperative view of recurrency b: Intraoperative view after wide excision
apparently obtaining a clinical after conservative surgery
good control of local disease.
The patient then underwent
mastectomy with wide excision
of the skin of the anterior chest
wall and reconstruction with
bipedicled TRAM flap. A second
LRR, 2 years later, was successfully
treated with further resection, flap
advancement and breast mound
reshaping: a Preoperative view of
breast skin LRR after BCS. b Intra-
operative view after wide excision.
c Intraoperative view of bipedicle
TRAM flap reconstruction. d Post-
operative result after 1 month. e
Further recurrence: preoperative c: Intraoperative view of bipedicle d: Postoperative result after 1month
view. f Intraoperative further TRAM flap reconstruction
excision. g Flap advancement and
breast mound reshaping. h Post-
operative result

e: Further recurrency: preoperative view f: Intraoperative futher excision

g: Flap advancement and h: Postoperative result

breast mound reshaping

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 270 R. Agresti et al.
a
Sentinel node in the controlateral axillary region
..      Fig. 22.4  Patient aged 49, previously operated with left breast
quadrantectomy and axillary sentinel node biopsy/sampling, because
of an IDC pT2 (22 mm) (G3, ER and PgR−, Her2+, Ki67: 70%); N0(0/7);
M0 tumour. The patient was treated with CT (FEC x6), RT and trastu-
zumab. Eleven years later, mammography and ultrasound detected a
suspicious nodule in the same area of the breast parenchyma. Biopsy
patients with a recruitment period of 7 years. In this world-
22 wide, open label trial patients were randomized to physician’s
choice of chemotherapy (polychemotherapy for at least four
cycles) or no chemotherapy. The primary endpoint was DFS.
Globally, 162 patients were enrolled with a median age of
56. Most patients in both groups had ILRR surgery at least
after 2 years from diagnosis of breast cancer. At a median fol-
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Sentinel node in left
internal mammary chain
Injection in site of breast recurrence
confirmed the presence of IDC, G3, ER and PgR−, Her2−, MIBI 90%.
Lymphoscintigraphy depicted one sentinel node in left internal mam-
mary chain and one in contralateral axillary region a, but PET scan
examination showed breast recurrence without evidence of nodal
uptake b
low-up of 4.9 years, the 5-year DFS was 69% (95% CI 56–79)
in patients treated with chemotherapy versus 57% (95% CI
44–67) in patients randomized to no chemotherapy (the haz-
ard ratio was 0.59 and p  =  0.046). Chemotherapy reduced
both distant and second local relapse event. Overall survival
(OS) was also significantly longer in patients randomized to
chemotherapy (5-year OS was 88% in the chemotherapy
Surgery for Locally Recurrent Breast Cancer
group versus 76% in the control arm (HR 0.41, p = 0.024)).
For DFS the interaction between treatment group and oestro-
gen receptor status suggests a larger benefit in patients with
oestrogen receptor negative cancers, but the sample size is too
small to address this issue more specifically [73].
Similarly few trials have addressed the use of endocrine
treatment after locoregional relapse. A Swiss trial, SAKK
23.82, compared tamoxifen (TAM) with observation after
complete excision of the ILRR and adequate radiotherapy. At
a median follow-up time of 11.6 years, the median post-ILRR
disease-free survival (DFS) was 6.5  years with TAM and
2.7  years with observation (P  =  0.053). The difference was
mainly due to reduction of further local relapses (P = 0.011).
The OS was 11.2 and 11.5 years in the observation and TAM
groups, respectively [74]. Decisions about the use of adjuvant
chemotherapy or endocrine treatment for locoregional
recurrence, the type and duration used, follow the criteria
used in the adjuvant setting for a primary tumour. As adju-
vant chemotherapy and hormonal treatment reduce the risk
of local and distant relapse and increase overall survive after
primary breast surgery, adjuvant hormonal and chemother-
apy should also act on the risk of relapse and death in patients
with completely excised locoregional recurrence.
22.8 Conclusion
In conclusion, surgery for treating IBTR is complex and sur-
geons should try to first establish whether the new lesion is a
true IBTR or a less aggressive new primary breast cancer. All
patients with IBTR must undergo full staging to diagnose
metastatic disease, especially in women with recurrence after
mastectomy or others with high-risk characteristics. Patients
must have complete information about the benefits and risks
of their planned surgery, discussing cosmetic outcomes, the
potential for asymmetry and the need for some type of bilat-
eral reshaping in case of second breast-conserving surgery
and, if not possible, about the limitation of reconstructive
options in case of previous mastectomy and whole breast
radiotherapy. Furthermore, the correct evaluation of histo-
logic and biomolecular characteristics of the locally recur-
rent breast cancer should be made for correct postoperative
planning. Finally, a multidisciplinary approach is mandatory
for the best clinical results, and specific consideration is
needed regarding whether further radiotherapy is advised or
possible and whether further systemic therapies are war-
ranted. The evidence base for these decisions is currently
poor however.
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Nguyen PL, et al. Age, breast cancer subtypes approximation, and
local recurrence after breast-conserving therapy. J Clin Oncol.
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 275 23

Management of the Axilla:
Sentinel Lymph Node Biopsy
Leif Bergkvist and Jan Frisell

23.1 Management of the Axilla: Sentinel Lymph Node Biopsy – 276

23.1.1 Definition – 276
23.1.2 Rationale for SLNB – 276
23.1.3 Development of the Concept – 276
23.1.4 Methods for Detection – 276
23.1.5 Surgery – 278
23.1.6 Indications for SLNB – 278
23.1.7 Accuracy of SLNB – 278
23.1.8 Intraoperative and Pathological Analysis of the Sentinel Node – 279
23.1.9 Morbidity After SLNB – 280
23.1.10 Evidence Base for Clinical Decision-­Making After SLNB – 281
23.1.11 Conclusions – 282

References – 282

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_23

rares1geo@gmail.com
 276 L. Bergkvist and J. Frisell
23.1  anagement of the Axilla: Sentinel
M 23.1.3 Development of the Concept
Lymph Node Biopsy
Sentinel lymph node biopsy (SLNB) has evolved as the stan-
dard method for staging of the axilla in clinically node-­
negative patients with breast cancer. If the sentinel node is
free from cancer, no axillary lymph node dissection (ALND)
is needed, which saves numerous patients from unnecessary
operations and postoperative discomfort, or from lifelong
problems with pain or arm swelling. With more extensive
histopathology of sentinel nodes, the procedure results in a
more accurate staging of the axillary region than with
ALND. For patients with minimal involvement of the axilla,
SLNB is increasingly being accepted as the sole surgical treat-
ment of the axilla. However, controversies exist and long-­
term results are still lacking. In the following chapter, a
discussion of techniques and an evaluation of available
results will be presented.
23.1.1 Definition
A sentinel node is defined as the first lymph node that drains
a breast tumour along a direct lymphatic pathway from the
primary tumour. It is believed to harbour the first metastatic
deposits before second-tier nodes, which assumes a mecha-
nistic, orderly spread of tumour cells.
23.1.2 Rationale for SLNB
Lymph node status is still one of the most important prog-
nostic factors for women with breast cancer and is consid-
ered in any decision-making about adjuvant treatment.
Therefore, knowledge of axillary lymph node status is funda-
mental. Traditionally, an axillary clearance of levels I, II or III
nodes was the method of choice, but these procedures are
associated with troublesome complications. Shoulder pain,
impaired movements and numbness are common complaints
after axillary clearance, and some 20–40% of patients suffer
from some degree of arm swelling (lymphedema) [1, 2]. In
the past, noninvasive methods for staging of the axilla have
not been sensitive enough. Clinical examination has a low
sensitivity even among experienced examiners [3], and
mammography, computed tomography (CT) scans or ultra-
sound with or without biopsy [4, 5] are not sensitive enough.
However, with modern ultrasound techniques, sensitivity
has been improved [6] but still cannot replace invasive meth-
ods. Lately, positron emission tomography (PET)-CT and
the use of superparamagnetic iron oxide-enhanced MRI have
shown promising results, but the techniques are not well
validated and not available everywhere [7].
Therefore, invasive methods are still needed, but should
23 preferably be burdened by as few side effects as possible.
SLNB has been extensively evaluated and is considered the
optimal way to get a reliable picture of axillary lymph node
status, with reasonably few side effects [1, 8].
rares1geo@gmail.com
The modern era of SLNB started with the pioneering work of
Donald Morton in patients with malignant melanomas [9].
However, the original idea came from Dr. Cabanas, who had
presented the concept of a sentinel lymph node draining penile
cancer several years earlier [10]. The theoretical background is
simple: a tracer is transported from the affected organ or skin
area in an orderly manner within the same lymph vessels as the
metastases to the first lymph node on the pathway and stays
there through a mechanism of active phagocytosis. Metastatic
cells from the tumour are supposed to follow the same path
and to settle and grow in this first lymph node, the sentinel
node, before they spread to other nodes. Thus, identifying the
sentinel node should give a true picture of whether there is a
metastatic deposit in the regional nodal basin without remov-
ing all of the nodes. However, in real life, the lymph node sys-
tem is more complicated, and often more than one sentinel
node are detected. Depending on the size of the particles used,
different tracers may have different affinities for the nodes.
Therefore, the recommendation is to remove all blue-dyed or
radioactive nodes or nodes marked with any other tracer sub-
stance (see below). However, sensitivity is seldom increased
after removing more than four to five nodes [11–13]. The sen-
tinel node procedure also includes the removal of any enlarged,
suspicious lymph nodes lacking the presence of a tracer. This is
because a node which is heavily involved by tumour is likely to
have blocked lymphatic channels.
23.1.4 Methods for Detection
Most commonly, the combination of a radioactive tracer (see
. Fig.  23.1) and a vital blue dye (see . Fig.  23.2) has been
used for the detection of sentinel nodes. The technique of
injection has varied substantially: intradermal, subdermal,
subcutaneous, peritumoural, intratumoural or subareolar. In
essence, all techniques can work, but there are some differ-
ences: superficial injection results in more rapid distribution
of the tracer, whereas deep injection results in the detection
of more extra-axillary sentinel nodes [14, 15]. Whether there
is any benefit from the detection of extra-axillary nodes has
been a topic for debate. On rare occasions there might be a
metastatic deposit in, for example, the parasternal nodes,
without any nodes being involved in the axilla. In patients
without axillary metastases, positive internal mammary
nodes indicate a worse prognosis [16], and such findings
could change the choice of postoperative treatment [17].
However, surgical treatment of parasternal nodes has not
proven effective [18], whereas a recent meta-analysis of
radiotherapy to internal mammary nodes showed increased
disease-free survival (DFS) and overall survival (OS) rates
[19]. The sensitivity of internal mammary sentinel node
biopsy is unknown and so is the status of non-sentinel nodes
in case of a positive biopsy. This renders internal mammary
node biopsy inaccurate for targeting radiotherapy to the
internal mammary lymph nodes.
Management of the Axilla: Sentinel Lymph Node Biopsy
..      Fig. 23.1 Lymphoscintig-
raphy, frontal and lateral view.
Injection site in the left breast
and sentinel node in the left axilla
clearly visible already after 5 min
..      Fig. 23.2  Sentinel node stained with patent blue, afferent and
efferent lymph vessels also stained
There is no standard for the amount of radioactive tracer
to be injected. More than 40–60 MBq is not needed. A higher
dose is used if the injection is given the day before any surgi-
cal intervention. The volume of vital blue dye injected has
varied widely in the range of 0.5–5 ml.
The type of tracer used differs, depending on the avail-
ability in different countries. The use of both a vital dye and a
radioactive tracer results in a higher detection rate and lower
rate of false-negative findings.
rares1geo@gmail.com
277 23
Preoperative lymphoscintigraphy can be performed for
mapping of sentinel nodes. In most instances this is not nec-
essary [20], especially if one is interested only in the presence
of a sentinel node in the ipsilateral axilla. A handheld detec-
tion probe is sufficient for identification of the radioactive
node. However, in cases of previous operations to the breast
or axilla, when distortion of the lymphatic drainage is often
present, a lymphoscintigram can be of help to identify nodes
outside the axilla.
Recently, alternative substances for mapping of sentinel
nodes have been used. Thus, the use of superparamagnetic
iron oxide (Sienna+®) combined with a magnetic probe
(SentiMag®) has been developed as a nonradioactive alterna-
tive. Initial validation studies have shown results similar to
those of the conventional techniques [21, 22]. Indocyanine
green is another vital fluorescent dye that can be used for
detecting sentinel nodes. It requires a special infrared light to
be used in the operating field to identify the node and pro-
duces virtually the same detection rates as conventional meth-
ods [23, 24]. A recent development for spatial mapping of the
sentinel node is the use of a hybrid single-photon emission
computed tomography camera with integrated CT (SPECT/
CT) [25], which can help the surgeon to find nodes in unusual
anatomical locations. Finally, radioactive seeds and micro-
bubbles have also been used. However, the results were disap-
pointing and a planned large study was abandoned [26].
Detection rates in recent studies (when participating sur-
geons are familiar with the technique) are generally high at
 278 L. Bergkvist and J. Frisell

97–98%, irrespective of the tracer used. The major drawback
of vital dyes is their ability to induce serious allergic reac-
tions. Handling of radioactivity is highly regulated and con-
trolled by several legislative restrictions, and because of the
short half-life of the isotope, a nuclear medicine department
is necessary in or near the hospital, to be able to use the sub-
stance. This limits the availability of the method to larger
hospitals in developed countries. The use of paramagnetic
Sienna+® nanoparticles could overcome these obstacles and
might prove a useful method in the future. The technique is
not without problems; however, nonferrometalic instru-
not based on solid evidence, nodes with 10% or more of the
activity measured in the first sentinel node are often also
regarded as sentinel nodes and removed. Also, any additional
blue nodes and any suspicious hard and enlarged nodes
should be removed and sent for histopathology. It is seldom
necessary to remove more than 4–5 nodes.
23.1.6 Indications for SLNB
Indications for SLNB are summarized in . Table  23.1. and

ments must be used during surgery, and the injected sub- will be discussed further in the section below concerning
stance may be retained in the breast tissue for lengthy periods accuracy of the procedure.
which may cause discoloration and, more importantly, MRI
artefacts.
23.1.7 Accuracy of SLNB

23.1.5 Surgery The accuracy of SLNB is dependent on several factors.

The surgical procedure for removal of the sentinel node is
often simple and straightforward. A short incision is placed
either in the lower hairline of the axilla or above the area
where the probe indicates the highest radioactivity. Careful
blunt dissection is performed towards the radioactive node.
If a blue dye has been used, a blue-stained lymph vessel can
usually be identified and followed to a blue node. The senti-
nel node is most often located in the lower medial part of the
axilla alongside the lateral thoracic vein, below the second
intercostobrachial nerve (87%) or above the nerve (11.5%),
but rarely lateral in the axilla (1.8%) (see . Fig.  23.3) [27].
There is a certain learning curve for the method, but it is
brief, and the vast majority of breast surgeons can use this
method after a few cases. The anatomical drainage system
of the breast has both superficial and deep pathways. As
mentioned above, the depth of injection may influence the
drainage pattern, but even after standardized superficial
..      Table 23.1  Indications for SLNB
Condition Remark

T0–T2 tumour SLNB recommended

After harvesting of the first sentinel node, the probe is used
to search for additional radioactive nodes. As a rule of thumb, T3 tumour SLNB useful, but fewer patients
can be spared ALND

T4 tumour and inflamma- ALND still standard procedure

tory cancer

DCIS – mastectomy and GIII SLNB recommended

DCIS GI–II or breast-­ Refrain from SLNB

conserving surgery

Multicentric/multifocal SLNB recommended but slightly

tumour higher FNR reported
11.5%
0% Previous breast operation SLNB recommended with
lymphoscintigraphy

Previous SLNB New SLNB recommended

86.8% Previous ALND SLNB can be tried, but lower

1.8 % detection rate expected

Neoadjuvant treatment SLNB recommended before start

of treatment in cN0 patients

Neoadjuvant treatment SLNB after treatment controver-

sial, low detection rate, high FNR

Old age SLNB recommended

23 Obesity SLNB recommended

Pregnancy SLNB can be used, low dose to

..      Fig. 23.3  Distribution of sentinel nodes in different areas of the foetus, avoid blue dye
axilla (After Clough [27])

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Management of the Axilla: Sentinel Lymph Node Biopsy
injections, different pathways have been seen, so there is an
inbuilt possibility that the sentinel node identified during
the operation might be falsely without metastasis, whereas
some other nodes might contain metastases. This results in
a false-negative rate (FNR) for SLNB and is the major dis-
advantage of the procedure. The true FNR of the procedure
is probably in the range of 5–7%, but this is based on figures
from early validation studies and might be lower in trained
hands [28].
The SLNB approach has been applied to most types and
stages of breast cancer. It is feasible for small non-palpable
tumours [29]. Injection of tracers can be done after preopera-
tive marking of the index tumour (stereotactically or by
ultrasound), if an anatomical association is sought, or under
the areola. This group of patients gains the greatest benefit
from the procedure, because metastases are rare, and most
patients do not need an ALND.  SLNB also works for large
[30] and multifocal tumours [31], even if the proportion of
patients who do not need axillary clearance is lower in this
group. In patients who have undergone previous breast sur-
gery, the lymphatic drainage may be distorted, but the tech-
nique may still be feasible [32, 33]. Because of a less
predictable drainage pattern, a preoperative lymphoscinti-
gram is of help for detecting sentinel nodes outside the ipsi-
lateral axilla. A sentinel node in the opposite axilla is seen in
3–4% of cases previously treated for breast cancer [34].
In patients with recurrent breast cancer, previous surgical
procedures have most often included some interference with
the axilla. In cases of a previous SLNB, a new SLNB can be
performed without any expected problems. Even in cases
where a formal axillary lymph node clearance has been done,
a SLNB can be attempted [35, 36]. A higher rate of non-­
detection should be expected, and in such cases, individual
assessment has to be done and discussed beforehand with the
patient: whether to refrain from clearing the axilla once again
or to explore it. In cases where a negative sentinel node can
be retrieved, the results are as accurate as for surgery-naïve
patients. In cases of a positive node, individual assessment
should be done and the risks and benefits of clearance dis-
cussed with the patient.
The role of SLNB in the context of primary systemic
therapy is still unclear [37]. When primary systemic therapy
is planned, a SLNB may be recommended before the start of
treatment in patients with a clinically negative axilla. The
FNR for SLNB in this group of patients is at the same level as
SLNB in cases not planned for primary systemic therapy,
which means that ALND may be avoided. If there is a suspi-
cion of lymph node involvement at the preoperative workup,
fine-needle aspiration or core-needle biopsy is recom-
mended; but if they are negative, SLNB can be used for stag-
ing. In patients who have completed primary systemic
therapy, more than one-third and up to a half have patho-
logically node-negative disease at the time of surgery [38]
and require no further axillary treatment. The German
SENTINA trial studied the detection rates and FNR for
SLNB both before and after neoadjuvant chemotherapy
(NAC) [39]. It found that the detection rate was lower after
rares1geo@gmail.com
279 23
NAC, especially if a first SLNB had been performed before
starting treatment. They also found a high FNR when SLNB
was performed after treatment. The SENTINA trial did not
study the FNR in sentinel node-negative cases before NAC,
as they did not do ALND in all patients after NAC.  In a
nationwide Swedish study with 220 patients, the FNR was
7% (Frisell personal communication). The use of SLNB after
NAC has been the subject of lively debate. A recent meta-
analysis of published data showed a lower detection rate and
higher FNR than for SLNB performed in patients undergo-
ing primary surgery [40]. The American Alliance study,
ACOSOG Z1071 [41], designed to determine the FNR in
patients with node-positive breast cancers before the start of
treatment  – subject to the SLNB and at least two nodes
examined after chemotherapy  – found a FNR greater than
10%, which was higher than the predetermined limit of
acceptability. Thus, the results did not support the use of
SLNB after neoadjuvant treatment as an alternative to
ALND. However, an Italian study with 5-year follow-up after
SLNB in patients who had received primary systemic therapy
showed excellent overall survival among those whose
tumours converted from cN1/N2 to cN0 after treatment and
very few axillary recurrences [42]. These results suggest that
SLNB is acceptable for patients who become cN0 after pri-
mary systemic therapy.
SLNB should not be performed in cases of true ductal
carcinoma in situ (DCIS) [43–45]. However, in many
instances the diagnosis before operation is based on a core
biopsy, and in 10–25% of cases, invasive areas are found on
definitive pathology workup after the operation [46, 47]. A
retrospective Swedish study showed that neither the size nor
the histological grade of DCIS was correlated with the risk of
metastases in the sentinel node and that in most cases a
SLNB can be avoided except if mastectomy is performed
[48]. It is therefore recommended that SLNB should only be
considered for patients with large areas of high-grade DCIS
when mastectomy is performed.
23.1.8 Intraoperative and Pathological
Analysis of the Sentinel Node
Intraoperative analysis of the sentinel node has been used
widely, to enable the surgeon to proceed to immediate axil-
lary clearance in case of a positive finding (metastases in the
node). In the past, this was highly desirable when the goal of
sentinel node mapping was to identify patients without
metastases who did not need any axillary clearance and those
with metastases in the era when this always mandated clear-
ance. Today, not all node-positive patients will be subjected
to clearance, so the need for immediate results from the
biopsy is less important.
The examination of frozen sections is probably the most
frequently used intraoperative assessment. It is reasonably
quick and inexpensive and available at most institutions. The
sensitivity depends on the number of sections processed and
the type of metastasis. Frozen section can be used to identify
 280 L. Bergkvist and J. Frisell

almost 100% of patients with macrometastases, but is less

sensitive in identification of micrometastases or isolated
tumour cells [49, 50]. Adding immunohistochemical (IHC)
staining to frozen sections in combination with conventional
haematoxylin-eosin staining slightly increases the detection
of micrometastases [51]. In a few institutions, serial sections
have been used perioperatively and have been claimed to be
almost 100% sensitive [52]. However, both serial sectioning
and IHC consume both time and resources and are not used
at many sites.
Imprint cytology is quick but with less accuracy than fro-
zen sections [51, 53]. Automated evaluation with the use of
one-step nucleic acid amplification (OSNA) has been devel-
oped and is in use in numerous institutions globally. It mea-
sures cytokeratin 19 mRNA in homogenized sentinel nodes
and quantifies the copy number. Three levels are identified:
no metastases, micrometastases and macrometastases. The ..      Fig. 23.5  Histologic section of a lymph node containing micro-
method is sensitive in detecting positive nodes. However, metastatic deposits, routine staining
some criticism has been raised against the method because of
its low positive predictive value, leading to overdiagnosis of
macrometastases, that would have been classified as micro-
metastases using conventional histopathology [54].
Postoperative workup is not standardized worldwide, but
many local guidelines exist. Serial sectioning would be the
ideal method, but it is time consuming and expensive. The
primary goal is to detect macrometastases, which is done by
taking sections every 2 mm. If they are found, then no fur-
ther sectioning is needed, whereas if micrometastases or no
metastases are found, additional sections at 200 μm should
be taken. Routine IHC is not recommended in most guide-
lines, but might be of value, especially in cases of lobular can-
cers which may be otherwise missed. Any pathology report
should include a description of the size of metastases and the
number of affected nodes. Metastases are classified into mac-
rometastases >2  mm, micrometastases 0.2–2  mm and iso-
lated tumour cells (ITCs) if <0.2 mm (see . Figs. 23.4, 23.5,
 

and 23.6).
..      Fig. 23.6  Histologic section of a lymph node containing isolated
tumour cells, immunohistochemical staining

23.1.9 Morbidity After SLNB

One of the motives for the concept of SLNB aims to

diminish the side effects of the axillary staging procedure.
Conventional axillary clearance is associated with a high risk
of permanent complaints from the shoulder region and arm,
including lymphedema [2]. SLNB has been shown to cause
fewer problems. The ALMANAC trial, a British randomized
study, designed to compare arm morbidity and quality of
life between patients undergoing SLNB and ALND, showed
a significantly lower incidence of arm morbidity (oedema
5% vs. 13% and sensory loss 11% vs. 31%, respectively) [55]
and a better quality of life [56]. These results were repeated
23 in a randomized Italian study [57] and have been confirmed
in review articles and meta-analyses [2]. However, SLNB is
..      Fig. 23.4  Histologic section of a lymph node containing macro- not free from side effects. In an Italian study, patients with
metastatic deposits routine staining small breast cancers without lymph node metastases on

rares1geo@gmail.com
Management of the Axilla: Sentinel Lymph Node Biopsy
preoperative ultrasound were randomized to SLNB or simple
observation. Patients in the observation arm had signifi-
cantly less disability in the early postoperative period than
those subjected to SLNB [58].
A prospective Swedish study included 550 patients
treated with either SLNB alone for node-negative patients or
with ALND for patients with and without metastases in the
axilla. Patients were followed yearly for 3 years, and arm vol-
umes and arm morbidity were recorded. The patients under-
going SLNB alone had a significantly lower risk of arm
morbidity and lymphoedema than those who underwent
ALND.  It seems that extensive axillary surgery per se was
associated with arm morbidity [1, 8].
Another important side effect from SLNB is the risk of
allergic reaction to the vital dye. Isosulfan blue seems to be a
little more prone to evoking an allergic reaction than patent
blue. Montgomery and colleagues [59] reviewed almost 2400
SLNB procedures where isosulfan blue had been used and
found an incidence of an allergic reaction of 1.6%. Most reac-
tions were mild – urticaria, rash or pruritus – but in 0.5% the
reaction caused hypotension sometimes accompanied by
bronchospasm. Corresponding figures for patent blue have
been calculated among almost 8000 British patients. In total
0.9% of the patients experienced allergic reactions, but only
0.06% had a severe reaction requiring postponement of the
planned operation, or needing intensive care [60]. Although
most reactions were mild and no deaths have been recorded,
both surgeons and anaesthetists should be aware of the pos-
sibility of a severe reaction, and patients should be supervised
accordingly after any injection of a vital dye. There is also the
problem of blue discoloration of the breast which may be
unsightly and persist for many months.
No allergic reactions have been reported as a result of
superparamagnetic iron oxide, but the substance has a ten-
dency to leave a brownish discoloration in the skin of the
breast for a long time after superficial injections. The tracer
might also stay in the breast for a long time and interfere with
subsequent magnetic resonance imaging (MRI).
23.1.10  vidence Base for Clinical Decision-­
E axillary clearance with or without postoperative radiother-
Making After SLNB
There are numerous follow-up studies showing that the risk
of axillary recurrence after a negative sentinel node biopsy
and no further axillary dissection is very low [61–64]. Most
of the studies included in the reviews were relatively small
with a short follow-up time. However, the Italian study by
Galimberti and colleagues [64] reported on 5262 sentinel
node-negative patients with 7 years of follow-up and found a
1.7% axillary recurrence rate and a 91.3% 10-year survival
rate. Likewise, the latest follow-up of the Swedish Multicentre
Cohort Study showed an isolated axillary recurrence rate of
1.6% after a median follow-up time of 10  years of 2216
patients with negative SLNB findings and no further axillary
dissection [65] and a breast cancer-­ specific survival at
10  years of 94.3% and overall survival of 85.4%. Moreover,
rares1geo@gmail.com
281 23
OS and DFS after a negative SLNB and no axillary dissection
were excellent in a large randomized study, and no difference
was found between those who had an axillary clearance and
those who had not [66]. Omitting axillary clearance after a
negative SLNB is therefore regarded as safe and should be the
routine standard of care.
Further surgical management of the axilla, when tumour
deposits are found in the sentinel node, depends on the
extent of node involvement. The relevance of ITC findings is
unclear. They could be transient cells without the potential to
grow to manifest metastases, or they could be the first appear-
ance of a true metastasis. In most studies, no prognostic
importance has been ascribed to ITC findings [67–69], so
patients with ITC should be regarded as node negative. This
means that no further axillary surgery is needed, and deci-
sions on adjuvant medical and radiological treatment should
be based on primary tumour characteristics, not on ITC
findings.
The prognostic value of micrometastases has been
debated extensively, but recent evidence suggests that they
are potentially hazardous [68, 70], and the patients should be
handled as if they were node positive in terms of systemic
treatment. However, the benefit of axillary clearance when
only micrometastases are found is doubtful. Galimberti and
colleagues randomized 931 patients to either clearance or
follow-up after SLNB showing micrometastases. After 6 years
of follow-up, no differences in DFS or OS rates were seen; in
fact, those patients who did not undergo axillary dissection
did a little better [71]. The recommendation of the American
Society of Clinical Oncology is to refrain from axillary clear-
ance when micrometastases are identified [44]. However, the
long-term effects on survival after omission of axillary lymph
node clearance are still unknown.
The standard of care for patients with macrometastases
has long included axillary clearance. However, the develop-
ment of new effective drugs for adjuvant treatment, together
with an increasing proportion of screen-detected cancers,
has led to a questioning of the need for this procedure. The
long-term results from the NSABP-04 study, randomizing
patients to radical mastectomy or total mastectomy without
apy, failed to show any difference between the arms [72]. An
IBCSG-initiated randomized study showed no difference in
survival or recurrence after 5  years, comparing tamoxifen
treatment without axillary clearance to axillary clearance
among patients older than 65 years [73]. In cases of minor
deposits of macrometastases, many institutions have aban-
doned axillary clearance, based on one randomized study,
ACOSOG Z0011 [74]. In this, 891 patients were randomized
to either SLND alone or SLND followed by axillary clearance
in cases of one or two positive sentinel nodes. After 6.3 years
of follow-up, no differences in DFS or OS were noted.
However, most patients in this study were at a low risk of
recurrence. All had breast-conserving therapy with postop-
erative whole-breast irradiation, in many cases including
level I of the axilla, and there were many cases with microme-
tastases included. Only 891 patients were recruited out of the
 282 L. Bergkvist and J. Frisell
1900 that should have been included according to a power
analysis, and very few events were recorded. Thus, there is
still uncertainty about the best treatment approach for
patients with node-positive disease. An EORTC study in
clinically node-negative patients who had metastases in
SLNB randomized patients to ALND or radiotherapy. At
5-year follow-­up, there was no difference in the occurrence
of axillary metastases but significantly fewer arm symptoms
in the radiation arm [75]. As for patients with micrometasta-
ses, the long-term results for omission of axillary clearance in
patients with macrometastases are still awaited.
23.1.11 Conclusions
Sentinel node biopsy can be offered to all patients with inva-
sive breast cancer with a clinically negative axilla at primary
surgery. However, it should not be used in patients with
DCIS, except for a small proportion in whom the preopera-
tive core biopsy indicates a high-grade DCIS and the tumour
size indicates the need for a mastectomy. If the biopsy is
negative, or in the presence of ITC or micrometastases, no
further surgical treatment of the axilla is necessary. Decisions
on adjuvant treatments should be based on the characteris-
tics of the primary tumour together with the histopathology
of the SLNB. In patients with limited involvement of the sen-
tinel nodes (one or two positive nodes) and a primary tumour
with a low risk of recurrence, refraining from axillary dissec-
tion may be considered, or substituted with radiotherapy.
However, ideally, these patients should be entered into ongo-
ing clinical trials. For patients with more than two positive
nodes, axillary clearance is still the preferred option.
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G.  The problem of the accuracy of intraoperative examination of
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817–20.
53. Arlicot C, Louarn AL, Arbion F, Leveque J, Lorand S, Kinn J, Chaze B,
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54. Tiernan JP, Verghese ET, Nair A, Pathak S, Kim B, White J, Thygesen H,
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55. Mansel RE, Fallowfield L, Kissin M, Goyal A, Newcombe RG, Dixon
JM, Yiangou C, Horgan K, Bundred N, Monypenny I, England D, Sib-
bering M, Abdullah TI, Barr L, Chetty U, Sinnett DH, Fleissig A, Clarke
D, Ell PJ. Randomized multicenter trial of sentinel node biopsy ver-
sus standard axillary treatment in operable breast cancer: the
ALMANAC Trial. J Natl Cancer Inst. 2006;98:599–609.
56. Fleissig A, Fallowfield LJ, Langridge CI, Johnson L, Newcombe RG,
Dixon JM, Kissin M, Mansel RE.  Post-operative arm morbidity and
quality of life. Results of the ALMANAC randomised trial comparing
sentinel node biopsy with standard axillary treatment in the man-
agement of patients with early breast cancer. Breast Cancer Res
Treat. 2006;95:279–93.
57. Del Bianco P, Zavagno G, Burelli P, Scalco G, Barutta L, Carraro P,
Pietrarota P, Meneghini G, Morbin T, Tacchetti G, Pecoraro P, Belardi-
nelli V, De Salvo GL. Morbidity comparison of sentinel lymph node
biopsy versus conventional axillary lymph node dissection for
breast cancer patients: results of the sentinella-GIVOM Italian ran-
domised clinical trial. Eur J Surg Oncol. 2008;34:508–13.
58. Gentilini O, Botteri E, Dadda P, Sangalli C, Boccardo C, Peradze N,
Ghisini R, Galimberti V, Veronesi P, Luini A, Cassano E, Viale G, Vero-
nesi U. Physical function of the upper limb after breast cancer sur-
gery. Results from the SOUND (Sentinel node vs. Observation after
axillary Ultra-souND) trial. Eur J Surg Oncol. 2016;3:00062–7.
59. Montgomery LL, Thorne AC, Van Zee KJ, Fey J, Heerdt AS, Gemig-
nani M, Port E, Petrek J, Cody HS 3rd, Borgen PI. Isosulfan blue dye
reactions during sentinel lymph node mapping for breast cancer.
Anesth Analg. 2002;95:385–8.
60. Barthelmes L, Goyal A, Newcombe RG, McNeill F, Mansel RE. Adverse
reactions to patent blue V dye: the NEW START and ALMANAC expe-
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61. Bergkvist L, de Boniface J, Jonsson PE, Ingvar C, Liljegren G, Frisell
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breast cancer: three-year follow-up of the Swedish Multicenter
Cohort Study. Ann Surg. 2008;247:150–6.
62. van der Ploeg IM, Nieweg OE, van Rijk MC, Valdes Olmos RA, Kroon
BB.  Axillary recurrence after a tumour-negative sentinel node
biopsy in breast cancer patients: a systematic review and meta-­
analysis of the literature. Eur J Surg Oncol. 2008;34:1277–84.
63. Pepels MJ, Vestjens JH, de Boer M, Smidt M, van Diest PJ, Borm GF,
Tjan-Heijnen VC.  Safety of avoiding routine use of axillary dissec-
tion in early stage breast cancer: a systematic review. Breast Cancer
Res Treat. 2011;125:301–13.
64. Galimberti V, Manika A, Maisonneuve P, Corso G, Salazar Moltrasio L,
Intra M, Gentilini O, Veronesi P, Pagani G, Rossi E, Bottiglieri L, Viale
G, Rotmensz N, De Cicco C, Grana CM, Sangalli C, Luini A. Long-term
follow-up of 5262 breast cancer patients with negative sentinel
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65. de Boniface J, Frisell J, Bergkvist L, Andersson Y, on behalf of the
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node resection compared with conventional axillary-lymph-node
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68. Reed J, Rosman M, Verbanac KM, Mannie A, Cheng Z, Tafra L. Prog-
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P, Chifu C, Sargenti M, Intra M, Gentilini O, Mastropasqua MG, Maz-
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1303–10.
 285 24

Axillary Node Clearance

Tuomo J. Meretoja

24.1 Introduction (History and Rationale

for Axillary Clearance) – 286

24.2 Indications for Axillary Clearance – 286

24.2.1 Staging – 286
24.2.2 Preoperatively Detected Axillary Metastases – 286
24.2.3 Sentinel Node Metastasis – 286

24.3 Anatomy of the Axilla – 287

24.4 Surgical Technique of Axillary Clearance – 288

24.5 Pathological Analysis – 289

References – 290

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_24

rares1geo@gmail.com
 286 T.J. Meretoja
24.1 I ntroduction (History and Rationale
for Axillary Clearance)
Axillary clearance (AC) and axillary lymph node dissection
(ALND) are synonyms for the removal of an anatomically
defined area of axillary fat which contains the axillary lymph
nodes. Historically, AC was the only method for staging the
axilla and was performed in all breast cancer patients prior to
the SLNB era. A historical landmark trial, the NSABP B04,
randomized breast cancer patients to AC vs. no axillary sur-
gery and concluded that AC in clinically node-negative
breast cancer patients was purely a staging procedure with no
impact on survival [1]. However, this study was considered
underpowered to detect a small survival benefit from AC. A
later meta-analysis of six historical randomized trials from
1951 to 1987 comparing breast cancer surgery with or with-
out AC concluded that prophylactic AC conferred an average
5.4% survival benefit [2]. All of these studies were conducted
prior to modern adjuvant therapies, and thus the survival
benefit from AC in modern clinically node-negative patient
material is unclear.
Axillary clearance, both in clinically node-negative and
node-positive breast cancer patients, provides accurate stag-
ing information by indicating the total number of tumour-­
positive and tumour-negative axillary lymph nodes.
24.2 Indications for Axillary Clearance
24.2.1 Staging
The indications for AC as a staging procedure in clinically
node-negative breast cancer are currently very limited, as
SLNB has almost completely replaced AC due to its reduced
morbidity. Failure to detect the sentinel node occurs in
approximately 2% of patients. There is no robust evidence on
the preferred staging procedure of these patients, and the
options include a level I or level I–II AC or a four-node sam-
ple, which is mainly used in the UK. One needs to keep in
mind that failure to localize the sentinel node intraopera-
tively may be due to gross axillary tumour burden [3].
In addition, there are subgroups of breast cancer patients
in whom SLNB is not recommended as a staging procedure
due to a lack of evidence of accuracy. Inflammatory breast
cancer and locally advanced breast cancer are both, typically,
administered neoadjuvant or primary systemic chemother-
apy followed by surgery, and axillary management in the
neoadjuvant setting is covered in a later chapter (7 Chap. 25)
[4]. If primary surgical treatment is planned due to contrain-
dications for primary systemic chemotherapy, AC is the pre-
ferred staging procedure both in inflammatory and locally
advanced breast cancer, even if clinically node negative [5].
Furthermore, the American Society of Clinical Oncology
(ASCO) Clinical Practice Guideline recommends perform-
ing an AC as the staging procedure in pregnant women with
24 breast cancer, due to a lack of evidence for SLNB in this set-
rares1geo@gmail.com
ting [5], whereas European practice guidelines do not con-
sider pregnancy a contraindication for radiotracer-­ based
SLNB [6]. Nevertheless, there is national and local variance
in SLNB contraindications.
An algorithm summarizing standard axillary manage-
ment is shown below (. Fig. 24.1).
24.2.2  reoperatively Detected Axillary
P
Metastases
A direct AC without SLNB remains the standard of care in
clinically node-positive breast cancer patients, with preoper-
atively detected axillary lymph node metastases [5, 7]. In
these patients, AC provides accurate knowledge of the total
number of metastatic lymph nodes, which is an important
prognostic indicator, although it may not have much value in
adjuvant therapy decision-making [8].
The high sensitivity of modern preoperative axillary
ultrasound may detect single axillary metastases even with
no suspicious nodes on palpation, which poses an obvious
overlap with the patient population with SLNB-detected axil-
lary macrometastasis. This overlap and inconsistency in
treatment protocols (see 7 Chap. 23 on SLNB) is the subject
of ongoing research. In patients with preoperatively detected
high-volume tumour burden in the axilla, primary systemic
chemotherapy is commonly considered.
24.2.3 Sentinel Node Metastasis
The matter of the tumour-positive sentinel node is covered in
detail in 7 Chap. 23. In summary, axillary clearance is not
indicated in cases with tumour-negative sentinel nodes.
Similarly, neither isolated tumour cells nor micrometastasis
in the sentinel node is usually considered an indication for
axillary clearance [5, 9]. However, in cases of macrometa-
static sentinel node(s), there is considerable variation in
treatment protocols between countries and centres with
many centres adopting individualized treatment algorithms
based on patient-specific characteristics and multidisci-
plinary team evaluations.
A number of risk prediction tools and nomograms have
been published to evaluate the patient-specific risk of addi-
tional metastases or N2 disease risk after tumour-positive
sentinel node findings [10–12]. Many of these prediction
tools are published as online calculators that provide the
patient-specific risk as a risk percentage. Such aids may be
used in the decision-making process for AC after finding a
metastatic sentinel node. Nonetheless, there is no consensus
on clinically applicable risk thresholds for non-sentinel node
metastases or N2 disease that would indicate the need for AC
or axillary radiotherapy. Furthermore, the accuracy and per-
formance of a specific prediction model should be assessed
and validated for use in each centre before adoption into
clinical practice.
Axillary Node Clearance
Preoperative axillary ultrasound and
core needle biopsy or fine needle Clinically node positive
aspiration cytology
Clinically node negative Inflammatory breast cancer
All other early stage breast cancers Locally advanced breast cancer
>2 Macrometastases or
Sentinel lymph node biopsy matted nodes
Isolated tumour cells or
1-2 Macrometastasis
micrometastasis
Breast conserving surgery and
No further axillary treatment
whole breast radiotherapy
..      Fig. 24.1  Algorithm summarizing standard axillary management
24.3 Anatomy of the Axilla
The axillary lymph node basin is a triangular space bordered
laterally by the latissimus dorsi muscle, medially by the ser-
ratus anterior muscle and the thoracic wall, cranially by the
axillary vein, anteriorly by the pectoralis major and minor
muscles and posteriorly by the latissimus dorsi, teres major
and subscapularis muscles.
The axillary lymph nodes are divided into three anatomi-
cal levels according to Berg [13]: Level I lymph nodes are
located lateral to the pectoralis minor muscle, whereas level
II lymph nodes are posterior, and level III lymph nodes are
medial to the pectoralis minor muscle (. Fig. 24.2).  
The axillary lymph nodes are surrounded by axillary fat,
which is also crossed by a number of nerves and vascular
structures. The long thoracic nerve is the motor nerve of the
serratus anterior muscle. It lies deep in the axilla running in
a cranio-caudal direction along the serratus anterior muscle,
lateral to the chest wall. Damage to the long thoracic nerve
may cause paresis to the serratus anterior muscle, which can
be clinically manifest by ‘winging of the scapula’. The thora-
codorsal bundle includes the motor nerve, artery and vein
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287 24
Direct axillary clearance
Neoadjuvant chemotherapy
(see chapter of axillary
management in the
neoadjuvant setting)
Axillary clearance
Axillary radiotherapy
according to amaros-trial
Mastectomy
No further axillary treatment
according to ACOSOG Z0011-trial
Variability in treatment protocols
which supply the latissimus dorsi muscle. The thoracodorsal
bundle crosses the axillary fat lateral to the long thoracic
nerve. The vein of the bundle intersects with the axillary vein
at the cranial border of the axilla, whereas the nerve and the
artery dive posterior to the axillary vein. The intercostobra-
chial nerve(s) is a sensory nerve innervating a variable area
of the skin of the dorsum of the upper arm. Generally the
nerve(s) branches from the intercostal nerves and runs
through the serratus anterior muscle, crosses the level I axil-
lary fat parallel but caudally to the axillary vein and enters the
arm. However, there is substantial anatomical variation in
the course and branching of this nerve [14–16]. Damage or
transection of the intercostobrachial nerve causes variable
sensory changes to the area it innervates. The lateral thoracic
vein and artery run along the serratus anterior muscle, ante-
riorly to the long thoracic nerve. The medial pectoral pedicle
comprises the medial pectoral nerve and accompanying vas-
cular vessels. It is located at the lateral border of the pectora-
lis minor muscle. The medial pectoral nerve innervates both
pectoralis minor and part of the pectoralis major muscles.
Damage to the medial pectoral pedicle therefore may cause
paresis of the pectoralis muscles [17].
 288 T.J. Meretoja
..      Fig. 24.2  Axillary lymph node
levels I–III, according to Berg
Axillary vein
Pectoralis
minor muscle
24.4 Surgical Technique of Axillary
Clearance
When axillary clearance is indicated in breast cancer patients,
a dissection of Berg levels I and II should be conducted as
routine. If clinically suspicious nodes are palpable medial to
level II, level III should also be cleared, although this is often
done as routine. Generally, if axillary clearance is performed,
all clinically suspicious nodes should be removed, and some-
times neurovascular structures may have to be sacrificed in
order to achieve radical removal of all cancerous tissue.
There is undoubtedly abundant variation in the surgical
technique in dissecting the axillary lymph nodes. The dissec-
tion can be performed either via the same incision as the breast
operation, such as mastectomy or lateral breast-conserving
surgery, or through a separate incision to the axilla. The
­dissection is typically begun from the caudal part of the axilla,
proceeding up towards the axillary vein and then continuing
medially to the Berg level II. The long thoracic nerve and the
thoracodorsal bundle should be identified and carefully sepa-
rated from the axillary fat. The dissection may then follow the
route of the thoracodorsal bundle to the axillary vein.
There is currently no consensus on the optimal handling
of the intercostobrachial nerve(s) during AC [14–16, 18–20]
and whether to preserve or perform a planned clean transec-
tion of the nerve(s) thus remains unclear. If the nerve(s) is
cut, it should be performed sharply close to the thoracic wall
medially and at the level of subcutaneous fat laterally.
24 The AC is continued by dissection of the axillary fat from
the lateral border of the pectoralis muscles, and the medial
rares1geo@gmail.com
Lymph nodes
Level I
Level II
Level III
pectoral pedicle is identified and preserved. The pectoralis
muscles are then retracted anteriorly to facilitate the dissec-
tion of levels II and III by following the axillary vein medially.
The lateral thoracic vein unites with the axillary vein at the
border of levels I and II, and the lateral thoracic vessels may be
spared if feasible. In special cases with challenging dissection
of the level III nodes through the standard axillary approach,
a direct transpectoral approach may be considered. In this
approach the pectoralis major muscle is split anteriorly, and
the pectoralis minor is retracted laterally, with the level III
axillary fat accessed directly from the anterior direction [21].
There is considerable individual variation in the axillary
anatomy regarding the neurovascular structures [16, 20, 22].
The axillary arch or Langer’s arch is perhaps the most impor-
tant anatomical variation concerning the AC [23]. It is an
aberrant muscular slip of varying dimension, which typically
arises from the latissimus dorsi muscle, crosses the axilla
anteriorly to the axillary fat and connects with the pectoralis
muscles. The axillary arch may need to be divided in order to
facilitate axillary clearance.
After the axillary clearance, a careful palpation of the
entire axilla must be performed, and all remaining suspicious
nodes should be removed. In particular the interpectoral
space, i.e. the space between the pectoralis minor and major
muscles, should be palpated, and palpable nodes should be
removed. The space between the thoracodorsal bundle and
the long thoracic nerve and especially the lateral aspect of the
junction of the thoracodorsal vein and axillary vein are typi-
cal locations for retained lymph node metastasis and subse-
quent lymph node recurrences (. Fig. 24.3).
 
Axillary Node Clearance
289 24
..      Fig. 24.3  Key anatomical
structures of the axilla

Pectoralis minor

Pectoralis major

Intercostobrachial Axillary vein

nerves

Medial pectoral
nerve

Thoracodorsal Lateral thoracic

bundle including vein and artery
vein, artery and nerve
Long thoracic
Latissimus dorsi nerve

Serratus anterior
muscles

Finally, meticulous haemostasis is performed, and closed-­
suction drainage may be left in the axilla, but this is a contro-
versial subject at present. Seroma formation is common after
axillary clearance, and a number of studies have looked at
measures to reduce seroma incidence. Surgical obliteration
of the dead space by quilting sutures seems to reduce seroma
incidence both in the axilla and in the mastectomy area [24–
26]. A 2013 Cochrane systematic review and meta-analysis
concluded that based on seven randomized trials, there is
limited quality evidence that wound drainage reduces seroma
formation and the number of postoperative seroma aspira-
tions [27]. A subsequent randomized trial of 596 breast can-
cer patients contested this finding by concluding that
drainage did not reduce symptomatic seroma formation or
interventions to treat seromas after axillary clearance [28].
Chronic postoperative morbidity after axillary clearance is
covered in later chapters on lymphoedema and chronic pain.
In summary, possible complications during and after AC
include intraoperative damage to the neurovascular struc-
tures, seroma formation, postoperative haematoma, sensory
disturbances, acute and chronic pain and lymphoedema. All
of these complications are more common after AC than SLNB.
24.5 Pathological Analysis
The apical node may be marked with a suture to orientate the
specimen. The extent of nodal involvement, including the
highest extent, may influence RT indications and extent.
Indications for irradiation of a wider lymph node area, such
as the supraclavicular area, differ considerably between cen-
tres, and heavy nodal involvement or level III involvement
may influence adjuvant radiotherapy field planning. At least
ten lymph nodes should be found and examined in the
pathology analysis of the axillary clearance specimen [29].
An increasing number of examined lymph nodes also
increase the number of metastatic lymph nodes found and
subsequently improve the accuracy of pathologic nodal
staging [30].
Key Points
55 Axillary clearance is used in staging the axilla only
when sentinel lymph node biopsy is contraindi-
cated.
55 Axillary clearance is currently the standard of care in
clinically node-positive patients.
55 There is considerable variation in treatment algo-
rithms regarding axillary clearance after metastatic
sentinel lymph node finding.
55 When axillary clearance is indicated, a routine dis-
section of Berg levels I and II should be performed.
55 Axillary clearance aims at removing all cancerous
tissue from the axilla.
55 Key anatomical structures including the long tho-
racic nerve, thoracodorsal pedicle and medial pec-
toral pedicle need to be identified and preserved
during axillary clearance.
55 Complications, including seroma formation, chronic
pain, sensory disturbances and lymphoedema, are
more common after axillary clearance than sentinel
lymph node biopsy.

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 290 T.J. Meretoja

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nerve handling and pain after axillary lymph node dissection for
breast cancer. Acta Anaesthesiol Scand. 2014;58(10):1240–8.
1. Fisher B, Redmond C, Fisher ER, Bauer M, Wolmark N, Wickerham DL,
16. Soares EW.  Anatomical variations of the axilla. Springerplus.

et al. Ten-year results of a randomized clinical trial comparing radi-
2014;3:306.
cal mastectomy and total mastectomy with or without radiation. N
17. Nadkarni MS, Raina S, Badwe RA. Medial pectoral pedicle: a critical
Engl J Med. 1985;312(11):674–81.
landmark in axillary dissection. ANZ J Surg. 2006;76(7):652–4.
2. Orr RK.  The impact of prophylactic axillary node dissection on
18. Andersen KG, Duriaud HM, Jensen HE, Kroman N, Kehlet H. Predic-
breast cancer survival--a Bayesian meta-analysis. Ann Surg Oncol.
tive factors for the development of persistent pain after breast can-
1999;6(1):109–16.
cer surgery. Pain. 2015;156(12):2413–22.
3. Heuts E, van der Ent F, van der Pol H, von Meyenfeldt M, Voogd
19. Bruce J, Thornton AJ, Powell R, Johnston M, Wells M, Heys SD, et al.
A. Additional tracer injection to improve the technical success rate
Psychological, surgical, and sociodemographic predictors of pain
of lymphoscintigraphy for sentinel node biopsy in breast cancer.
outcomes after breast cancer surgery: a population-based cohort
Ann Surg Oncol. 2009;16(5):1156–63.
study. Pain. 2014;155(2):232–43.
4. Kuehn T, Bauerfeind I, Fehm T, Fleige B, Hausschild M, Helms G, et al.
20. Zhu JJ, Liu XF, Zhang PL, Yang JZ, Wang J, Qin Y, et al. Anatomical
Sentinel-lymph-node biopsy in patients with breast cancer before
information for intercostobrachial nerve preservation in axillary
and after neoadjuvant chemotherapy (SENTINA): a prospective,
lymph node dissection for breast cancer. Genet Mol Res.
multicentre cohort study. Lancet Oncol. 2013;14(7):609–18.
2014;13(4):9315–23.
5. Lyman GH, Temin S, Edge SB, Newman LA, Turner RR, Weaver DL,
21. Hadjiminas DJ, Zacharioudakis KE.  Direct transpectoral approach
et  al. Sentinel lymph node biopsy for patients with early-stage
for level III axillary lymph node clearance. Ann R Coll Surg Engl.
breast cancer: American Society of Clinical Oncology clinical prac-
2014;96(6):481–2.
tice guideline update. J Clin Oncol. 2014;32(13):1365–83.
22. Aripin YM, Ibrahim N, Muhammad R.  Medial pectoral pedicle is a
6. Giammarile F, Alazraki N, Aarsvold JN, Audisio RA, Glass E, Grant SF,
reliable landmark for axillary lymph node dissection. Asian J Surg.
et al. The EANM and SNMMI practice guideline for lymphoscintigra-
2013;36(4):150–3.
phy and sentinel node localization in breast cancer. Eur J Nucl Med
23. Jelev L, Georgiev GP, Surchev L.  Axillary arch in human: common
Mol Imaging. 2013;40(12):1932–47.
morphology and variety. Definition of "clinical" axillary arch and its
7. Senkus E, Kyriakides S, Ohno S, Penault-Llorca F, Poortmans P, Rut-
classification. Ann Anat Anat Anz Off Organ Anat Ges.
gers E, et  al. Primary breast cancer: ESMO Clinical Practice Guide-
2007;189(5):473–81.
lines for diagnosis, treatment and follow-up. Ann Oncol.
24. ten Wolde B, van den Wildenberg FJ, Keemers-Gels ME, Polat F,
2015;26(Suppl 5):v8–30.
Strobbe LJ.  Quilting prevents seroma formation following breast
8. Bundred NJ, Barnes NL, Rutgers E, Donker M. Is axillary lymph node
cancer surgery: closing the dead space by quilting prevents seroma
clearance required in node-positive breast cancer? Nat Rev Clin
following axillary lymph node dissection and mastectomy. Ann
Oncol. 2015;12(1):55–61.
Surg Oncol. 2014;21(3):802–7.
9. Galimberti V, Cole BF, Zurrida S, Viale G, Luini A, Veronesi P, et  al.
25. Ouldamer L, Bonastre J, Brunet-Houdard S, Body G, Giraudeau B,
Axillary dissection versus no axillary dissection in patients with
Caille A.  Dead space closure with quilting suture versus conven-
sentinel-node micrometastases (IBCSG 23-01): a phase 3 ran-
tional closure with drainage for the prevention of seroma after mas-
domised controlled trial. Lancet Oncol. 2013;14(4):297–305.
tectomy for breast cancer (QUISERMAS): protocol for a multicentre
10. Van Zee K, Manasseh D, Bevilacqua J, Boolbol S, Fey J, Tan L, et al. A
randomised controlled trial. BMJ Open. 2016;6(4):e009903.
nomogram for predicting the likelihood of additional nodal metas-
26. Kottayasamy Seenivasagam R, Gupta V, Singh G.  Prevention of
tases in breast cancer patients with a positive sentinel node biopsy.
seroma formation after axillary dissection--a comparative random-
Ann Surg Oncol. 2003;10(10):1140–51.
ized clinical trial of three methods. Breast J. 2013;19(5):478–84.
11. Meretoja TJ, Leidenius MH, Heikkilä PS, Boross G, Sejben I, Regitnig
27. Thomson DR, Sadideen H, Furniss D. Wound drainage after axillary
P, et al. International multicenter tool to predict the risk of nonsen-
dissection for carcinoma of the breast. Cochrane Database Syst Rev.
tinel node metastases in breast cancer. J Natl Cancer Inst.
2013;10:Cd006823.
2012;104(24):1888–96.
28. Taylor JC, Rai S, Hoar F, Brown H, Vishwanath L. Breast cancer sur-
12. Meretoja TJ, Audisio RA, Heikkila PS, Bori R, Sejben I, Regitnig P, et al.
gery without suction drainage: the impact of adopting a 'no drains'
International multicenter tool to predict the risk of four or more
policy on symptomatic seroma formation rates. Eur J Surg Oncol.
tumor-positive axillary lymph nodes in breast cancer patients with
2013;39(4):334–8.
sentinel node macrometastases. Breast Cancer Res Treat.
29. Del Turco MR, Ponti A, Bick U, Biganzoli L, Cserni G, Cutuli B, et al.
2013;138(3):817–27.
Quality indicators in breast cancer care. Eur J Cancer.
13. Berg JW.  The significance of axillary node levels in the study of
2010;46(13):2344–56.
breast carcinoma. Cancer. 1955;8(4):776–8.
30. Schaapveld M, de Vries EG, van der Graaf WT, Otter R, de Vries J,
14. Warrier S, Hwang S, Koh CE, Shepherd H, Mak C, Carmalt H, et  al.
Willemse PH. The prognostic effect of the number of histologically
Preservation or division of the intercostobrachial nerve in axillary
examined axillary lymph nodes in breast cancer: stage migration or
dissection for breast cancer: meta-analysis of randomised con-
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trolled trials. Breast. 2014;23(4):310–6.

24

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 291 25

Axillary Management in the

Neoadjuvant Setting
K. Wimmer, F. Fitzal, R. Exner, and M. Gnant

25.1 Introduction – 292

25.2 Management of the Axilla in Patients with Node-Negative

Disease Before, as Well as After, PST (cN0/cN0) – 292

25.3 Management of the Axilla in Patients with Initial

Node-Positive Disease Downstaged to Clinical
Node Negativity After PST (cN1/cN0) – 293
25.4 Technical Considerations – 294

25.5 Management of the Axilla in Patients

with Micrometastases and Isolated Tumour Cells – 295

25.6 Timing – 296

25.7 How to Assess Lymph Node Status Clinically – 296

25.8 Adjuvant Radiotherapy – 298

25.9 Conclusion – 298

References – 299

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_25

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 292 K. Wimmer et al.

25.1 Introduction Recently, SLNB has become an established and frequently

25 used treatment in patients with locally advanced and local-
Neoadjuvant or primary chemotherapy (PST) is increasingly ized early breast cancer undergoing PST; consequently, new
used in modern breast practice, even in localized early breast controversial questions arise:
cancer. The recent NCCN Guidelines recommend PST for 1. Does SLNB provide an accurate assessment of nodal
patients with locally advanced or inoperable breast cancer, status when performed after PST in cN0 patients?
including patients with inflammatory breast cancer, patients
2 . Is there a difference between patients with initially
with N2 and N3 regional lymph node disease and those with node-negative vs. node-positive disease?
T4 tumours. Even patients with operable tumours may ben-
3 . What is the optimal timing of SLNB in the neoadjuvant
efit if the cancer subtype is associated with a high probability setting?
of response to certain systemic therapy regimes [1], a fact
4 . Which method should be chosen to confirm nodal status
that has led some centres to routinely use PST in triple-­ prior to PST?
negative (TN) and HER2-overexpressing BCs, almost irre-
spective of tumour size. Primary systemic therapy will not 25.2 Management of the Axilla in Patients
only induce tumour downstaging to facilitate breast conser-
with Node-Negative Disease Before,
vation or to enable less extensive surgery but may also achieve
complete pathological response (pCR), which is an impor-
as Well as After, PST (cN0/cN0)
tant beneficial long-term outcome indicator in certain breast
Recently, SLNB gained popularity in the neoadjuvant setting
cancer subtypes. pCR may occur in about 20–45% of primary
and is currently becoming a standard procedure in these
breast cancer cases [2–8]. Regarding the incidence of pCR in
patients, at least when they are clinically node negative prior
axillary lymph nodes, similar but not necessarily concordant
to PST. Trials, as well as meta-analyses, show that SLNB is a
rates are found [9–11]. Achieving a pCR appears to be pre-
reliable tool for staging in patients who undergo PST [18–
dictive regarding disease-free survival (DFS) and overall sur-
21]. Study results are displayed in . Table 25.1.
vival (OS), at least in TN and HER-positive BC [12]. While
 

The meta-analysis of Xing and colleagues [19] included

breast surgery within the new tumour boundaries after PST
21 studies with a total of 1,273 patients, who had previously
downstaging is of undisputed safety, controversial issues
undergone SLNB after PST followed by ALND during the
remain with respect to axillary surgery approaches.
surgical removal of the primary breast tumour. Overall, an
In general, axillary lymph node status is a prognostic fac-
identification rate of 90% and a false-negative rate of 12%
tor in patients with breast cancer. The presence or absence of
for SLNB were found. They reported a negative predictive
nodal involvement influences surgical and systemic treat-
value of 90% and an overall accuracy of 94%. In 5 of the 21
ment decisions. The finding of a SLN metastasis was previ-
included studies, a within-study comparison of IFRs and
ously usually followed by an axillary lymph node dissection
FNRs in patients with and without PST was performed.
to levels I and II (ALND). In patients not undergoing PST,
Neither for the IFR nor for the FNR could statistically sig-
this policy has changed over the last 10 years based on trials
nificant differences be found; therefore, SLNB was consid-
such as ACOSOG-Z011 [3], reducing the overall frequency
ered to be oncologically safe even in the neoadjuvant
of ALND; however, there are less convincing data regarding
setting.
this issue after PST.  Moreover, PST may change lymphatic
In 2009 a large trial led by Hunt and colleagues confirmed
drainage influencing the identification rate (IFR) and thus
these findings. In 3,736 patients with clinically lymph node-­
the false-negative rate (FNR) of SLNB. Another explanation
negative disease, axillary status was confirmed by palpation
for higher FNRs after PST might be that metastases in non-
and US or computed tomography. Regarding IFR and FNR, a
SLN may not respond to chemotherapy, while tumour cells in
minimal difference was found in patients with (IFR 97.4%,
the SLN do.
Clearly, the institutional identification rate of the SLN
should be as high as possible, whereas FNRs should be mini-
mized. In the beginning of the SLNB era in the early 1990s, ..      Table 25.1  Results of SLNB in clinically lymph node-­negative
identification rates of about 65%–81% [13, 14] were reported patients after PST
in patients without PST. Today, SLNB in patients undergoing
First Year No. of IFR FNR SLNB
primary surgery achieves an IFR of more than 90% [15, 16]
author patients (%) (%) oncologi-
and a FNR below 10% [16, 17]. If the FNR of this procedure cally safe?
does not exceed 10% – by the way an arbitrarily chosen cut-
off value – it is considered to be oncologically safe. If these Xing [19] 2006 1273 90 12 √
rates can be achieved, SLNB is an effective and appropriate Hunt [18] 2009 3736 97.4 5.9 √
staging tool for patients with clinically lymph node-negative
breast cancer undergoing primary surgery. The oncological Kelly [20] 2009 1799 89.6 8.4 √
safety of SLNB in the neoadjuvant setting, however, has still Classe [21] 2009 135 94.6 9.4 √
to be clarified.

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Axillary Management in the Neoadjuvant Setting
FNR 5.9%) and without PST (IFR 98.7%, FNR 4.1%).
Consequently, SLNB seems to be an accurate staging proce-
dure. Between patients with and without PST, no significant
­differences were observed regarding local, regional and dis-
tant recurrence rates [18].
Another comprehensive meta-analysis was published in
2009 by Kelly and colleagues. They included 24 trials with a
total of 1,799 patients with clinically lymph node-negative
breast cancer, who underwent SLNB after PST.  With an
observed IFR of 89.6% and a FNR of 8.4%, they recommended
SLNB as an accurate staging alternative to ALND [20].
The German AGO recommendations for patients with
advanced breast cancer suggested that a SLNB in a cN0 situ-
ation is a feasible procedure. If no SLN can be identified,
ALND should not be performed. However, if suspicious axil-
lary lymph nodes are found, an exploratory axillary dissec-
tion is indicated [22, 23].
The S3 German guidelines stated that patients with cN0
disease should undergo SLNB; however, the guidelines are
one of the few which recommend the procedure before PST
is administered [24].
In summary, SLNB is the standard of care for axillary
staging in patients with clinically node-negative breast can-
cer before and after PST. Taking the above-mentioned argu-
ments regarding the timing of SLNB into account, there are
advantages to performing SLNB after PST.
25.3  anagement of the Axilla in Patients
M The panel of the 2015 NCCN Guidelines group also rec-
with Initial Node-Positive Disease
Downstaged to Clinical Node
Negativity After PST (cN1/cN0)
Several authors state that ALND remains the standard proce-
dure in patients with initially lymph node-positive breast
cancer. The rationale for this notion is the high false-­negative
rates of SLNB in this setting and a low SLNB identification
rate [25–27]. Shen and colleagues investigated 69 patients
with histologically proven axillary lymph node metastases
and observed a false-negative rate of 25%. In conclusion,
SLNB in this study population was found to be an inaccurate
tool for staging the axillary nodes [25].
In contrast, Classe and colleagues suggested that SLNB
was an accurate staging tool after PST. They found a FNR of
15% in patients with cN+ disease who underwent SLNB after
PST [21].
To clarify the accuracy of SLNB in patients with initial
node-positive disease, the results of three prospective, multi-
centre studies are presented below:
The SENTINA study is a four-armed study with the pri-
mary endpoint “accuracy of SLNB after PST” measured by
the false-negative rate in patients with initially node-positive
disease who convert under PST to clinically node negative.
rares1geo@gmail.com
293 25
Secondary outcomes were the IFR of the SLNB before
and after PST, the IFR and the FNR of a SLNB after PST when
a positive SLN was already removed prior to PST. . Figure 25.1
shows the trial design of the SENTINA study. In patients
with cN1, who underwent a second SLNB after PST (arm B),
a very high FNR of 51.6% was found. In comparison, in those
patients who converted from cN+ to ycN− (arm C), the FNR
was 14.2%. The highest IFR (99.1%) was found in patients
who underwent SLNB before PST (arms A and B). In those
who converted from cN+ to ycN0 and SLNB had been per-
formed after PST (arm C), an IFR of 80.1% was achieved. The
lowest IFR was reported when a second SLNB was performed
after PST.  In this case the SLN could only be identified in
60.8%. The SLNB seems to be a less reliable tool for staging
when performed after PST.
The ACOSOG Z1071 study (Alliance) focused on the
assessment of the reliability of the SLNB after PST in patients
with initially node-positive breast cancer [29]. Distinguishing
between N1 and N2 disease, at least one SLN could be found
in 92.9% in patients with N1 breast cancer and in 89.5% in
patients with N2 nodal status. An overall FNR of 12.6% was
reported. However, if some factors, which are mentioned
below, are taken into consideration, a lower rate may be
achieved.
The SN FNAC study assessed the accuracy of SLNB after
PST in patients with biopsy-proven node-positive breast can-
cer [8]. They reported an IFR of 87.6% and a FNR of 8.4%.
The results of these studies are shown in . Table 25.2.
ommended ALND for patients with histologically proven
lymph node metastasis at presentation. Patients who do not
undergo ALND are supposed to have an increased risk for
locoregional recurrence in the axilla [27]. An update of the
American Society of Clinical Oncology clinical practice
guideline in 2014 stated that patients undergoing PST might
be offered SLNB.  If the biopsy is performed after PST, a
higher FNR must be expected. Due to insufficient data, no
unambiguous statements were issues [26]. In contrast to the
NCCN Guidelines, the panel of the St. Gallen International
Expert Consensus 2017 considered SLNB to be feasible in
patients with clinically node-positive breast cancer who were
downstaged during PST.  However, in consideration of the
high FNR after PST, it was recommended that at least three
SLNs be examined.
Nevertheless, advances in systemic breast cancer thera-
pies and the above-mentioned rates of axillary pCR during
PST provide hope that even node-positive disease will be
convertible for many patients, and therefore SLNB poten-
tially gains in importance in these cases. To increase the
accuracy and feasibility of SLNB in patients with node-­
positive disease prior to PST, it is important to identify the
factors that influence identification rates and false-negative
rates of SLNB in this setting.
 294 K. Wimmer et al.

..      Fig. 25.1  SENTINA trial

25 design (Modified from Kuehn
et al. [28], © The Lancet 2013)
Clinically node- Clinically node-
negative (cN0) positive (cN1 or cN2)

SLNB

Pathologically Pathologically
node-negative node-positive
(pN0sn) (pN1sn)

Neoadjuvant chemotherapy

Conversion to Disease remains

clinically node- clinically node-positive
negative disease (yc N0) (ycN1)

SLNB and SLNB and

NO ALND ALND
ALND ALND

Arm A Arm B Arm C Arm D

25.4 Technical Considerations

..      Table 25.2  Study results of SENTINA, ALLIANCE and SN
FNAC trials
Several trials have shown that the IFR of the SLN may be
Study SENTINA [28] ALLIANCE [29] SN FNAC favourably influenced by the selection of suitable mapping
[8] agents. The SENTINA trial reported that the use of blue dye
pN1/ pN1/ cN1/ypN0 cN1/ypN0
in addition to the application of a radiocolloid was associated
ycN0 ypN0 with a higher IFR when the SLNB was performed after
PST. When the biopsy was performed before PST, no differ-
Procedure SLNB X X FNA or ence in the IFR was found between single-agent mapping
before PST core
(radiocolloid alone) and combined mapping (radiocolloid
biopsy
and blue dye).
Procedure SLNB + SLNB + SLNB + ALND SLNB + The study protocol specified the use of a radiocolloid as
after PST ALND ALND ALND mapping agent because it is assumed to be an objective, highly
No. of 360 592 649 153 reproducible and measurable technique. They further implied
patients that the use of blue dye is less reproducible and that the classifi-
IFR (%) 60.8 80.1 92.9 87.6 cation of whether a lymph node turns blue is subjective.
Nevertheless, in 7.3% of patients who converted from clinically
FNR (%) 51.6 14.2 12.6 8.4
node positive to node negative under PST, no SLN could be
detected, although lymphoscintigraphy revealed a r­ adiocolloid

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Axillary Management in the Neoadjuvant Setting
hot spot. The technically more challenging ­procedure after PST
is thought to be caused by fibrosis and structural changes in
lymphatic vessels [28].
The SNFNAC trial didn’t describe the influence of dual map-
ping on the IFR, but the authors reported a lower FNR of 5.2% if
radiocolloid and dye were used. If only single mapping was per-
formed by using an isotope, the FNR increased to 16.0% [8].
Boughey and colleagues (2015) published a multivariate
logistic regression model to assess the factors, which influ-
enced the IFR of SLN in the ACOSOG Z1071 study in 2013.
No significant influence on the IFR of the SLN was found for
patient’s age, body mass index, tumour subtype, type of breast
surgery, nodal response during PST and length of chemo-
therapy. However, it was shown that the method of SLN map-
ping was the only factor that affected the identification of the
SLN. If dual mapping was used, a significant higher IFR was
found than if only a single mapping agent was used [30].
Once again, fibrosis of the axilla after PST was proposedds as
a possible reason. Further, the different molecular sizes and
the varying time of transmission in the lymphatic tissue of
both mapping agents could be responsible for the increased
IFR if both agents were used [29].
One of the factors that might be able to improve the accu-
racy of SLNB is the number of harvested SLNs. The SENTINA
trial demonstrated that there was a significant relation between
the number of resected SLNs and the FNR. In patients with
one removed SLN, the FNR was 24.3%. In patients with two
removed SLNs, a FNR of 18.5% was found, whereas in those
with more than three harvested SLNs, a FNR of less than 10%
was found [28].
The ACOSOG Z0171 trial reported an overall FNR of
12.6%, which was higher than their predefined primary end-
point of 10%. When two SLNs were removed, the FNR
reached 19.6%, while it decreased to 8.3% in patients with
three removed SLNs [21].
Similar results were described by Boileau and colleagues
in the SNFPST trial. If two or more SLNs were harvested, the
FNR decreased to 4.9%. If less than two SLNs were removed,
the FNR increased to 18.2–20.8% [7, 8]. Van Nijnatten and
colleagues reported in their meta-analysis a FNR of 15.1%
(12.7–17.6%). After a subgroup analysis, it could be shown
that the FNR significantly increased when only one SLN was
harvested and that it decreased when more than two SLNs
were removed (23.9% vs. 10.4%) [31].
The pathological examination technique of harvested
SLNs also influences the accuracy of SLNB. According to the
results of a meta-analysis, Fu and colleagues reported a lower
FNR of the SLNB after PST in patients with initially node-­
positive disease if IHC was combined with haematoxylin and
eosin (H&E) staining than if H&E staining was used alone
(8.7% vs. 16.0%) [32]. The use of mandatory immunohisto-
chemistry was also supported by the results of the SN FNAC
trial. They found a low FNR of 8.4% if IHC was used in
patients with biopsy-proven lymph node-positive breast can-
cer [8]. In contrast, a recently published meta-analysis [33]
rares1geo@gmail.com
295 25
didn’t find any significant differences in FNRs of the SLNB
between studies using H&E alone and those using H&E in
combination with IHC (FNR 11% (95% CI, 4%–18%) vs. 4%
(95% CI, 1%–7%), p = 0.241). Further studies to determine if
the routine combination of IHC and H&E has a clinical rel-
evance for patients undergoing PST are needed.
A retrospective analysis from of the Alliance Z1071 trial
showed that clip placement during initial node biopsy can
reduce the FNR of SLNB after PST. In patients with cN1 dis-
ease, who underwent SLNB where at least two SLNs were
removed and the clip was found within the SLNB specimen,
a FNR of 6.8% could be achieved. The ability to identify for-
mer suspicious nodes and to extend the SLNB by the addi-
tional removal of clip-marked nodes may increase the
accuracy of this procedure [34]. Further evaluation of the
effect of clip placement in suspicious nodes prior to PST on
the SLNB as a staging tool is required.
In conclusion, SLNB seems to be an appropriate way to
stage axillary lymph nodes even in patients with initially
node-positive disease that converts to node negative under
the influence of PST. Nevertheless, long-term data regard-
ing oncologic outcomes is still pending. However, there
are some factors that have to be taken into account to
improve the accuracy of this procedure in this particular
setting: To achieve a lower FNR, at least three SLNs should
be removed, and the use of dual-tracer mapping and
­immunohistochemistry are mandatory. Clip placement in
clinically positive nodes prior to PST and additional resec-
tion of those clipped nodes during SLN surgery may also
help to decrease the FNR.
25.5  anagement of the Axilla in Patients
M
with Micrometastases and Isolated
Tumour Cells
The prognostic impact of micrometastasis (pN1mi) and iso-
lated tumour cells (pN0[i+]) seems to be different in patients
without PST from patients with PST. In patients undergoing
primary surgery, ALND is not recommended if only micro-
metastases or isolated tumour cells are identified in the SN
specimen. In the absence of PST, IHC is still not mandatory
if initial H&E staining is negative. However, in patients
undergoing PST, minimal nodal disease after PST represents
remnant tumour cells that did not respond to systemic treat-
ment adequately [35, 36]. The presence of remaining meta-
static axillary nodes is significantly associated with a
decreasing DFS [10]. As a result, ALND should remain the
standard procedure in patients with any size of axillary lymph
node metastases after PST. Even micrometastases or isolated
tumour cells are considered to be node positive. It should be
noted that the use of IHC – while not being routine practice
in most centres – facilitates the detection of micrometastases
and isolated tumour cells in SLNs, which were negative on
initial H&E staining [8].
 296 K. Wimmer et al.
Boileau and colleagues reported that finding sentinel
25 lymph node metastases of any size, including micrometasta-
ses or isolated tumour cells, should be considered as node
positive after PST, which was one of the most important
results of their trial because, thus, they were able to achieve a
FNR of <10%. If micrometastases and isolated tumour cells
were considered “node positive”, the FNR was 8.4%. If iso-
lated tumour cells (<0.2 mm) were considered “negative”, the
FNR increased to 13.3%, whereas it increased to 16.9% even
if micrometastases (>0.2–2  mm) were considered as nega-
tive. Although no statistically significant correlation was
found between the size of SLN metastases and the rate of
positive non-SLNs, they observed a rate of positive non-SLNs
after PST of 57% in patients with isolated tumour cells, of
38% in patients with micrometastases and of 56% in patients
with metastases exceeding 2  mm, respectively [8]. Due to
these findings, micrometastases and isolated tumour cells
should be considered as node-positive disease after PST.
In the neoadjuvant setting (i.e. after PST), any size of
lymph node metastases should be considered as node posi-
tive. Based on the currently available data, ALND represents
the standard treatment for the axilla in patients with macro-
metastases, micrometastases and isolated tumour cells in the
SLN after PST. Nevertheless, further studies have to evaluate
the prognostic value of isolated tumour cells in the neoadju-
vant setting.
25.6 Timing
With respect to the optimal timing of SLNB in the context of
PST, unanimous recommendations can be found in the lit-
erature: If SLNB is performed before PST, similar FNR and
IFR can be found as in primary surgery patients without
PST. The SENTINA trial, for example, found an IFR of 99.1%
when the SLNB was scheduled before PST.  In comparison,
after PST, a significantly lower IFR of 80.1% was observed
[28]. Other trials confirmed the finding of lower IFRs and
higher FNRs when biopsy is performed after PST [18, 19, 28,
29]. These findings are commonly used arguments to support
SLNB before PST. Furthermore, the assessment of pathologi-
cal axillary status before PST might also influence pre-­
surgical therapeutic strategies such as recommending
immediate versus delayed implant reconstruction where
knowledge of the need to give chest wall radiotherapy is
important, for example.
Based on these findings, it seems reasonable to schedule
the SLNB before PST. However, one argument against SLNB
before PST might be that nodal tumour response to systemic
therapies can’t be assessed. One might argue that the pri-
mary tumour is left in situ, which means that the assessment
of the tumour response to PST is still possible.
Further, if an above-mentioned axillary pCR rate of about
40% is kept in mind, it also means that about 40% of ALND
could theoretically be spared if the SLNB is performed after
PST. Of course, further studies have to confirm the safety of
omitting ALND in patients with cN+ before chemotherapy
rares1geo@gmail.com
and a tumour-free SLN after chemotherapy. Long-term data
regarding recurrence-free and overall survival in patients
with cN+/ycN- is still pending. It must be kept in mind that
a tumour-free SLN after PST is perhaps not of equivalent
accuracy in predicting the status of the axillary nodes as a
tumour-free SLN before PST.
When SLNB is performed before PST, fewer ALNDs may
be spared because the default treatment of biopsy-proven
lymph node metastasis would be an axillary dissection [8].
Additionally, a SLNB before PST also means a second surgi-
cal procedure for the patients.
A further consideration might be that a two-staged SLNB
could be a useful approach to multiply benefits of both set-
tings. Concerning this issue, the SENTINA trial demon-
strated that a second SLNB in patients with a positive SLN
before PST is not a reliable staging tool. In this subgroup, a
FNR of 51.6% was found. In comparison, in patients who did
not undergo pre-chemo SLNB and converted from cN+ to
ycN-, the FNR was 14.2%. The reason for this might be that
the original lymph ducts have been damaged or destroyed by
PST, and thus the “regular” lymphatic spread of tumour cells
in the lymphatic vessels could have been altered [28]. In con-
trast to these findings, Khan and colleagues reported a FNR
of 4.5% in patients with a repeated SLNB after PST; however,
only 33 patients were included in this subgroup [37].
In summary of the above-mentioned arguments, the
advantages of a SLNB after PST appear to outweigh the
­disadvantages: On the one hand, a reduction of ALNDs can
be achieved, and on the other hand, a second surgical proce-
dure can be spared. Nevertheless, long-term oncologic out-
comes for patients who convert from cN+ to ycN- and who
do not undergo ALND are still awaited.
25.7  ow to Assess Lymph Node Status
H
Clinically
Different ways to confirm nodal status prior to PST can be
found in the recent literature. In the ACOSOG Z1071
(Alliance), nodal status was confirmed by fine-needle aspira-
tion or core needle biopsy. In comparison, in the SENTINA
study, the assessment of lymph node status was restricted to
palpation and axillary ultrasound. They argued that core
needle biopsy and fine-needle aspiration were not clinical
standards, therefore often not used, and so the study protocol
recommended these techniques only as optional. It is remark-
able that in those patients who converted from clinically
node positive to clinically node negative after PST (arm C),
47.7% of patients were ypN1. Thus, almost half of these
patients had histologically proven lymph node metastasis
although they were graded as clinically node negative.
Other studies also show that the clinical assessment of
axillary status is associated with a high error rate as demon-
strated by Specht and colleagues. Clinical examination was
inaccurate in 41% of patients, and false-positive results could
be observed in 53% of patients with moderately suspicious
lymph nodes [38].
Axillary Management in the Neoadjuvant Setting
A secondary endpoint of the ACOSOG Z1071 (Alliance)
trial was to determine the impact of axillary ultrasound
(AUS) after PST.  Patients with a suspicious US result after
PST had significantly more often a SLN metastasis and had a
greater number of positive lymph nodes and a greater size of
the metastasis than those with normal US findings.
Additionally, a reduction of the FNR from 12.6% to 9.8%
could be found in those patients with a normal AUS after
PST and at least two removed SLNs. On the basis of these
findings, axillary US after PST allows selection of patients
with the greatest likelihood to benefit from the omission of
ALND [39] and should be considered a standard procedure.
Moorman and colleagues stated that AUS is an accurate
staging tool in the preoperative setting when it is combined
with fine-needle aspiration cytology. A sensitivity and speci-
ficity of 42.4% and 97.1%, respectively, were achieved in this
study population including 1,124 patients. In 18.9%, a false-­
negative US result was found. Patients with false-negative US
findings were significantly younger and more frequently had
oestrogen-receptor-positive tumours, larger tumours and
lymphovascular invasion. The sensitivity of AUS and fine-­
needle aspiration cytology increased with an increasing
number of lymph node metastases. In conclusion, AUS in
combination with cytology has a greater sensitivity in patients
with more than three lymph node metastases, whereas in
younger patients with larger and oestrogen-receptor-positive
tumours, higher false-negative rates must be expected [40].
Before PST
Date 07.04.2016
Size 16.4 mm
..      Fig. 25.2  Initial radiologically node-positive disease converting to node negative under the influence of PST (Source: Department of
Diagnostic and Interventional Radiology, Hospital Barmherzige Schwestern, Linz, Austria, by Courtesy of Maria Miesbauer, MD)
rares1geo@gmail.com
297 25
The Z0011 trial also addressed the question of whether
US is still an appropriate tool for staging of the axilla. In total
679 patients underwent AUS, and in cases with a suspicious
US, lymph nodes were biopsied. Patients with a negative AUS
underwent SLNB.  They reported a sensitivity of 86.2%, a
specificity of 100%, a positive predictive value of 100% and a
negative predictive value of 71.9% for AUS with sampling of
suspicious nodes and concluded that AUS is an important
guiding tool for the management of the axilla in patients with
breast cancer [41].
Schipper and colleagues investigated whether AUS accu-
rately predicts pN0, pN1 and pN2–3 status. In patients with a
negative AUS (cN0), a NPV of 95.5% could be achieved,
whereas in patients with one to three suspicious nodes (cN1),
a NPV of 58.5% was described. In conclusion, a negative AUS
can generally exclude pN2/pN3 disease, though it cannot
accurately differentiate between pN1 and pN2–3 [42].
The predictive value of a negative AUS was evaluated by
Jackson and colleagues. It was reported that the combination of
normal findings on physical examination and a negative AUS
could reliably exclude patients with “heavy” nodal disease. The
sensitivity and specificity for AUS to predict three or more
lymph node metastases were 71% and 83%, respectively [43].
. Figure  25.2 demonstrates the conversion from radio-
logically node-positive to node-negative disease during PST.
The diagnostic abilities of 18F-FDG PET/CT compared
to those of US and MRI were evaluated by An and colleagues.
After PST
11.10.2016
8.7 mm
 298 K. Wimmer et al.
25
..      Fig. 25.3  An 18F-FDG-positive lymph node in PET-CT prior to PST
(Source: Department of Biomedical Imaging and Image-Guided
Therapy, Medical University of Vienna, Austria)
The PPV and the NPV were 66.7% and 81.6% for US, 65.9%
and 79.2% for MRI and 77.6% and 79.1% for 18F-FDG PET/
CT.  Among the imaging modalities, no significant differ-
ences in diagnostic ability could be observed. However, com-
bining 18F-FDG PET/CT with US or MRI could improve the
diagnostic ability compared to 18F-FDG PET/CT alone [44],
while it has to be admitted that PET-CT may not be available
in most centres for this purpose.
. Figure  25.3. shows an image of an 18F-FDG-positive
lymph node in PET-CT prior to PST.
To summarize, 18F-FDG PET/CT and/or AUS combined
with fine-needle aspiration or core biopsy represent the
methods with the highest PPV for diagnosis of metastatic
lymph node involvement. For confirmation of node-negative
disease, AUS is – with its high NPV – an accurate alternative
to more invasive staging procedures. Clinical assessment
alone is often associated with high error rates.
25.8 Adjuvant Radiotherapy
The increasing number of patients undergoing PST and the
higher rates of axillary pCR make it necessary to consider
how to optimize locoregional treatment after PST. The role of
rares1geo@gmail.com
radiotherapy to the nodal basins in the neoadjuvant setting
remains unclear. The effect of radiotherapy on survival if
axillary pCR is achieved after PST is questionable, and fur-
ther evaluation is needed. The DEGRO practical guidelines
2014 stated that in patients who converted from clinical
node-positive to ypN0 disease after PST, the decision for
regional nodal irradiation should depend on the pre-­
neoadjuvant stage, irrespective of the response to chemo-
therapy [45]. If no remnant tumour cells are expected, the
disadvantages of RT might outweigh its benefits. In contrast,
if ALND could be omitted in patients who convert from
node positive to node negative, axillary radiotherapy might
play an important role in adjuvant axillary treatment. In the
non-neoadjuvant setting, the AMAROS trial showed that
axillary radiotherapy can achieve equal locoregional control
with a lower morbidity than ALND in patients with a posi-
tive SLNB [46]  – however, the trial was criticized for poor
results in the surgery arm (wound infections, frequency of
level III dissections). The ongoing NSABP B-51 trial may
more accurately answer some of the remaining questions.
This trial plans to evaluate the effect of radiotherapy on axil-
lary lymph node basins in patients who convert from node
positive to node negative after PST.
Another study may provide insights into potential treat-
ment strategies in patients with lymph node metastases who
do not convert following PST. The Alliance A11202 trial will
randomize patients with histologically proven remaining
SLN metastasis after PST to either ALND and additional
chest wall and nodal RT or chest wall and nodal RT alone.
25.9 Conclusion
The controversy about the feasibility and accuracy of SLNB
after PST is currently ongoing. Evidence to date suggests that
SLNB is a useful staging tool in patients with clinically node-­
negative disease, both prior and after PST.  In patients who
convert from node-positive to node-negative disease, SLNB
should be scheduled after PST, even if the detection of the
SLN is more difficult and associated with higher FNRs than if
performed before PST. The most important advantage of this
sequence is the potential to safely avoid ALND in cases where
the SLNB is negative due to pCR. To achieve a lower FNR, at
least three SLNs should be removed; the use of dual-tracer
mapping and immunohistochemistry are mandatory to
increase the accuracy of the SLN surgery. For patients with
node-positive disease after PST, ALND continues to be the
best surgical approach although “definitive” radiotherapy
forges ahead as a locoregional treatment alternative.
The recommended surgical management of the axilla in
the neoadjuvant setting is illustrated by a flowchart in
. Fig. 25.4.
Axillary Management in the Neoadjuvant Setting
299 25
..      Fig. 25.4  Axillary manage-
ment in the neoadjuvant setting
Clinically node-positive
Clinically node-negative (cN0)
(cN1 or cN2)

Neoadjuvant chemotherapy

ycN0 ycN1 ycN0 ycN1

SLNB ALND SLNB ALND

Remove at least 3 SLNs if ypN1 or

Use dual tracer mapping ypN1mi or ALND
place Clip in initial cN1 node ypN0[i+]

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301 25
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 303 26

Axillary Reverse Mapping: ARM

Isabel T. Rubio, Ernest J.T. Luiten, and V. Suzanne  Klimberg

26.1 Introduction – 304

26.1.1 Lymphatic’s Pathways – 304

26.2 Description of the ARM Technique – 304

26.2.1 ARM Node Location – 305
26.2.2 Identification of ARM Lymphatics and Nodes
During SLNB and ALND – 306
26.2.3 Crossover – 306

26.3 Metastatic Involvement of ARM Nodes – 307

26.3.1 Involvement of ARM Node in Patients Undergoing SLNB – 307
26.3.2 Involvement of ARM Nodes in the Pathologically Positive Axilla – 307
26.3.3 Involvement of ARM Nodes in Patients with a Positive
SLN and ALND – 307
26.3.4 Involvement of ARM Nodes in the Neoadjuvant Setting – 309

26.4 The Impact of ARM on Lymphoedema Rates – 309

26.4.1 Oncological Safety of Preserving ARM Nodes – 309

26.5 Other Techniques to Reduce Lymphoedema – 311

26.5.1 Microvascular Anastomosis – 311

26.6 Conclusion – 311

References – 311

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_26

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 304 I.T. Rubio et al.
26.1 Introduction
Despite improvements in the last two decades in the manage-
26 ment of breast cancer, axillary lymph node dissection
(ALND) remains a common surgical intervention for some
women with clinically involved nodes or positive sentinel
nodes (see 7 Chap. 24 for a detailed review of indications).
One of the most functionally debilitating morbidities from
ALND is lymphoedema [1]. Axillary dissection is associated
with a more than threefold increased risk of lymphoedema
compared with no dissection. Lymphoedema has been
reported to develop from 7% to 77% of patients although the
true incidence is uncertain due to wide variations in mea-
surement techniques and diagnostic criteria. When ALND is
combined with radiation therapy (RT), lymphoedema rates
are higher than with ALND alone and are reported to range
from 30% to 50% [2]. Studies have shown that an increased
risk of lymphoedema following breast cancer treatment may
be related to mastectomy (rather than lumpectomy), axillary
dissection, radiotherapy, chemotherapy and lymph node sta-
tus. Lymphoedema is known to have detrimental effects on
quality of life due to body image changes, alterations in arm
function and increased complications such as infection and
cellulitis [3, 4].
With the incorporation of sentinel lymph node biopsy
(SLNB) into routine protocols for staging of the clinically
uninvolved axilla, rates of lymphoedema have decreased,
although lymphedema has not been avoided completely. In
most studies, rates of lymphoedema after SLN are signifi-
cantly lower when compared to ALND (<11% versus >20%,
respectively) [5, 6]. Even in those patients with a positive
SLN biopsy who undergo RT, the 2-year cumulative inci-
dence of lymphoedema was 10%, compared with 19% for
ALND without RT and 30% for ALND with RT as it has been
shown in the study by Miller and colleagues [7].
So although the rate of lymphoedema is much less with
the use of SLNB, it remains clinically significant (range,
0–13%), and in the randomized National Surgical Adjuvant
Breast and Bowel Project (NSABP) trial B-32, lymphoedema
in the SLNB group was found to be 8% at 36  months [8].
Measures to reduce damage to the lymphatic drainage to the
arm during both procedures are therefore highly desirable.
26.1.1 Lymphatic’s Pathways
ALND has been described as the removal of level I and II
axillary nodes, and this dissection is done following anatom-
ical boundaries. The findings from multiple studies support
the common belief that only treatments which disrupt the
flow of lymph through the axilla will lead to the development
of lymphoedema. This disruption can happen during ALND
or, to a lesser extent, SLNB.
Suami and colleagues [9] described the gross lymphatic
anatomy of the lymphatic drainage and lymph node connec-
tions in the arm using a radiologic technique which involved
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injecting hydrogen peroxide into the fingertips of cadavers to
identify lymphatic vessels in the arm. They found that the
superficial lymphatic vessels course within the subcutaneous
fat in close proximity to the main subcutaneous veins. Most
lymph vessels from the hand and the forearm always flow
into the lymph nodes in the axillary region. Some go above
the axillary vein and/or directly into the subclavian vein.
They showed that in the axilla, more than one lymph node
was always detected that received lymph channels from the
upper limb, although it appeared that the major lymphatic
drainage from the upper limb is usually to one lymph node.
Nevertheless this main or dominant lymph node connects
with other lymph nodes situated more proximally in the
axilla.
Subsequent to the publication of the axillary reverse map-
ping (ARM) procedure [10, 11], Pavlista and colleagues [12]
used direct contrast lymphography of the lymphatic drainage
of the upper extremity and demonstrated that it was fully
separable from the lymphatic drainage of the chest and breast
in an effort to find an explanation for lymphoedema after
SLNB. They found that the first SLN image, which was usu-
ally localized most laterally in the axilla, was the one into
which the afferent lymphatic drainage of the upper extremity
flowed. They also showed contrast media was not limited to
flowing centrally towards higher nodes in a sequential man-
ner but could drain into any of the axillary nodes including
the sentinel nodes of the breast.
In another study, the same group [13] showed that a cer-
tain portion of lymph is fed into the caudal part of the axilla
near to the sentinel nodes of the breast (24% of all cases) and,
in five cases, even entered them directly. The concordance of
the sentinel node of the upper extremity and the sentinel
nodes of the breast or their intimate vicinity is the probable
cause of lymphoedema after SLN biopsy in breast cancer.
They assumed that any surgical intervention in the axilla may
potentially result in the development of lymphoedema of the
upper extremity, the severity of which is dependent upon the
variability and location of damage to the lymphatics.
The potential to identify afferent lymphatics and nodes
coming from the lymphatics draining the arm and to prevent
damaging or removing them in order to prevent or reduce
lymphoedema is the main concept underpinning the ARM
technique.
26.2 Description of the ARM Technique
Two separate authors (Klimberg and colleagues [10] and Nos
and colleagues [11]) simultaneously developed the concept
that modification of the surgical procedure may prevent
lymphoedema following axillary surgery. The concept of
ARM [10] described the split mapping of the drainage of the
arm with blue dye and radioisotope from the breast to deter-
mine the existence of distinct SLNs for the arm and the breast
and to assess the anatomical variation in these lymphatics
and how much overlap there would be. By mapping the
lymph channels and nodes draining the arm, it is feasible to
Axillary Reverse Mapping: ARM
..      Fig. 26.1  Split mapping of the drainage of the arm and the breast.
SLN and ARM node
identify and preserve them (. Fig. 26.1). The preservation of
 
these lymphatics should consequently prevent disruption of
lymphatic drainage from the arm and resulting lymphoe-
dema. The concept of ARM must include this split mapping
from the breast and the arm to determine when the ARM
node is also the SLN and should be excised and remaining
lymphatics re-approximated.
The original ARM technique [10, 11] was performed by
injecting 1–5 mL of blue dye (isosulfan blue, patent blue or
methylene blue) subcutaneously in the inner upper part of
the ipsilateral arm. The injection can be made subcutane-
ously or intradermally although the preferred technique is
subcutaneous injection as there are rich lymphatics in this
area and the drainage is rapid. Also the time to visualization
as well as the tattoo from the blue dye injection is less visible
if injected in the upper inner volar surface of the arm versus
the hand.
After injection, massage is performed in the area of injec-
tion, and the arm is elevated in order to facilitate drainage,
similar to the injection of blue dye in the breast for SLNB [10,
11, 14–16]. In the early reports, a time interval of at least
15 min between the injection and surgery was recommended
[17], although from other reports, it seems that the arm mas-
sage and elevation are more important for drainage than the
time interval since the injection [18]. Other authors have not
reported improved detection when massaging the arm [14].
In patients undergoing SLNB and an ARM technique, it is
crucial that technetium-99 (99Tc) is injected for SLN identi-
fication and blue dye for the ARM technique [10]. The SLNB
can be performed through a mastectomy incision or an inci-
sion in the axilla. The ARM procedure always includes both
radioactivity in the breast and blue dye in the arm because, in
a small fraction of patients, the ARM node will also be the
SLN from the breast [10, 19]. In cases where the SLN is posi-
tive and a mastectomy is performed, the ALND can be com-
pleted through the same incision; otherwise, a separate
axillary incision can be made.
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305 26
For patients undergoing only ALND, other groups
injected patients with 99Tc-labelled nanocolloid alone or
combined with blue dye, into the back of the hand on the
ipsilateral side or in the upper inner part of the arm [18, 20,
21]. However, it must be emphasized that injecting into the
arm only does not allow identification when the ARM node
is also draining the breast and would be more likely to con-
tain tumour cells. Split mapping is recommended in all cases.
In those cases where an ALND is performed, an anatomic
resection of levels I and II lymph nodes is completed, taking
care to identify and preserve blue lymphatics [17–19, 22].
One of the complications of the ARM technique has been
the temporary blue tattooing at the injection site. The tattoo
fades away but may last from days to years [10, 23, 24] although
usually after the first 6 months it is practically invisible [22].
Other authors have used fluorescence imaging technique
with subcutaneous injection of indocyanine green (ICG) in
the upper inner arm to avoid the blue dye tattoo and to try to
improve ARM node identification rates [25–29]. The ICG is
injected subdermally into the inner side of the wrist [27] or
intradermally in the upper inner ipsilateral arm [26], and the
doses used have varied between 0.1 and 1.0 mL [26–28]. In
372 patients, ICG was used combined with blue dye: more
than 2 h before surgery, 0.15 mL of ICG was subcutaneously
injected into the interdigital area, and immediately before
surgery, 1.5 mL of blue dye was subcutaneously injected in
the upper third of the arm [28].
The fluorescence signal flowing to the axilla from the
upper extremity was detected using a near-infrared fluores-
cence imaging system as the wavelength is not visible to the
naked eye. One of the disadvantages of using an invisible
tracer is that the lymphatic channels cannot be followed dur-
ing surgery and therefore are more likely to be damaged
which may increase lymphoedema rates. In the study by
Noguchi [29] using a fluorescence imaging system, the SLN
was the same as the ARM node in 77 (27%) of 286 patients,
and the mean number of removed ARM nodes was 7.2 (range
0–25) in patients who underwent ALND, whereas the mean
number of SLNs removed was 1.6 (range 1–7). The clinical
importance of the first ARM node or secondary ARM nodes
in the lymphatic drainage of the arm is still unknown, but the
chances of preserving the ARM node will decrease if the con-
cordance rate between the SLN and the ARM node is higher.
However, preserving up to seven nodes while doing an
ALND may impact on the oncological safety of the proce-
dure.
26.2.1 ARM Node Location
The lymphatic pathway of the arm is usually described as
crossing the lower part of the axilla below the axillary vein,
although there is significant variability in reported studies.
Most studies have shown that the ARM blue node usually lies
in the lateral pillar of the axillary dissection, lateral to the
thoracodorsal bundle [14, 25, 30, 31]. The most common pat-
tern identified during SLN is the sling pattern, occurring in
 306 I.T. Rubio et al.
26
..      Fig. 26.2  Axillary reverse mapping sling
71.4% of the cases as showed by Tummel and colleagues [32]
(. Fig. 26.2). The ARM lymphatics have been described to be
 
as low as 3–4  cm below the axillary vein, in the medial or
lateral apron or even positioned above the vein, although less
commonly [19, 22]. The size of the ARM lymphatics is also
variable, and they may be as large as 6 mm in diameter [23,
26]. Boneti and colleagues reported that blue lymphatics
draining from the arm were visible through the SLNB inci-
sion and were located near the field of the SLN in 42% of the
131 patients they reported. This may explain why even with
SLNB there are cases of lymphoedema [14].
Regardless of the tracer used for the ARM technique,
almost all of the ARM nodes are located in the same area,
between the axillary vein and the second intercostobrachial
nerve, lateral to the thoracodorsal bundle and close to the
latissimus dorsi muscle or in the vicinity.
26.2.2 I dentification of ARM Lymphatics
and Nodes During SLNB and ALND
Early studies describing the technique showed ARM identifi-
cation rates of only 61% [10], but with more experience using
the technique and increased knowledge of the variations in
lymphatics, blue arm drainage identification increased to
nearly all patients [31]. Other studies have reported rates of
ARM lymphatic and node identification rates of between
27% and 100% [15, 16, 23]. In the meta-analysis by Han and
colleagues [33] in eight studies, they found that the pooled
results revealed an overall identification rate of 38.2% (95%
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CI 32.9–43.8%), with statistically significant heterogeneity
(I2 = 70.5%, P < 0.05) [11, 14, 15, 19, 24, 25, 28, 34]. Slight
differences in the rate of identification have been shown
when using two tracers (78–91%) [11, 21] or using only 99Tc
(75–100%) [20, 35]. In this meta-analysis, when they strati-
fied by mapping materials, the pooled identification rate
remained similar [33].
Identification rates varied depending on whether an SLN
or an ALND was performed. In this way, identification rates
in ALND ranged from 70% to 95% in reported studies [18,
20, 21, 25, 26, 28]. The identification rates of ARM nodes
have been lower in the SLN biopsy field when compared with
those in the ALND field. And this may be explained by the
fact that the majority of ARM nodes are located in the upper
axilla, whereas the SLNs are located particularly in the lower
axilla.
Studies have tried to find if there are variables that impact
on ARM node identification rates. Some authors have found
that operator experience with the technique improves the
identification rate [10, 25], while others have not [17]. Apart
from experience with the technique, no statistically signifi-
cant differences can be observed although in some studies a
trend towards a decreased identification rate in patients with
a high body mass index [17], following neoadjuvant treat-
ment [22] and in patients with extensive nodal metastases
[11, 18, 25, 36], has been observed.
26.2.3 Crossover
Because anatomical studies have shown that the lymphatic
drainage from the arm cannot be separated completely from
the lymphatic drainage of the breast [9, 13], one would expect
to find drainage to the same node from both the arm and the
breast in some cases and that has been called crossover,
where the ARM node is the SLN. In this situation, the ARM
node has to be excised, as it is the SLN, for reasons of onco-
logical safety.
Rates of crossover of the SLN and ARM node have ranged
from 0% to 30% [14, 15, 19, 22, 24, 25, 27, 34, 37] in different
studies. One important issue to consider is why there is so
much difference between studies with some of them showing
<5% [14, 19, 32] crossover and others >20% [22, 24, 25, 27,
35]. There are two potential explanations for this: one is vari-
ance due to the mapping agent used. The mean number of
ARM nodes identified is 7.2 when ICG is used [29], and this
may increase the concordance rate, while when the blue dye
is used, the mean number of ARM nodes is reduced to
between 1.3 and 1.5 [21–23]. On meta-analysis, the crossover
rate was 19.6% (95% CI 14.4–26.1%), and when stratified by
mapping materials, 8 studies with blue dye showed an overall
crossover rate of 7.8% (95% CI 4.2–14.2%), and the only
study by fluorescence showed a crossover rate of 28.1% (95%
CI 20–37.9%) [33].
Axillary Reverse Mapping: ARM
307 26
The other explanation may be the number of patients of the studies [17, 19, 22] showed rates of ARM node positiv-
enrolled in the study, and in the regression analysis of studies
ity that ranged from 11% to 25%, and all patients with posi-
[33], sample size was a significant factor, meaning that the tive ARM nodes also had extensive axillary disease. In the
number of enrolled patients may influence the crossover rate study by Noguchi [25], using fluorescence ICG, known to go
of SLN-ARM nodes. to more than just the SLN, in 32% of patients, the ARM nodes
contained metastasis. In the study by Ochoa [19], 5 of 27
resected ARM nodes (18.5%) contained tumour. Two of
26.3 Metastatic Involvement of ARM Nodes these ARM nodes were in cases of crossover (i.e. the ARM
nodes were the SLNs) with N1 and N2 diseases. The other
Involvement of ARM nodes is important, as the objective of three cases were nonconcordant in patients with clinically
the ARM technique is preserving the ARM nodes to achieve palpable or fixed nodes in a heavily positive axilla (N2 or N3)
lower lymphoedema rates. The issue of the oncological safety without crossover. In the study by Gobardhan and colleagues
of ARM arises as crossover nodes between the arm and breast [38] with 93 patients, they found that in the SLN-positive
lymphatics may be found in the axilla and can provide a route group, none of the ARM nodes contained metastases versus
for metastatic cancer cells to spread. In order to appreciate 11 patients (22%) in the group with cytologically proven axil-
the possible role of ARM and subsequent preservation of lary metastasis identified by preoperative US (P = 0.001). In
ARM lymph nodes and corresponding lymphatics when per- the meta-analysis by Han [33], the pooled metastatic rate of
forming axillary surgery for breast cancer, patients may be ARM nodes was 16.9% (95% CI 14.4–21.8%) without signifi-
categorized according to their axillary clinical status. cant heterogeneity. The studies of blue dye, blue dye with
radioisotope or fluorescence showed pooled metastatic rates
of 17.8% (95% CI 14.4–21.8%), 12% (95% CI 8.2–17.3%) and
26.3.1 Involvement of ARM Node in Patients 28.6% (95% CI 16.2–45.4%), respectively. One explanation
Undergoing SLNB may be that in patients with a heavily positive axilla, the
tumour can cause obstruction of the lymphatic drainage and
Rates of involvement of SLN-ARM nodes have been found to may lead the tumour to flow in a retrograde direction into
be from 0% to 100% [10, 15, 19, 24, 33, 37] (. Table 26.1). the nodes primarily draining the arm. It should be noted that
 

Only in the study by Deng and colleagues [37] with 69 positive non-SLN-ARM nodes have been reported in patients
patients, in 12 patients with positive SLNs, the ARM node with N2 or higher-stage disease, and as such these patients
was not involved among 50 of 69 patients whose ARM nodes would likely be receiving radiation as well. In addition, when
did not coincide with SLN nodes. In the remaining six suspected, these nodes should be resected and afferent and
patients, all metastatic ARM nodes coincided with SLN-­ efferent lymphatics re-anastomosed where possible to reduce
ARM nodes. They suggest that perhaps the ARM node the risk of subsequent lymphoedema [32].
involvement only occurs in those patients with crossover,
although this has not been proven in other studies. Kuusk
and colleagues [24] identified 1 of 5 crossover nodes to be 26.3.3 Involvement of ARM Nodes
involved, and Ochoa and colleagues [19] found that of the in Patients with a Positive SLN
4% of cases where there was crossover and the SLN-ARM and ALND
was resected, 2 of 15 nodes (14.3%) were positive. This
reflects the fact that in those patients with a positive SLN, Although ARM nodes were involved even in patients with a
where there is no crossover with the ARM nodes, preserving low axillary tumour burden in some studies [23, 41], patients
the ARM node may be beneficial. Recent data indicates that with a positive SLN may be also good candidates for the ARM
one can remove such nodes and re-approximate the afferent procedure as it may be oncologically safe for patients with cN0
and efferent lymphatics with a very low lymphoedema rate as disease [14, 17, 25, 33, 37, 38]. Noguchi and colleagues [29] in
it is thought that these recanalize [32]. 292 patients found that non-SLN and ARM node was not
involved in 51 (97%) of 54 patients with a positive SLN, even
though 40 (95%) of 42 patients with positive SLN had one or
26.3.2 Involvement of ARM Nodes two positive ALNs. The ARM node was involved in three
in the Pathologically Positive Axilla patients. Crossover rates in this study were 27%, and they con-
cluded that when ARM nodes were involved in patients with
Rates of involvement of ARM nodes in patients undergoing cN0 disease, these nodes were most often the SLN-ARM nodes.
ALND for a clinically positive axilla ranged from 8% to 45% From these studies, we can draw the conclusion that the
[10, 11, 17–19, 23, 24, 26, 34, 36, 38–40]. Nos and colleagues ARM node is positive mainly in the crossover ARM-SLN
[39] reported 14% of patients with positive ARM nodes in nodes where the lymphatic interconnections drain to the same
their series, all of whom had extensive axillary disease. Most node and in those patients with extensive axillary disease.

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 308 I.T. Rubio et al.

..      Table 26.1  Oncological results of ARM lymph nodes

Study Inclusion criteria No. of patient NAC (%) Metastatic involve- SLN = ARM (%)
26 study (No. of
procedures)
ment of the ARM
nodes (%)

Deng et al. [37] SLNB 69 (69) – 6/69 (9) 19/69 (28)

Rubio et al. [22] (SLNB + ALND)/CPN+ 36 (36) 29/36 (81) 4/30 (13) 2/14 (14)

Casabona et al. [15] SLNB/SLN+ 72 (72) – 0/3 (0) N/A

Boneti et al. [14] SLNB/SLN+ 200 (220) – 0/15 (0) 6/214 (3)

Han et al. [16] SLNB/SLN+ 148 (156) 47/156 (30) 2/12 (17) 8/156 (5)

Boneti et al. [31] SLNB/SLN+ 97 (97) – 2/17 (12) 7/97 (7)

Kuusk et al. [24] SLNB/CPN+ 52 (53) – 1/11 (9) 4/52 (8)

Connor et al. [34] SLNB/SLN+/CPN+ 184 (212) 81/212 (38) 0/18 (SLNB) (0) 22/196 (11)
0/4 (SLN+) (0)
4/15 (CPN+) (27)

Thompson et al. [10] SLNB/SLN+/CPN+ 40 (50) – 0/7 (0) 0/46 (0)

Ochoa et al. [19] SLNB/SLN+/CPN+ N/A (360) – 5/27 (19) 15/348 (4)

Noguchi et al. [27] SLNB/SLN+/CPN+ 20 (20) – 0/2 (SLN+) (0) 2/14 (14)
3/5 (CPN+) (60)

Noguchi et al. [25] SLNB/SLN+/CPN+ 131 (131) 19/131 (15) 5/42 (SLNB/SLN+) (12) 27/96 (28)
11/29 (CPN+) (38)

Ponzone et al. [17] SLN+ 49 (49) 8/49 (16) 3/27 (11) N/A

Bedrosian et al. [23] SLN+/CPN+ 30 (30) 22/30 (73) 2/15 (13) N/A

Gobardhan et al. [38] SLN+/CPN+ 93 (93) 57/93 (61) 0/37 (SLN+) (0) N/A
11/47 (CPN+) (23)

Nos et al. [39] SLN+/CPN+ 23 (23) 11/23 (48) 3/21 (14) N/A

Tausch et al. [18] SLN+/CPN+ 143 (143) 25/143 (17) 14/55 (24) N/A

Ikeda et al. [26] SLN+/CPN+ 98 (98) 20/98 (20) 17/53 (32) N/A

Khandelwal et al. [42] cT3/cT4/N2–3 51 (51) 51/51 (100) 0/30 (USG+) (0) N/A
12/15 (USG–) (80)

Nos et al. [11] CPN+ 21 (21) 7/21 (33) 0/10 (0) N/A

Beek et al. [40] CPN+ 112 (112) 91/112 (81) 13/79 (NAC+) (16) N/A
7/19 (NAC–) (37)

Beek et al. [48] CPN+ 98 (98) 98/98 (100) 5/64 (MRI+) (8) N/A
10/34 (MRI–) (29)

Yue et al. [21] CPN+ 265 (265) – 11/129 (9) N/A

Tummel et al. [32] SLNB/SLN+/CPN+ 654 (685) – 2/44 (4.5) 18/472 (3.8)

SLN sentinel lymph node, SLNB patients who underwent a sentinel lymph node biopsy, SLN+ patients with micro- or macrometastatic
lymph node involvement in the sentinel lymph node who were advised to undergo a complementary axillary lymph node dissection,
CPN+ patients with axillary metastases proven by preoperative cytology who were advised to undergo a complementary axillary lymph
node dissection, ALND patients who underwent an axillary lymph node dissection, NAC+ patients who underwent ALND following
neoadjuvant chemotherapy, NAC- patients who underwent ALND without NAC, MRI+ patients with a radiological complete response of
the axillary lymph nodes on the final MRI after NAC, MRI- patients without a radiological complete response of the axillary lymph nodes
on the final MRI after NAC, USG+ patients with a radiological complete or partial response of the axillary lymph nodes on ultrasound scans
after NAC, USG- patients with a radiological stable or progressive disease of the axillary lymph nodes on ultrasound scans after NAC, N/A
not applicable

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Axillary Reverse Mapping: ARM
309 26
26.3.4 I nvolvement of ARM Nodes develop lymphoedema was different: the SLNB cases demon-
in the Neoadjuvant Setting strated lymphoedema at 18 months, whereas the ALND cases
demonstrated lymphoedema at 6 and 12 months [32]. Of the
The ARM technique has also been reported in patients three patients in whom the blue lymphatics were re-­
undergoing neoadjuvant treatment (NAC). Rates of ARM anastomosed, there were no cases of lymphoedema.
node involvement have been reported to be between 13% In the study by Tummel [32], of those patients with objec-
and 18% [22, 23, 38, 40]. In the study by Rubio [22], 4 out of tive findings of lymphoedema, the lymphoedema rate was
30 patients (13%) had metastases in the ARM nodes, and 0.8% (3/350) after SLNB and 6.5% (10/154) after ALND. When
none corresponded to the SLN. When compared to rates of they looked at the group of patients in whom blue lymphatics
ARM involvement between patients who underwent NAC vs. were able to be identified and preserved, the post-SLNB
not, the study by Beek [40], which included 91 patients in the lymphoedema rate was 1.2% (1/79), and the post-­ALND was
NAC+ and 21 patients in the NAC- group, showed that there 6.9% (5/72). Of the 15 (48.3%) patients in whom the blue
was no difference in the ARM visualization rate between the lymphatics were re-anastomosed at the time of the SLNB and
two groups (86.8% for NAC+ group versus 90.5% for NAC- of the 18 (36%) patients at the time of ALND, there were no
group, P = 0.647). In the NAC+ group, 16.5% of the patients cases of lymphoedema.
had metastatic involvement of the ARM nodes versus 36.8% In a prospective randomized single-centre study by Yue
of the patients in the NAC- group (P = 0.048). This decrease and colleagues, of 265 patients with an average follow-up of
following NAC has also been reported by Khandelwal and 20  months, lymphoedema was significantly reduced after
colleagues using ultrasound of the axillary pre- and post-­ ALND from 33 to 6% (. Table  26.2) using circumference
 

NAC. In this study, none of the ARM lymph nodes contained measurement [21]. Pasko and colleagues using a question-
metastatic involvement in patients with partial or complete naire survey also reported a reduction from 50% to 27% in
axillary response following NAC [42]. patients in whom ARM lymph nodes and lymphatics were
preserved [43].
One lesson learned from the ARM procedure is that the
26.4 The Impact of ARM on Lymphoedema inability to identify ARM lymphatics is not necessarily a
Rates «failed» ARM procedure, as it was thought at the beginning
of these studies. It is probably that the lymphatic drainage of
Eleven studies have reported on the incidence of upper the arm and breast is not in close proximity in the SLN field
extremity lymphoedema in patients who underwent ALND and that they do not significantly co-localize, leading to a
with and without preserving the ARM lymph nodes and/or minimal risk of lymphoedema [44].
lymphatics (. Table 26.2). The incidence of upper extremity
 

lymphoedema was evaluated by different measurement

methods: five studies used water displacement to evaluate the 26.4.1 Oncological Safety of Preserving
incidence of upper extremity lymphoedema [14, 18, 19, 31, ARM Nodes
32], five studies measured arm circumference and one study
used a questionnaire survey [15, 16, 20, 21, 26, 43]. Axillary recurrences are a measure of the oncological safety
Four of the ten studies reported an absence of upper of ARM in those patients where the ARM node has been
extremity lymphoedema in patients in whom the ARM preserved. Kuusk and colleagues [24] reported a median
lymph nodes were preserved, compared to 13% (reported by follow-­up of 24 months, and Gennaro and co-workers [20]
Boneti et al.) and 6% [16] rates of upper extremity lymphoe- reported follow-up of 18  months, and neither found any
dema in the population who had ARM lymph nodes resected. axillary recurrences. One axillary recurrence was identified
However, all of them had a short follow-up of between 12 and by Ochoa at 12  months, although it was on a patient in
24  months. Since only 51 of the 182 patients had pre- and whom no identification of the ARM node had been made
postoperative arm volumes recorded, conclusions regarding [19]. From the same group, at a median follow-up of
true incidence rates have to be interpreted with caution [14]. 26  months, Tummel and colleagues [32] reported 2.4%
Furthermore, two studies reported a non-significant reduc- (7/289) of patients who developed locoregional recurrences.
tion of upper extremity lymphoedema in patients in whom Of these LRR, two involved an axillary recurrence, neither of
the ARM lymph nodes were preserved [18, 26]. which had blue nodes preserved. Three patients (0.8%)
In the study by Ochoa, of those patients with objective where blue ARM lymphatics were not identified during sur-
findings of lymphoedema, the post-SLNB lymphoedema rate gery developed LRR.  Longer duration of follow-up will be
was 2.5% (4/158), and the post-ALND lymphoedema rate necessary to assess the oncological safety of ARM as it has
was 3.7% (3/80). When the group of patients in whom blue been reported that the median time to axillary recurrence is
lymphatics were identified and preserved were evaluated, the 33  months (range,19–61  months) for patients treated with
post-SLNB lymphoedema rate was 1.7% (1/58), and the post-­ breast-conserving surgery without surgical intervention to
ALND was 4.8% (3/62) [19]. In this group, the time taken to the axilla [45].

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 310 I.T. Rubio et al.

..      Table 26.2  The incidence of upper extremity lymphoedema in breast cancer patients (ARM lymph nodes/lymphatics preserved versus
ARM lymph nodes/lymphatics removed)

26 Study (year) ARM-P ARM-R LE ARM-P

(%)
LE ARM-R
(%)
p Mean
follow-
Method for
evaluation of LE
Criteria of LE

­up time
(month)

Casabona 8 (N) 3 (N) 0/35 (0) 0/3 (0) N/A 9 Arm circumference Difference
et al. (2009) 27 (L) between two arms
[15] increased >1 cm

Boneti et al. 36 (L) 15 (N) 0/36 (0) 2/15a (13) N/A 6 Water displacement An asymmetrical
(2009) [14] method and clinical increase >20%
diagnoses from baseline or
clinical diagnoses

Boneti et al. 140 (N) 16 (L) 4/140 (2.9) 3/16 (18.7) 0.003 14.6 Water displacement An asymmetrical
(2012) [31] method increase >20%
from baseline

Han et al. 80 (N) 17 (N) 0/80 (0) 1/17 (5.9) N/A 9.6 Arm circumference As measurement
(2012) [16] change of >2 cm
during follow-up

Tausch et al. 61 (N) 55 (N) 14/61 (23) 22/55 (40) 0.046b 19 Water displacement Difference in
(2013) [18] method volume > 10%
between two arms

Gennaro et al. 45 (L) 15 (N) 4/45 (8.9) 5/15 (33.3) 0.035 16 Arm circumference, As measurement
(2013) [20] clinical diagnoses or change of >2 cm
comparative during follow-up
lymphoscintigraphy

Ochoa et al. 120 (L) 22 (L) 4/120 (3.3) 1/22 (4.5) N/A 12 Water displacement Volume increase of
(2014) [19] method the affected side
over the opposite
side of >20%

Ikeda et al. 19 (N) 57 (N) 5/19 (26) 19/57 (33) NS 24 Arm circumference A 2 cm increase at
(2014) [26] any level relative
to the baseline or
the healthy
opposite arm

Yue et al. 118 (N) 127 7/118 (5.9) 42/127 (33.1) 0.001 20 Arm circumference Difference
(2015) [21] (N) between two arms
increased >2 cm

Pasko et al. 22 (N/A) 24c 6/22 (27) 12/24 (50) N/A N/A Questionnaire Patients identified
(2015) [43] themselves as
suffering from LE

Tummel et al. 103 50 5/72 33/154 N/A 26 Water displacement Volume increase of
(2016) [32] method the affected side
over the opposite
side of >20%

ARM-P patients where ARM lymph nodes (N) or ARM lymphatics (L) were preserved, ARM-R patients where ARM lymph nodes (N) or ARM
lymphatics (L) were removed or transected, LE upper extremity lymphoedema, N/A not applicable, NS not significant
aOne patient had clinical diagnosis of lymphoedema but did not have arm volume checked
bIn the multivariate logistic regression model, this correlation was not evident
c24 patients underwent non-ARM procedure but a normal ALND

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Axillary Reverse Mapping: ARM
In summary, despite the small size of some of the studies,
different measurement methods, short follow-up and/or dif-
ferent definitions of upper extremity lymphoedema, saving
ARM lymph nodes and lymphatics may contribute to the
reduction of upper extremity lymphoedema rates following
axillary surgery for breast cancer.
Ongoing randomized multicentre trials (ALND with or
without preservation of ARM lymph nodes and correspond-
ing lymphatics in SLN+ patients) will further contribute to
the debate about the value of these procedures [46].
26.5 Other Techniques to Reduce
Lymphoedema
26.5.1 Microvascular Anastomosis
In those cases where the ARM nodes need to be excised,
other surgical options are available in order to try to decrease
rates of lymphoedema. Ochoa and colleagues [19] re-­
anastomosed the remaining afferent and efferent lymphatics
by re-approximation of the transected ends of the lymphatic
channels. These transected lymphatics underwent end-to-­
end re-approximation by the operating breast surgeons using
6–0 to 9–0 prolene, dependent upon size [19, 32]. Of the
three patients in whom the blue lymphatics were re-­
anastomosed, there were no cases of lymphoedema. Tummel
and colleagues [32] from the same group reported that of the
15 (48.3%) patients in whom the blue lymphatics were re-­
anastomosed at the time of the SLNB and of the 18 (36%)
patients at the time of ALND, there were no cases of lymph-
oedema.
Other studies have shown that lymphatic-venous micro-
anastomoses using the lymphatic channels coming from the
arm and one of the collateral branches of the axillary vein
(named LYMPHA) may reduce lymphoedema when the
ARM nodes are excised. Casabona and colleagues [15] and
Boccardo and colleagues [47] performed lymphatic-venous
microanastomosis whenever the blue lymphatics and nodes
are well seen. In their series, in 8 out of 9 patients (88.9%), the
procedure was performed. At 6-month and 9-month follow-
­up, none of them had a diagnosis of lymphoedema. Further
studies with larger numbers of patients are warranted to fully
evaluate whether these techniques are really effective in the
prevention of lymphoedema.
26.6 Conclusion
Preservation of ARM lymph nodes and corresponding lym-
phatics is oncologically safe in patients scheduled for SLNB if
ARM lymph nodes are not concordant with the SLN, as well
as in SLN-positive breast cancer patients who are advised to
undergo a complementary ALND. In case of clinical node-­
rares1geo@gmail.com
311 26
positive disease, proper selection of patients scheduled for
ALND and a combined ALND plus ARM should be consid-
ered. Although still with only short-term follow-up, the ARM
procedure has been shown to reduce the incidence of upper
extremity lymphoedema without compromising oncological
outcomes. Longer-term follow-up of patients in whom the
ARM nodes were preserved and a surgical refinement of
combined ALND and the ARM technique will provide a real
insight into the scope of this technique.
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S. Feasibility of axillary reverse mapping during sentinel lymph node
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32. Tummel E, Ochoa D, Korourian S, Betzold R, Adkins L, et  al. Does
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Eur J Surg Oncol. 2012;38(8):657–61.
39. Nos C, Kaugmann G, Clough KB, et  al. Combined axillary reverse
mapping (ARM) technique for breast cancer patients requiring axil-
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40. Beek MA, Gobardhan PD, Klompenhouwer EG, Rutten HJ, Voogd AC,
Luiten EJ. Axillary reverse mapping (ARM) in clinically node positive
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 313 IV

Reconstructive Surgery
Contents

Chapter 27 Immediate Reconstruction: General and Oncological

Considerations – 315
Maria João Cardoso and Giuseppe Catanuto

Chapter 28 Delayed Breast Reconstruction: General and

Oncological Considerations – 325
Zoltán Mátrai

Chapter 29 Breast Implants: Design, Safety and

Indications for Use – 355
Jana de Boniface and Inkeri Schultz

Chapter 30 Specific Implant-Based Techniques for

Breast Reconstruction – 365
Lorna J. Cook and Michael Douek

Chapter 31 Specific Autologous Flap Techniques – 381

Sinikka Suominen and Maija Kolehmainen

Chapter 32 Goldilocks Procedure – 393

Fiona MacNeill

Chapter 33 Nipple Reconstruction – 401

Valentina Lefemine and Kelvin F Gomez

Chapter 34 Complications of Breast Surgery and

Their Management – 411
Michalis Kontos and Christos Markopoulos

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 315 27

Immediate Reconstruction:
General and Oncological
Considerations
Maria João Cardoso and Giuseppe Catanuto

27.1 Introduction/Historical Background – 316

27.2 Indications and Contraindications for Immediate

Breast Reconstruction – 316
27.2.1 Indication for Immediate Breast Reconstructions
and Overview of Current Guidelines – 316

27.3 Surgical and Oncological Safety – 317

27.4 Integration of Adjuvant and Neoadjuvant Treatments – 318

27.4.1 Effects of Neoadjuvant Chemotherapy on IBR – 318
27.4.2 Effects of Adjuvant Chemotherapy on IBR – 318
27.4.3 Effects of Adjuvant Radiotherapy on IBR – 319

27.5 Impact of Immediate Breast Reconstruction

on Quality of Life – 320

27.6 Evaluating Aesthetic Outcomes in Postmastectomy

Reconstruction – 321

27.7 Decision Algorithms for Postmastectomy

Reconstruction Selection – 321
27.7.1 Surgical Decision in Patients with Small- and 
Medium-Sized Breast and Minimal/No Ptosis – 322
27.7.2 Surgical Decisions in Patients with Large and Ptotic Breasts – 322

27.8 Conclusions – 322

References – 322

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_27

rares1geo@gmail.com
 316 M.J. Cardoso and G. Catanuto
27.1 Introduction/Historical Background
Reconstruction of the breast has been an aspiration for over
100 years. The first article was published by Czerny in 1895
and concerned the transplantation of a large lipoma to
replace a breast removed for benign disease [1]. Since then,
27 the search for alternatives to reconstruct the breast has con-
tinued relentlessly. Fat grafts from several sources were used,
but they atrophied relatively quickly, failing to provide a
durable recreation of the breast mound. Fat and dermal grafts
were then used, and less shrinkage occurred but still usually
failed to achieve an adequate breast size. Although there were
some isolated attempts, at the beginning of the last century,
to use muscular and musculocutaneous flaps, they were not
successful and were rapidly dismissed mainly due to the
focus on radical resection (as defended by Halstead) in this
period [2]. As a result of the Halsted paradigm for breast can-
cer spread in the first half of the twentieth century, mastecto-
mies became even more radical, and interest in immediate
reconstructions declined. Furthermore, it was believed that
autologous tissues could hide a local recurrence, and there-
fore attempts to reconstruct the breast were discouraged in
general [3]. Although some further trials were described at
the beginning of the twentieth century, it was only during the
1960s and 1970s that breast reconstructions were considered
again in a positive light, but as delayed operations in the large
majority of the cases. In 1978 however the latissimus dorsi
flap was reintroduced by Bostwick and Scheflan for one-stage
breast reconstructions [4].
The development of silicone breast implants during the
1960s gave a great boost to immediate reconstructions.
Initially these were just put underneath the mastectomy flaps,
with a high rate of capsular contracture and extrusion. The
two-stage reconstruction evolved rapidly to help reduce
these problems and progressively gained popularity [3, 5].
Often, implants were integrated into breast reconstruction
with a latissimus dorsi flap to enhance the final volume of the
breast mound. In 1984 Becker introduced a dual chamber
silicone implant that could be filled with saline in an inner
chamber in an attempt to reduce the need for a second oper-
ation and to better mould the shape of the reconstructed
breast [6].
The gradual ascendency of Fisher’s theory of breast can-
cer as a systemic disease rather than Halstead’s principle of
radical local control led to a much lesser radical approach to
cancer surgery. Ultimately this led to the acceptance of
breast-conserving treatment and skin-­sparing approaches to
mastectomy. Along with the acceptance of skin-sparing tech-
niques, other technical developments and refinement of ana-
tomically stable implants in the 1990s and the introduction
of new devices such as acellular dermal matrices (ADMs)
and meshes for implant coverage, in the last 5–10  years,
greatly reduced the need for two-stage breast reconstruc-
tions.
Autologous reconstruction with myocutaneous flaps
became an established reconstructive technique during the
1980s when Hartrampf transferred a horizontal skin island
rares1geo@gmail.com
from the lower abdomen on a vascular pedicle within the
rectus abdominis muscle [7]. This technique, in contrast to
the autologous latissimus dorsi flap, had the potential to
provide substantial fatty tissue volumes while providing
rewarding cosmetic results. However, it required a long
operating time and was associated with higher complication
rates.
Despite a huge number of studies, mainly retrospective,
the quality of evidence supporting the use of immediate
breast reconstruction versus delayed is still of a relatively low
level. D’Souza and colleagues performed a systematic review
to assess the effects of immediate v­ersus delayed breast
reconstructions following mastectomy for breast cancer. The
results of this study demonstrated that only one randomized
trial was available at the time of the review. A generalized
inadequacy of outcome evaluation (in terms of cosmetic out-
come and psychosocial well-being) was reported. The authors
concluded that the evidence base for immediate reconstruc-
tion is presently of poor methodological quality (a single
RCT with flaws and a high risk of bias) which precludes con-
fident decision-making [8]. This Cochrane review reports
study results up until 2011. In the ensuing 5 years, the mate-
rials and techniques have grown exponentially but with little
application of scientific rigor. In the absence of good-quality
randomized data, it is vital that a critical evaluation of the
current evidence, even if retrospective, is undertaken. It is
unlikely that randomized trials will take place due to the
extreme difficulty of randomization between immediate and
delayed reconstruction due to lack of surgical and patient
equipoise.
27.2 Indications and Contraindications
for Immediate Breast Reconstruction
27.2.1  I ndication for Immediate Breast
Reconstructions and Overview
of Current Guidelines
International guidelines on the oncological treatment of
breast cancer regarding indications and contraindications for
reconstructive surgery are reviewed below, although, as men-
tioned above, they are based on low-level evidence.
The Physician Data Query (PDQ) is a comprehensive
source of cancer information from the National Cancer
Institute [9]. The summaries reported in this database are
comprehensive and evidence based and deal with topics that
cover most of the aspects of cancer care, screening and pre-
vention. In the chapter for health professionals, it is stated
that «for patients who opt for a total mastectomy, reconstruc-
tive surgery may be performed at the time of the mastectomy
(i.e., immediate reconstruction) or at some subsequent time
(i.e., delayed reconstruction)». No other specific information
on the timing of the reconstruction is provided. Some details
on surgical techniques (implants or flaps) are available, but
no data on the surgical or oncological safety of immediate
reconstruction are reported.
Immediate Reconstruction: General and Oncological Considerations
The National Comprehensive Cancer Network (NCCN)
guidelines provide complex decisional algorithms for the
majority of known cancers. These are continuously updated
and revised to reflect new data and clinical information that
may add to or alter current clinical practice standards. The
NCCN guidelines for breast cancer in chapter BINV-H 2016
[10] discuss the principles of breast reconstruction. It is
clearly indicated that patients should have proper informa-
tion and that breast reconstruction can be performed soon
after mastectomy. However, timing is not subject to clear
indications and contraindication with the exception of an
absolute contraindication for IBR in the setting of inflamma-
tory breast cancer [11].
In Europe, the European Society for Medical Oncology
(ESMO) guidelines from 2015 [12] contain general recom-
mendations for the treatment of invasive breast cancer and
are not very detailed regarding both the timings and specific
procedures for reconstructive surgery, except in favouring
autologous reconstruction in the setting of postmastectomy
radiotherapy.
In the UK, two groups have been working to establish
guidelines and standards for breast reconstruction: the
Association of Breast Surgery (ABS) and the British
Association of Plastic, Reconstructive and Aesthetic Surgeons
(BAPRAS). In 2012 they produced guidelines for best prac-
tice for oncoplastic breast reconstruction [13]. These guide-
lines are very specific and not only help in establishing the
indications for breast reconstruction but deal in great detail
with the technical aspects of breast reconstruction and also
with complications and outcomes.
From the analysis of these guidelines, it is concluded that
immediate breast reconstruction can and should be offered
to the majority of patients in whom mastectomy is indicated
or preferred, with the exception of patients with inflamma-
tory breast cancer or in the presence of severe comorbidities
where prolongation of surgical time would increase risks.
However, patients should be made aware of the possible
influence on aesthetic outcomes and morbidity if postmas-
tectomy RT is needed and consideration given to autologous
reconstruction, where outcomes may be better following flap
irradiation, in these cases [14].
27.3 Surgical and Oncological Safety
One of the most frequent questions about breast reconstruc-
tion regards safety.
Immediate breast reconstruction may require more com-
plex procedures, with longer operating times, and therefore
can be associated with a higher risk of complications. If com-
plications occur, extra time may be needed to recover and to
start adjuvant treatments. If the start of adjuvant treatments
is delayed, would this longer interval impact on patient out-
comes in terms of both disease-free survival and overall sur-
vival?
Fisher and colleagues evaluated wound complications,
other medical complications and wound infections using
rares1geo@gmail.com
317 27
bivariate and multivariate analyses to identify predictors of
outcome in two subgroups of patients from the ACS-NSQIP
datasets who underwent either mastectomy and immediate
reconstruction with a tissue expander (TE) or mastectomy
alone [15]. They confirmed that IBR using tissue expansion
(TE) was not associated with a greater risk of wound (3.3%
vs. 3.2%, P = 0.855), medical (1.7% vs. 1.6%, P = 0.751) or
overall (9.6% vs. 10.0%, P = 0.430) complications. The study
reported an association with a higher risk of deep wound
infections (2.0% vs. 1.0%, P < 0.001) and unplanned reopera-
tions (6.9% vs. 6.1%, P = 0.025). A logistic regression analysis
failed to demonstrate significantly associated independent
risk of wound, medical or overall complications with the
addition of TE reconstruction.
A further study by Jagsi and colleagues [16] extended
the observation period up to the first 2 post-operative
years and reported on postmastectomy complications in a
sample of 14,894 women treated by mastectomy from 1998
to 2007 who underwent immediate autologous reconstruc-
tion (n  =  2637), immediate implant-based reconstruction
(n = 3007) or no reconstruction within the first 2 postopera-
tive years (n = 9250). Wound complications were diagnosed
in 2.3% of patients without reconstruction, 4.4% patients
with implants and 9.5% patients with autologous reconstruc-
tion (P < 0.001). In conclusion, an extended period of obser-
vation revealed an increase in the complication rate in the
population undergoing IBR.
It has been suggested that this slightly higher complica-
tion rate associated to immediate breast reconstruction
might generate delays in the administration of adjuvant
treatments and as a consequence have an impact on the
oncological outcomes of breast cancer patients. A systematic
review by Xavier Harmeling and colleagues [17] investigated
the impact on immediate reconstruction in terms of delay in
time to chemotherapy (TTC). Fourteen studies were
included, representing 5270 patients who had received adju-
vant chemotherapy, of whom 1942 had undergone IBR and
3328 mastectomy only. Only one study identified a signifi-
cantly shorter mean TTC, four studies found a significantly
delay of 6.6–16.8 days and seven studies found no significant
difference. In conclusion, the authors confirmed that IBR
does not necessarily delay the start of adjuvant chemotherapy
to a clinically relevant extent.
Hamahata and colleagues [18] confirmed a slight increase
in the time to treatment in a subgroup of patients undergoing
IBR (61.0 ± 10.5 days in IBR group and 58.0 ± 12.3 days in
non-IBR group). The post-operative complication rate was
10.0% in the IBR group and 6.1% in the non-IBR group.
These results have been confirmed by Eck and colleagues
[19] who observed that patients who underwent immediate
breast reconstruction did not have a delay in adjuvant treat-
ment when compared to patients with no reconstruction
(41 days vs. 42 days, P = 0.61). However, complicated cases
can have a small but significant impact on the adjuvant treat-
ment start date (47 days vs. 41 days, P = 0.027).
In 2012 a meta-analysis from Gieni and colleagues [20]
investigated local control rates after IBR.  Ten articles were
 318 M.J. Cardoso and G. Catanuto
considered suitable for inclusion. Data including recurrence
rates, cancer stage, type of mastectomy and reconstruction,
adjuvant treatments and duration of follow-up were reviewed.
The odds ratio (OR) for recurrence of breast cancer for mas-
tectomy with IBR as compared to mastectomy alone was 0.98
(95% CI, 0.62, 1.54). This meta-analysis demonstrated no
27 evidence for an increased frequency of local breast cancer
recurrence with IBR compared with mastectomy alone.
Another study by Eriksen and colleagues [21] confirmed
no differences in terms of local control between 300 patients
who underwent breast reconstruction compared to a second
cohort of matched patients identified from the Regional
Breast Cancer Register of the Stockholm-Gotland health-­
care region treated with mastectomy alone (8.2% in the IBR
group and 9.0% in the control group or, in the regional
recurrence rate, 8.2% versus 9.7%). The authors also reported
no significant differences in the timing of adjuvant treat-
ments.
Risk factors for complications were extensively investi-
gated by Fischer [22] in a large review of the ACS-NSQIP
2005–2011 dataset of patients who underwent immediate
breast reconstruction either with implants or autologous tis-
sues. A «model cohort» of 12,129 patients was randomly
selected from the study cohort to derive predictors. Weighted
odds ratios derived from logistic regression analysis were
used to create a composite risk score and to stratify patients.
The remaining one-third of the cohort (n = 6065) was used as
the «validation cohort» to assess the accuracy of the risk
model. A risk score was created with stratification of patients
into four subgroups based on their total risk score (p < 0.001):
risk categories were low (0–2, risk  =  7.14%), intermediate
(3–4, risk = 10.90%), high (5–7, risk = 16.70%) and very high
(8–9, risk = 27.02%). This score by Fisher may therefore be of
value for the identification of patients at high risk who may
be better served by avoiding or delaying breast reconstruc-
tion until the end of adjuvant treatments or until modifiable
risk factors have been recovered, i.e. smoking, obesity, etc. It
may also be valuable in patient counselling.
To conclude, and based on the available evidence from
the literature, immediate breast reconstruction is generally
safe when surgical complications are minimized by careful
case selection, choice of procedure and consideration of the
wider cancer treatment pathway. Correct selection of patients
may help to stratify those high-risk individuals more prone
to complications which may delay the time to adjuvant treat-
ment with a potential subsequent impact on outcomes.
27.4 Integration of Adjuvant
and Neoadjuvant Treatments
27.4.1   ffects of Neoadjuvant Chemotherapy
E tions is very low [26].
on IBR
Preoperative chemotherapy is a good tool to reduce the size
of cancer that otherwise should be treated by mastectomy.
However, some patients may be poor responders and still
require mastectomy after treatment. This may raise c­ oncerns
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when considering immediate breast reconstruction: immu-
nosuppression may theoretically contribute to higher infec-
tion rates or other postsurgical sequelae. The impact of
neoadjuvant chemotherapy on immediate breast recon-
struction was investigated in a meta-analysis by Song and
colleagues [23] who confirmed that neoadjuvant chemo-
therapy did not increase the overall rate of complications
after immediate breast reconstruction (odds ratio
[OR]  =  0.59; 95% confidence interval [CI]  =  0.38–0.91). At
the same time, no increase in hematomas and seromas was
reported, and the risk of expander or implant loss was not
higher among patients after neoadjuvant chemotherapy
(OR   =   1.59; 95% CI   =   0.91–2.79). The large majority of
patients included in this meta-analysis had an implant-
based reconstruction. Only two studies reported on autolo-
gous tissue-based reconstructions. Both studies confirmed
no association between total flap loss and preoperative che-
motherapy.
The same conclusion was published by Abt reporting for
the American College of Surgeons National Surgical Quality
Improvement Program 2005–2011 databases [24] about the
short-term morbidity in patients undergoing mastectomy
with and without breast reconstruction. This study included
a population of 19,258 patients (22.4%) treated by immediate
breast reconstruction, with 820 (4.3%) receiving neoadjuvant
chemotherapy (NAC). After multivariate analysis and adjust-
ment for confounding factors, NAC was independently asso-
ciated with a lower overall morbidity in the immediate tissue
expander reconstruction subgroup (OR, 0.49; 95% CI, 0.30–
0.84), confirming also the safety of NAC in this subgroup of
patients.
There are however also some studies reporting a higher
rate of failure, specifically related to the use of expander/
implants [25], but unfortunately these studies are mainly ret-
rospective and don’t allow firm conclusions to be drawn.
Analysis of the existent body of evidence regarding the
use of NAC and subsequent immediate breast reconstruction
after mastectomy concludes that there is no proof that imme-
diate reconstruction should be contraindicated in patients
who were submitted to NAC.
27.4.2   ffects of Adjuvant Chemotherapy
E
on IBR
This topic is discussed above, and the evidence suggests little
impact of IBR on the timing of adjuvant chemotherapy and
suggests that it has no negative impact on wound healing or
infection rates. In fact, adjuvant chemotherapy usually only
starts when wounds are completely healed. There is the
exception of expansion, but even there the rate of complica-
One area of continued uncertainty is the safety of com-
mencing adjuvant chemotherapy in patients with «red
breast» syndrome as a consequence of the use of acellular
dermal matrices. Whether this impacts on rates of implant
loss and longer-term cosmesis is not yet known, and research
is urgently needed in this area [27].
Immediate Reconstruction: General and Oncological Considerations
27.4.3   ffects of Adjuvant Radiotherapy
E radiotherapy-treated patients. Less fibrosis was reported
on IBR
The indications for postmastectomy radiotherapy have
increased recently due to a demonstrated increase in overall
survival in a recent large meta-analysis. This not only found
benefit in the long-established indication of more than three
nodes but also found a survival benefit for thoracic wall irra-
diation in cases with 1–3 positive axillary nodes [28].
According to the latest St. Gallen consensus of 2015, the
exception to the use of RT should only be in patients with
very good tumour biology [29].
Radiotherapy has an inevitable effect on tissues and may
generate chronic inflammation of the subcutaneous tissues
resulting in long-term fibrosis, atrophy, retraction, ulcers and
telangiectasia that are usually classified using the SOMA
scale [30]. These changes may compromise the results of
immediate breast reconstructions both with tissue expand-
319 27
when radiotherapy was performed first. Implant failure
occurred more often if applied after radiotherapy (odds ratio
(OR) 3.03 [1.59–5.77]). No differences in the complication
rates for autologous tissue according to the timing of
­radiation were demonstrated.
This study follows a previous meta-analysis form Barry
and colleagues [32]. In keeping with other reports, patients
undergoing PMRT and BR are more likely to suffer morbid-
ity compared with patients not receiving PMRT (OR = 4.2;
95% CI, 2.4–7.2 [no PMRT vs. PMRT]). Autologous recon-
struction is associated with less morbidity in the RT setting
(OR = 0.21; 95% CI, 0.1–0.4 [autologous vs. implant-based]).
PMRT has a generally detrimental effect on BR outcome.
These results suggest that when immediate reconstruction
is undertaken in women likely to be advised to have PMRT, an
autologous flap results in less morbidity when compared with
implant-based reconstruction [33] (. Figs. 27.1 and 27.2).

ers/implants and autologous tissues. However, radiotherapy

techniques have greatly improved in the last decade, with
better targeting, reducing skin doses and better schedules.
Consequently severe reactions (ulceration and telangiecta-
sia) are much less common, but fibrosis still occurs and may
impact on reconstruction outcomes.
In many countries, radiotherapy is still regarded as either
a relative or absolute contraindication for immediate breast
reconstruction due to the well-documented problems associ-
ated with this combination.
In the last 5 years, several systematic reviews and meta-­
analyses have clarified the effect of radiotherapy on breast
reconstruction paving the way for more confidence when
this option is considered by both the doctor and patient.
A systematic review by Lam and colleagues [31] about the
effects of postmastectomy adjuvant radiotherapy on immediate
two-stage prosthetic breast reconstruction compared the out-
comes of those who had radiotherapy after placement of a tis-
sue expander and after the second surgical stage. The primary
..      Fig. 27.1  Right nipple-sparing mastectomy with immediate
endpoint of this study was the reconstruction failure rate with reconstruction with latissimus dorsi and implant with post-­operative
implant loss. Secondary endpoints were the rate and degree of radiotherapy – capsular contracture
capsular contracture and aesthetic outcomes. A significantly
higher reconstruction failure rate after immediate two-stage
prosthetic breast reconstruction was reported in comparison to
patients who did not have radiotherapy. Interestingly the
authors commented that their conclusions were based on a
lower level of evidence as no randomized controlled trials were
identified, and only one prospective, non-randomized, multi-
centre trial was found. Despite these considerations, there is a
clear trend indicating that radiotherapy increases the failure
rate of two-stage breast reconstructions.
A further systematic review by Berbers and colleagues
[14] identified five subgroups of patients according to the
timing and type of reconstructions (autologous tissue based
after RT, permanent implant after RT, autologous tissue
before RT, permanent implant after RT and overall).
The authors reported a very large variation in complica-
tion rates and in cosmetic outcome between groups. A higher
complication rate and revision rate were associated with ..      Fig. 27.2  Right immediate TRAM flap reconstruction with post-
implant-based reconstruction performed in previously operative radiotherapy

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 320 M.J. Cardoso and G. Catanuto
According to the current evidence, radiotherapy has a con-
sistent negative impact on breast reconstruction, and patients
should be thoroughly informed of this risk. If the decision is to
proceed with the reconstruction, an autologous tissue-based
intervention has a higher probability of success. As an alterna-
tive, a two-stage (radiotherapy with expander inflated) or an
27 immediate-delayed reconstruction (in case of doubts regard-
ing the need for radiotherapy) would also be considered a pos-
sible option. Delaying reconstruction should always be
discussed, but patients’ preferences should always be respected
once they are fully aware of the possible consequences.
More recently acellular dermal matrices (ADMs) have
become increasingly popular in implant-based breast
reconstruction. ADMs are products derived from human
or animal dermis which has been treated to remove the cel-
lular (antigenic) components. ADMs provide an extra layer
of coverage and support for breast implants, particularly
over its lower lateral parts. They are used in expander/
implant-­ based breast reconstruction after mastectomy.
Radiotherapy seems to have a negative impact in recon-
struction with expander/implant and ADMs, but evidence
is of very poor quality, and some recent studies start to sug-
gest a decrease in capsular contracture with the use of
ADMs [34].
27.5 I mpact of Immediate Breast
Reconstruction on Quality of Life
While the oncological aspects of breast cancer surgery have
been extensively investigated, quality of life after mastectomy
and reconstruction have received less attention although the
development of good-quality QoL instruments specific to
breast cancer outcomes has improved our understanding of
these issues considerably in the past decade.
There are now a number of breast-specific QoL tools
which have been validated to varying degrees [35]. Among
those which have been adequately validated, three (EORTC
QLQ BR-23, FACT-B, HBIS) focus on non-surgical treat-
ment issues; the BIBCQ does not address aesthetic concerns
after breast reconstruction, and only one, the BREAST-Q,
was specifically developed for use in patients undergoing
mastectomy and reconstruction. Another tool developed on
behalf of EORTC is currently undergoing a process of valida-
tion [36].
Using these tools, QoL comparisons have been made
between mastectomy and BR versus breast conservation,
mastectomy alone versus mastectomy plus reconstruction
and skin-sparing versus non-skin-sparing techniques. These
are reviewed below.
Heneghan and colleagues [37] reviewed a prospectively
collected database in order to evaluate the differences in
terms of quality of life between breast-conserving surgery
and skin-sparing mastectomy followed by immediate recon-
struction. Questionnaires specific for breast cancer were
employed (EORTC QLQ B23/B30, FACT-B) to assess
patient-reported QoL outcomes. Interestingly both cohorts
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achieved similar scores in each of the scales used for com-
parison reporting no significant differences. The authors
concluded that skin-sparing mastectomy and immediate
breast reconstruction can safely be offered to patients requir-
ing mastectomy with similar outcomes to those who undergo
breast-conserving surgery.
This observation was confirmed by a recent [16] survey
from the SEER database [16]. They evaluated 1450 patients
(963 underwent breast-conserving surgery, 263 mastec-
tomy without reconstruction and 222 mastectomy with
reconstruction). They measured quality of life using the
FACT-B questionnaire and two measures of patient-
reported satisfaction including cosmetic outcomes: one
was applied to all patients and one specifically to patients
who received breast reconstruction (both derived from
existing validated tools). No significant differences in well-
being by surgery type were observed when comparing mas-
tectomy plus no reconstruction, breast conservation, and
mastectomy and immediate breast reconstruction, except
that there seemed to be a greater improvement in physical
well-being by the time of the follow-up survey for patients
who received mastectomy with breast reconstruction.
Among patients receiving mastectomy with reconstruction,
radiation receipt was associated with inferior scores for
patients receiving implant reconstruction plus radiation
therapy. Autologous reconstruction cases fared better. In
conclusion, this study confirms that immediate breast
reconstruction generates QoL scores not dissimilar from
breast-conserving surgery and confirmed the positive role
of autologous reconstruction in mitigating the deleterious
effects of radiotherapy.
Skin-sparing mastectomies preserving more of the skin
envelope and sometimes the nipple have been evaluated in
the context of QoL and cosmesis [38, 39]. Patient satisfaction
and nipple-areola sensitivity after bilateral prophylactic mas-
tectomy and immediate implant breast reconstruction have
been evaluated using the BREAST-Q questionnaire [39].
Interestingly, satisfaction with the (reconstructed) nipple-­
areolar complex was similar after skin-sparing mastectomies
(SSMs) and nipple-sparing mastectomies (NSMs). Nipple-­
areola complex sensitivity was lower in the NSM group
(mean score, 1.9; 95% confidence interval, 1.5–2.3) compared
with the control group – reconstructed nipple (mean score,
4.7; 95% confidence interval, 4.6–4.9; P < 0.01).
Psychosocial and sexual well-being after NSM has also
been studied [40] using the BREAST-Q.  These results par-
tially contradict the previous study. Two groups of patients
(with nipple preservation/without nipple preservation)
belonging to a prospectively maintained database were eval-
uated in multivariate linear regression analysis that con-
trolled for potential confounding factors. Nipple-sparing
mastectomy patients reported significantly higher scores in
the psychosocial (p = 0.01) and sexual well-being (p = 0.02)
domains compared to SSM patients. There was no significant
difference in the BREAST-Q domains relating to physical
well-being, satisfaction with the breast or satisfaction with
outcomes between the NSM and SSM groups.
Immediate Reconstruction: General and Oncological Considerations
In conclusion, quality of life after immediate breast
reconstruction can be evaluated effectively using several vali-
dated tools. Modern reports confirm good results after
immediate reconstruction and outcomes comparable to
those of breast-conserving surgery. Postmastectomy radia-
tion may compromise patient’s satisfaction, but this negative
impact can be diminished with the choice of autologous
reconstructions.
Autologous reconstructions are more stable regarding
long-term aesthetic outcomes, while implant-based recon-
structions tend to decay in the medium to long term. Patients
should be correctly informed about these results in order to
make a fully informed choice. The benefits of nipple preser-
vation are less well defined with some studies reporting
advantages for nipple reconstruction after skin-sparing mas-
tectomy and other studies reporting an increase of physical
and sexual well-being with nipple preservation.
27.6  valuating Aesthetic Outcomes
E rithms are based on a combination of morphological, clinical
in Postmastectomy Reconstruction
It is a generalized concept that mastectomy and immediate
reconstruction have a better aesthetic outcome than mastec-
tomy with delayed reconstruction. This is probably due to the
fact that usually patients submitted to immediate reconstruc-
tion have smaller and less aggressive cancers with a lesser
need for radiotherapy, and also in this subgroup are the
majority of prophylactic mastectomies.
321 27
features like asymmetry and colour differences can be deter-
mined even in mastectomy and reconstruction patients.
There is a major need to develop objective tools that will
allow us to make meaningful comparisons between tech-
niques allowing the identification of factors that can have a
real impact on outcomes [42].
27.7  ecision Algorithms for
D
Postmastectomy Reconstruction
Selection
This spectrum of choices and all the factors previously dis-
cussed can make the final decision about reconstruction very
difficult. Decision algorithms have been widely used to help
to make informed selection across a range of breast cancer
treatment choices with perhaps the most widely used relating
to the decision to have chemotherapy or not (e.g., Adjuvant!
Online). Usually in reconstructive surgery, decision algo-
characteristics and patients’ preferences [43].
Factors used in the decision process are acquired during
the first consultation after cancer diagnosis. The morphologi-
cal characteristics (height, weight, thoracic perimeter, breast
cup size and degree of ptosis) of the patients should be recorded.
Breast volume and ptosis can be precisely calculated using
models like the ones described by Longo [44] and Kim [45].
With these factors, a simple decision algorithm can help doc-
tors and patients to make more informed decisions (. Fig. 3).

However, as in breast-conserving surgery, there is no
standardized objective way of evaluating cosmetic outcomes
[41], and in the great majority of cases, cosmetic results are
not recorded.
The breast cancer conservative treatment cosmetic results
(BCCT.core) software [42] was developed for the evaluation
of breast cancer-conserving surgery, and it is not validated
for use in breast reconstruction cases. However, objective
The advantage of using decision algorithms is not only to
support choices based on more objective factors but also to
increase patient engagement in the decision-making process
[46]. Medical language is complex, and sometimes patients
struggle to understand straightforward medical concepts
[47]. For this reason, the use of booklets, photographs and
videos of diverse surgical techniques can be very helpful, if
the patient feels comfortable and expresses interest to have

..      Fig. 27.3  Decision tree

regarding type of mastectomy o Small/Medium
(skin sparing or nipple sparing) o Minimal Ptosis NAC sparing
considering volume and ptosis

Volume Ptosis
Small<200cc None
Assess Medium 200-500cc Minor
morphology
Large 500-700cc Moderate
Very large>700cc Major Nipple to
NAC
Sternal notch
sparing
< 25 cm
o Large /
very Large Skin
o Moderate / Reducing
Major Ptosis
Nipple to
NAC
Sternal notch
removal
< 25 cm

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 322 M.J. Cardoso and G. Catanuto
this type of information. This is normally done during a sec-
ond or third visit once the complexity of emotional responses
engendered by the initial visit has abated somewhat.
27.7.1   urgical Decision in Patients
S If the patient selects an implant-based reconstruction, a two-
27 with Small- and Medium-Sized Breast
and Minimal/No Ptosis
In patients with small to medium breast volumes and minimal
to moderate ptosis, preservation of the breast skin envelope is
usually possible and may include the nipple-areolar complex if
oncologically appropriate to do so (nipple preservation is con-
traindicated in women with tumours close to the nipple, usually
defined as less than 10 mm). Reconstruction of the breast
mound may be achieved in a variety of ways depending on the
patient’s preferences and the availability or otherwise of autolo-
gous donor sites. Depending on the patients’ wishes, a contralat-
eral adjustment can be performed in a single stage or as a second
stage. Sub-muscular implant reconstructions are less suitable for
moderate breast size and moderate ptosis cases where the use of
an ADM may be preferable to augment the implant pocket.
27.7.2   urgical Decisions in Patients
S
with Large and Ptotic Breasts
In these patients, skin preservation is technically challenging,
and several approaches have been described in this situation
like the one used by Nava and colleagues [48, 49]. This is a
modification of type IV skin-sparing mastectomies as
described by Carlson [50] that uses a de-epithelialized der-
mal adipose flap sutured to the pectoralis major and the fas-
cia of the serratus anterior as a component of a compound
pouch in which a permanent implant could be easily allo-
cated (dermal sling technique). The final inverted T scar
resulting from this method may be symmetrized by a wise
pattern breast reduction or mastopexy on the other side.
Nipple-sparing skin-reducing mastectomy is indicated in
patients with large or medium breast volumes, but only mod-
erate ptosis. When breast ptosis is significant, the ability to
safely preserve the nipple-areolar complex without necrosis
is reduced. In those cases, a careful discussion with the
patients of a possible free nipple graft in the setting of no
postmastectomy radiotherapy or resection of the nipple-­
areolar complex with a delayed nipple reconstruction should
be advised.
27.8 Conclusions
Immediate breast reconstruction has become widely avail-
able in modern breast practice with good oncological safety,
enhanced cosmesis and quality of life and few absolute con-
traindications. Radiotherapy does impact on outcomes but
should be considered as a relative, rather than an absolute,
contraindication. Patients should be fully aware of the
rares1geo@gmail.com
c­onsequences before choosing between immediate and
delayed breast reconstruction.
In cases of planned immediate breast reconstruction where
postmastectomy radiotherapy is likely to be offered, an autolo-
gous flap-based reconstruction should be the preferred option.
stage reconstruction with an expander inflated during radio-
therapy and an immediate/delayed reconstruction are also
possibilities. The benefits of ADMs in the radiotherapy setting
are still unclear, and evidence suggests that while the risks may
be lower, radiotherapy is still associated with inferior outcomes.
Measures of quality of life and cosmetic outcomes are
fundamental to the assessment of reconstructive surgery. The
BREAST-Q questionnaire is a valuable and validated option
which is simple to use. Regarding cosmetic outcome, there is
no validated tool for the evaluation of immediate breast
reconstruction results, but the use of the BCCT.core software
can help to evaluate simple values like asymmetry in a stan-
dard and simple way.
The use of decision trees with the inclusion of the more
important factors involved in surgical technique selection
can help doctors and patients to make a safer and better
informed choice.
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16. Jagsi R, Jiang J, Momoh AO, Alderman A, Giordano SH, Buchholz TA,
et al. Complications after mastectomy and immediate breast recon-
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2016;263(2):219–27.
17. Xavier Harmeling J, Kouwenberg CA, Bijlard E, Burger KN, Jager A,
Mureau MA. The effect of immediate breast reconstruction on the
timing of adjuvant chemotherapy: a systematic review. Breast Can-
cer Res Treat. 2015;153(2):241–51.
18. Hamahata A, Kubo K, Takei H, Saitou T, Hayashi Y, Matsumoto H,
et al. Impact of immediate breast reconstruction on postoperative
adjuvant chemotherapy: a single center study. Breast Cancer.
2015;22(3):287–91.
19. Eck DL, McLaughlin SA, Terkonda SP, Rawal B, Perdikis G. Effects of
immediate reconstruction on adjuvant chemotherapy in breast
cancer patients. Ann Plast Surg. 2015;74(Suppl 4):S201–3.
20. Gieni M, Avram R, Dickson L, Farrokhyar F, Lovrics P, Faidi S, et  al.
Local breast cancer recurrence after mastectomy and immediate
breast reconstruction for invasive cancer: a meta-analysis. Breast.
2012;21(3):230–6.
21. Eriksen C, Frisell J, Wickman M, Lidbrink E, Krawiec K, Sandelin
K. Immediate reconstruction with implants in women with invasive
breast cancer does not affect oncological safety in a matched
cohort study. Breast Cancer Res Treat. 2011;127(2):439–46.
22. Fischer JP, Wes AM, Tuggle CT, Serletti JM, Wu LC. Risk analysis and
stratification of surgical morbidity after immediate breast recon-
struction. J Am Coll Surg. 2013;217(5):780–7.
23. Song J, Zhang X, Liu Q, Peng J, Liang X, Shen Y, et al. Impact of neo-
adjuvant chemotherapy on immediate breast reconstruction: a
meta-analysis. PLoS One. 2014;9(5):e98225.
24. Abt NB, Flores JM, Baltodano PA, Sarhane KA, Abreu FM, Cooney
CM, et al. Neoadjuvant chemotherapy and short-term morbidity in
patients undergoing mastectomy with and without breast recon-
struction. JAMA Surg. 2014;149(10):1068–76.
25. Dolen UC, Schmidt AC, Um GT, Sharma K, Naughton M, Zoberi I,
et al. Impact of neoadjuvant and adjuvant chemotherapy on imme-
diate tissue expander breast reconstruction. Ann Surg Oncol.
2016;23(7):2357–66.
26. Caffo O, Cazzolli D, Scalet A, Zani B, Ambrosini G, Amichetti M, et al.
Concurrent adjuvant chemotherapy and immediate breast recon-
struction with skin expanders after mastectomy for breast cancer.
Breast Cancer Res Treat. 2000;60(3):267–75.
27. Myckatyn TM, Cavallo JA, Sharma K, Gangopadhyay N, Dudas JR,
Roma AA, et al. The impact of chemotherapy and radiation therapy
on the remodeling of acellular dermal matrices in staged, prosthetic
breast reconstruction. Plast Reconstr Surg. 2015;135(1):43e–57e.
28. EBCTCG, McGale P, Taylor C, Correa C, Cutter D, Duane F, et al. Effect
of radiotherapy after mastectomy and axillary surgery on 10-year
recurrence and 20-year breast cancer mortality: meta-­analysis of
individual patient data for 8135 women in 22 randomised trials.
Lancet. 2014;383(9935):2127–35.
29. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-­
Gebhart M, et al. Tailoring therapies – improving the management
of early breast cancer: St Gallen international expert consensus on
the primary therapy of early breast cancer 2015. Ann Oncol.
2015;26(8):1533–46.
30. Pavy JJ, Denekamp J, Letschert J, Littbrand B, Mornex F, Bernier J, et al.
EORTC Late Effects Working Group. Late effects toxicity scoring: the
SOMA scale. Int J Radiat Oncol Biol Phys. 1995;31(5):1043–7.
31. Lam TC, Hsieh F, Boyages J. The effects of postmastectomy adjuvant
radiotherapy on immediate two-stage prosthetic breast reconstruc-
tion: a systematic review. Plast Reconstr Surg. 2013;132(3):511–8.
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32. Barry M, Kell MR. Radiotherapy and breast reconstruction: a meta-­
analysis. Breast Cancer Res Treat. 2011;127(1):15–22.
33. Schaverien MV, Macmillan RD, McCulley SJ.  Is immediate autolo-
gous breast reconstruction with postoperative radiotherapy good
practice?: a systematic review of the literature. J Plast Reconstr Aes-
thet Surg. 2013;66(12):1637–51.
34. Valdatta L, Cattaneo AG, Pellegatta I, Scamoni S, Minuti A, Cheru-
bino M. Acellular dermal matrices and radiotherapy in breast recon-
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36. Winters ZE, Balta V, Thomson HJ, Brandberg Y, Oberguggenberger
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naire module for women undergoing breast reconstruction. Br J
Surg. 2014;101(4):371–82.
37. Heneghan HM, Prichard RS, Lyons R, Regan PJ, Kelly JL, Malone C,
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38. Nava MB, Rocco N, Catanuto G.  Conservative mastectomies: an
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40. Wei CH, Scott AM, Price AN, Miller HC, Klassen AF, Jhanwar SM, et al.
Psychosocial and sexual well-being following nipple-sparing mas-
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41. Cardoso MJ, Cardoso JS, Vrieling C, Macmillan D, Rainsbury D, Heil J,
et al. Recommendations for the aesthetic evaluation of breast can-
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629–37.
42. Cardoso MJ, Cardoso J, Amaral N, Azevedo I, Barreau L, Bernardo M,
et al. Turning subjective into objective: the BCCT.Core software for
evaluation of cosmetic results in breast cancer conservative treat-
ment. Breast. 2007;16(5):456–61.
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vative mastectomies. Gland Surg. 2016;5(1):69–74.
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F. The BREAST-V: a unifying predictive formula for volume assess-
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45. Kim MS, Reece GP, Beahm EK, Miller MJ, Atkinson EN, Markey
MK. Objective assessment of aesthetic outcomes of breast cancer
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and cost. Health Aff (Millwood). 2008;27(3):759–69.
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48. Nava MB, Ottolenghi J, Pennati A, Spano A, Bruno N, Catanuto G,
et al. Skin/nipple sparing mastectomies and implant-based breast
reconstruction in patients with large and ptotic breast: oncological
and reconstructive results. Breast. 2012;21(3):267–71.
49. della Rovere GQ, Nava M, Bonomi R, Catanuto G, Benson JR.  Skin-­
reducing mastectomy with breast reconstruction and sub-­pectoral
implants. J Plast Reconstr Aesthet Surg. 2008;61(11):1303–8.
50. Losken A, Carlson GW, Bostwick J 3rd, Jones GE, Culbertson JH,
Schoemann M. Trends in unilateral breast reconstruction and man-
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Reconstr Surg. 2002;110(1):89–97.
 325 28

Delayed Breast Reconstruction:

General and Oncological
Considerations
Zoltán Mátrai

28.1 Introduction – 326

28.2 Indications and Special Considerations for 

Delayed Breast Reconstruction – 327
28.2.1 Oncological Considerations for Delayed-Immediate
and Delayed Breast Reconstruction – 327
28.2.2 Patient-Related Factors – 330

28.3 Practical Considerations in Delayed Breast

Reconstruction – 335
28.3.1 Technical Assessment – 335
28.3.2 Delayed Breast Reconstruction Techniques
for Partial Mastectomy Defects – 345
28.3.3 Delayed Breast Reconstruction Techniques
for Total Mastectomy Defects – 345
28.3.4 Autologous Flaps in Delayed Breast Reconstruction – 346

28.4 Outcomes of Delayed Breast Reconstructions – 349

28.4.1 Information Given to Women Before Their Breast Surgery – 349
28.4.2 Types of Breast Reconstruction Techniques – 349
28.4.3 Types of Contralateral and Secondary Reconstructive
Procedures – 349
28.4.4 Complication Rates for DBR – 349
28.4.5 Pain Management in the First 24 h After Surgery – 350
28.4.6 Access to Postoperative Psychological Support – 351
28.4.7 Long-Term Clinical and Patient Satisfaction Results
of Delayed Breast Reconstructions – 351

References – 352

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_28

rares1geo@gmail.com
 326 Z. Mátrai
28.1 Introduction
Reconstructive surgery techniques provide a range of safe
methods to recreate the breast mound and restore the skin
envelope following mastectomy and also for the restoration
of symmetry [1, 2]. Breast reconstruction (BR) should opti-
mally result in a soft natural looking and feeling breast which
retains its properties over time [1]. Breast reconstruction is a
28 critical step for many women to restore their body image and
improve self-esteem and quality of life after breast cancer
surgery [3, 4]. The importance and popularity of BR have
increased substantially in the last three decades due to an
increased range of techniques, wider availability of appropri-
ate surgical skills, improved oncological management and
higher patient expectations [1]. In fact, modern multidisci-
plinary breast care integrates optimal oncological care with
support of the psychological and aesthetic needs of women
with breast cancer, and reconstructive surgery is now a core
component of multidisciplinary cancer care. Women should
be offered access to the full range of procedures in this new
era of oncoplastic breast surgery [1, 3].
Oncoplastic breast surgery covers a wide range of proce-
dures to maintain or improve the cosmetic outcome of sur-
gery while maintaining optimal oncological outcomes and
includes reconstruction after mastectomy (immediate or
delayed), wide excision plus volume replacement or displace-
ment to restore the defect and correction of asymmetry
between the breasts [1, 2]. According to the guidelines of the
UK Association of Breast Surgeons (ABS), all patients, for
whom mastectomy is a treatment option, should have the
opportunity to receive advice on BR [5]. Breast reconstruc-
tion can be performed either at the time of the primary oper-
ation (oncoplastic volume displacement/replacement or
immediate BR) or later as a separate surgical procedure
(delayed breast reconstruction (DBR)) [1, 3]. Traditionally
general surgeons performed the majority of breast cancer
surgeries, and reconstructions were delayed procedures done
mostly by plastic surgeons [1]. Modern oncoplastic breast
surgery is increasingly being performed by breast surgeons or
oncoplastic breast surgeons who are able to combine onco-
logical and reconstructive plastic surgical techniques [1]. In
2002, the National Institute for Health and Clinical Excellence
(NICE) in the United Kingdom (UK) published guidelines on
improving breast cancer outcomes and recommended that
«reconstruction should be available to all women with breast
cancer at the initial surgical operation» [2, 6, 7]. According to
the Fourth Annual Report of the National Mastectomy and
Breast Reconstruction Audit (NMBRA) in the UK during an
audit period between 1 January 2008 and 31 March 2009,
16,485 patients underwent mastectomy [8]. Of these women
21% received a concurrent immediate breast reconstruction
(IBR) and 10.5% underwent DBR.  If BR is not offered, the
reasons should be recorded [2, 5].
Providing adequate information about oncoplastic sur-
gery from the outset is important to avoid discouraging
patient interest and uptake [2] and should include discussion
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of not only the available techniques but the timing of such
surgery [1–3]. Depending on the timing of reconstruction,
numerous non-randomized studies have reported differ-
ences in the type of surgery, the psychological benefits, aes-
thetics and complication rates [3]. In the Third NMBRA, the
most common type of procedure for women undergoing IBR
was implant-only or tissue expander-based reconstruction
(36.8%) versus DBR where the most common ­technique was
autologous flap based (58.5%) [2].
Although high-level evidence is not available to explore
differences between BR types in terms of quality of life or
patient safety, there are significant differences in terms of the
reconstructive techniques between IBR and DBR, which
reflects the basic difference of the initial status of the breast
skin, soft tissue and volume loss to be restored [3, 9].
Nipple-sparing mastectomy (NSM), areola-sparing mas-
tectomy (ASM) and skin-sparing mastectomy (SSM) are
increasing popular, as evidence of their oncological safety
grows and commercial products to facilitate BR are being
developed continually, such as acellular dermal matrices
(ADM), shaped and textured implants and expanders and
lipomodelling equipment. Consequently IBR and DBR tech-
niques have an increased range of indications and usually
provide a good to excellent aesthetic result with a low mor-
bidity to an increasing number of women [9, 10].
Despite the advantages of IBR, DBR will always be needed
in certain cases [11]. Immediate reconstruction may be rela-
tively contraindicated in some women with high-risk cancers
for oncological reasons (e.g. the likely need for radiotherapy
(RT)), and the procedure is not available in all cancer centres
[11]. Other reasons include patients’ preference for delayed
reconstructive surgery or a delayed decision to undergo such
surgery once the cancer treatments are complete and they are
psychologically ready to face a new challenge [11]. Although
DBR is technically more challenging than IBR, good results
can be achieved [11].
A number of special issues should be considered with
regard to DBR [3]. Compared to IBR, delayed reconstruction
is generally expected to recover a worse initial situation,
characterized by previously irradiated poor-quality residual
skin in limited amounts, an excessive loss of soft tissue and
volume, extensive scar tissue, incisional scars running sub-
optimally, blood vessels meant to supply flaps located in
fibrotic surrounding tissue, partial or complete lack of aes-
thetic subunits such as the inframammary fold (IMF) and/or
lateral mammary fold or nipple-areola complex (NAC) [3, 9,
11]. It should be highlighted that patients choosing DBR
have substantially more time to consider the surgical options,
seek advice from plastic and/or breast surgeons and evaluate
the various reconstructive techniques available once onco-
logical treatment has been completed, which is potentially
advantageous compared to women in the IBR setting who
are often struggling with the burden of the initial cancer
diagnosis [3, 9, 11]. However DBR patients may also suffer
psychologically. These women have completed complex
oncological therapies and experienced a period of living
Delayed Breast Reconstruction: General and Oncological Considerations
without a breast or with the significant deformity of a breast
remnant and may have struggled with external prosthetics
for a while [3]. Some studies have identified these factors as
leading to decreased self-esteem and body image, causing
depression and anxiety [3, 12].
Planning BR has become more complex due to the
increasing use of RT in early-stage breast cancer [9]. Some
surgeons advocate use of a temporary tissue expander to pre-
serve the breast skin envelope if RT is indicated or expected
[9]. In 2002 Steven J. Kronowitz from the University of Texas
M.  D. Anderson Cancer Center implemented a two-stage
approach, the delayed-immediate breast reconstruction
(D-IBR) [13]. This revolutionary staged approach was able to
bridge the time frame of oncological uncertainty, between
the primary surgery and the final pathological report while
preserving the skin envelope, IMF and breast shape maxi-
mizing the chance for an improved aesthetic outcome.
A staged multiple-step approach is often implemented in
cases of planned DBR, including symmetrization surgery,
minor revision surgeries, NAC reconstruction and areola tat-
tooing [9] (. Fig. 28.1).
According to Kronowitz the decision of when to perform
BR remains controversial and will often depend on individ-
ual circumstances in addition to the need for adjuvant RT
[9]. In planning BR, effective oncological treatment is con-
sidered the top priority, and the aesthetic goals of reconstruc-
tion are subordinate to this [3].
28.2 I ndications and Special Considerations
for Delayed Breast Reconstruction
Breast reconstruction may be an option for any breast cancer
patient undergoing surgery [1, 5, 14] and who is physically
and mentally suitable without compromising definitive
oncological therapy or likely to be at high risk of surgical
morbidity or mortality [14]. Even stage IV disease is not a
contraindication for BR if the patient’s predicted life expec-
tancy is relatively long, and surgery will not delay or prevent
life-prolonging systemic treatments. MDT involvement in
such cases is mandatory [5]. Patients should be provided
with appropriate sources of both written and verbal informa-
tion, detailing the risks and benefits of different types of BR
[14]. The assessment should take into account all of the onco-
logical and reconstructive factors, in light of the individual
circumstances and preferences of each patient, irrespective of
whether the optimal reconstructive method is available
locally or not [14]. Oncological principles must not be com-
promised and should always be prioritized [14].
When DBR is considered, the results of a full clinical
assessment and staging should be available for assessment
[1]. Maintaining close communication between plastic or
oncoplastic surgeons and other team members is essential
[14]. For each patient a plan of the reconstructive procedure
must be drawn up. The plan defines the expected staged
(multiple-step) approach, the risk of morbidity, estimated
rares1geo@gmail.com
327 28
operation time, length of hospital stay and rehabilitation
therapies [14]. MDT members should agree on the offered
DBR options, and the patient should be fully involved in the
decision-making process [5, 14].
28.2.1  Oncological Considerations
for Delayed-Immediate and Delayed
Breast Reconstruction
If DBR is considered, full clinical assessment and staging are
mandatory [14]. Preoperative unrecognized locoregional
recurrences can result in major difficulties, for example, if
there is a need to perform an axillary lymphadenectomy
shortly after microsurgery in the axilla. The first step of DBR
is complete excision of the scar tissue [9]. Tissue excised
from the former cancer site should be sent for histopathol-
ogy. If the tissue is suspicious for malignancy, it should be
investigated intraoperatively by frozen section before pro-
ceeding, and if a recurrence is identified, the tumour must be
removed radically, and BR may need to be delayed and
replaced by salvage surgery which may require use of flaps
(see 7 Chap. 22, Surgery for Recurrent Disease).
For D-IBR, the probability of adjuvant treatment (espe-
cially RT) is an important factor in decision-making [14]. RT
may exert a harmful effect on the reconstructed breast par-
ticularly following implant-based procedures [1, 14, 15]. The
metal ports of some tissue expanders may interfere with RT
dosage and dose distribution [14]. The surgery to exchange
the expander to the permanent implant may be performed
prior to or after completion of the RT; however, expander to
implant change prior to RT is associated with a higher rate of
capsular contracture, malposition, poor cosmesis and
implant exposure [9, 15] (. Fig. 28.2, . Table 28.1).
The timing of DBR, or a staged expander to implant
exchange in case of a D-IBR, is recommended at the earliest
1–3 months after the completion of the adjuvant chemother-
apy or 3–6 months after RT [9]. An important consideration
in DBR is that of concern that IBR may result in delayed
adjuvant systemic therapy if there are complications; how-
ever, data suggests this effect is minimal (. Fig. 28.3) [17].
The effect of adjuvant RT following autologous flap
reconstruction is controversial [18]. When postmastectomy
RT is indicated, autologous tissue reconstruction is either
delayed until the end of the RT or D-IBR could be performed
followed by flap transposition [18] (. Fig. 28.4). Some expe-
rienced breast cancer teams have implemented protocols in
which IBRs are followed by RT without significantly affecting
breast volume after deep inferior epigastric perforator (DIEP)
flap reconstruction [18]. Women requiring postoperative RT
should not be discouraged from undergoing immediate
DIEP flap reconstruction, but RT is generally preferred to
precede the flap transfer, because of the reported decreased
aesthetic end result [18].
Tissue expansion of previously irradiated skin can result
in a significantly increased risk of capsular contracture,
 328 Z. Mátrai

a b

28

c d

..      Fig. 28.1  a, b 45-year-old patent had a skin-sparing mastectomy plus profile 200 cm3 implant with a mastopexy was performed for sym-
and SLNB with a D-IBR using a tissue expander. c Five months after metrisation on the left side. d, e Additionally the reconstruction of the
the primary operation, a textured, anatomic shaped 600 cm3 silicone nipple and tattooing was completed
implant was placed to the right side and a textured, round, moderate

rares1geo@gmail.com
Delayed Breast Reconstruction: General and Oncological Considerations
329 28

a b

c d

e f

..      Fig. 28.2  a 51-year-old patient had a right BCS and SLNB in
2011 and subsequent radiotherapy. BRCA2 mutation subsequently
identified. In 2013 a second primary tumour in the left breast was
diagnosed. b SSM of the right side and SSM and SLNB on the left side
and D-IBR using tissue expanders were performed. On the right side
the differences in colour, texture and elasticity of the former irradiated
major pectoral muscle can be seen. c, d After the partial expansion on
the right side, a Baker IV capsular contracture occurred, causing the
impression of the thoracic wall. e Six months later the fibrotic breast
skin remnant was excised, the expander was explored and removed
and the soft tissue was reconstructed with an LDmc flap and place-
ment of a tissue expander. f Three months later a symmetrization was
done by using a textured anatomic-shaped 545 cm3 silicone implant
on both sides. g Nipple reconstruction and tattooing were performed

rares1geo@gmail.com
 330 Z. Mátrai

g and cosmetic outcomes. The meta-analysis of Schaverien and

colleagues (no randomized controlled trials met the inclusion
criteria only observational studies were analysed) regarding
outcomes of autologous IBR with postoperative RT compared
with no RT, as well as with autologous DBR following post-
mastectomy RT, revealed no significant differences in total
prevalence of complications or revisional surgery and a sum-
mary measure for fat necrosis favouring the group without
28 RT (OR 2.82, 95% CI 1.35–5.92, p = 0.006) [19]. Most of the
studies comparing IBR and postoperative RT with DBR fol-
lowing adjuvant RT reported satisfactory outcomes following
IBR. There was no significant difference in overall incidence
of complications and fat necrosis (OR 0.63, 95% CI 0.29–1.38,
p = 0.25) and a summary measure for revisional surgery (OR
0.15, 95% CI 0.05–0.48, p = 0.001) favouring the DBR group.
This meta-analysis reported satisfactory outcomes and a
similar incidence of complications for autologous IBR and
adjuvant RT when compared with no RT or delayed recon-
struction following RT, although the proportion that required
revisional surgery was higher for immediate than DBR. The
authors highlighted that these findings are limited by the
paucity of high-quality data in the published literature, and
until better data is available, the findings of this review sug-
gest that autologous IBR should at least be considered when
..      Fig. 28.2 (continued) adjuvant chest wall RT is ­anticipated [19] (. Table 28.2).
 

According to the consensus statement of the St. Gallen

International Expert Consensus on the Primary Therapy of
..      Table 28.1  Forest plot of 20 studies by Valdatta et al. [16]. Early Breast Cancer in 2015 for patients whose breast cancer
The authors reported the complications occurring in ADM-
assisted immediate implant breast reconstruction, with or
was diagnosed during pregnancy, IBR in the first instance
without radiotherapy. Odds ratios and confidence intervals at and D-IBR with a submuscularly placed tissue expander can
95% are plotted. The black diamond at the bottom is the pooled be considered [20].
odds ratio, and it is CI 95%. It completely falls to the left of 1.0 [16] IBR is contraindicated in conjunction with mastectomy
Study name Model Odds ratio and 95% Cl for inflammatory breast cancer (IBC) because of the high
recurrence rate, aggressive nature of the disease and the need
Gamboa-Bobadilla, 2006
Bindingnavele et al., 2007
for adjuvant RT without any potential delay [18]. Skin-­
Nahabedian, 2009 sparing mastectomy has not yet been proven to be safe in
Namnoun, 2009
Colwell et al., 2011 IBC.  According to the National Comprehensive Cancer
Israeli and Feingold, 2011
Joanna Nguyen et al., 2011
Network (version 2.2016) guidelines, DBR can be recom-
Rawlani et al., 2011 mended to women with IBC who have undergone a modified
Nicolau et al., 2012
Salzberg et al., 2011 radical mastectomy [18].
Salzberg et al., 2013
Spear et al., 2012
Seth et al., 2012
Parks et al., 2012
Cheng and Saint-Cyr, 2012 28.2.2  Patient-Related Factors
Clements and Kronowitz, 2012
Hanna et al., 2013
Patel et al., 2013
Potter et al., 2013
Patient-related factors play an important role in the timing and
Weichman et al., 2013 choice of reconstructive technique. These factors include per-
formance status, comorbidities, body mass index (BMI), ASA
0.1 0.2 0.5 1 2 5 10
score, drug and smoking history, psychological suitability,
Fixed occupation, daily activities and lifestyle, pre-existing shoulder
or musculoskeletal problems, patients’ expectations and
choice, goals, attitudes to risk and the likely impact of recovery
implant malposition, poor cosmesis, implant exposure and time on family [14]. The psychological status of the patient
failed BR and is therefore relatively contraindicated [9, 18]. should be assessed preoperatively [14]. If additional risks exist,
In these cases autologous tissue reconstruction is the pre- they should be clearly stated when consenting the patient [14].
ferred method [18]. According to the current evidence-based clinical practice
There is some controversy to whether autologous IBR guideline, breast reconstruction with expanders and implants,
with adjuvant RT is associated with acceptable complication of the American Society of Plastic Surgeons, smoking

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Delayed Breast Reconstruction: General and Oncological Considerations
331 28

a
12 120

10 Mean = 31.47 100 Mean = 24.86

SD = 9.593 SD = 9.49
n = 43 n = 552
Frequency (%)

Frequency (%)
8 80

6 60

4 40

2 20

0 0
10 20 30 40 50 60 70 20 40 60 80
Time (day) Time (day)

b
Without
With wound
wound
complications
complications
Characteristics IBR + p-value
IBR mastectomy
mastectomy
group (a) only group (b)
only group (c)
(n = 9) (n = 14)
(n = 572)
Age (yr) 46.67±8.7 49.4±5.2 47.8±9.2 0.743
Body mass index 22.8±2.0 24.8±4.5 23.1±3.0 0.133
Interval to remove 15.3±5.0 15.0±9.8 7.1±3.6 <0.0001
of drains (day) (a, b>c)
Hospital day 16.0±5.0 14.9±7.2 7.7±3.7 <0.0001
(a, b>c)
Interval to chemo- 45.2±9.9 44.2±12.4 24.6±5.5 <0.0001
therapy (day) (a, b>c)

..      Fig. 28.3  Effect of immediate reconstruction on chemotherapy complications and the impact on chemotherapy timing (Values are
timing. a Time interval to chemotherapy in women who have or have presented as mean ± SD. IBR immediate breast reconstruction, SD
not undergone chemotherapy. b Comparison of complication rates standard deviation) (Reproduced from Lee et al. [17] with permission
in women undergoing reconstructive surgery with/without wound from The Journal of Breast Cancer)

increases the risk of postoperative wound complications and
implant loss in patients undergoing postmastectomy
expander/implant BR [21]. The overall complication rates
were 2.2–3.07 times higher among smokers than non-­
smokers. Smokers were 2.9 times more likely than non-­
smokers to develop wound necrosis (p = 0.003) and 5.9 times
more likely to experience reconstruction failure (p = 0.001).
Evidence shows that obesity increases the risk of postop-
erative complications in patients undergoing postmastec-
tomy expander/implant BR [21]. BMI >30 was significantly
associated with postoperative wound infections and
expander/implant failures. Wound infections among patients
with immediate expander/implant reconstructions were 3.3
times higher among patients with a BMI of 25–30 (p = 0.002)
and 18.5 times higher among those with a BMI >30 when
compared to patients with a BMI <25 (p < 0.001). The risk of
implant loss was 3 times higher for those with a BMI of 25–30
(odds ratio 3.1 [95% CI 1.0–9.3]; p  =  0.043) and almost 6
times higher for those with a BMI >30 when compared to
those with a BMI of <25 (odds ratio 5.9 [95% CI 1.2–29.5];
p = 0.032). Several studies found a statistically significant link
between obesity and an increased risk of mastectomy skin
flap necrosis, fat necrosis, wound dehiscence, infection,
seroma, hematoma and implant extrusion. Obese patients
were almost twice as likely as patients of a normal weight to
develop an expander/implant complication (odds ratio 1.8
[95% CI 1.1–3.0]; p = 0.02).
Evidence suggests that patients with a preoperative breast
cup size of C or larger may be at an increased risk for postop-
erative complication with immediate expander/implant BRs
compared to those with a preoperative breast cup size of A or
B [21]. A preoperative breast cup size larger than C remained a
statistically significant risk factor for infection. Patients with a
breast cup size of D or DD were nearly three times more likely
than patients with smaller breasts to experience an infection
(odds ratio 2.89 [95% CI 1.59–5.26]; p < 0.001). A ­retrospective

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 332 Z. Mátrai
a b
28
c d
..      Fig. 28.4  a, b The 38-year-old patient was operated in 2007 on
the right breast with BCS and SLNB and adjuvant RT. In 2008 she had
cancer on the left side treated with BCS and SLNB and RT. BRCA testing
was negative. In 2013 bilateral mastectomy and reSLNB on the right
comparative study observed a greater rate of skin necrosis in
breasts larger than 600  g (> C cup) compared with breasts
smaller than 600 g (A or B cup) (19% vs. 1.8%, respectively,
p < 0.001) [22]. This may relate to tension in the wound close
and on the flaps of heavier implants to some degree.
According to evidence, among patients with expander/
implant BRs, diabetes is not a significant risk factor for post-
operative complications, including implant failure, pulmo-
nary embolism, seroma, necrosis, mastectomy flap necrosis,
wound dehiscence, infection and capsular contracture or
reconstructive failure, defined as the premature removal of
expander or implant [21].
The review of Fisher and colleagues aimed to characterize
factors associated with postoperative complications following
breast reconstruction using the National Surgical Quality
Improvement Program (ACS-NSQIP) database from 2005–
2010 [22]. The database included either implant-based
­reconstruction (immediate, delayed and tissue expander) or
autologous reconstruction (pedicled transverse rectus
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e
side was performed due to a rpT1cpN0(sn) recurrent NOS cancer c–e.
In 2014 bilateral muscle-sparing TRAM reconstruction was performed
after flap delay
a­ bdominus myocutaneous (TRAM), free TRAM and latissi-
mus dorsi flap with or without implant). During the study
period, 16,063 breast reconstructions were performed.
Autologous reconstructions were performed in 20.7% of
patients and implant based in 79.3%. The incidence of major
surgical complications was 8.4%, and the incidence of medical
and wound complications was 1.6% and 3.5%, respectively.
Independent risk factors for major surgical complications
included immediate and autologous reconstructions, obesity,
smoking, previous percutaneous cardiac surgery, recent weight
loss, bleeding disorder, recent surgery, ASA ≥3, intraoperative
transfusion and prolonged operative times. Risk factors for
medical complications included autologous reconstruction,
obesity, tumour involving CNS, bleeding disorders, recent sur-
gery, ASA ≥3, intraoperative transfusion and prolonged opera-
tive times. Key identifiable risk factors associated with both
surgical and medical morbidity included autologous breast
reconstruction, obesity, ASA ≥3, bleeding disorders and pro-
longed operative time (. Table 28.3).
Delayed Breast Reconstruction: General and Oncological Considerations
333 28

..      Table 28.2  Complications of autologous breast reconstruction with or without postoperative radiotherapy according to the meta-
analysis by Schaverien et al. a Forest plot of prevalence of complications. b Forest plot of prevalence of fat necrosis. c Forest plot of
prevalence of revisional surgery

a Overall complications
Radiotherapy Control Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl
Berry et al., 2010 20 78 89 274 47.0% 0.72 [0.41, 1.26]
Carlson et al., 2008 11 25 51 149 13.2% 1.51 [0.61, 3.56]
Lee et al., 2010 11 36 78 371 15.4% 1.65 [0.78, 3.51]
Spear et al., 2005 17 34 39 78 19.0% 1.00 [0.45, 2.24]
Williams et al., 1997 6 19 10 57 5.5% 2.17 [0.66, 7.09]

Total (95% Cl) 192 929 100.0% 1.10 [0.78, 1.54]

Total events 65 267
Heterogeneity: Chi2 = 5.16, df = 4 (P = 0.27); I2 = 22%
Test for overall effect: Z = 0.54 (P = 0.59) 0.01 0.1 1 10 100
Favours radiotherapy Favours control
b Fat necrosis
Radiotherapy Control Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Random, 95% Cl M-H, Random, 95% Cl
Carlson et al., 2008 8 25 22 149 20.1% 2.72 [1.05, 7.06]
Lee et al., 2010 4 36 43 371 18.3% 0.95 [0.32, 2.83]
Rogers and Allen, 2002 7 30 0 30 5.3% 19.47 [1.06, 358.38]
Spear et al., 2005 8 34 9 78 18.7% 2.36 [0.82, 6.77]
Tran et al., 2000 14 41 101 1443 24.1% 6.89 [3.50, 13.55]
Williams et al., 1997 3 19 6 57 13.5% 1.59 [0.36, 7.11]
Total (95% Cl) 185 2128 100.0% 2.82 [1.35, 5.92]
Total events 44 181
Heterogeneity: Tau2 = 0.47; Chi2 = 12.63, df = 5 (P = 0.03); I2 = 60%
Test for overall effect: Z = 2.75 (P = 0.006) 0.01 0.1 1 10 100
Favours radiotherapy Favours no radiotherapy
c Revisional surgery
Radiotherapy Control Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl
Carlson et al., 2008 3 25 28 149 61.3% 0.59 [0.16, 2.11]
Chatterjee et al., 2009 3 22 8 46 38.7% 0.75 [0.18, 3.15]
Rogers and Allen, 2002 5 30 0 0 Not estimable

Total (95% Cl) 77 195 100.0% 0.65 [0.25, 1.68]

Total events 11 36
Hetetogeneity: Chi2 = 0.06, df = 1(P = 0.81); I2 = 0%
Test for overall effect: Z = 0.88 (P = 0.38) 0.01 0.1 1 10 100
Favours radiotherapy Favours control
a Overall complications

Pre-recon radiotherapy Post-recon radiotherapy Odds Ratio Odds Ratio

Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl
Adesiyun et al., 2011 14 43 9 35 13.1% 1.39 [0.52, 3.76]
Berry et al., 2011 31 101 20 78 30.6% 1.28 [0.66, 2.49]
Carlson et al., 2008 5 15 11 25 10.8% 0.64 [0.17, 2.41]
Lee et al., 2010 14 43 11 36 15.8% 1.10 [0.42, 2.85]
Spear et al., 2005 22 38 17 34 14.8% 1.38 [0.54, 3.49]
Williams et al., 1997 27 108 6 19 15.0% 0.72 [0.25, 2.09]

Total (95% CI) 348 227 100.0% 1.13 [0.77, 1.65]

Total events 113 74
2 2
Heterogeneity: Chi = 1.89, df = 5 (P = 0.86); I = 0%
Test for overall effect: Z – 0.63 (P – 0.53) 0.01 0.1 1 10 100
Favours pre-recon dxt Favours post-recon dxt
b Fat necrosis

Pre-recon radiotherapy Post-recon radiotherapy Odds Ratio Odds Ratio

Study or Subgroup
Adesiyun et al., 2011
Carlson et al., 2008
Lee et al., 2010
Mckeown et al., 2009
Spear et al., 2005
Tran et al., 2001
Williams et al., 1997
Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl
7 43 4 35 15.4% 1.51 [0.40, 5.64]
2 15 8 25 11.9% 0.33 [0.06, 1.81]
5 43 4 36 14.6% 1.05 [0.26, 4.25]
1 11 2 13 7.0% 0.55 [0.04, 7.03]
9 38 8 34 17.9% 1.01 [0.34, 3.00]
6 70 14 32 17.9% 0.12 [0.04, 0.36]
19 108 3 19 15.3% 1.14 [0.30, 4.30]

Total (95% CI) 328 194 100.0% 0.63 [0.29, 1.38]

Total events 49 43
Heterogeneity: Tau2 = 0.58, Chi2 – 13.08, df = 6 (P – 0.04); I2 = 54%
Test for overall effect: Z = 1.16 (P = 0.25) 0.01 0.1 1 10 100
Favours pre-recon DXT Favours post-recon DXT
c Revisional surgery
Pre-recon radiotherapy Post-recon radiotherapy Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% Cl M-H, Fixed, 95% Cl
Carlson et al., 2008 0 15 3 25 13.1% 0.21 [0.01, 4.30]
Lee et al., 2010 0 43 2 36 13.7% 0.16 [0.01, 3.41]
Mckeown et al., 2009 2 11 2 13 7.6% 1.22 [0.14, 10.48]
Tran et al., 2001 0 70 9 32 65.6% 0.02 [0.00, 0.31]

Total (95% CI) 139 106 100.0% 0.15 [0.05, 0.48]

Total events 2 16
2 2
Heterogeneity: Chi = 5.79, df = 3 (P = 0.12); I = 48%
Test for overall effect: Z = 3.24 (P = 0.001) 0.01 0.1 1 10 100
Favours pre-recon dxt Favours post-recon dxt

Reprinted from Schaverien et al. [19] with permission from Elsevier

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334 Z. Mátrai

..      Table 28.3  Patient-related factors associated with major postoperative surgical complications in breast reconstruction according to
the reviewed database (16,063 cases) of the National Surgical Quality Improvement Program (ACSNSQIP)

No complication Major surgical complication P-value

N = 14,716 N = 1347

Number Percent Number Percent

28 Race

  White 11,587 78.7% 1079 80.1% 0.046

  Black 1007 6.8% 110 8.2%

  Asian 402 2.7% 22 1.6%

  Hispanic 139 0.9% 19 1.4%

  American Indian 26 0.2% 2 0.1%

  Hawaii Indian 30 0.2% 2 0.1%

Unknown 1525 10.4% 113 8.4%

Age n/a 51.2 (10.6) n/a 51.6 (10.1) 0.11

Immediate reconstruction 12,451 84.6% 1189 88.3% <0.001

Type of reconstruction

  Implant based 11,767 80.0% 962 71.4% <0.001

  Autologous 2949 20.0% 385 28.6%

Body mass index (kg/m2) (SD) n/a 27.0 (6.2) n/a 29.0 (7.1) <0.001

Obesity (BMI > 30 kg/m2) 3802 25.8% 519 38.5% <0.001

Diabetes 692 4.7% 81 6.0% 0.03

Smoking 1901 12.9% 235 17.4% <0.001

Alcohol use 177 1.2% 24 1.8% 0.067

Dyspnoea

  None 14,174 96.3% 1282 95.2% 0.044

  Moderate 530 3.6% 65 4.8%

  At rest 12 0.1% 0 0.0%

Functional status

  Independent 14,676 99.7% 1341 99.6% 0.25

  Partial dependence 40 0.3% 6 0.4%

History of chronic obstructive pulmonary 126 0.9% 12 0.9% 0.9

disease

History of congestive heart failure 7 0.0% 0 0.0% 0.42

History of myocardial infarction 2 0.0% 0 0.0% 0.67

Previous coronary intervention 97 0.7% 14 1.0% 0.11

Prior cardiac surgery 75 0.5% 14 1.0% 0.01

History of angina 11 0.1% 2 0.1% 0.36

History of peripheral vascular disease 14 0.1% 4 0.3% 0.034

Renal failure 1 0.0% 1 0.1% 0.034

Dialysis 10 0.1% 1 0.1% 0.93

Prior transient ischemic attack 77 0.5% 11 0.8% 0.16

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Delayed Breast Reconstruction: General and Oncological Considerations
335 28

..      Table 28.3 (continued)

No complication Major surgical complication P-value

N = 14,716 N = 1347

Number Percent Number Percent

CNS tumour 7 0.0% 1 0.1% 0.68

Active wound infection 88 0.6% 14 1.0% 0.051

Current use of steroids 132 0.9% 15 1.1% 0.42

Recent weight loss (>10% in 6 months) 47 0.3% 10 0.7% 0.012

Bleeding disorder 89 0.6% 15 1.1% 0.026

Chemotherapy in last 30 days 639 4.3% 46 3.4% 0.11

Radiotherapy in last 30 days 65 0.4% 7 0.5% 0.68

Operation within 30 days 384 2.6% 50 3.7% 0.02

Malnutrition (albumin <3.5 g/dl) 177 1.2% 21 1.6% 0.3

Haemoglobin (g/dl) n/a 13.3 (1.2) n/a 13.3 (1.3) 0.3

Anaemia (haemoglobin <12 g/dl) 1458 9.9% 147 10.9% 0.3

Reprinted from Fischer et al. [22] with permission from Taylor and Francis

Major surgical complications were defined as a deep (. Fig.  28.5), and, in general, more skin and tissue volume
 

wound infection, graft or prosthetic loss or an unplanned
return to the operating room within 30 days (. Table 28.4).
 
In case of failure of a previous reconstruction (complete
failure or need for later substantial revision), DBR, using
autologous flaps or reimplantation, may be necessary [24].
Indications for DBR include symptomatic capsular contrac-
ture, asymmetry, implant extrusion and exposure and previ-
ous partial or total flap loss.
28.3  ractical Considerations in Delayed
P steroid consumption, heavy smoking or tattoos on the poten-
Breast Reconstruction
28.3.1  Technical Assessment
Undoubtedly one of the skills of the oncoplastic surgeon is
their ability to judge what will give a good aesthetic outcome
for a particular woman, best fulfilling her wishes for the
shape and volume of the new breast and how this relates to
her body size and shape before surgery. For some women her
contralateral current breast shape and size may not be her
ideal, and many women wish for augmentation, reduction or
correction of ptosis.
The assessment of other objective factors forms the next
step in the assessment process: the records from previous
surgery, length and position of scars, estimation of the weight
and volume of resected tissue and skin [14]. The lack of an
adequate skin envelope is a key consideration in DBR
are required from the flap that will be used for the recon-
struction compared to IBR [11]. Finding enough skin to per-
form an adequate BR is usually not problematic if the patient
is suitable for an abdominal pedicled or free flap (transverse
rectus abdominis myocutaneous (TRAM) or DIEP flap)
reconstruction, but it may pose an obstacle if the patient has
a low BMI [11]. The surgeon needs to consider this preopera-
tively and plan the BR so that sufficient skin will be available.
The surgeon should assess the texture and elasticity of the
skin especially following RT [14]. Sun-damaged skin, chronic
tial donor areas should be taken into consideration [11].
The presence of scar tissue makes DBR complicated [11].
Scar tissue must be completely released so that the mastectomy
flaps can expand to their original dimensions, only then may
the missing tissue be accurately and successfully replaced [11].
The previously irradiated chest wall poses special surgical
problems since chronic radiation damage leads to progressive
fibrosis [9, 11]. Damaged, fibrotic tissues surrounding an
autologous flap are less likely to blend into the tissues of the
BR as well as they would without RT [11]. Radiation-­damaged
skin often needs to be discarded, and thus more skin may be
required from the flap [11]. The quality of the aesthetic result
that may be obtained in a patient who has had previous RT is
therefore lower than that in a nonirradiated patient. If ade-
quate information is provided such that patients have realistic
expectations of the cosmetic end results, then disappoint-
ment may be avoided [11].

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 336 Z. Mátrai

v­ olume, some based on MRI, 3D photography or on measured

..      Table 28.4  Significant risk factors for the development of
implant-based breast reconstruction infection and proposed
breast parameters. Simple in-­clinic methods, such as use of a
interventions [23, 24] series of sizers or surgeon judgement, may be helpful but are
less accurate and dependent on experience. The excised volume
Risk factor Measures of prevention after BCS should be known from the pathological report but
may be an underestimate as baseline breast size may have dif-
Patient-related risk factors
fered and subsequent radiotherapy may have caused further
Age >50 years Autologous reconstruction to be volume loss. The mean volume and size of the skin surface of
28 considered the different autologous flaps have to be known for adequate
Smoking Advise against smoking for at least planning of an autologous BR [11, 15, 25, 26] (. Table 28.5).
 

Hypertension
Diabetes mellitus
Obesity
Hypercholesterolaemia
Low white blood cell
count
Larger breast size
Disease-related risk factors
Axillary lymph node
dissection
Mastectomy skin necrosis
Immediate reconstruc-
tion
Bilateral surgeries
Therapy-related risk factors
Radiotherapy
Chemotherapy
Prolonged drain use
Late expansion
The estimation or objective measurement of breast volume
using MR volumetry is very helpful in planning reconstruction,
as well as the classification of the degree of breast ptosis. Ideally
the volume of the resected breast should have been recorded at
the time of mastectomy which is very helpful. There are numer-
ous technologies available to permit calculation of breast
2 weeks prior to and 2 weeks
following surgery
Ensure adequate medical
treatment and optimize blood
pressure
Optimize blood glucose level
(recommended interval: 4.4–
6.1 mmol/L (79.2–110 mg/dL))
Autologous reconstruction to be
considered
Encourage dietary changes and
optimize cholesterol levels with
medication if necessary
Achieve normal white blood cell
count or consider autologous
reconstruction
Autologous reconstruction to be
considered
Procedure to be performed in a
separate session
Wound therapy. The implant
should be placed submuscularly
Delayed and/or autologous
reconstruction to be considered
Delayed and/or autologous
reconstruction to be considered
Autologous reconstruction to be
considered
Intensive follow-up to detect
infection in time
Early drain removal may help
avoid infections
Early tissue expansion is associ-
ated with early drain removal
To create a reconstructive plan, the surgeon should envi-
sion the final shape and volume of the reconstructed and
contralateral breast which has to be harmonized with the
patient’s body habitus and preferences. This part of surgical
planning requires ongoing consultations with the patient.
Generally, in case of an implant-only postmastectomy BR,
the final shape and volume of the breast are basically deter-
mined by the chosen implant covered by a relatively thin
layer of soft tissue. Consequently, the shape, width, height
and projection of the implant play the most important role in
sculpting the final form. In implant-based postmastectomy
BR the contralateral breast is the «variable factor» and may
be shaped relatively flexibly by the use of mastopexy with or
without reduction and/or implant placement and/or autolo-
geous fat grafting (FG) to achieve optimal symmetry [27]. If
the BR is autologous tissue based, than the reconstructed,
breast is the one to be shaped immediately at the time of
placement of the flap or at a later date. At the time of plan-
ning the symmetrization surgery for the contralateral breast,
the surgeon should holistically consider the patient’s prefer-
ence and possible risk-reduction surgery for high-risk
patients, remembering the principal rule: that symmetry is
optimal if the structure of both breasts is the same.
Technical assessment after BCS and RT necessitates more
competence in reconstructive surgery [9, 28–30]. The major-
ity of deformities following BCS result from scar contracture,
local glandular and skin deficiencies and radiation fibrosis
which together lead to progressive asymmetry and deforma-
tion of the breast [9]. Traditional surgical excision or quadran-
tectomy leaves an open cavity, and tissue discontinuity behind
the scar leads to uncontrolled scar formation resulting in
adhesions and tissue contracture with adjacent displacement
of the NAC causing major distortion in up to one-third of
BCS cases [9]. The main reason for significant breast defor-
mity after conventional BCS is a large volume of resected
breast parenchyma relative to breast volume. The importance
of the volume deficit is easily understandable if the excised
specimen is to be imagined as a sphere after a wide excision
and as a cylinder after a quadrantectomy, and so the resected
volumes are easily calculated by the Cavalieri formula (4r3π/3)
and Archimedes’ formula (Vcylinder/Vsphere = 3:2). These calcu-
lations show that even in T2 tumours the average resected
breast volume is 50–100 cm3 equalling 20–25% of the volume
of an average breast of 350–450 cm3. The impact of excision in
different breast quadrants further strengthens the correlation
of resected volume and cosmetic failure with medial breast
defects much more difficult to address [31, 32].

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Delayed Breast Reconstruction: General and Oncological Considerations
337 28
..      Fig. 28.5  a 41-year- a b
old patent had a
mastectomy and SLNB in
2013. b In 2014 an LDmc
was performed on the
left side. c Six months
later the reconstruction
was completed with
the use of a textured,
round ultrahigh profile
430 cm3 silicone implant,
and for symmetrization
a textured, round, high
profile 300 cm3 was
placed submuscularly on
the right side. d, e The
patient refused a masto-
pexy because of concerns
about additional scars

c d

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 338 Z. Mátrai

..      Table 28.5  Characteristics of autologous pedicled and free flaps often used in breast reconstruction [1, 15, 25, 26]

Name of the flap Blood supply Type of flap Maximum size of Surface of skin
skin island island (cm2)
length × width (cm)

Thoracal flaps

Latissimus dorsi myocutane- Thoracodorsal artery Pedicled or free 35 × 12 420

28 ous flap (LDmc)

Lateral thoracic flaps Lateral thoracic or superficial thoracic Pedicled 15 × 11 165
artery

Thoraco-epigastric flap Lateral branch of superior epigastric Pedicled 15–22 × 8–12 120–264

artery, intercostal perforator artery

Thoracodorsal artery Thoracodorsal perforator artery and vein Pedicled 16–22 × 7–11 112–242
perforator (TAP) flap

Intercostal artery perforator Intercostal perforator artery Pedicled 22–26 × 6–8 132–208

(ICAP) flap

Abdominal flaps

Transverse rectus abdominis Superior epigastric artery and vein for Pedicled or free 25 × 15 375
myocutaneous (TRAM) flap free-flap deep inferior epigastric artery

Deep inferior epigastric Deep inferior epigastric artery and vein, Free 45 × 15 675
perforator (DIEP) flap cutaneous perforators

Superficial inferior epigastric Superficial inferior epigastric artery and Free 25 × 15 375
artery (SIEA flap) vein

Lumbar artery perforator Four to eight lumbar perforator a. and v. Free 12 × 27
(LAP) flap emerging from the second and fourth
lumbar a

Gluteal flaps

Superior gluteal artery Superior gluteal a Free 20–25 × 6 × 13 120–325

perforator (SGAP) flap

Inferior gluteal artery Inferior gluteal a Free 18 × 8 144

perforator (IGAP) flap

Thigh flaps

Muscle tensor fascia lata Ascending branch of lateral circumflex Free 35 × 8 280
(MTFL) flap femoral a

Anterolateral thigh (ALTF) Descending branch of lateral femoral Free 25 × 8 200
flap circumflex artery

Transverse upper gracilis Vessels from the medial femoral Free 10–17 × 7–9 70–153
(TUG) flap circumflex system

Transverse upper gracilis and Ascending branch of the medial Free 27–30 × 7–9 189–270
the profunda artery circumflex femoral a. for TUG component
perforator (TUGPAP) flap and the profunda a. perforator for PAP
component

A prospective cohort study by Pukancsik and colleagues
aimed to determine the critical tumour-to-breast volume
ratio for each quadrant of the breast beyond which conven-
tional BCS could no longer offer acceptable cosmetic and
functional results or satisfactory quality of life for the patient
[32]. Three-hundred and fifty patients with early-stage uni-
focal (T ≤ 30 mm) breast cancer were enrolled in the study
and underwent wide excision and axillary sentinel lymph
node biopsy followed by whole breast RT.  Using validated
assessment tools and software (Breast Cancer Treatment
Outcome Scale [BCTOS], EORTC Cancer Quality of Life
Questionnaire C30-BR23, the Breast Cancer Conservative
Treatment – cosmetic results [BCCT.core] software), quality
of life, aesthetic and functional parameters and their changes
were correlated with the percentage of breast volume excised
(. Table 28.6).

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 ..      Table 28.6  The maximal percentage of breast volume (cut-off value) that may be excised for each breast subregion

Upper-outer quadrant (n = 79) Upper-inner quadrant (n = 40)

Maximal cut-off p AUC Sensitivity (%) Specificity (%) Maximal cut-off p AUC Sensitivity (%) Specificity (%)
value (%) value (%)

Quality of life

  Emotional functioning 18.26 <0.0001 0.992 97.37 97.56 9.48 <0.0001 0.983 88.24 95.65
Delayed Breast Reconstruction: General and Oncological Considerations

  Social functioning 17.56 <0.0001 0.947 87.8 97.37 9.48 <0.0001 0.947 75 95

  Body image 18.85 <0.0001 0.959 80 97.73 8.88 <0.0001 0.973 87.5 95.83

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Subjective aesthetic and 18.76 <0.0001 0.955 97.40 97.20 8.88 <0.0001 0.983 100 88.24
functional results

Objective aesthetic results 18.26 <0.0001 0.955 97.56 97.37 8.88 <0.0001 1 100 88.24

Reprinted from Pukancsik et al. [32] with permission from Elsevier

28 339
 340 Z. Mátrai
The maximum percentage breast volume resectable in
conventional BCS without resulting in unacceptable aes-
thetic and functional outcomes or a decreased quality of life
was 18–19% in the upper-outer quadrant (p  <  0.0001),
14–15% in the lower-outer quadrant (p < 0.0001), 8–9% in
the upper-inner quadrant (p  <  0.0001) and 9–10% in the
lower-inner quadrant (p < 0.0001) [32]. With the help of the
calculated cut-off values for each breast quadrant, breast sur-
28 geons can make more objective decisions when performing
conventional BCS, oncoplastic techniques or even mastec-
tomy with immediate reconstruction.
Delayed partial reconstruction aims to restore the shape
of the breast and to achieve better symmetry using volume
displacement or replacement techniques [9]. To replace skin
and volume, local dermoglandular, fasciocutaneous flaps
(e.g. intercostal artery perforator (ICAP) flap, thoracodorsal
artery perforator (TDAP) flap), distant pedicled (e.g. LD) or
even free myocutaneous flaps (e.g. transverse upper gracilis
myocutaneous (TUG) flap) or fasciocutaneous flaps are
potential options [9, 11, 33, 34] (. Table  28.7). Controversy
 
surrounds the optimal timing for repair of a partial mastec-
tomy defect in terms of before or after adjuvant RT [9, 28–
30]. Mastopexy techniques are preferred for patients
presenting after BCS but before RT due to the lower compli-
cation rates compared to those who present after completing
RT as there may be a higher risk of wound complications and
nipple necrosis when operating on irradiated tissues [9].
When choosing a flap, the possible limitations and com-
plications of the donor site should be taken into account, for
instance, the average length (26 cm) of an LD myocutaneous
(LDmc) flap donor scar on the back or the loss of this large
myocutaneous flap in case of a subsequent need for a total BR
[11, 33]. After BR with LD flap transfer, muscle function may
be compromised, but functional deficits due to such muscle
weakness are seen with specific activities only and are gener-
ally well tolerated [11, 35]. Therefore LD flap reconstruction
is relatively contraindicated in women who undertake sports
requiring increased upper body strength, including rowers,
swimmers and mountain climbers [35]. A good combined
technique for DBR after BCS can be performed with local
flaps for soft tissue reconstruction and allogenic volume
replacement; however, contracture rates and the risk of
implant extrusion are significantly higher than for conven-
tional implant-based postmastectomy BR [9, 35] (. Fig. 28.6).
 
The use of glandular flaps in delayed remodelling of irra-
diated breast tissue is technically challenging, and surgical
complications occur often [9]. Contralateral reduction mas-
topexy is a simple and safe approach to correct asymmetry
of volume [9] (see . Table  28.7). Pedicled flaps unaffected
 
by RT instead of glandular flaps should be employed if the
shape of the treated breast is distorted markedly to bring
undamaged well-vascularized tissue into the defect in the
breast mound [9].
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In cases of extremely damaged residual breast tissue (e.g.
severe radiation fibrosis or severe and extensive fat necro-
sis), a completion mastectomy with autologous total BR pro-
vides an additional option for delayed partial-breast
reconstruction [9].
Preoperative assessment of vascular anatomy for autolo-
gous flaps is mandatory [14]. A simple physical test is used to
examine whether the motor innervation of the LD muscle is
intact or serves as a reasonable proxy of vascular integrity. To
assess the muscle, both sides should be examined simultane-
ously. The examiner stands behind the patient and feels
between the thumb and fingers bilaterally as the patient
coughs. The contractions should be compared between the
two sides. Doppler ultrasonography (US) and computed
tomographic (CT) angiography of both donor and recipient
sites provide valuable information for planning and perform-
ing microsurgery [36]. In free-flap BR the use of preoperative
CT angiography helps to reduce the duration of the surgical
procedure and overall postoperative morbidity [36].
After marking up the midline and the footprint of the
breasts, the assessment of breast morphology should include
at minimum the measurements and documentation of breast
width, sternal notch to nipple distance, nipple to inframam-
mary fold distance, objectives for degree of desired breast
asymmetry and bra cup size.
Autologous fat grafting (FG) has become a widely
implemented technique for secondary breast reconstruc-
tion [9, 37, 38]. The indications include improving con-
tour, shape and volume following autologous flap
reconstruction (with or without implants), implant-only
reconstructions and deformity correction following breast
conservation therapy [9]. Fat can be harvested from the
abdomen, thighs and buttocks. Complications are usually
rare and include fat necrosis, erythema, keloid scarring
and pain. Repeat FG may be necessary, mainly by patients
with a history of prior RT [9]. FG is a safe and effective tool
for the revision of reconstruction, to improve contour, vol-
ume, breast shape and symmetry. It may also help in
improving the quality and thickness of mastectomy flaps if
very thin or radiotherapy damaged. This may be done as a
staged procedure before the actual reconstruction. The
popularity of the use of FG in BR will likely continue to
increase [9]. Further information on lipomodelling is cov-
ered in 7 Chap. 20.
Assessment of the results of BR should be highly consis-
tent and objective [14]. Preoperative and successive postop-
erative photographs should also form part of the assessment
[14]. Photographs of the anterior, oblique (at 45° both sides)
and lateral (both sides) views of the breasts and, when appli-
cable, specific views of flap donor sites should be acquired
[14]. Images must be stored on a secure server with limited
access and should never be used for teaching purposes or
publication without the patient’s consent [14].
 ..      Table 28.7  The alternatives of delayed breast reconstruction techniques according to the size of the breast and the initial parenchyma defect

Parenchyma Initial status DBR

resection (%)
Affected breast Contralateral Affected breast Contralateral breast
breast
Tissue defect Status post Tissue remnant (+/−RT) DBR alternatives (and/or) Symmetrization alternatives

Small sized breast (<200 g)

<25 WE, Small −/+ ptosis FG Nothing,

level I OPS, mastopexy, mastopexy +/−reduction,
+/− NAC resection local flaps, +/− implant,
LD, +/− NAC reconstruction
implant,
FG

25–50 Q, FG Mastopexy
level II OPS, Local flaps, +/− reduction
+/− NAC resection LD+/−implant +/− implant,
mastopexy + implant ASM,
free flaps, NSM SSM + implant/free flaps,
+/− NAC reconstruction +/− FG,
+/− NAC reconstruction
Delayed Breast Reconstruction: General and Oncological Considerations

50< Q, Local flaps, Mastopexy +/−reduction,

level II OPS, FG, +/− implant,
SM, LD+/−implant ASM,
SSM, ASM, NSM, ASM, NSM, NSM,
+ expander/ SSM + expander/implant/ SSM + implant/free flaps,

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implant, free flaps, +/−FG,
+/− NAC resection SM + free flap +/−NAC reconstruction
+/−NAC reconstruction

ASM areola-sparing mastectomy, DBR delayed breast reconstruction, FG fat grafting, LD latissimus dorsi muscle or myocutaneous flap, NAC nipple-areola complex, NSM nipple-sparing mastec-
tomy, OPS oncoplastic breast-conserving surgery, Q quadrantectomy, SM simple mastectomy, SSM skin-sparing mastectomy, WE wide excision
(continued)
28 341
 28
342

..      Table 28.7 (continued)

Parenchyma Initial status DBR

resection (%)
Affected breast Contralateral Affected breast Contralateral breast
Z. Mátrai

breast
Tissue defect Status post Tissue remnant (+/−RT) DBR alternatives (and/or) Symmetrization alternatives

Medium sized breast (200–500 g)

<25 WE, Q, Medium sized Mastopexy, Mastopexy

level I /II OPS, +/− ptosis FG, +/−reduction,
+/− NAC resection local flaps, +/− implant,
LD, +/− FG,
implant +/− NAC reconstruction

25–50 Q, Mastopexy + implant, Mastopexy

level II OPS, +/−FG, +/−reduction,
+/−NAC resection Local flaps/ +/−Implant,
LD ASM,
+/−implant, NSM,
Free flaps, SSM + implant,
+/−NAC reconstruction +/−FG,
+/−NAC reconstruction

50< Q, LD + implant Mastopexy

level II OPS, ASM, NSM, +/−reduction,
SM, SSM + expander/implant/ +/−Implant,
SSM, ASM, NSM, free flaps, ASM,

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+expander/ +/−FG, NSM,
implant, +/−NAC reconstruction SSM + implant/free flaps,
+/−NAC resection +/−FG,
+/−NAC reconstruction

ASM areola-sparing mastectomy, FG fat grafting, LD latissimus dorsi muscle or myocutaneous flap, NAC nipple-areola complex, NSM nipple-sparing mastectomy, OPS oncoplastic breast-­
conserving surgery, Q quadrantectomy, SM simple mastectomy, SSM skin-sparing mastectomy, WE wide excision
 Large-sized breast (<500 g)

<25 WE, Q, Large-sized + ptosis Mastopexy +/−reduction, Mastopexy + reduction,

level I /II OPS, +/−FG, +/− NAC reconstruction
+/− NAC resection local flaps,
LD,
+/− NAC reconstruction

25–50 Q, Mastopexy, Mastopexy + reduction,

level II OPS, local flaps, SSM
+/− NAC resection LD +/− implant,
+/− implant +/− free flaps
+/− FG, +/− FG,
free flaps, +/− NAC reconstruction
+/− NAC reconstruction

50< Q, Mastopexy + implant, Mastopexy + reduction,

level II OPS, LD+ SSM
SM, implant, +/− implant,
SSM SSM +/−implant, +/− free flaps
+ expander/ +/− free flaps, +/− FG,
implant, SM + free flaps, +/− NAC reconstruction
+/− NAC resection +/− FG,
+/− NAC reconstruction
Delayed Breast Reconstruction: General and Oncological Considerations

ASM areola-sparing mastectomy, FG fat grafting, LD latissimus dorsi muscle or myocutaneous flap, NAC nipple-areola complex, NSM nipple-sparing mastectomy, OPS oncoplastic breast-­
conserving surgery, Q quadrantectomy, SM simple mastectomy, SSM skin-sparing mastectomy, WE wide excision

Modified with permission from Medicina Publishing House

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28 343
 344 Z. Mátrai

a b

28

c
d

f
e

..      Fig. 28.6  a 50-year-old patient had a wide excision in the upper-­
outer quadrant of the right breast and postoperative RT resulting in
significant asymmetry between the breasts regarding breast volume,
shape and position of the NAC. b–d Because of the nonexpandable
radially positioned scar and skin deficit in the affected quadrant, an
autologous soft tissue reconstruction was performed with a laterally
based ICAP flap. e, f Ten months later symmetrization was performed
with a textured round high profile 450 cm3 silicone implant on the
right side and a round high profile 300 cm3 on the left side in submus-
cular position in combination with a mastopexy

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Delayed Breast Reconstruction: General and Oncological Considerations
345 28
28.3.2   elayed Breast Reconstruction
D with locally advanced breast cancer (LABC) to whom pri-
Techniques for Partial Mastectomy mary systemic treatment and adjuvant RT are indicated
Defects resulting in favourable long-term tumour control and sur-
vival. In 2003 Kronovitz and colleagues implemented a mul-
Delayed reconstruction after whole breast irradiation usually tidisciplinary protocol of «delayed-delayed breast
necessitates the transfer of an autologous flap [9]. Local or reconstruction» (D-DBR) for skin-preserving delayed BR
distant, pedicled or free and fasciocutaneous or myocutane- after radiotherapy in patients with LABC known preopera-
ous flaps can be used (see . Table 28.5). Autologous FG with tively to require RT [9, 39]. The purpose of this protocol was
 

percutaneous needle release of scar bands may be an option to improve aesthetic outcomes, decrease complication rates
for DBR, if the breast skin envelope is complete after BCS [9]. and reduce the psychological impact associated with stan-
After partial-breast irradiation, some parts of the breast tis- dard non-skin-sparing DBR after RT [9]. Patients with
sue may not have been completely irradiated and can be used inflammatory BC and those whose skin cannot be preserved
to improve the defect by volume displacement mastopexy due to negative tumour margins must not undergo skin-­
techniques [9]. preserving DBR.  After the completion of neoadjuvant che-
In cases of small breast volume (cup sizes A and B), motherapy and downsizing or downstaging, patients
reconstruction before RT is often more complicated due to underwent skin-preserving mastectomy with immediate
the small amount of residual breast parenchyma [9, 28–30] placement of a tissue expander. The expander should be par-
(see . Table 28.7). These patients may benefit from a comple- tially deflated to allow for radiotherapy, before three-­
 

tion NSM with total BR rather than BCS + RT [9]. Because of dimensional CT planning [9]. Reinflation of the tissue
the paucity of autologous tissue options, an implant-based expander can usually be done 2  weeks after completion of
BR is the method of first choice [9]. Among patients who postmastectomy RT.  The expander can be changed to the
present for DBR after RT, percutaneous needle release of scar implant or autologous deepithelialized flap approximately
bands along with FG can be helpful [9]. 3–6 months after the RT and reinflation. Since by D-DBR the
In cases of more voluminous breasts (cup sizes C and D) breast skin envelope can be preserved for subsequent DBR
and in the presence of ptosis the partial mastectomy, defects after radiotherapy, the technique has brought about a para-
can be successfully repaired by displacement of the remain- digm shift in the care of patients with LABC [9].
ing breast tissue using mastopexy techniques and/or rota- Several techniques are available which aim to enhance the
tion/advancement flaps [9, 28–30] (see . Table  28.7). Fat
 
outcomes of implant-based breast reconstruction. These
grafting is used to fill diffuse volume loss due to RT in the include the use of tabbed tissue expanders, autologous fat
second stage of these types of DBR techniques [9]. In repair- grafting and use of acellular dermal matrices (ADM) [9].
ing BCS defects, local flaps (ICAP, TDAP, LD) for DBR are ADMs are connective tissue grafts that improve the quality of
safe to use after confirmation of negative surgical margins soft tissue in implant-based BR [40]. An ADM can incorporate
[9]. The inferior pedicled Wise pattern mastopexy, or its into the recipient tissue with associated cellular and microvas-
modifications, tends to be the most versatile technique for cular ingrowth. It begins to be vascularized from surrounding
BR [9]. Superior pedicled mastopexy techniques may be nec- tissue as early as 2 weeks post-implantation, and mature vascu-
essary to deal with defects located in the lower breast quad- lar structures are usually present at 6 months [40, 41].
rants [9]. In the case of therapeutic mammoplasty and The application of expanders with suture-secure tabs
delayed contralateral breast symmetrization, it is recom- helps to prevent postoperative displacement or rotation of
mended to delay the operation by 3–6 months after comple- shaped implants. The lower pole of the expander can be cov-
tion of the RT to allow resolution of post-irradiation oedema ered with the use of ADM, while the pectoralis major muscle
and volume stabilization in the ipsilateral breast [9]. Revision can be used for the upper pole [9]. Capsular contracture rates
of an already-reduced breast may be necessary, and using FG may be decreased by providing complete coverage of the
in the ipsilateral breast may be helpful [9]. expander with ADM and by sewing the pectoralis major
muscle over it using vest-over-pants sutures [9]. Intraoperative
filling of the expander with saline is facilitated by the ADM
technique. Symmetry with the contralateral native breast is
28.3.3  Delayed Breast Reconstruction also easier to achieve which reduces the number of postop-
Techniques for Total Mastectomy erative visits [9]. ADM that has been placed over the tissue
Defects expander allows for injection of FG into the lower mastec-
tomy flap at the exchange of expander to permanent implant
D-IBR is a potential option for patients who are at an [9, 42, 43]. ADMs facilitate repositioning of a malpositioned
increased risk for needing postmastectomy RT [9]. Since the implant and, in combination with FG, may help to correct
D-IBR technique ensures preservation of the skin envelope, implant rippling [9, 42]. ADM and FG have also decreased
an implant-only reconstruction is feasible even after post- the need for the addition of local flaps and changed how the
mastectomy RT.  Therefore the use of skin replacement is revision of implant-based reconstruction is approached. It is
unnecessary [9]. Delayed-immediate techniques with skin-­ also very valuable in cases where there is very thin chest wall
preserving mastectomy may be appropriate even for patients muscle coverage, and although undoubtedly not immune

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 346 Z. Mátrai

from the risks associated with RT, there is some low-level evi- the anatomical limits of this traditional LD flap. Santanelli di
dence that suggests that ADMs may help reduce the risks of Pompeo and colleagues published their experiences with the
implant reconstruction in a post-RT setting [40, 41]. Moyer use of the pedicled LDmc flap with fat grafting in total autol-
and colleagues compared clinical outcomes to determine ogous immediate breast reconstruction without implants (23
whether ADM use altered capsular tissue architecture in irra- patients between 2010 and 2013) [44]. Fat was harvested
diated and nonirradiated breasts following matrix-assisted using the Coleman technique and was injected into the adi-
expander reconstruction (number of involved patients pose layer and muscle fascia of the LD flap skin paddle. The
n = 27) [40]. Mean follow-up was 28 months. Grade III/IV mean size of the harvested skin paddle was 19.7 × 11.04 cm
28 contractures were identified in all patients on the irradiated (range, 18 × 10 cm to 21 × 12 cm). The mean harvested fat
side versus 75% on the nonirradiated side [40]. Postirradiation volume was 126 ml (range, 90–180 ml), and the mean injected
biopsy specimens were taken of the peri-implant capsule in fat volume was 101 ml (range, 60–150 ml). All flaps healed
six patients at the time of secondary surgery. Elastin content uneventfully, no seroma occurred at the flap donor site, and
and the total cellular infiltrate were significantly greater in no fat grafting-related complications were observed. The
the irradiated versus nonirradiated native capsules authors concluded that fat transfer to achieve immediate
(p = 0.0015). Conversely, the irradiated matrix capsule was LDmc flap volume augmentation could successfully serve as
composed of similar amounts of cellular infiltrate and colla- an alternative for total autologous BR, avoiding implant-­
gen as the nonirradiated matrix capsules and nonirradiated related complications.
native capsules. Irradiated ADM showed the least amount of The free TRAM flap is derived from the lower abdomen
alpha-smooth actin staining but a similar number of blood and transferred to the chest wall where the blood vessels of
vessels. The authors concluded that ADMs appear to limit the the flap are joined to the internal mammary vessels [3]. The
elastosis and chronic inflammation seen in irradiated implant pedicled TRAM flap requires the entire rectus abdominis
reconstructions and are potentially beneficial in these muscle to be mobilized, significantly disrupting the integrity
patients. of the abdominal wall [3]. Ischaemia and flap loss may be
prevented or minimized by ligating the inferior epigastric
vessels 1–3  months prior to the transfer of the pedicled
28.3.4  Autologous Flaps in Delayed Breast TRAM flap. A microvascular or free TRAM flap requires a
Reconstruction smaller proportion of the muscle (muscle-sparing TRAM
flap) [3]. When using free flaps in the DBR setting, it is
In autologous BR a patient’s own tissue is used to replace the important that consideration is given to whether the recipi-
breast defect [3]. Contraindications include previous major ent vessel may have been damaged by previous surgery or
surgery in the required donor tissue, hypertension, chronic radiotherapy.
obstructive pulmonary disease, diabetes, smoking and too The DIEP flap is also created from the lower abdomen but
high or too low BMI [3]. without removing any of the rectus abdominis muscle [3, 9].
The LDmc flap can either be pedicled or a free flap, and it This flap is optimal for patients who underwent total mastec-
is used alone (in women with smaller breasts) or as fat-­ tomy followed by RT [9]. The double-DIEP (bipedicled) flap
grafted volume-enhanced LDmc flap to maximize the vol- can provide good cosmesis to thin patients with much less
ume of an autologous-only procedure or the flap may be used subcutaneous fat and excess skin; in addition it can be folded
to cover an implant [3, 44, 45]. Although the need for an or rotated to increase the projection and width of the recon-
LDmc in DBR has significantly reduced due to the increasing structed breast [9].
use of skin-preserving mastectomies and ADM, the LD mus- Although traditionally gluteal artery perforator flaps
cle flap (LDm) or the deepithelialized TDAP flap is still (SGAP, IGAP) were considered a second-line option, but
important in DBR [9]. Patients with a risk of vascularly com- recently their popularity has been increasing [9]. The flaps
promised skin, those at a high risk of infection, or who have consist of the skin and subcutaneous tissue supplied by
undergone RT, can benefit from the use of these flaps [9] the inferior or superior gluteal vessels [3, 9, 46]. The stan-
(. Fig. 28.7).
  dard flap used to be elliptical-shaped, but it was revised
Nowadays the LDmc flap for total autologous IBR or DBR and called a «boomerang flap». The boomerang flap is
without implants is becoming more popular again, extending more appropriate for BR, especially in patients with large

..      Fig. 28.7  a, b 34-year-old patient had an SSM and axillary lymph-
adenectomy with D-IBR using tissue expander after primary systemic
chemotherapy. c, d On the left side the skin coverage was very thin
with a potential for implant exposure, so an endoscopically assisted LD
muscle-only flap transposition was done through an axillary incision.
eThe muscle flap was positioned and adapted with resorbable sutures
along the footprint of the breast. f, g The expander was again placed
fully submuscularly. h Six months later the expander was changed to a
textured round high-profile 650 cm3 silicone implant on the left side, and
for symmetrization a textured round moderate-profile 275 cm3 implant
was placed in submuscular position on the right side. The reconstruction
of the nipple was completed waiting for the tattooing of the NAC

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Delayed Breast Reconstruction: General and Oncological Considerations
347 28

a b

c d

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 348 Z. Mátrai

e f

28

..      Fig. 28.7 (continued)

breast volumes. Indications include new breast cancer fol-
lowing previous TRAM flap reconstruction for contralat-
eral breast cancer, BRCA gene mutation confirmed after
unilateral TRAM flap reconstruction in women request-
ing contralateral risk reducing surgery, flap failure,
medical history, patients with limited abdominal subcuta-
neous tissue or no laxity in the abdominal musculofascial
system [9].
Reconstruction of the nipple is the last step of DBR. Several
surgical techniques are available (see 7 Chap. 34). Using cos-

previous aesthetic abdominoplasty in the woman’s past tochondral cartilage grafts in nipple reconstruction can

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Delayed Breast Reconstruction: General and Oncological Considerations
improve the outcome, since it does not reabsorb and main-
tains durable nipple projection [9].
28.4  utcomes of Delayed Breast
O Type of surgery
Reconstructions
The National Mastectomy and Breast Reconstruction Audit
(NMBRA) in the UK began on 1 January 2007 [2, 8]. The
principal aims of the audit were to describe the provision of
BR services across England and to investigate the determi-
nants and outcomes of care for women with breast cancer
having a mastectomy with or without BR [2, 8]. Data were
prospectively collected by clinicians on women treated
between 1 January 2008 and 31 March 2009 in a large num-
ber of institutes where mastectomy and BR surgery are pro-
vided: all 150 NHS acute trusts in England, 114 independent
sector hospitals and 6 NHS trusts in Wales and Scotland.
During the audit period, 16,485 women underwent mastec-
tomy. Of these women 20.6% had a concurrent IBR, while
10.5% women underwent BDR. A questionnaire was sent to
8159 women (51.2%) 3  months after their surgery. The
response rate was excellent at 85.3%.
28.4.1  I nformation Given to Women Before
Their Breast Surgery
In the 3-month questionnaire, patients needed to indicate
how much information they received before their surgery [2,
8]. Overall, nine out of ten women felt that they had received
the right amount of information about their chosen type of
procedure (mastectomy, mastectomy with IBR, DBR). The
majority were satisfied with the information. Patients who
underwent mastectomy only were asked how much informa-
tion they had received on BR.  Only 65% felt that they had
received the right amount. Furthermore, 42% felt that the
lack of information contributed to not choosing to have IBR.
28.4.2   ypes of Breast Reconstruction
T those undergoing mastectomy only so it is not possible to
Techniques
Most IBR patients underwent an implant-based reconstruc-
tion (with or without a flap). In contrast, the majority of DBR
patients had BR using only an autologous flap (. Table 28.8).
28.4.3   ypes of Contralateral and Secondary
T ing DBR were affected by mastectomy site complications.
Reconstructive Procedures
Only 4% of women underwent contralateral symmetriza-
tion surgery, and DBR patients were more likely than IBR
patients to undergo such intervention at the time of their
operation (18% vs. 11%) or to have this type of procedure
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349 28
..      Table 28.8  Type of reconstruction techniques according to
the Third Annual Report of the National Mastectomy and Breast
Reconstruction Audit, UK [4]
IBR (%) DBR (%)
Implant/expander only 1246 (36.8) 281 (16.2)
Pedicle flap + implant/expander 735 (21.7) 438 (25.3)
Pedicle flap (autologous) 932 (27.5) 446 (25.8)
Free flap 476 (14.0) 566 (32.7)
Total 3389 1731
Copyright © 2016, Reused with the permission of the Health
and Social Care Information Centre, also known as NHS Digital.
All rights reserved
planned for a later date (27% vs. 13%) [4, 10]. Overall, 49%
had planned nipple reconstruction and 41% areolar tattoo-
ing. Only 1% of patients had their nipple reconstructed at
the time of their BR.
28.4.4  Complication Rates for DBR
Inpatient complications were defined as complications
requiring specific and additional treatment and thus affect-
ing the patient experience. Mastectomy patients were hospi-
talized for 2–5 days. For patients having an IBR or DBR, the
inpatient stay was typically between 4 and 7 days. Following
mastectomy and BR, significant adverse events were rare.
During the audit, the mortality rate was only 0.19% during
their inpatient stay, and emergency transfer to the intensive
care unit was necessary for 0.61%. These rates were similar
for all three surgery types. Reoperation rates were higher
following BR than mastectomy alone due to the additional
risk of reconstruction-specific complications associated
with these more complex procedures [2, 8]. However it is
likely that the selection criteria for women having more
complex surgery were biased in favour of fitter women than
say that BR surgery is as safe as mastectomy only.
Risk Profiles of the Different Surgery Types
Mastectomy site complications were the most common for
all reconstruction types (10%), and the majority of these
were haematoma (8.9%). Only about 5% of women undergo-
Implant-Related Complications
Implant-related complications include displacement, infec-
tion and rupture. Of the women undergoing implant-based
reconstruction, 3% had an implant-related complication,
regardless of the type of procedure or timing. The most
 350 Z. Mátrai

..      Table 28.9  Unadjusted national complication rates stratified by type of surgery. Rates given with 95% confidence intervals. Third
Annual Report of the National Mastectomy and Breast Reconstruction Audit, UK [4]

Type of surgery Percentage with Percentage with Percentage with Percentage with Percentage with
mastectomy site mastectomy site mastectomy site mastectomy site mastectomy site
complications (%) complications (%) complications (%) complications (%) complications (%)

Mastectomy 10.30 (9.78– N/A N/A N/A N/A N/A N/A 0.91 (0.75–
(n = 12,841) 10.84) 1.09)
28 Immediate reconstruction

Implant/expander 9.20 (7.63– 3.48 (2.52– N/A N/A N/A N/A 1.24 (0.70–
only (n = 1207) 10.97) 4.67) 2.04)

Pedicle flap with 7.48 (5.67– 3.32 (2.14– 0.69 (0.23– 8.45 (6.52– 2.77 (1.70–
implant (n = 722) 9.65) 4.91) 1.61) 10.72) 4.25)

Autologous pedicle 7.17 (5.59– N/A N/A 1.96 (1.16– 9.67 (7.84– 3.37 (2.30–
flap (n = 920) 9.04) 3.07) 11.77) 4.75)

Free flap (n = 455) 9.45 (6.92– N/A N/A 9.45 (6.92– 5.49 (3.59– 7.91 (5.60–
12.52) 12.52) 8.00) 10.79)

Delayed reconstruction

Implant/expander 2.86 (1.24– 2.14 (0.79– N/A N/A N/A N/A 0.36 (0.01–
only (n = 280) 5.55) 4.61) 4.75)

Pedicle flap with 3.24 (1.78– 2.31 (1.12– 1.16 (0.38– 6.02 (3.97– 1.39 (0.51–
implant (n = 432) 5.38) 4.22) 2.68) 8.69) 3.00)

Autologous pedicle 7.85 (5.50– N/A N/A 3.70 (2.13– 10.85 (8.09– 4.39 (2.66–
flap (n = 433) 10.80) 5.93) 14.17) 6.77)

Free flap (n = 554) 4.69 (3.09– N/A N/A 7.94 (5.83– 3.43 (2.08– 3.61 (2.22–
6.80) 10.52) 5.30) 5.52)

Copyright © 2016, Reused with the permission of the Health and Social Care Information Centre, also known as NHS Digital. All rights
reserved

c­ ommon complication was infection requiring the removal
of the implant. Complications requiring the implant to be
removed occurred in 8.9% of women having IBR with
implant and in 6.9% of patients having a DBR with implant
(. Table 28.9).
Flap-Related Complications
Free-flap procedures were associated with the highest rate of
local complications. The risk of complications was lower in
those who underwent autologous pedicle flap reconstruction
and was lowest in women who had BR with a pedicle flap and
implant [2, 8]. This pattern was observed in both IBR and
DBR procedures. Flap re-exploration was the most common
complication, particularly for free-flap procedures. The reop-
eration rate was 11.8% among patients who had a free-flap
reconstruction. Rates of partial and total flap failure were
1.20% and 0.20% following pedicled flap reconstructions.
For free-flap reconstructions, these rates were 2.18% and
1.98%, respectively. The most frequent flap donor site com-
plications were haematoma and seroma. Excluding haema-
toma or seroma, the donor-site complication rate was around
2% for each type of flap-based reconstruction.
 ost-discharge Complications at 3 Months
P
After Surgery
Women were asked to report post-discharge complications
associated with mastectomy and BR in the questionnaire
3 months after their surgery. Readmission due to unplanned
further treatment or surgery was required in 10% of
mastectomy-­only patients and almost 1  in 6 BR patients.
Post-discharge wound infection occurred in 25% of BR
patients. One-third of all DBR patients required aspiration or
drainage of seroma. Among women who had a flap recon-
struction, the rates of complete and partial flap failure were
1% and 5%, respectively.
28.4.5   ain Management in the First 24 h
P
After Surgery
Low levels (6.2%) of severe pain were reported in patients
undergoing mastectomy in the first 24 h following surgery.
Women undergoing IBR and DBR reported higher rates than
women having mastectomy only at 16.5% and 20.1%, respec-
tively [2, 8].

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Delayed Breast Reconstruction: General and Oncological Considerations
351 28

..      Table 28.10  Patients’ rating of the results of their surgery and of reconstructive information provision 18 months after their breast
surgery (Fourth Annual Report of the National Mastectomy and Breast Reconstruction Audit, UK [10])

Mastectomy only Immediate breast reconstruction Delayed breast reconstruction

Patients’ rating of the results of their surgery at 18 months postoperatively

Overall, how would you describe

the results of your operation?

Excellent 1513 (36) 520 (34) 368 (47)

Very good 1565 (37) 505 (33) 242 (31)

Good 786 (19) 288 (19)0 101 (13)

Fair 304 (7) 145 (9) 43 (5)

Poor 74 (2) 74 (5) 28 (4)

Patients’ rating of reconstructive information provision 18 months after their surgery

Overall, how satisfied are you with

the options you have been given
about breast reconstruction
surgery since the time of your
original diagnosis?

Very satisfied 1842 (50) 993 (65) 572 (73)

Somewhat satisfied 1142 (31) 418 (27) 162 (21)

Somewhat dissatisfied 454 (12) 80 (5) 30 (4)

Very dissatisfied 274 (7) 46 (3) 20 (3)

Copyright © 2016, Reused with the permission of the Health and Social Care Information Centre, also known as NHS Digital. All rights
reserved

28.4.6   ccess to Postoperative Psychological

A time. Tenderness in the breast area (4%) and arm pain (9%)
Support most or all of the time was also reported. Sixty percent of the
women confirmed that they were satisfied with their sex life
During the audit, psychological support or counselling was most or all of the time.
required for 30.3% of mastectomy-only patients, 27.6% of
IBR patients and 16.9% of DBR patients after their surgery. Satisfaction with Implants
High satisfaction rates were reported by the audit among
women who were reconstructed with an implant-based pro-
28.4.7  Long-Term Clinical and Patient cedure: over 85% were either satisfied or very satisfied. About
Satisfaction Results of Delayed Breast 50% of patients who had implant-only DBR were very satis-
Reconstructions fied with the extent to which the implant could not be seen.
The proportion was slightly higher (64%) among women
The Fourth NMBRA used both clinician- and patient-­ with concurrent pedicle flap coverage.
reported data to provide information on mastectomies and
BRs performed between January 2008 and March 2009 in the Satisfaction with Flap Donor Site
UK [8]. Three-quarters of DBR patients and two-thirds of IBR The use of flap-based BR requires the transposition of tissue
treated described the results of their surgery as excellent or most often from the back or the abdomen [8]. Only a small
very good [8]. Mastectomy-only patients were much less sat- proportion of patients were bothered most or all of the time
isfied than those who underwent reconstruction; just half of with the appearance of their back, while problems with activ-
them were very satisfied with their results [8] (. Table 28.10). ities involving back and shoulder muscles were reported
 

Among patients undergoing DBR, 93% were satisfied more frequently. Autologous DBR was associated with a
with how they looked with clothes on, and 76% were satisfied greater level of dissatisfaction regarding the appearance of
with how they looked unclothed. Ninety-two percent of the the back than implant-based DBR.  Although the skin
women reported feeling confident in a social setting; 88% requirements to reconstruct the breast mound were similar
answered that they felt emotionally healthy most or all of the in both cases, those in whom an implant was not used prob-

rares1geo@gmail.com
 352 Z. Mátrai

ably needed more tissue taken from the back, reducing their 14. Association of Breast Surgery, British Association of Plastic

satisfaction with the appearance of the donor site. Reconstructive and Aesthetic Surgeons. Oncoplatsic breast
reconstruction. Guidelines for best practice. 2012. http://www.
Functional problems related to the abdominal donor site associationofbreastsurgery.org.uk/media/23851/final_oncoplas-
were reported by only a small minority of women who had tic_guidelines_for_use.pdf.
TRAM, DIEP or SIEA flap-based DBR.  More than 80% of 15. Strauch B, Vasconez LO, Hall-Findlay EJ, Lee BT. Grabb’s encyclope-
patients were satisfied with the appearance of their abdomen dia of flaps. 3rd ed. Philadelphia: Lippincott Williams Wilkins; 2009.
and how it looked and felt 18 months after their reconstruc- 16. Valdatta L, Cattaneo AG, Pellegatta I, Scamoni S, Minuti A,

Cherubino M.  Acellular dermal matrices and radiotherapy in
­
tion. Around 45% of women reported themselves to be very breast reconstruction: a systematic review and meta-analysis of
28 satisfied with how their abdomen looked and felt at 18 months the literature. Plast Surg Int. 2014;2014:472604. Epub 2014 May 21
after surgery compared to before their surgery. 17. Lee J, Lee SK, Kim S, Koo MY, Choi MY, Bae SY, Cho DH, Kim J, Jung
The results of the NMBRA have highlighted that the over- SP, Choe JH, Kim JH, Kim JS, Lee JE, Yang JH, Nam SJ. Does imme-
all experience of care for women undergoing mastectomy diate breast reconstruction after mastectomy affect the initia-
tion of adjuvant chemotherapy? J Breast Cancer. 2011;14(4):
and BR was very good. These national data have demon- 322–7.
strated the positive effect of BR on quality of life following 18. National Comprehensive Cancer Network Breast Cancer. Version
mastectomy. 2.2016. NCCN.org https://www.nccn.org/professionals/physi-
cian_gls/pdf/breast.pdf. Last access 20 June 2016.
19. Schaverien MV, Macmillan RD, McCulley SJ. Is immediate autolo-
gous breast reconstruction with postoperative radiotherapy good
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Surgery at BAPRAS, Training Interface Group in Breast Surgery, Gebhart M, Thürlimann B, Senn HJ, Panel Members. Tailoring
Baildam A, Bishop H, Boland G, Dalglish M, Davies L, Fatah F, therapies-improving the management of early breast cancer: St
Gooch H, Harcourt D, Martin L, Rainsbury D, Rayter Z, Sheppard C, Gallen international expert consensus on the primary therapy of
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2007;33:1–23. Practice Guideline: Breast Reconstruction with Expanders and
2. National Mastectomy and Breast Reconstruction Audit. Third
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reconstruction following surgery for breast cancer. Cochrane LC.  Complications and morbidity following breast reconstruc-
Database Syst Rev. 2011;6(7):CD008674. doi:10.1002/14651858. tion—a review of 16,063 cases from the 2005-2010 NSQIP datas-
CD008674.pub2. ets. J Plast Surg Hand Surg. 2014;48(2):104–14.
4. Drucker-Zertuche M, Robles-Vidal C.  A 7 year experience with 23. Ooi ASH, Song DH.  Reducing infection risk in implant-based
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6. National Institute for Clinical Excellence (NICE). Guidance on can- 25. Kato H, Hasegawa M, Takada T, et al. The lumbar artery perforator
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report. 2011. http://www.hscic.gov.uk/catalogue/PUB02731/clin- agement algorithm and practical oncoplastic surgical techniques
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F, Longo B.  Latissimus dorsi flap for total autologous immediate
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 355 29

Breast Implants: Design, Safety

and Indications for Use
Jana de Boniface and Inkeri Schultz

29.1 History of Breast Implants – 356

29.2 Implants: Design, Composition, Surface and Shape – 356

29.2.1 Tissue Expanders – 356
29.2.2 Composition – 356
29.2.3 Surface – 357
29.2.4 Shape – 357

29.3 Safety Issues and Complications – 358

29.3.1 Safety: Systemic Disease – 358
29.3.2 Safety: Incidence of Breast-Implant-­Associated
Anaplastic Large Cell Lymphoma (BIA-ALCL) – 358
29.3.3 Safety: PIP Implants – 359
29.3.4 Complications – 359

29.4 Capsule Formation: A Foreign Body Response – 360

29.5 Breast Implants: Indications for Use – 362

References – 362

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_29

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 356 J. de Boniface and I. Schultz
29.1 History of Breast Implants
The evolution of breast implants really stems from the nine-
teenth century, when Czerny first transplanted a lipoma in
order to fill a defect left after a partial mastectomy.
Subsequently, it was mainly the demand for breast augmenta-
tions that drove the development of different materials to
either implant (e.g. polyurethane, polytetrafluoroethylene and
expanded polyvinyl alcohol formaldehyde) or inject (e.g.
epoxy resin, shellac, beeswax, paraffin, petroleum and jelly)
29 into the breast. Also silicone in its liquid form was experi-
mented with for direct injection, with significant complica-
tions as a consequence. The era of modern breast implants
started with an innovative idea by the two surgeons Cronin
and Gerow in 1962, who were inspired by the then revolution-
ary packaging of blood products into flexible plastic bags. The
first silicone breast implant, produced by the Dow Corning
Corporation, contained silicone gel in a silicone elastomer
shell and was implanted into a lady originally requesting the
removal of a tattoo on her breasts and asked to volunteer for
the first implant-based breast augmentation in history.
In 1965, the first inflatable implant was engineered by
Laboratoires Arion in France; the saline filling was injected
after the placement of the implant, allowing for a much
smaller scar than before. Since then, modern breast implants
have developed considerably in technical details such as
design, fillers, surface and shape, all of which will be described
below.
29.2 I mplants: Design, Composition,
Surface and Shape
29.2.1 Tissue Expanders
The development of expandable implants derived from the
demand for a smaller incision for insertion but has today
broad implications mainly in reconstructive breast surgery.
The possibility to insert a partly deflated implant at the index
operation helps to protect the blood supply of mastectomy
skin flaps by decreasing tissue tension and allows for a larger
final implant volume. This is especially useful if mastectomy
flaps, or a preserved nipple-areola complex, are at risk of
necrosis or if the resected breast volume clearly exceeds the
volume that is provided by the submuscular implant pocket.
There are two main designs used in tissue expanders: one
provides a combination of silicone with a saline filling cham-
ber, and the other contains only saline held by an elastomer
silicone shell. In the first design category, two independent
shells are commonly combined: a silicone gel outer lumen
and an adjustable saline-filled inner lumen. These tissue
expanders come in different shapes, such as round or ana-
tomical. In the latter type, the inflatable chamber is often
placed at the inferior pole of the implant, offering more pro-
rares1geo@gmail.com
nounced lower pole expansion with time. Expansion is per-
formed by injecting saline solution into a small dome
connected to the implant filling chamber by plastic tubing.
This type of implant is sometimes referred to as permanent
or long-term expanders, as they may be left in place once
fully expanded; the dome and tubing can be easily removed
by minor surgery under local anaesthesia without interfering
with the implant itself. While some implants feature a self-
sealing valve allowing the surgeon to gently pull out the
dome and tubing, other designs provide a separate plug kit;
here, the surgeon has to insert a small silicone plug into the
tubing once it is cut and removed.
Saline-only tissue expanders are often referred to as tem-
porary expanders and are usually used as part of a two-stage
breast reconstruction. They feature an integrated magnetic
filling dome integrated in the implant shell; this dome is
located by an external magnetic detection device and saline
solution and then injected straight into the filling chamber.
Temporary tissue expanders come in different shapes, i.e.
round, anatomical (teardrop) or crescent shape; the latter fea-
tures an integrated magnetic filling valve which may create
interference in postoperative radiotherapy planning by CT.
29.2.2 Composition
Modern fixed-volume breast implants can be classified
according to the filling material (saline versus silicone), sur-
face (smooth versus textured) and shape (round versus ana-
tomical). Regarding silicone implants, there are further
differences in gel cohesiveness, filling degree and viscosity of
the silicone content.
Both in saline and silicone implants, the implant shells
are manufactured using silicone elastomers, commonly com-
bined with a barrier layer of further elastomers containing
either phenyl or trifluoropropyl. As strong evidence is lack-
ing [1], much of the comparison between silicone and saline
implants is based on clinical experience. It is claimed that
saline implants provide a less natural feel due to their firm-
ness once fully inflated; there are also drawbacks concerning
form stability as saline is less resistant to pressure from sur-
rounding tissues and will eventually yield to a sphere-like
shape more easily than a modern silicone implant. Even
though the safety of silicone has been confirmed in a number
of studies [2, 3], many patients are still concerned about
issues of silicone bleed and migration to lymphatics, and
saline implants may in these cases offer a safe alternative.
They also offer the surgeon some flexibility in terms of filling
degree as they are inflatable much like tissue expanders and
are easily inserted even through small and remote incisions.
In addition, clinical signs of leakage and deflation are entirely
obvious, and saline is rapidly absorbed by the body, while
suspected leakage from a silicone implant may warrant
extensive investigation including surgical exploration [4].
Breast Implants: Design, Safety and Indications for Use
29.2.3 Surface
In the early years of silicone implants, it became clear that
capsular contracture (discussed in detail below) was one of
the major complications to be dealt with. It was thought that
the smooth surface of silicone implants increased the risk of
capsular contracture, and the first attempt at a textured sur-
face was by coating the silicone implants with a layer of poly-
urethane foam in the 1970s [5]. While this presented a
significant improvement in capsular contracture rates, safety
issues were soon raised due to the carcinogenicity of a degra-
dation product, 2,4 toluene diamine, in animal models [6].
As safety concerns could not be confirmed, the use of
polyurethane-­coated implants was continued, even if not by
all manufacturers and all countries [7, 8]. It was shown that
the coating disintegrated in most cases, leaving the silicone
surface exposed which resulted in late capsular contracture
rates not unlike those in silicone implants. Today, improved,
thin-coated polyurethane implant options are available on
the market, but despite numerous studies the oncological
safety of their use is still a matter of debate [9, 10].
It was equally the risk for capsular contracture in smooth
implants that pushed the development of textured silicone
surfaces. The first textured implant was patented in 1968 and
coated with a thin layer of polyurethane, creating a strong fixa-
tion between tissue and the implant surface (reviewed in [11]).
The rate of capsular contracture was reduced [5, 12], propel-
ling further development in the design of textured surfaces.
Textured surfaces are created in specific ways by different
manufacturers, such as the «salt-loss» technique (Biocell; salt
crystals are added to the silicone mandrel and later washed
off) or negative contact imprinting (Siltex; the dipped silicone
mandrel is pressed into polyurethane foam). A review of 18
trials by Liu and colleagues [13] found that capsular contrac-
ture was more frequent in smooth than in textured implants,
and another study reported a higher satisfaction rate among
patients with textured compared with those with smooth
implants [14]. An interesting small study found higher con-
tracture rates in smooth than textured implants in patients
undergoing bilateral augmentation surgery, using one type of
implant per side [15]. Similar results have been reported else-
where [16, 17]. In addition, textured implants may retain their
position better than smooth implants and are less prone to
infection [18]. On the other hand, especially in round implants
where, in contrast to shaped implants, rotation is not an issue,
lack of adherence may create a softer and more flexible result.
29.2.4 Shape
The development of form-stable anatomical implants requires
a highly cohesive silicone gel that resists upper pole collapse
in the standing position and maintains its maximum projec-
tion despite surrounding tissue pressure. This is accomplished
rares1geo@gmail.com
357 29
by extensive cross-linking of silicone polymers during the
manufacturing process. Form stability is equivalent with a
firmer gel maintaining its distribution within the shell, giving
the surgeon significantly more control over the resulting
breast shape and dimensions. It could be argued that the
increased firmness of form-stable implants may be compen-
sated by their lower rate of capsular contracture [19], but clear
evidence is lacking. Shapes are most commonly classified into
round and anatomical shapes, with the latter imitating a natu-
ral breast form («teardrop»). With anatomical implants, there
is a certain risk of rotational deformity which is not an issue
in round implants. Most manufacturers offer different heights,
profiles and degrees of projection in anatomical implants,
while round implants vary in volume, base diameter and pro-
jection. It is believed that form-stable implants may result in
less capsular contracture than round implants; this compari-
son, however, was not performed within the same study, and
the different textures of implants may play a significant role
[20–23]. When choosing the right implant, there are crucial
differences between reconstruction and augmentation cases;
with a more generous soft tissue envelope such as in the aug-
mentation setting, implant shape is less obvious than in cases
with poor tissue coverage (the mastectomy setting). Naturally,
this problem arises more commonly in reconstructive surgery
than in augmentation. It is argued that anatomical implants
may provide a more natural breast shape [19], simultaneously
maintaining upper pole fullness by volume loading of the
lower pole. Thus, the upper pole would be pronounced by dis-
placement of the natural breast tissue in augmentation, while
it would be potentially over-enhanced in patients with round
implants and thin tissue coverage. In reconstruction, the
inherent complexity of creating symmetry between one
reconstructed and one natural and often ptotic breast tends to
favour form-­ stable anatomical implants adapted to the
dimensions of the contralateral breast, while round implants
are relatively more common in bilateral reconstructive proce-
dures, especially in the United States. . Figure 29.1 shows a
dual chamber expandable implant, and . Fig. 29.2 shows two
textured surface implants, one with a round shape and the
other an anatomic cohesive gel implant.
..      Fig. 29.1  Dual chamber expandable implant
 358 J. de Boniface and I. Schultz
29
..      Fig. 29.2  Two textured surface implants, one with a round shape
and the other an anatomic cohesive gel implant
29.3 Safety Issues and Complications
29.3.1 Safety: Systemic Disease
The health-related safety of silicone implants was questioned
based on animal studies in the 1990s that suggested a possible
link between silicones and connective tissue disease [24, 25].
After case reports describing cancer and connective tissue dis-
ease in women with breast implants, the US Food and Drug
Administration (FDA) requested a moratorium on silicone
gel breast implants in 1992. The FDA deemed that the manu-
facturers had not adequately addressed public concerns about
complications as implant rupture and silicone leakage and
required them to submit premarket approval applications that
contained data on safety and effectiveness. Silicone implants
were subsequently permitted only for breast reconstruction
after mastectomy and for replacement of existing implants.
This resulted in an increase in the use of saline-­filled implants
in the United States, while silicone implants continued to be
used in Europe and many other countries. In 1999, the
Institute of Medicine (IOM) released a report on published
literature and ongoing studies regarding breast implants, enti-
tled «Safety of Silicone Breast Implants» [26]. The report made
a distinction between local complications and systemic health
concerns. It concluded that local complications were the pri-
mary safety issue and that there was no evidence that silicone
breast implants caused systemic health effects. A meta-analy-
sis published in 2000 [3] found no evidence of an association
between breast implants and connective tissue disorders. In
2006, silicone gel implants were reintroduced in the United
States. The FDA approved two different silicone gel breast
implants (fourth generation) based on the manufacturers’
clinical studies, which had followed hundreds of women for
3–4 years. As a condition of approval, the manufacturers of
silicone gel-filled breast were required to evaluate long-term
performance and safety after 10 years [20–23].
The first so-called core study results at 10 years were pub-
lished in 2014 for Allergan’s® round silicone-filled breast implants
(Allergan®, Irvine, California, US) [23]. Of 715 included sub-
rares1geo@gmail.com
jects, 98 were postmastectomy reconstruction patients, and 15
had revisions of reconstructions. Across all cohorts, 56.2% of
implants were smooth, and 43.8% were textured. Follow-up
over the course of the 10 years was complete in 73.0% for the
reconstruction group. The risk of having an implant replaced
with a different size/style implant was 31.5% for the reconstruc-
tion group. By the end of the study, 63% in this group still had an
implant, and 41% retained the same implant that was first
implanted.
The Mentor® (Mentor®, Santa Barbara, California, US)
core studies [27] included 2003 women with 9 years of follow-
­up, divided into approximately equal proportions of women
with round versus shaped implants. As in the Allergan® stud-
ies, the majority of patients had implants for breast augmenta-
tion, 441 were reconstruction patients and 129 had undergone
revision related to breast reconstruction. In this study, the
cumulative rate for any reoperation after primary reconstruc-
tion was 45% for round and 52% for shaped implants. The risk
for capsular contracture was 20% and 13%, respectively, and
for implant loss 30% and 35%, respectively.
Numerous studies have been published reporting data on
silicone gel implants and systemic disease without finding
strong evidence regarding an association between implants
and cancer, immunological or systemic disease. A systematic
review from 2016 [28] aiming at evaluating specific long-­
term health outcomes including cancer, connective tissue,
rheumatologic and autoimmune diseases, neurologic disor-
ders, reproductive and mental health issues found 32 studies
meeting their eligibility criteria. There were possible associa-
tions with a decreased risk for primary breast and endome-
trial cancer and an increased risk for lung cancer, rheumatoid
arthritis, Sjögren’s syndrome and Raynaud’s syndrome. The
evidence, however, was most often not specifically regarding
silicone gel implants as other implants were also included. In
addition, many studies were not adequately adjusted for
potential confounders. Thus, the authors concluded that
«further investigation is required to determine whether any
true associations exist between silicone gel implants and
long-term health outcomes».
29.3.2  afety: Incidence of Breast-Implant-­
S
Associated Anaplastic Large Cell
Lymphoma (BIA-ALCL)
Anaplastic large cell lymphoma is a rare condition that can
affect various tissues. It may present as a nodal lymphoma or
in various other locations. The first case of breast-implant-­
associated ALCL was reported in 1997 [29], and today almost
200 cases are known [30]. According to the FDA, breast lym-
phomas are very rare with three cases in 100 million women
per year diagnosed in the United States (reviewed in [31]).
One well-described finding associated with BIA-ALCL is
a late-onset seroma surrounding the implant. Other symp-
toms are nonspecific swelling, pain, tenderness or capsular
contracture [31, 32]. A late seroma should raise the suspicion
of BIA-ALCL, and cytology should be obtained by fine-­needle
Breast Implants: Design, Safety and Indications for Use
aspiration. Biopsy or resection specimens with BIA-­ALCL
show large pleomorphic tumour cells of T-cell lineage that
strongly and uniformly express CD30, as shown by immuno-
histochemistry or flow cytometry [33]. Treatment is by surgi-
cal removal of the implant and complete capsulectomy. The
capsule surrounding the implant may be thickened and
fibrous or deceptively normal in appearance. Patients who
present with a palpable mass or extension of the tumour out-
side the capsule might benefit from adjuvant treatment after
surgical removal of the mass [31, 33, 34]. After clinical follow-
up [33] of 87 patients with BIA-ALCL, the 5-year overall sur-
vival was 89%. Patients with lymphoma confined to the
capsule and undergoing complete surgical excision had better
overall and event-free survival than those who were treated
with partial capsulectomy, chemotherapy or radiotherapy.
Those patients who died had local or regional extension of
the disease, while no patient developed disseminated disease.
Miranda and colleagues [35] reviewed the literature for all
published cases of BIA-ALCL from 1997 to 2012. They found
that most patients with BIA-ALCL confined to the fibrous
capsule achieved complete remission. Patients receiving
breast implants should be advised of the risk of developing
BIA-ALCL, as well as the common presenting symptoms.
29.3.3 Safety: PIP Implants
In 2010, the French authorities suspended the sale of implants
from the French manufacturer Poly Implant Prothèse (PIP)
because of a high rate of ruptures and silicone leakage. PIP
implants were introduced in France in 1991 and obtained the
Conformité Européenne (CE) Marking in 1997. In 2010, sev-
eral laboratory studies on PIP breast implants conducted by
the French health authorities (AFSSAPS) showed that these
had not been manufactured according to the documented
procedures provided to obtain the CE Marking: The barrier
layer had been removed from the shell in 2007, and the med-
ical grade silicone gel was replaced by inferior industrial
grade gels. The contents of the PIP silicone breast implants
tested negative for cytotoxicity and genotoxicity, but an
in vivo test for irritancy was positive [36]. In an update from
the Scientific Committee on Emerging and Newly Identified
Health Risks (SCENIHR) in 2014, it was stated that several
cyclic siloxanes (D4, D5 and D6) had been identified at
higher concentrations in PIP devices than in other silicone
breast implants. Investigating the possible toxicological con-
sequences of cyclic siloxanes release from damaged PIP
implants was not possible as these chemicals are frequently
found also in women without breast implants, as siloxanes
are present in many domestic products. The cyclic siloxanes
D4, D5 and D6 are nontoxic and not irritant in standard
tests. In some women, however, implant gel bleed or rupture
has been associated with an inflammatory reaction either
locally or in regional lymph nodes. Neither implant rupture
nor local inflammation has been found to be associated with
breast cancer or anaplastic large cell lymphoma [37]. The
committee concluded that removal of all intact PIP implants
rares1geo@gmail.com
359 29
was not recommended but left the final decision to affected
women and their surgeon or physician.
The reported PIP implant rupture rate in the literature
varies between 3.9% and 31.6% [38–40]. Comparison is dif-
ficult as the authors use different definitions, and patient
groups are not homogeneous. Most included patients had
undergone breast augmentation. An Italian report including
578 women who had PIP implants for postmastectomy
reconstruction found 18.5% ruptured implants after a mean
implant lifespan of 57.5 months [41]. In the Netherlands, 224
PIP implants were evaluated with a mean implant age of
122  months. One third of the women who had undergone
breast augmentation with PIP implants were shown to have
at least one ruptured implant after 10 years; 45.9% had bilat-
eral rupture, and 13.5% had extracapsular leakage. Most
implant ruptures were asymptomatic [40].
29.3.4 Complications
Complications related to breast implant surgery are common.
Reported incidences vary widely in the literature; diverging
study designs, mixtures of patient groups and definitions of
follow-up variables make comparisons difficult. Naturally,
complication rates after breast augmentation are lower than
after breast reconstruction. Obesity, smoking, large breast
size, hypertension and diabetes [42–45] are associated with
an increased risk of wound complications and reconstructive
failure, which should be thoroughly discussed before plan-
ning surgery. Tobacco users should be recommended to stop
smoking 4  weeks before and 4  weeks after surgery, as this
substantially reduces the risk of complications [46].
The Danish Registry for Plastic Surgery of the Breast pro-
spectively collects pre- and postoperative data for women
undergoing breast surgery. In one report, 189 immediate
breast reconstructions (therapeutic in 167 women) were ana-
lysed, 40 one-stage and 149 two-stage procedures. None of
the women had radiotherapy, and median follow-up was
3.9 years. A postoperative complication was reported in 144
procedures (76%), 74 (39%) of whom also had a reoperation
during the follow-up period. Immediate complications, i.e.
infection, haematoma and seroma, occurred primarily within
the first postoperative year, with risk estimates of 19.0%,
11.1% and 12.2%, respectively. Overall, the estimated risk for
reoperation within the first postoperative year was 23.3%,
increasing to 40.6% within 8 years [47]. In a recent review on
breast reconstruction, common complication rates such as
mastectomy skin flap necrosis (2–8.7%), haematoma (0.4–
1.7%) and infection (2.5–4.95%) are discussed [45].
Today, the importance of avoiding complications is further
stressed by the hypothesis that local and systemic inflamma-
tory mediators may interact with tumour cells and stimulate
tumour growth. A retrospective study in 229 patients with
breast cancer and immediate breast reconstruction with differ-
ent techniques showed a significantly lower 5-year recurrence-
free survival rate in patients who had suffered a postoperative
wound complication compared with those who had not [48].
 360 J. de Boniface and I. Schultz
Bleeding in the early postoperative period should be evac-
uated as a haematoma increases the risk for capsular contrac-
ture, infection and an inferior cosmetic result. Infection is a
serious complication reported after approximately 6%
(0–29%) of reconstructions, leading to additional surgery
and implant removal in 3% (1.5–8%) [49–51].
Mastectomy skin flap necrosis is most commonly seen
after skin-sparing or nipple-sparing mastectomy and imme-
diate reconstruction. Reported frequencies are varying,
reported in 2–30% of patients. Careful dissection preserving
29 the subcutaneous fat layer and if possible the internal mam-
mary perforators reduces the risk of necrosis. Fluorescent
angiography has been suggested as a means of evaluating tis-
sue perfusion, and care must be taken when choosing the size
of implant or expander and not putting too much strain on
the skin envelope [52].
The frequency of rupture is not easily assessed, as clinical
evaluation and patient history are unreliable. Magnetic reso-
nance imaging (MRI) has the highest accuracy of detecting
silicone implant rupture with sensitivities ranging from 77%
to 95% and specificities from 85% to 100%, while the corre-
sponding figures are lower for ultrasound (47% to 74% and
55% to 96%, respectively). MRI is recommended for implant
follow-up by the FDA, but the evidence for this recommen-
dation is not generally accepted, and the cost is high [53]. In
a 10-year follow-up of silicone implants for augmentation
and reconstructive purposes, the overall Kaplan-Meier rup-
ture rate was 13.0% for individual patients and 7.7% for
implants by serial magnetic resonance imaging [23].
. Figure 29.3 shows an MRI of a ruptured implant.
Silicone lymphadenopathy is a foreign body reaction due
to silicone leakage into the tissues surrounding the breast
implant. Patients may present with a palpable mass in their
axilla or in the chest wall which should be investigated as
any other suspicious finding using ultrasound, fine needle
aspiration or biopsy. The incidence and prevalence in
women with breast implants are largely unknown. In a
review [54] of 178 cases with silicone lymphadenopathy, the
mean age of all implants at removal was 11 years. This figure
was lower (2–6  years) in Poly Implant Prothèse (PIP)
implants. Silicone lymphadenopathy does not warrant treat-
ment unless it is symptomatic or interferes with breast
­cancer detection.
..      Fig. 29.3  MRI of a ruptured implant
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29.4  apsule Formation: A Foreign Body
C
Response
First of all, it is important to understand the difference
between the formation of a capsule surrounding any foreign
object implanted into the body and the contracture of that
same capsule. The formation is initiated by the recognition of
a foreign body, i.e. the implant, by the host immune system,
staging an inflammatory response in order to eliminate the
intruder. The term «biofouling» describes the formation of a
matrix around an implant that is fuelled by vascular injury
and the deposition of blood proteins and thrombotic sub-
stances. Inflammatory cells, including phagocytes, macro-
phages and foreign body giant cells, are recruited to the site
of injury but enter a stage of chronic inflammation due to the
inability to remove the foreign body. The ensuing granulation
tissue around the implant subsequently develops into a
fibrous capsule (reviewed in [55, 56]). Attempts to mitigate
the foreign body response include the mimicking of human
tissue by newer biomaterials, the designing of modified sur-
faces as well as molecular and cell-based strategies.
One should not forget that the formation of a capsule con-
tributes to the maintenance of the implant position, while
capsular contracture may result in cosmetically inferior out-
comes, pain, lack of softness and deformity. It is the most
common reason for revision surgery following breast aug-
mentation; even after revision surgery, most commonly
including the division or removal of the capsule, recurrence
of capsular contracture is frequent. The risk for capsular con-
tracture is increased by bacterial contamination, subclinical
infection with the development of a biofilm, smooth versus
textured surface structure, subglandular versus submuscular
placement of the implant, smoking, postoperative haema-
toma or seroma, long implantation time and radiotherapy
(reviewed in [13, 44]). The rate of capsular contracture is
20–40.4% after immediate and 17% to 26.4% after delayed
breast reconstruction [44, 57, 58] but depends significantly on
follow-up time and method of evaluation. The bacteria most
commonly found in cases of capsular contracture are
Staphylococcus epidermidis, deriving from contaminated
ducts and breast parenchyma and readily adhering to silicone
surfaces [59]. Therefore, many strategies to avoid capsular
contracture, such as funnel-aided implant insertion, nipple
coverage and antiseptic or antibiotic irrigation, are aiming at
the avoidance of bacterial contamination [60]. Histologically,
the contracted capsule is characterized by increased thick-
ness, collagen fibre alignment and the presence of contractile
myofibroblasts [61]. Clinically, degrees of contracture are
most commonly measured using the subjective Baker scale
(. Table 29.1a) which was, however, not designed for implant-­
based breast reconstruction. An attempt at a modified scale
was therefore undertaken by Spear and Baker in 1995 [62],
adding one subgroup to the four-grade Baker scale
(. Table 29.1b). Applanation tonometry, using a transparent
standard-weight Plexiglas disk with concentric imprinted
circles may present a somewhat less subjective method for the
Breast Implants: Design, Safety and Indications for Use
361 29

..      Table 29.1a  Original Baker classification of capsular

contracture after breast augmentation

Class I Breast absolutely natural; no one could tell breast

was augmented

Class II Minimal contracture; I can tell surgery was per-

formed, but patient has no complaint

Class III Moderate contracture; patient feels some firmness

Class IV Severe contracture; obvious just from observation

..      Table 29.1b  Spear modification of Baker classification of

capsular contracture after breast reconstruction

Class IA Absolutely natural; cannot tell breast was recon-

structed

Class IB Soft, but the implant is detectable by physical

examination or inspection because of mastectomy

Class II Mildly firm reconstructed breast with an implant

that may be visible and detectable by physical
examination

Class III Moderate firm reconstructed breast. The implant is

readily detectable, but the result may still be
acceptable

Class IV Severe capsular contracture with an unacceptable

aesthetic outcome and/or significant patient
..      Fig. 29.4  Mammogram showing capsular contracture and rupture
symptoms requiring surgical intervention

evaluation of breast compressibility [63]; breast MRI offers an

even less subjective yet expensive measure. . Figure  29.4  

shows a mammogram showing capsular contracture and rup-

ture, . Fig. 29.5 shows a patient with asymmetry as a result of
 

capsule formation on the right and . Fig.  29.6 shows an

 

explanted implant and capsule after explantation and capsu-

lectomy.
Radiotherapy is a strong risk factor for capsular contrac-
ture and has become a significant problem in breast recon-
structive surgery with the increasing use of postmastectomy
radiotherapy following an EBCTCG overview in 2005 [64]
showing a benefit of postoperative irradiation even in patients
with 1–3 positive axillary lymph nodes. Rates of Baker grade
..      Fig. 29.5  Patient with asymmetry as a result of capsule formation
III/IV capsular contracture are significantly increased [65– on the right
67] as are overall revision rates, postoperative complications,
inferior cosmetic results and reduced patient satisfaction
[68–73]. The delivery of postoperative radiotherapy is not nanoscale surface analysis have been reported [78]. This
hampered [74–76] by the presence of a breast implant, at being said, one should not forget that autologous flaps are
least not as long as no integrated magnetic dome is used that also exposed to radiation damage in case of immediate autol-
might disturb computed tomography (CT)-based radiother- ogous reconstruction and postoperative radiotherapy; this
apy planning. It has also been argued that in the event of a choice is therefore not very commonly used.
radiation field covering the internal mammary nodes, which In the few reports comparing prior to post-­reconstruction
may again become more common after recent oncological radiotherapy, the former has a significantly higher rate of
results [77], a breast implant increases the lung volume unin- complications and implant failure and thus predisposes more
tentionally irradiated. The effect of irradiation on the implant to delayed autologous reconstruction [73, 79, 80]. While
itself has been little described, but, recently, changes in a prior radiotherapy therefore should be regarded as a strong

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 362 J. de Boniface and I. Schultz
29
..      Fig. 29.6  Explanted implant and capsule after explantation and
capsulectomy
caveat for implant-based options, postoperative radiotherapy
is no longer viewed as a contraindication against immediate
breast reconstruction in the well-informed patient [81]. A
majority of patients still keep their implant-based recon-
struction, and relatively few are converted to autologous tis-
sue reconstruction [82]. It must be stressed, however, that the
discussion of implant-based reconstructive surgery in the
face of radiotherapy must weigh together all risk factors,
patient wishes and planned oncological treatment in order to
achieve safe reconstructive surgery.
29.5 Breast Implants: Indications for Use
Even though the most common use of breast implants is for
breast augmentation in cosmetic surgery, implant-based
breast reconstruction has become more and more common.
Implants may be used for breast reconstruction in most
women, both for immediate and delayed reconstructions.
The advantages of implant reconstruction include a relatively
short and economically advantageous procedure with no
additional scars or other potential complications at a donor
site [70]. If performed immediately, the three-dimensional
breast envelope and in selected cases also the nipple-areola
complex may be preserved, and a number of women may
prefer the relatively limited extent of surgery and the fact that
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breast reconstruction already has begun once waking up
from the primary cancer operation. There is no strong evi-
dence favouring immediate versus delayed reconstruction
[83], the discussion of which would exceed the scope of this
chapter. Known disadvantages of implant-based reconstruc-
tion are the relative firmness and fixation of the breast to the
thoracic wall, its inability to age with the patient and adapt to
weight changes and recognised difficulties to achieving natu-
ral ptosis. Whether this dilemma, which is accentuated in the
face of radiotherapy, may be mitigated by the use of acellular
dermal matrix [84] and other materials to preserve natural
breast ptosis and the inframammary fold will need to be
shown in future trials. Another strategy managing possible
irradiation consequences and maintaining the option of
implant-based immediate reconstruction is the concept of
immediate-delayed reconstruction, using a tissue expander
in the immediate setting which may then be exchanged for
autologous tissue with or without an implant once postoper-
ative radiotherapy has been delivered [85–87].
Permanent breast implants may ideally be chosen for the
slim woman with small- to medium-sized breasts if a bilat-
eral reconstruction is planned. For a unilateral reconstruc-
tion, the best candidate is a woman with a contralateral breast
that is relatively small and not ptotic. Tissue expanders are
generally used for women who need a bigger size and for
those who have had radiotherapy to the chest wall or who
might be advised to have postoperative radiotherapy. With a
bigger or ptotic breast, a contralateral mastopexy or reduc-
tion mammoplasty has to be performed for symmetrization.
Despite contralateral surgery, it may be difficult to achieve
optimal symmetry; in this scenario it may be important to
create realistic expectations in the individual patient and to
differentiate between in-bra and out-of-bra symmetry.
Obesity may be considered a relative contraindication for
implant-based reconstruction as it is difficult to create a large
breast with an adequate projection and shape using implants
in women with a thick subcutaneous layer. Age per se is no
contraindication, and older patients have similar complica-
tion rates and QoL outcomes as younger patients [44, 88, 89].
Before any decision about breast reconstruction, it is
important that the woman understands the limits of the differ-
ent technical options and differences between various available
timing strategies in order to take an individually adapted, well-
informed decision. Obviously, the oncological outcome is
always the main goal in any breast cancer patient, and choices
and alternatives must always be discussed bearing this in mind.
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36. Commission E. The safety of Poly Implant Prothèse (PIP) silicone breast
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37. (SCENIHR) SCoEaNIHR. The safety of Poly Implant Prothèse (PIP) sili-
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38. Leckenby J, Chana J, Harrison D, Grobbelaar A. Poly Implant Proth-
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39. Berry MG, Stanek JJ. The PIP mammary prosthesis: a product recall
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42. Bamba R, Gupta V, Shack RB, Grotting JC, Higdon KK. Evaluation of
diabetes mellitus as a risk factor for major complications in patients
undergoing aesthetic surgery. Aesthet Surg J. 2016;36(5):598–608.
43. Goodwin SJ, McCarthy CM, Pusic AL, Bui D, Howard M, Disa JJ, et al.
Complications in smokers after postmastectomy tissue expander/
implant breast reconstruction. Ann Plast Surg. 2005;55(1):16–9; dis-
cussion 9-20.
44. Quinn TT, Miller GS, Rostek M, Cabalag MS, Rozen WM, Hunter-­
Smith DJ. Prosthetic breast reconstruction: indications and update.
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45. Voineskos SH, Frank SG, Cordeiro PG. Breast reconstruction follow-
ing conservative mastectomies: predictors of complications and
outcomes. Gland Surg. 2015;4(6):484–96.
46. Coon D, Tuffaha S, Christensen J, Bonawitz SC. Plastic surgery and
smoking: a prospective analysis of incidence, compliance, and com-
plications. Plast Reconstr Surg. 2013;131(2):385–91.
47. Hvilsom GB, Friis S, Frederiksen K, Steding-Jessen M, Henriksen TF,
Lipworth L, et  al. The clinical course of immediate breast implant
reconstruction after breast cancer. Acta Oncol. 2011;50(7):1045–52.
48. Beecher SM, O’Leary DP, McLaughlin R, Sweeney KJ, Kerin MJ. Influ-
ence of complications following immediate breast reconstruction
on breast cancer recurrence rates. Br J Surg. 2016;103(4):391–8.
49. Reish RG, Damjanovic B, Austen WG Jr, Winograd J, Liao EC, Cetrulo
CL, et al. Infection following implant-based reconstruction in 1952
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50. Phillips BT, Bishawi M, Dagum AB, Khan SU, Bui DT.  A systematic
review of antibiotic use and infection in breast reconstruction: what
is the evidence? Plast Reconstr Surg. 2013;131(1):1–13.
51. Cohen JB, Carroll C, Tenenbaum MM, Myckatyn TM. Breast implant-
associated infections: the role of the national surgical quality
improvement program and the local microbiome. Plast Reconstr
Surg. 2015;136(5):921–9.
52. Nahabedian MY. Implant-based breast reconstruction: strategies to
achieve optimal outcomes and minimize complications. J Surg
Oncol. 2016;113(8):895–905.
53. Shah M, Tanna N, Margolies L.  Magnetic resonance imaging of
breast implants. Top Magn Reson Imaging. 2014;23(6):345–53.
29 54. Zambacos GJ, Molnar C, Mandrekas AD. Silicone lymphadenopathy
after breast augmentation: case reports, review of the literature,
and current thoughts. Aesthet Plast Surg. 2013;37(2):278–89.
55. Major MR, Wong VW, Nelson ER, Longaker MT, Gurtner GC. The for-
eign body response: at the interface of surgery and bioengineering.
Plast Reconstr Surg. 2015;135(5):1489–98.
56. Chong SJ, Deva AK. Understanding the etiology and prevention of
capsular contracture: translating science into practice. Clin Plast
Surg. 2015;42(4):427–36.
57. Sullivan SR, Fletcher DR, Isom CD, Isik FF. True incidence of all com-
plications following immediate and delayed breast reconstruction.
Plast Reconstr Surg. 2008;122(1):19–28.
58. Singh N, Reaven NL, Funk SE. Immediate 1-stage vs. tissue expander
postmastectomy implant breast reconstructions: a retrospective
real-world comparison over 18 months. J Plast Reconstr Aesthetic
Surg. 2012;65(7):917–23.
59. Virden CP, Dobke MK, Stein P, Parsons CL, Frank DH.  Subclinical
infection of the silicone breast implant surface as a possible cause
of capsular contracture. Aesthet Plast Surg. 1992;16(2):173–9.
60. Wixtrom RN, Stutman RL, Burke RM, Mahoney AK, Codner MA. Risk
of breast implant bacterial contamination from endogenous breast
flora, prevention with nipple shields, and implications for biofilm
formation. Aesthet Surg J. 2012;32(8):956–63.
61. Bui JM, Perry T, Ren CD, Nofrey B, Teitelbaum S, Van Epps DE. Histo-
logical characterization of human breast implant capsules. Aesthet
Plast Surg. 2015;39(3):306–15.
62. Spear SL, Baker JL Jr. Classification of capsular contracture after pros-
thetic breast reconstruction. Plast Reconstr Surg. 1995;96(5):1119–
23; discussion 24.
63. Gylbert LO. Applanation tonometry for the evaluation of breast com-
pressibility. Scand J Plast Reconstr Surg Hand Surg. 1989;23(3):223–9.
64. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans E, et al.
Effects of radiotherapy and of differences in the extent of surgery for
early breast cancer on local recurrence and 15-year survival: an over-
view of the randomised trials. Lancet. 2005;366(9503):2087–106.
65. Gross E, Hannoun-Levi JM, Rouanet P, Houvenaeghel G, Teissier E,
Ellis S, et  al. Evaluation of immediate breast reconstruction and
radiotherapy: factors associated with complications. Cancer Radio-
ther. 2010;14(8):704–10.
66. Behranwala KA, Dua RS, Ross GM, Ward A, A’Hern R, Gui GP.  The
influence of radiotherapy on capsule formation and aesthetic out-
come after immediate breast reconstruction using biodimensional
anatomical expander implants. J Plast Reconstr Aesthetic Surg.
2006;59(10):1043–51.
67. Cordeiro PG, McCarthy CM.  A single surgeon’s 12-year experience
with tissue expander/implant breast reconstruction: part I.  A pro-
spective analysis of early complications. Plast Reconstr Surg.
2006;118(4):825–31.
68. Kronowitz SJ, Robb GL. Radiation therapy and breast reconstruction:
a critical review of the literature. Plast Reconstr Surg. 2009;124(2):
395–408.
69. Lee BT, Adesiyun T, Colakoglu S, Curtis MS, Yueh JH, Anderson KE,
et al. Postmastectomy radiation therapy and breast reconstruction:
an analysis of complications and patient satisfaction. Ann Plast
Surg. 2010;64(5):679–83.
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70. Kronowitz SJ.  Current status of implant-based breast reconstruc-
tion in patients receiving postmastectomy radiation therapy. Plast
Reconstr Surg. 2012;130(4):513e–23e.
71. Roostaeian J, Pavone L, Da Lio A, Lipa J, Festekjian J, Crisera C. Imme-
diate placement of implants in breast reconstruction: patient selec-
tion and outcomes. Plast Reconstr Surg. 2011;127(4):1407–16.
72. Jhaveri JD, Rush SC, Kostroff K, Derisi D, Farber LA, Maurer VE, et al.
Clinical outcomes of postmastectomy radiation therapy after
immediate breast reconstruction. Int J Radiat Oncol Biol Phys.
2008;72(3):859–65.
73. Eriksson M, Anveden L, Celebioglu F, Dahlberg K, Meldahl I, Lager-
gren J, et  al. Radiotherapy in implant-based immediate breast
reconstruction: risk factors, surgical outcomes, and patient-­reported
outcome measures in a large Swedish multicenter cohort. Breast
Cancer Res Treat. 2013;142(3):591–601.
74. Ohri N, Cordeiro PG, Keam J, Ballangrud A, Shi W, Zhang Z, et  al.
Quantifying the impact of immediate reconstruction in postmas-
tectomy radiation: a large, dose-volume histogram-based analysis.
Int J Radiat Oncol Biol Phys. 2012;84(2):e153–9.
75. Ho AY, Patel N, Ohri N, Morrow M, Mehrara BJ, Disa JJ, et al. Bilateral
implant reconstruction does not affect the quality of postmastec-
tomy radiation therapy. Med Dosim. 2014;39(1):18–22.
76. Liljegren A, Unukovych D, Gagliardi G, Bjohle J, Wickman M, Johans-
son H, et al. No difference in dose distribution in organs at risk in
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77. Thorsen LB, Offersen BV, Dano H, Berg M, Jensen I, Pedersen AN,
et al. DBCG-IMN: a population-based cohort study on the effect of
internal mammary node irradiation in early node-positive breast
cancer. J Clin Oncol. 2016;34(4):314–20.
78. Ribuffo D, Lo Torto F, Giannitelli SM, Urbini M, Tortora L, Mozetic P,
et  al. The effect of post-mastectomy radiation therapy on breast
implants: unveiling biomaterial alterations with potential implica-
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2015;57:338–43.
79. Barry M, Kell MR. Radiotherapy and breast reconstruction: a meta-­
analysis. Breast Cancer Res Treat. 2011;127(1):15–22.
80. Berbers J, van Baardwijk A, Houben R, Heuts E, Smidt M, Keymeulen K,
et al. ‘Reconstruction: before or after postmastectomy radiotherapy?’ A
systematic review of the literature. Eur J Cancer. 2014;50(16):2752–62.
81. Ribuffo D, Monfrecola A, Guerra M, Di Benedetto GM, Grassetti L,
Spaziani E, et al. Does postoperative radiation therapy represent a
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cation rates of radiation on tissue expander and autologous tissue
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85. Kronowitz SJ. Immediate versus delayed reconstruction. Clin Plast
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Reconstr Surg. 2004;113(6):1617–28.
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of breast reconstruction in older women  – a systematic review of
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 365 30

Specific Implant-Based
Techniques for Breast
Reconstruction
Lorna J. Cook and Michael Douek

30.1 Introduction – 366

30.2 Patient Selection and Preoperative Counselling – 366

30.2.1 Breast Size and Degree of Ptosis – 366
30.2.2 Unilateral Procedures and the Need for Symmetrisation Surgery – 366
30.2.3 Risk Factors for the Development of Complications – 366
30.2.4 Need for Revision Surgery in the Future – 366
30.2.5 One-Stage Versus Two-Stage Reconstruction – 366

30.3 Specific Techniques – 368

30.3.1 Immediate Implant-Based Reconstruction – 368
30.3.2 Delayed Implant-Based Breast Reconstruction – 373

30.4 Complications of Implant-Based Reconstruction – 374

30.4.1 Risk Factors for Implant Loss – 374
30.4.2 Infection – 375
30.4.3 Skin Necrosis – 375
30.4.4 The Impact of Radiotherapy on Complication Rates – 375

30.5 Oncological Aspects of Implant-Based Reconstruction – 376

30.5.1 Risk of Local and Systemic Recurrence – 376
30.5.2 Surveillance of the Reconstructed Breast for Local Recurrence – 376
30.5.3 Anaplastic Large Cell Lymphoma – 377

30.6 Conclusion – 377

References – 377

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_30

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 366 L.J. Cook and M. Douek
30.1 Introduction
Breast reconstruction after mastectomy has become an
increasingly popular option over the last 10 years. However,
whilst the rate of autologous reconstruction has remained
relatively stable, there has been a dramatic increase in the rate
of implant-based reconstruction [1–3]. Analysis of the
American Nationwide Inpatient Sample database has shown
an increase in the rate of uptake of 11% per year, overtaking
autologous reconstruction as the leading method of breast
reconstruction surgery from 2002. There is now evidence of
a similar pattern emerging in the UK [4].
Implant-based reconstructions offer patients the option
30 of less invasive surgery without the need for an additional
donor site, a shorter procedure, a shorter hospital stay and
faster recovery period. Whilst autologous reconstruction
has traditionally been associated with superior aesthetic
outcomes [5], advances in surgical techniques and implant
design have challenged this attitude, and excellent out-
comes have been reported with implant-based procedures.
The reconstructive technique may be either «one stage»
(direct to implant) or «two stage» (tissue expander/
implant). Alternatively, anatomical expandable implants
can also be used to expand the tissue but with the aim of
leaving the saline-filled expander as a permanent implant if
the cosmetic outcome is satisfactory.
In this chapter the main techniques currently in use will
be described before discussing some of the issues surround-
ing the post-operative complications and oncological safety
of implant-based breast reconstruction.
30.2  atient Selection and Preoperative
P
Counselling
In contrast to autologous reconstruction, where patient
choice of procedure may be limited by a lack of donor site,
medical comorbidities or lifestyle factors, most patients
undergoing mastectomy can be offered an implant-based
reconstruction. Despite this, several factors must be taken
into account when determining patient suitability and should
be incorporated into preoperative discussions.
30.2.1 Breast Size and Degree of Ptosis
Whilst traditionally the «ideal» candidate is often described
as having small- to medium-sized breasts with minimal pto-
sis, development of new techniques has meant the majority
of women having skin- or nipple-sparing mastectomy can
undergo an implant-based reconstruction. Larger preopera-
tive breast size or mastectomy weight is, however, associated
with a greater risk of skin necrosis such that skin-reducing
techniques are often employed resulting in a reduction in
breast size and/or ptosis [6]. Women with very large breasts
rares1geo@gmail.com
who wish to maintain their preoperative breast size should be
counselled regarding a higher risk of skin necrosis and should
generally be advised to undergo a two-stage procedure [7].
30.2.2  nilateral Procedures and the Need
U
for Symmetrisation Surgery
Whilst it is possible to achieve excellent symmetry with bilat-
eral procedures, patients undergoing unilateral procedures
should be counselled about the likelihood of requiring future
contralateral symmetrisation surgery (such as augmentation,
mastopexy or reduction) to adequately match the recon-
structed and non-reconstructed breast in terms of size and
shape. In the longer term, natural ageing of the contralateral
breast, as well as capsule formation and implant displace-
ment on the reconstructed side, may cause further asymme-
try, which may necessitate repeated further surgeries.
30.2.3  isk Factors for the Development
R
of Complications
There are several risk factors associated with a higher rate of
complications or reconstructive failure. These include smok-
ing, obesity, diabetes, older age and exposure to radiotherapy.
None of these risk factors are absolute contraindications to
performing the procedure, but patients should be counselled
regarding the elevated risk. Patients should also be advised to
stop smoking completely as this can reduce wound complica-
tions as much as threefold [8].
30.2.4  eed for Revision Surgery
N
in the Future
The effects of ageing, weight gain, pregnancy and capsular con-
tracture may result in an unacceptable discrepancy between
the appearance of the reconstructed and non-­reconstructed
breast. Patients should be counselled that they are likely to
require adjustment surgery and or replacement of their implant
(e.g. due to rupture, capsule formation, displacement) at some
point in the future, rates of which can be as high as 50% [9].
30.2.5 One-Stage Versus Two-Stage
Reconstruction
This is strongly influenced by individual surgeon preference.
Two-stage procedures may be preferred in patients with a
large breast size, excessively thin mastectomy flaps or ques-
tionable skin blood perfusion at the time of surgery. Some
may also prefer the two-stage technique as it allows an oppor-
tunity to reappraise the reconstruction following expansion
and adjuvant therapy, select the most appropriate definitive
Specific Implant-Based Techniques for Breast Reconstruction
367 30
..      Fig. 30.1  One- versus
two-stage implant-based breast
reconstruction

Skin

Muscle

Tissue
expander

Saline
solution

Implant

implant to achieve the best symmetry and improve the over-
all appearance and contour by adjusting the position of the
inframammary fold and performing a capsulotomy. Whilst a
modest increase in breast size is achievable with the one-­
stage technique, a two-stage procedure is generally preferred
if a substantial increase in volume is desired. One-stage tech-
niques are often preferable from a patient perspective as they
eliminate the need for a second procedure and regular outpa-
tient hospital visits for expansion (. Fig. 30.1 shows the dif-
 
ference between the two techniques). The skin quality in the
case of prior radiotherapy should be carefully assessed, and
those with multiple risk factors for reconstructive failure
should be appropriately counselled. There are dual-purpose
expander implants which may both be used to expand and
then left in situ as permanent implants which may be a useful
alternative to a two-stage procedure in some women. These
have both a stable gel fill component and a variable saline fill
chamber and either an integral or external filler port.

rares1geo@gmail.com
 368 L.J. Cook and M. Douek
30.3 Specific Techniques
30.3.1 Immediate Implant-Based
Reconstruction
Immediate implant-based breast reconstruction after mas-
tectomy is associated with significant psychosocial and qual-
ity of life benefits [10]. Four commonly used techniques for
immediate implant-based reconstruction are described
below: (i) sub-muscular implant placement, (ii) sub-­muscular
placement with a lower pole sling, (iii) sub-muscular place-
ment with a dermal sling/autograft and (iv) pre-pectoral or
subcutaneous implant placement. Whilst the majority of
30 immediate breast reconstructions currently performed are of
the two-stage «tissue expander/implant» type (TE/I) [11], all
of the techniques described below can also be carried out as
a single-stage procedure using either a «direct-to-implant»
method or by using an anatomical expandable implant.
Sub-muscular Technique
Early implant-based reconstructions involved the placement
of implants directly under the mastectomy flap in a «subcuta-
neous» position. This technique fell out of favour as it was
found to be associated with a high degree of complications,
as well as unsatisfactory cosmesis. Consequently, techniques
were developed in which chest wall musculature was used to
provide coverage of the implant, with the aim of reducing
implant exposure, palpability and visible rippling by provid-
ing an additional soft tissue layer between the incision and
the implant. Sub-muscular implant coverage may be «total»
(in which sub-pectoral and sub-serratus muscular pockets
are created and joined together to provide complete implant
coverage) or «partial» (where just a sub-pectoral pocket is
created and the lower pole of the implant therefore lies sub-
cutaneously).
(i) Total sub-muscular technique (. Fig. 30.2)
 
55After completion of the mastectomy and haemosta-
sis, the sub-muscular pocket is prepared. The
pectoralis major muscle is elevated from its lateral
edge and the sub-­muscular pocket dissected
medially to the sternal edge. This sub-muscular
dissection is continued superiorly to the level of the
desired position of the new breast cleavage in the
relatively avascular space between pectoralis major
and minor. This is usually, but not always, at the level
of the second rib. Care should be taken to preserve
the large perforator of the second intercostal space
because of its significant contribution to the mastec-
tomy flap blood supply. It is important not to extend
the pocket too far superiorly as this will result in a
high riding implant.
55The pectoralis major muscle is elevated from its
insertion at the level of the fifth rib to enable implant
placement medially. It may be necessary to also
elevate part of the anterior rectus fascia, in continu-
ity, to maintain complete coverage. This must be
done with care as this layer is often thin and friable.
rares1geo@gmail.com
Breast
muscle
Implant
..      Fig. 30.2  Sub-muscular implant placement
55The lower slips of serratus anterior are elevated in
order to provide coverage to the inferolateral portion
of the implant. The sub-serratus and sub-pectoral
pockets extend down to below the level of the
inframammary fold. In a fully sub-muscular
technique, if the lower pocket is at the level of the
IMF, the implant will appear too high and should be
placed approximately 2 cm lower. This is not the case
for a partially sub-muscular, dermal sling or mesh
supplemented techniques where the IMF is used as
the lower border of the implant pocket.
55The implant is then inserted into the sub-muscular
pocket, and once the position is satisfactory, the
lateral border of pectoralis major is sutured to
serratus anterior and therefore completely covering
the implant with muscle and separating it from the
mastectomy space.
55The expander (if used) is then expanded to a level
which minimises dead space, but without causing
tension on the mastectomy or muscle flaps, closed
suction drains are inserted inferolaterally, usually
with some degree of tunnelling to reduce infection
risk, and skin closed over the muscle to complete the
procedure.
(ii) Partial sub-muscular technique
55The pectoralis muscle is elevated as described above
but without any further dissection of the chest wall
muscles. The implant is placed in the sub-pectoral
pocket such that the inferior pole remains subcuta-
neous when the mastectomy flaps are closed.
Both total and partial sub-muscular techniques are associated
with limitations. Firstly since the size of the implant pocket
that can be created with either approach is constrained by
available skin and muscle, immediate reconstruction gener-
ally requires a two-stage (tissue expander/implant) approach
Specific Implant-Based Techniques for Breast Reconstruction
unless the patient is very small breasted. With the partial sub-
muscular technique, only the superior part of the implant is
covered by muscle, which leaves the lower pole of the implant
vulnerable to exposure, should skin necrosis or infection
occur. In addition, if the flaps are initially thin, or atrophy with
time, then the implant and any creases or wrinkles in its sur-
face may be easily palpable. The released lower edge of the
pectoralis muscle can also adhere to the skin, such that when
it contracts, there is an unsightly deformity known as «win-
dow shading» that requires surgical correction. With total
muscular coverage, elevation of the serratus anterior muscle
can be associated with pain both at the time of surgery and
during the expansion phase. Furthermore, tight banding of
the raised muscle or fascia across the lower pole may result in
difficulty in controlling expansion vectors resulting in flatten-
ing and unnatural breast shape. Both techniques can result in
lack of control over the position of the IMF, in a flat unnatural
look, and make it difficult to achieve a natural looking ptosis.
Sub-muscular and Lower Pole Sling
The «lower pole sling» technique has been developed to avoid
the problems associated with partial or total sub-muscular
implant placement described above. This technique uses a
piece of mesh which is sutured superiorly to the lower border
of pectoralis major and inferiorly to the inframammary fold,
such that it augments the volume of the implant pocket, low-
ers the IMF and reduces muscular dissection [12]. Although
many different meshes, both biological and synthetic, are
now available on the market for this purpose, there is more
evidence on the use of «acellular dermal matrices» (ADMs) –
as this technique was first described with ADM.
ADMs are sterile, acellular, biological pieces of material
derived from human or animal tissue (usually skin), in which
the dermis is stripped of cellular components leaving a struc-
turally intact and biochemically inert, extracellular matrix
[13]. Whilst the human skin-derived ADM, «Alloderm,» was
the first ADM to be described in the literature [14], multiple
ADMs have now entered the market derived from both allo-
genic and xenograft (porcine and bovine) donor sources. As
well as dermally derived products, other tissues such as peri-
cardium and peritoneum have also been used to create
meshes with similar properties [15]. The first report of using
an ADM in reconstructive breast surgery was by Breuing and
Warren in 2005, with their series of ten patients who under-
went bilateral mastectomy and direct-to-implant single-stage
reconstruction using Alloderm [14]. The first series of ADM
use in two-stage expander/implant surgery was described by
Bindingnavale and colleagues in 2007 [16].
Proposed benefits of ADM use in implant-based recon-
struction are described below:
(i) Increase rate of direct to implant procedures
The use of ADM to extend the sub-pectoral pocket allows
one-stage breast reconstruction to be performed when there
is sufficient preservation of the skin at the time of mastec-
tomy. This eliminates the need for the tissue expansion phase.
It is suggested that this simplifies the process of reconstruc-
rares1geo@gmail.com
369 30
tion, potentially reduces the time to completion of recon-
struction and therefore minimises cost [17–19].
(ii) Reduction in post-operative pain
Reconstructions using ADMs may result in less pain by
reducing the extent of muscle elevation to create the implant
pocket, thereby reducing the degree of neuronal disruption com-
pared to a standard sub-muscular technique. However the evi-
dence that post-operative pain is reduced by ADM use is purely
anecdotal at present. McCarthy and colleagues randomised
patients undergoing mastectomy from two US hospitals into
cohorts who received two-stage immediate breast reconstruction
either with or without ADM and was unable to demonstrate a
significant difference in pain scores between the two cohorts
either post-operatively or during the expansion phase [20].
(iii) Increased fill volumes and fewer expansions resulting in
shorter reconstruction time
As a larger pocket may be developed when an ADM is
used, it is proposed that this may allow increased initial fill
volumes and faster expansions in two-stage procedures.
There is conflicting data in the literature with comparative
retrospective cohort studies both supporting and refuting
this [21]. Factors which may account for this discrepancy
include patient factors (the ability of different patients to tol-
erate varying fill volumes, patient availability and the patient’s
physical characteristics) and surgeon preferences for the fre-
quency and volumes of expansions.
(iv) Better cosmesis
The rationale behind this theory is that by securing the
ADM to the lateral and inferior borders of the breast pocket,
this defines the inframammary fold and enables reliable place-
ment of the implant whether placed as one stage or at the time
of exchange. Additionally, the alternative technique using
complete sub-muscular coverage of tissue expanders restricts
the ability of the lower pole to fully expand, whilst placement
of an ADM would allow less constriction. This therefore
enables full use of the mastectomy flap to allow a natural curve
of the lower pole. There are a few studies which report ADM-
based reconstructions as having a better cosmetic outcome
compared to standard sub-muscular implant placement based
on panel assessment of cosmesis from post-­operative photo-
graphs [22, 23], but follow-up is relatively short.
(v) Decreased incidence of capsular contracture
Initial experimental evidence which showed reduced
inflammatory reactions associated with ADM use in both ani-
mal models and human capsule specimens has been backed
up by some clinical studies but has not as yet been evaluated
in a prospective trial. Studies with long-term follow-­up of
ADM-assisted reconstructions have, however, demonstrated a
low cumulative rate of capsular contracture even in the setting
of radiotherapy [17, 24]. However there are no randomised
comparisons, and the rate of capsule formation is still higher
in ADM cases when radiotherapy is used so it clearly does not
abolish the problem completely [92].
 370 L.J. Cook and M. Douek

zz Surgical Technique sutures may be required laterally to fix the ADM to

55 Creating the sub-muscular pocket: after mastectomy,
the pectoralis major muscle is divided from its origin
inferiorly and released medially to the level of 3 (left)
or 9 (right) o’clock position. The muscle is then
separated from the underlying pectoralis minor and
chest wall.
55 Forming the ADM sling: the ADM is prepared
according to the manufacturer’s instructions.
fascia over serratus anterior to define the lateral
border and prevent lateral displacement of the
implant. When using the inframammary approach
and during a subcutaneous mastectomy, it may be
easier to suture the ADM to the lower boarder of the
pectoralis muscle and then to suture the ADM to the
chest wall, after the implant is placed in the pocket
(. Fig. 30.3).

Depending on the ADM type, this may require a
period of soaking or rehydration. The inferior ADM
edge is then sutured to the IMF using interrupted,
absorbable sutures. The implant is then put in
30 position in the pectoralis/ADM pocket before the
upper border of the ADM is sutured to the lower
border of the muscle. Placement of the ADM should
be without tension but should not be too loose such
as to allow excessive wrinkling or laxity. Extra
55 Drain placement: one (or two) large bore drains may
be placed deep or superficial to the ADM to enable
adherence of ADM to the skin flap and prevent
seroma formation. This is tunnelled and usually
removed within 7–10 days. Avoidance of seroma is
important in reducing rates of infection and encour-
aging flap and ADM adherence and integration.
Consequently many surgeons leave the drains until
drainage rates of less than 30 ml in 24 h are reached.

..      Fig. 30.3 Implant-based
reconstruction using an ADM
(lower pole sling). a Pectoralis
a b
major muscle is raised from the
inframammary fold and medially.
ADM is sutured to the inframam-
mary fold. b Implant is placed in
the newly created pocket and the
free upper border of the ADM is
sutured to the lower (detached)
part of the pectoralis major
muscle. c Implant in place within
the ADM- muscle pocket

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Specific Implant-Based Techniques for Breast Reconstruction
zz Complications Associated with the Use of Acellular
Dermal Matrices
Adverse outcomes associated with ADM use have been the
subject of several systematic reviews; some of which have
raised concerns that use of ADM may be associated with an
increased risk of complications such as infections and seroma
formation, when compared with a non-ADM cohort, whilst
others report no significant difference [21, 25–28]. The most
recent meta-analysis reports that whilst rates of complica-
tions such as infection, skin necrosis and seroma are signifi-
cantly higher, this does not translate into an increased risk of
implant loss associated with use of an ADM. It is suggested
that these complications are therefore either not serious or
that their management has improved such that implant loss
is avoided [21]. There is debate, however, as to whether the
primary studies used within existing systematic reviews are
of sufficient quality to enable such conclusions to be drawn,
with the majority being retrospective cohort studies of het-
erogeneous patient populations, with ill-defined, nonstan-
dardised outcome measures. Potter and colleagues carried
out a comprehensive critical appraisal of the evidence base
for ADM use in implant-based reconstruction and concluded
that the level of evidence from the available primary studies
was of such poor quality that combining their results in a
meta-analysis was largely inappropriate [29].
zz Alternative Materials for Lower Pole Support
Widespread acceptance of the lower pole support technique
pioneered through the use of ADMs together with a pressure
to reduce healthcare costs has led to the development and use
of alternative materials for use with the «lower pole sling»
technique, both biological and synthetic in nature
(. Table 30.1). At present comparative studies between prod-
 
ucts are scarce, and evidence for efficacy is generally based on
single centre case series. The considerable cost reduction of
using a synthetic material as opposed to an ADM means that
if they are found to have equivalent outcomes, they are likely
to become an attractive alternative. Furthermore, ADMs are
371 30
largely available in high-income countries and not available
in low- and middle-income countries. Synthetic materials
may thus be an attractive option in the latter countries. Use of
synthetic meshes has caused some concern due to the diffi-
culty of removal in cases where this is necessary, especially
when adherent to a thin skin flap.
Sub-muscular and Dermal Sling
The use of a dermal sling in implant-based reconstruction
was first described in 1980 by Tanski [30] and further refined
by Hammond and colleagues [31], Bostwick [32] and Nava
and colleagues [33]. This technique uses a similar principle
to the lower pole support offered by ADMs but uses instead
the de-epithelialised excessive skin of the lower pole of the
breast to provide an entirely autologous, well-vascularised
tissue coverage for the lower pole of the implant. This tech-
nique is generally offered to women with large ptotic breasts
who can be offered a skin-sparing mastectomy, as it makes
use of the redundant skin normally excised as part of the
skin-reducing Wise pattern incision. Since a skin-reducing
incision pattern is used, patients should be counselled that a
contralateral mastopexy/reduction is usually required for
symmetrisation.
zz Surgical Technique
55 Skin flaps are marked preoperatively as per the
standard Wise pattern.
55 Creating the dermal sling: the lower mastectomy flap
between and below the vertical limbs is de-epitheli-
alised prior to performing the mastectomy. The
de-­epithelialised skin is left in continuity with the
IMF.
55 Raising the muscle: the pectoralis major muscle is
then raised from its inferior border as described
above for the ADM technique. Often, however, there
is insufficient dermis to support the implant laterally,
in which case the sub-muscular pocket can be
extended by continuing the division of the pectoralis

..      Table 30.1  Examples of materials used for lower pole support as an alternative to ADMs

TIGR Matrix Synthetic mesh Macroporous mesh made up of two types of copolymer fibres – a fast-degrading fibre which
supports the implant during the wound healing phase and a slow-degrading fibre which retains
its mechanical properties for 6–9 months. Transient inflammatory reaction only. Cheaper than
ADMs

TiLOOP Bra Synthetic mesh Non-absorbable, titanium-coated polypropylene mesh (TCPM) made of a knitted monofilament
structure. Available in three different bra-like sizes. Histological studies indicate minimal
inflammatory reaction. Cheaper than ADMs

Vicryl mesh Synthetic mesh Dissolves rather than integrates into tissue but no evidence to date that by dissolving rather
than integrating, there is a greater risk of implant displacement. One third of the cost of ADMs

SeriSilk Biological scaffold Silk filament combined by helical twisting to form a multifilament fibre which assembled into a
three-­dimensional scaffold. Behaves like an ADM in vivo as absorption is associated with new
tissue generation such that the strength and load-bearing properties are transferred to the
newly ingrown tissue. Only a mild inflammatory response

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 372 L.J. Cook and M. Douek

origin laterally in a horizontal line, through the fascia
and costal digitations of serratus anterior, until the
desired pocket width is reached. The sub-serratus
pocket is then developed upwards until it joins the
sub-pectoral dissection.
55 Forming the implant pocket: the implant is placed
under both the elevated muscle and dermal sling.
The upper edge of the dermal sling is sutured to the
implant pocket using interrupted absorbable sutures.
Extra sutures may be placed at the IMF or lateral
border for better definition.
55 Drains are inserted in the sub-muscular and subcu-
taneous spaces, and the horizontal and vertical
incisions are closed over the dermal sling implant
pocket in the usual fashion.
55 . Figure 30.4 shows a series of photographs of the

lower border of the pectoralis muscle to form an stages of a dermal sling reconstruction.

a b

30

c d

e f

..      Fig. 30.4  Implant-based reconstruction using a dermal sling (From
Dietz [91]. With permission from Springer). a Intraoperative marking
showing the apex of the Wise pattern reduction markings at 22cm in
this patient. The vertical limbs are 10cm and close to the Nipple-Areola
complex (NAC). b Deepithelialization around the NAC prior to hard cut
around the nipple and creation of the superior flap. c Deepithelialized
superior flap after completion of the mastectomy. d Exposed pectoralis
muscle and inferior flap e Pectoralis sewn to inferior autoderm with
expansion of the tissue expander. f Final intraoperative view after
closure of the flaps

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Specific Implant-Based Techniques for Breast Reconstruction
373 30
There are only a limited number of case series in the litera-
ture reporting on outcomes of the dermal sling technique
[34–37]. Whilst earlier case series report high incidences of
skin necrosis and implant extrusion, the more recent ones
report equivalent outcomes to the use of an ADM [37]. In
particular, T-junction dehiscence, which commonly occurs
with the Wise pattern incision, is well tolerated due to the
underlying dermal sling which prevents implant exposure.
Safety and efficacy in the presence of radiotherapy have not
been studied to date.

zz Dermal Sling as an Autograft

A variation on the dermal sling technique makes use of
similarly de-epithelialised skin from the excess available
when performing a «tummy tuck» procedure and transfers
it as a free graft to be used in a similar fashion as an ADM
[34–36]. As a result, it is not necessary to use a Wise pattern
incision in this technique, but the patient is required to
have sufficient excess abdominal skin in order to harvest
the graft.

 re-pectoral or Subcutaneous Implant

P
Place ment
Pre-pectoral implant placement is commonly used for cos-
metic breast augmentation but until recently has not gener-
ally been used following skin-sparing mastectomy due to
unacceptable complication rates, poor cosmetic outcomes
and high rates of capsular contracture in early series [93].
With the introduction of biological and synthetic meshes,
which provide a replacement for soft tissue coverage, there
has been a recent resurgence in this technique. This is based
on the rationale that both ADMs and synthetic meshes can
be safely placed subcutaneously between the implant and
mastectomy flaps when providing support for the inferior
..      Fig. 30.5  Pre-pectoral implant placement
to allow for an increase in volume. The covered implant is
then fixed in position to the underlying chest wall using
anchoring sutures between the mesh and the underlying
pectoralis muscle. Drains are then placed and skin flaps
closed directly over this.
Although initial outcome data is promising, it is currently
too limited at present to make a definitive conclusion as to
whether pre-pectoral implant placement offers benefits over the
retro-pectoral lower pole sling technique (. Table 30.2 presents

pole in retro-pectoral reconstructions described above.
There are suggestions that pre-pectoral placement, as well as
simplifying the reconstruction overall, may improve patient
outcomes by avoiding some of the issues associated with the
use of retro-pectoral implant placement such as functional
impairment of the pectoralis muscle, breast animation asso-
ciated with muscle contraction and post-operative pain
associated with detachment of pectoralis major as well as
during the expander phase in two-stage breast reconstruc-
tion. Furthermore by recreating the natural anatomical posi-
tion of the breast in front of the pectoralis muscle, it is
suggested that a more natural appearance may result. Whilst
patient selection is generally limited to those with decent
subcutaneous tissue coverage, the concomitant use of lipo-
modelling to improve the quality of the subcutaneous tissue
layer may mean this technique becomes available to a larger
proportion of women. The technique has several variations,
but the general principle involves wrapping either a fixed
volume or expander implant within a mesh pocket [38–41].
This pocket may be an acellular dermal matrix or any of the
alternatives described above and is either constructed by the
surgeon or available in a preformed shape (. Fig. 30.5). In
 
the case of expanders, the mesh should be wrapped loosely
an overview of studies of pre-pectoral implant placement).
30.3.2  elayed Implant-Based Breast
D
Reconstruction
A delayed approach may be considered if there are serious
concerns about skin flap viability or to minimise the likeli-
hood of complications in high-risk patients where immediate
reconstruction would result in unacceptable risk of failure or
delay to adjuvant treatment (such as radiotherapy or chemo-
therapy). Whilst better outcomes are generally associated with
an autologous approach, particularly if there has been expo-
sure to radiotherapy [42], implant-based reconstruction may
be offered in the delayed setting if patients express a particular
preference or if they are considered unsuitable for an autolo-
gous technique. It is important that skin quality is assessed,
and if it is poor, patients are considered for a ­latissimus dorsi
flap or autologous reconstruction. For implant reconstruc-
tion, generally a two-stage tissue expander/implant approach
is used as the skin is often too contracted to accommodate a
fixed volume implant. The skin at the mastectomy site should
be carefully evaluated in terms of its quality and thickness

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 374 L.J. Cook and M. Douek

..      Table 30.2  Published studies on the use of pre-pectoral implant placement

Reference/ Study type Mesh used One stage/two Patients Outcome Follow-up
year stage (breasts)

Reitsamer and Case series Strattice One stage; fixed 13 (22) No implant loss; no Median
Peintinger (two sheets volume implant capsular contracture; 6 months
(2015) [38] sutured excellent patient (range 1–12)
together) satisfaction and
cosmetic outcome

Berna et al. Retrospective Braxon© One-stage; fixed 19 (25) Three implant losses Median
(2017) [40] series (proof of volume after first ten patients 14 months
concept) due to seroma and (range 7–20)
infection; improved
30 outcomes when mesh
to thinner chemical
free version. Excellent
cosmesis

Bernini et al. Non-randomised TiLOOP (one One stage; fixed Retro-­ Implant loss rate Retro-­pectoral:
(2015) [41] prospective cohort or two volume implant pectoral and significantly higher in median
sheets) TiLOOP: 29 pre-pectoral cohort 26 months
(34) (5.1% vs 0%) but (range 16–42);
Pre-pectoral significantly better pre-pectoral
and TiLOOP: cosmetic and patient 25 months
30 (35) reported outcomes in (range 16–40)
pre-pectoral cohort

Casella et al. Prospective cohort TiLOOP Two-stage tissue 25 (25) No expander or Median
(2014) [39] expander/implant implant losses, 14 months
infection rate 12% after implant
(first stage) and 4% exchange
(second stage); no (range 7–23)
seromas; excellent
levels of patient
satisfaction with
cosmesis

particularly if there has been exposure to radiotherapy, since
expansion of thin poor-quality skin is associated with an
increased risk of necrotic complications and implant expo-
sure. Another option for irradiated skin is the use of pre-
reconstruction autologous fat grafting which has been shown
to improve the quality, thickness and vascularity of the skin
and subcutaneous tissue resulting in low complication rates
and good cosmetic outcomes [43].
The technique used for delayed implant-based recon-
struction is similar to the partial or total sub-muscular tech-
niques described above. The mastectomy scar is excised and
skin flaps minimally raised just to the extent that the pectora-
lis muscle is visualised to allow elevation of its lateral border
from the underlying chest wall. Further dissection can then
proceed in either the subcutaneous plane or sub-muscularly
to provide lower pole coverage. Pre-pectoral expander place-
ment could be considered in cases where mastectomy skin
flaps are particularly thick and healthy. After pocket dissec-
tion, the expander is placed such that maximal expansion
occurs in the lower pole in order to produce a more natural
breast shape. Intraoperative fill volumes are generally limited
due to skin contracture.
30.4 Complications of Implant-Based
Reconstruction
30.4.1 Risk Factors for Implant Loss
Most commonly cited complications following implant-­
based reconstruction are infection, skin necrosis, seroma,
haematoma and implant exposure, all of which can result in
implant loss if not treated promptly. Even if implant loss does
not occur, such complications may have a negative impact on
cosmetic outcome. There are several reported risk factors for
the development of complications. Whilst there are no abso-
lute contraindications, patients who have such risk factors
should be appropriately counselled preoperatively. Identified
risk factors which are significantly associated with the devel-
opment of major complications include smoking, high BMI,
older age, large implants or high-volume intraoperative fills
of expanders and high ASA scores. Radiotherapy is also asso-
ciated with increased risk of complications [44–48].
Risk factors for implant loss in the early post-operative
period were evaluated in a review of the ACS-NSQIP data-
base by Fischer and colleagues [44]. Using a multivariate

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Specific Implant-Based Techniques for Breast Reconstruction
regression analysis of the outcomes of 14,585 patients who
underwent immediate implant-based breast reconstruction
between 2005 and 2011, they found that age over 55, obesity,
smoking, direct-to-implant and bilateral procedures were
significantly associated with early implant loss. Interestingly
they also found that a greater level of obesity was associated
with a greater level of risk.
30.4.2 Infection
Infection following implant-based breast reconstruction is
thought to originate from several potential sites including
contaminated implants, contaminated implant saline, infec-
tion introduced at the time of surgery from the surgical envi-
ronment, from the patient’s skin or mammary ducts or
seeding of the implant from a remote infection via the blood-
stream [49]. The usual causative organism identified is
Staphylococcus aureus with other commonly identified organ-
isms being coagulase-negative staphylococci, Pseudomonas
aeruginosa and Gram-negative bacilli [50, 51]. There are also
reports of more unusual bacteria causing infection as well as
fungi and mycobacteria. In addition to the risk factors
described above, the presence of ischaemia and prolonged
drain placement is also thought to increase the likelihood of
infection. Clinical presentation can be variable but usually
includes a combination of skin erythema and heat, pain,
swelling or post-operative seroma, wound discharge and fever
although severe sepsis can also develop [49].
There are currently no definitive guidelines for manage-
ment of an infected breast implant although some suggested
protocols have been published [52, 53]. Initial management
steps should include administering systemic broad spectrum
antibiotics after obtaining specimens for microbiological
analysis. Patients who do not have an obvious wound infec-
tion or purulent discharge should undergo ultrasound-­
guided aspiration of peri-prosthetic fluid in order to obtain a
specimen to guide management. An initial trial of intrave-
nous antibiotics is reasonable in mild cases with empiric
treatment guided by local policies and prevalence of methi-
cillin resistance, whilst awaiting the results of cultures.
In the past an infected implant would have necessitated
immediate removal, but strategies have been developed to
attempt «implant salvage» defined as the retention of a pros-
thetic device although not necessarily the original one.
Salvage techniques include combinations of:
55 Systemic antibiotics and drainage of infected fluid
55 Exchange of implant/wound washout (including for a
smaller volume)
55 Debridement of necrotic tissue +/− advancement flap
55 Pulse lavage/antibiotic washout
55 Continuous antibiotic irrigation
Implant salvage allows preservation of the skin envelope and
therefore a better chance of a successful cosmetic outcome
that would be possible following implant removal and a
delayed secondary procedure [54]. Several case series have
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375 30
reported success rates of between 37.7 and 76.7% [54–57] and
identified high white count at the time of presentation [55],
presence of atypical pathogens [57] or methicillin-­resistant
Staphylococcus aureus [55] are risk factors for failure of sal-
vage. Most infectious complications occur in the early post-
operative phase, but there are several reports of late infections
occurring several years following implant placement.
30.4.3 Skin Necrosis
Skin necrosis is a common complication of all reconstructive
techniques which use a skin- or nipple-sparing mastectomy
and occurs in between 10% and 30% of patients undergoing
implant-based procedures [7, 58, 59] with the main risk fac-
tors being smoking, high intraoperative expander fill volume,
over-dissection or thin mastectomy flaps, high BMI and
older age. There is conflicting evidence as to whether use of
tumescence when elevating the mastectomy flaps results in
higher rates of skin necrosis [60–62].
Strategies to avoid skin necrosis include careful preserva-
tion of the subcutaneous fat and the internal mammary per-
forators. Ideally post-operative development of skin necrosis
should be preempted intraoperatively by assessment of mas-
tectomy flap viability. However, clinical assessment based on
factors such as capillary refill, skin colour and temperature
has been shown to be unreliable in predicting post-operative
complications. Fluorescent angiography can be used for
intraoperative visualisation of skin flap vascularity allowing
intraoperative decisions to be made regarding management
of the skin flaps [63], but this may result in unnecessary skin
excisions. Supportive measures in the immediate post-­
operative period such as the use of warming blankets,
warmed fluids, correction of anaemia and prevention of
hypotension may help to prevent development of necrosis by
supporting adequate blood flow to the mastectomy skin flaps.
Management depends on the degree of skin loss.
Superficial epidermolysis is generally successfully managed
conservatively with wound care and antibiotics. Partial or
total necrosis requires prompt excision under local or general
anaesthetic to prevent further progression and development
of an associated infection. Depending on the degree of skin
involvement, debridement can be followed either with pri-
mary closure or with an advancement flap together with
exchange of the implant or expander for a smaller size to
allow skin apposition [58].
30.4.4  he Impact of Radiotherapy
T
on Complication Rates
Radiotherapy can cause unpredictable changes in tissues,
with the acute effects (consisting of swelling, erythema and
skin desquamation) occurring over days to weeks and a
delayed response (consisting of a fibrotic reaction affecting
skin and subcutaneous tissues) which can occur from months
to years after completion of the therapy. Radiotherapy has
 376 L.J. Cook and M. Douek
been identified as a risk factor for the development of both
early and late complications whether given pre- or post-­
reconstruction [47, 64]. Early complications include infec-
tion, skin necrosis, wound breakdown or dehiscence and
implant loss, whilst a later effect is the development of capsu-
lar contracture.
In a retrospective review of the outcomes of 1037 patients
who had undergone breast reconstruction, Berry and col-
leagues reported that those patients who had undergone two-­
stage tissue expander/implant reconstruction had a major
complication rate of 45.4% with radiotherapy compared to
24.4% without. Radiotherapy was also found to be the great-
est risk factor for the development of complications on mul-
30 tivariate analysis in this study, and most common
complications were implant exposure and capsular contrac-
ture [65]. A meta-analysis of the effect of postmastectomy
radiotherapy on complication rates of 1105 patients under-
going both autologous and implant-based reconstruction by
Barry and colleagues showed that for the 424 patients who
had undergone implant-based reconstruction, radiotherapy
was associated with a significantly greater morbidity (odds
ratio 4.2; 95% CI 2.4–7.2 radiotherapy vs no radiotherapy) as
well as having a negative effect on cosmetic outcomes [66].
The morbidity associated with radiotherapy was found to be
significantly less in those patients who underwent autolo-
gous reconstruction when compared to those who under-
went implant-based reconstruction (odds ratio 0.20; 95% CI
0.1–0.4 autologous vs implant).
There is debate as to whether the presence of an ADM in
a reconstructed breast may confer some protection against
the effects of radiotherapy or whether it results in worse out-
comes. Clemens and colleagues demonstrated through their
meta-analysis involving 273 irradiated patients that the pres-
ence of ADM did not statistically increase or decrease infec-
tion or overall complication rate, although complications
were higher overall in the irradiated cohort [67]. There is
some evidence to suggest that that use of an ADM may confer
protection from the development of capsular contracture in
irradiated patients [17, 21] although this has not as yet been
confirmed by any long-term prospective comparative studies.
The timing of radiotherapy in two-stage reconstruction is
an important consideration since exchanging the expander
for an implant through an irradiated incision results in sig-
nificantly higher rates of wound dehiscence when compared
to nonirradiated tissues (15% vs 1.3%) [68]. In Cordeiro and
colleagues’ series of 304 two-stage reconstructions, those
who underwent irradiation of the expander prior to exchange
were significantly more likely to suffer reconstructive failure
at 6 years than those in whom the second-stage permanent
implant was irradiated instead (32% vs 16.4%). Conversely,
however, aesthetic outcome scores were lower, and rates of
grade 3 or 4 capsular contracture were significantly higher in
those who had an irradiated permanent implant when com-
pared to those with an irradiated expander (50.9 vs 17.1%)
[69]. Similar findings have been reported elsewhere [70, 71].
Despite the risks associated with implant-based recon-
struction in the setting of radiotherapy, there has clearly been
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a change in attitude and an increase in acceptability amongst
surgeons towards this scenario. Women who are considered
preoperatively to be at high risk of requiring postmastectomy
radiotherapy are significantly more likely to receive an
implant-based rather than autologous reconstruction [2].
Although the risk of reconstructive failure and complication
rates may be higher, the vast majority who undergo implant-­
based reconstruction with radiotherapy have a successful
end outcome, with acceptable cosmetic results and excellent
patient-reported outcomes [72–74]. Patients and surgeons
are thus prepared to accept the trade-off of an increase in
complication rate because of the perceived benefits of
implant-based reconstruction.
30.5  ncological Aspects of Implant-Based
O
Reconstruction
30.5.1  isk of Local and Systemic
R
Recurrence
Concerns regarding an increased oncological risk associated
with breast reconstruction arise from the potential for resid-
ual breast tissue to be left behind within skin flaps following
skin-sparing mastectomy, the possibility of a delay in adju-
vant treatment as a result of post-operative complications
associated with reconstructive surgery and interference in
detection of local recurrence as a result of obscuring the
chest wall. Current evidence, however, including three recent
meta-analyses [75–77], has failed to demonstrate a signifi-
cant difference in local recurrence, disease-free survival and
overall survival rates between patients undergoing postmas-
tectomy breast reconstruction compared to those undergo-
ing mastectomy alone [78–82].
However, the majority of evidence on oncological out-
comes with adequate follow-up to date relates to those
patients with preinvasive disease. This lack of data prevents a
robust analysis on oncological outcomes following breast
reconstruction according to stage. Furthermore, most out-
come studies on breast reconstruction tend to amalgamate
outcomes for both implant and autologous procedures and,
also, do not include those patients who have undergone more
contemporary techniques of implant-based breast recon-
struction such as use of ADMs and pre-pectoral placement.
Therefore, whilst there is currently no evidence to suggest
that there is an elevated oncological risk as a consequence of
undergoing implant-based reconstruction, ongoing evalua-
tion of oncological outcomes is necessary.
30.5.2 Surveillance of the Reconstructed
Breast for Local Recurrence
In terms of post-operative surveillance of the reconstructed
breast for local recurrence, current guidelines recommend
clinical follow-up alone. There is insufficient evidence to
support a role for surveillance mammography [83]. With
Specific Implant-Based Techniques for Breast Reconstruction
s­ub-­muscular techniques of implant-based reconstruction,
the sub-pectoral placement of an implant means that the
entire mastectomy site and chest wall are displaced anteri-
orly, such that any recurrence, either superficial or posterior
to the mastectomy site, would most likely be readily appreci-
ated on clinical examination. Furthermore, mammography
is of limited value because there is minimal tissue to image
between the pectoralis major muscle and the skin. There is
also inadequate evidence to support a role for breast MRI in
routine post-operative surveillance, although it is the best
modality to evaluate implant-related complications such as
implant rupture and leak.
30.5.3 Anaplastic Large Cell Lymphoma
One important oncological consideration associated with
implant-based reconstructions (as well as with cosmetic aug-
mentations) is the reported association with anaplastic large
cell lymphoma (ALCL) – a rare form of non-Hodgkin’s lym-
phoma. Although not a cancer of the breast tissue, ALCL has
been linked to the use of breast implants. The first case of
implant-associated ALCL was described in literature in 1997,
and there have been several further case reports and series
since. However, it remains controversial as to the strength of
the association, with population studies reporting either no
evidence of an association [84, 85]or, if present, a very weak
one [86] compounded by the fact that this is a rare disease.
Clinical presentation of implant-associated ALCL is most
commonly described as an effusion-associated fibrous cap-
sule surrounding an implant or less frequently as a palpable
mass [87, 88]. From the limited long-term follow-up data
available, the condition is felt to be clinically indolent and
associated with an excellent long-term prognosis [88].
Treatment is largely limited to removal of the involved cap-
sule and associated implant [87–89].
Pending further long-term follow-up and epidemiologi-
cal data, current guidelines [89, 90] advise clinicians to be
vigilant to the possibility of this diagnosis and, if clinical sus-
picion exists, to send fresh seroma fluid for cytological evalu-
ation or, if an operative intervention is performed, to send the
capsule (or representative portions) for histological analysis.
30.6 Conclusion
Implant-based procedures have become an increasingly pop-
ular option for women who wish to have a breast reconstruc-
tion following mastectomy. Improvements and advances in
techniques, together with an apparent change in attitude
towards the impact of adjuvant radiotherapy, have meant that
the majority of women can now be offered an implant-based
procedure. High levels of reported satisfaction with cosmesis
mean that women who are unsuitable for autologous tech-
niques or wish to avoid the associated donor site morbidity
now have a very acceptable alternative. However, the speed
with which new techniques of implant-based reconstruction
rares1geo@gmail.com
377 30
are introduced means that reliable outcome data is often
lacking and is difficult to standardise over any period of time.
Ongoing research into factors such as patient selection, risk
factors for complications and oncological safety is required
to ensure the best possible outcomes are achieved in this
evolving field.
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 381 31

Specific Autologous Flap

Techniques
Sinikka Suominen and Maija Kolehmainen

31.1 Introduction – 382

31.2 Decision Making – 382

31.3 Flap Options – 382

31.3.1 Pedicled and Local Flaps – 383
31.3.2 Local Transposition Flaps – 384
31.3.3 Pedicled Perforator Flaps – 384
31.3.4 Microvascular Flaps – 386
31.3.5 Bilateral Reconstruction – 389

31.4 Conclusions – 390

References – 390

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_31

rares1geo@gmail.com
 382 S. Suominen and M. Kolehmainen
31.1 Introduction
Autologous reconstruction provides natural and long-lasting
results and is the state-of-the-­art method if enough donor
tissue is available [1–5]. Due to the longevity of the result, it
is cost-effective especially for young women [2], and patient
satisfaction even improves with time and age [3, 4]. It is
sometimes feasible even in thin patients who often have cor-
respondingly small breasts [6], and it is superior to implants
in obese patients [7]. As obesity increases wound complica-
tion rates, implant exposure is a risk, and autologous flaps are
more cost-­effective. Flaps are proportional in size to the
patient’s body, often yielding higher satisfaction rates [7].
Despite the strong evidence proving the superiority of
autologous reconstruction, there has been a worldwide trend
31 in the last decade towards increased use of implants instead
of flaps [8, 9]. Autologous immediate reconstruction
decreased in the USA from 59% in 1998 to 32% in 2008 [9],
and in the UK immediate implant reconstruction increased
from 30% to 54% between 2007 and 2014 [8].
There are many reasons for this phenomenon, and a
closer look at the data reveals that the total number of breast
reconstructions has increased, the use of autologous tissue
reconstructions has also slightly increased but the use of
implants has increased markedly. Free flaps, however, have
become more common in the delayed setting [8], and this
seems natural as larger flaps are needed in a scarred and often
irradiated setting.
Socio-economic and healthcare system-related reasons
may also affect the choice of reconstruction method. A recent
UK national survey observed that rates of immediate free
flap reconstructions ranged from 9% to 63% between centres,
indicating that surgeon availability and expertise may play a
significant role in which methods are offered. The same phe-
nomenon was noticed by Jeevan and colleagues in 2010, who
reported substantial regional variation in immediate recon-
struction rates in England which cannot be explained by the
characteristics of the local patient population [10]. An
Australian study found that financial constraints affected
women’s reconstruction choices, and private patients were
more likely to choose autologous reconstruction when not
faced with a 3-year waiting list [11].
Cultural reasons affect our decision making, often in
combination with body type variation and different ethnici-
ties. A UK study from 2016 found that women of Black and
Asian ethnicity were more likely to receive free flap recon-
struction compared to Caucasian women [8], a finding which
has previously been observed in the USA in 2000 by
Alderman and colleagues [12]. In our institute, the rate of
immediate reconstruction has steadily increased during the
last 20 years, but there is a strong preference among patients
and surgeons towards autologous tissue. Through the media
the patients have been well informed about the potential haz-
ards of implants and favour a more natural and long-lasting
autologous method that is not likely to require multiple reop-
erations within their lifetime.
rares1geo@gmail.com
Although autologous tissue reconstruction provides the
most natural and long-lasting result, it is also a major opera-
tion with a longer recovery period than implant-based recon-
structions. Therefore some medical systems may push the
surgeon to favour cheaper choices even if the result is only
short term. It is important that surgeons advise their patients
based on facts rather than health economic considerations
when advising on treatment choices.
31.2 Decision Making
The planning of a breast reconstruction involves all four of
Leroy Hoods P’s of medicine; it is predictive, preventative,
personalized and participatory [13]. Patients and their
breasts come in different sizes and shapes (. Fig. 31.1), and
a breast reconstruction service must offer several different
methods to cater to the needs of all kinds of patients. During
the first consultation, the surgeon must not only estimate
the possibilities of different donor sites in relation to the
patient’s breast size but also weigh these options in relation
to the patient’s cancer status, possible upcoming treatments
and her comorbidities. With this information the surgeon
must then thoroughly explain all options to the patient,
attempting to predict the outcome and the likelihood of
adverse effects of each method. The time spent on weighing
the pros and cons of different options is essential in pre-
venting complications and unsatisfactory results. Especially
in an immediate reconstruction situation, it is difficult for
the patient to comprehend the vast amount of information,
and it is advisable to provide them with written or online
objective information at least about the most common
options. A Polish study found higher levels of satisfaction
with life have a positive effect on the decision to undergo
breast reconstruction [14], and it is probable that the
patient’s preoperative situation will also affect post recon-
struction satisfaction.
Usually several consultations are necessary before reach-
ing the final decision about the donor site, and as the patient
will ultimately have to live with the result, as well as any poten-
tial complications, and the scars and defect of the donor area,
the decision making must be informed and participatory.
31.3 Flap Options
Although most flaps can be used in both immediate and
delayed settings, delayed breast reconstruction requires flaps
with greater volume and a larger area of skin for replacing the
skin envelope. In contrast, in an immediate situation the
patient may need adjuvant treatments or radiotherapy; hence
fast and reliable healing of wounds is a higher priority.
Postoperative radiotherapy may result in delayed volume loss,
scarring or lymphedema. As it is always easier to reduce than
to augment later, this can be taken into account by building a
larger than necessary breast if radiotherapy is anticipated.
Specific Autologous Flap Techniques
..      Fig. 31.1  Body types, apple
and pear
Apple Shape
Most flaps need refinements at 6–12 months postoperatively,
and patients should be informed that it takes months for the
scars to soften and the flap to settle into its final position.
Secondary scar corrections, «dog ear» removal and free fat
grafting can be performed subsequently to optimize out-
comes, often under local anaesthesia in an outpatient setting.
31.3.1 Pedicled and Local Flaps
Latissimus Dorsi Myocutaneous Flap
The pedicled latissimus dorsi (LD) flap was first introduced
to resurface a thoracic wall defect following a radical mastec-
tomy in 1953 [15]. Since the 1970s, a myocutaneous LD has
been the workhorse of breast reconstruction [16, 17]. Even in
the era of microsurgery and perforator flaps, it still has a role
as a safe, reproducible reconstructive method that can be
performed by a single surgeon. Flap failure is rare, vascular-
rares1geo@gmail.com
383 31
Pear Shape
ization of the muscle, and the skin island is reliable and its
pedicle reaches the anterior thoracic wall easily with no need
for microanastomosis. The LD flap is ideal for patients with
contraindications to microsurgery or if other donor sites
cannot provide the necessary volume and an implant is
needed. Shoulder problems or massive lymphedema of the
arm, occupations or hobbies with high physical demands are
relative contraindications to the use of this flap.
The latissimus dorsi muscle is the most extensive muscle
in the body and is important in the extension and internal
rotation of the upper arm. As a type V muscle in the Mathes
Nahai classification [18], it has one dominant vascular pedi-
cle and several secondary paravertebral pedicles. The thora-
codorsal pedicle has one artery and one to two veins which
arise from axillary vessels via subscapular vessels. The thora-
codorsal nerve runs parallel to the vascular pedicle and gives
motor function to the muscle. Both vascular pedicle and
nerve divide into two main branches at the entrance to the
 384 S. Suominen and M. Kolehmainen
muscle, which enables splitting of the muscle and thus har-
vesting of a muscle sparing LD (msLD) flap.
The skin island, revealed by a pinch grip, is marked pre-
operatively either horizontally or obliquely, depending on
the body shape and skin type. The patient is positioned in the
lateral decubitus position. The skin island and the maximally
harvested subcutaneous fat layer are kept intact with the
underlying muscle, which is mobilized on its pedicle, pro-
ceeding from the mediocaudal to craniolateral direction
towards the axilla. The serratus branch of the thoracodorsal
pedicle can often be left intact, but posterior attachments are
released. Division of the tendinous insertion of the muscle is
beneficial, in order to avoid lateral malposition of the recon-
structed breast. The thoracodorsal nerve is usually divided
and 1–2 cm of its length resected in order to reduce the risk
31 of muscle spasm making the reconstructed breast «jump»,
which may be disturbing especially if an implant has been
placed under the muscle. However, this results in some grad-
ual loss of muscle volume due to muscle atrophy, and some
surgeons prefer to leave the nerve intact if no implant is used.
The flap is tunnelled to its new position and fixed tempo-
rarily. After donor site closure, the patient is turned into a
supine or semi-sitting position. The axilla must be checked,
as intercostobrachial nerves and vascular serratus branches
may cause kinking of the pedicle, thus risking the flap viabil-
ity. After securing the pedicle, the flap is positioned and
shaped and augmented with an implant, if necessary.
The LD muscle gives good coverage to an implant. An
expander prosthesis is an option, if significant additional vol-
ume or ptosis of the flap is desired. The use of an expandable
implant is also a safe augmentation method in a delayed
reconstruction with bad axillary scarring or other risk fac-
tors, if flap viability might be compromised by a large volume
permanent implant.
In an extended LD myocutaneous flap, the dissection
plane is at the level of Scarpa’s fascia, and subcutaneous fat is
harvested on top of the muscle, as well as from subscapular
and suprailiac regions [19]. Development of free fat grafting
makes harvesting of some of the less accessible fat pads, such
as that which slides underneath the scapula, of questionable
necessity. Nowadays it is common to augment the flap with
fat injections to the pectoral and latissimus muscles both
during reconstruction and, if needed, in subsequent cosmetic
refining operations.
Several authors have proposed muscle sparing LD flap
techniques where additional volume from lumbar fat is rein-
forced with an additional perforator. Although muscle is
saved, these techniques are more arbitrary and include a
microanastomosis, and the donor site is not hidden as well as
in a conventional LD flap [20, 21].
The latissimus dorsi myocutaneous flap as a breast recon-
struction method has been criticized for the shape of the
reconstructed breast, as well as donor site problems. However,
the donor site has an inconspicuous scar on the back, which
is easily hidden under the bra and easily forgotten by the
patients as she cannot see it daily. Seroma formation in the
back donor site wound is common; thus prolonged postop-
rares1geo@gmail.com
erative suction drainage and later needle aspirations may be
necessary. Chronic seroma formation is rare, however.
Scar tension in underlying tissues and numbness of the
donor site are common, even if the skin island of the flap has
not been large. Shoulder muscle power (adduction, inner
rotation, extension) is weakened postoperatively but recovers
within a few weeks to permit normal daily activities. Some
functional deficit in physical activities may remain, which
must be taken into consideration in flap choice for breast
reconstruction. Postoperative active rehabilitation has an
important role in prevention of these problems [22, 23].
31.3.2 Local Transposition Flaps
Thoracodorsal Transposition Flap
(Holmström’s Flap)
The lateral thoracodorsal flap is a fasciocutaneous transposi-
tion flap from the posterolateral thoracic wall. It can be har-
vested as a 6–12 cm wide and up to 22 cm long flap, based
medially from the submammary fold. As a traditional local
flap with simple flap harvest, it is especially suitable in increas-
ing skin and volume in the inferior pole of the breast.
Combined with an implant or free fat grafting, this flap enables
even a total breast reconstruction for a morbid patient [24].
Abdominal Advancement Flap
Mobilization of large abdominal skin and subcutaneous flap
from the inframammary fold and sliding it up to create the
lower pole of the breast are versatile options to create a small
breast reconstruction, supplemented with an implant, for a
morbid patient. It is also of value in corrective surgery after
large volume breast conservation resection or reconstruction
[25]. The inframammary fold often drops to a lower level,
despite careful fixation, after this technique which may cause
asymmetry.
31.3.3 Pedicled Perforator Flaps
Pedicled perforator flaps offer a good choice for partial or
small volume breast reconstruction. Since the advent of pro-
peller flaps nearly 30 years ago [26] in reconstructive breast
surgery, several different flaps have been introduced [27–29].
In principle free style flaps [30, 31] can be harvested on any
perforator of sufficient calibre which supplies redundant tis-
sue. Local flaps allow reconstruction with a number of
advantages: a single region operation without the need for
microsurgery or a remote donor site, autologous tissue with
a more predictable volume than free fat grafting, an excellent
colour match and good texture. Suitable tissue sources in the
thoracic wall are the back (thoracodorsal artery perforator
(TDAP) flap) [32], lateral and anterior thoracic wall (lateral
and anterior intercostal artery perforator (LICAP and ICAP)
flaps) [33, 34] and contralateral breast (internal mammary
perforator (IMAP) flap) [35, 36]. The flap is designed from
the area with the greatest amount of redundant tissue, a
Specific Autologous Flap Techniques
pinch grip revealing the maximal width of the flap. Flap har-
vest demands microsurgical skills, careful perforator explo-
ration, appropriate mobilization and good tactical thinking
with several alternative plans depending on intraoperative
findings.
385 31
The perforator pedicle is usually short, which makes posi-
tioning of the flap challenging. The flap can be mobilized as a
pedicled perforator (TDAP), propeller (LICAP, IMAP), turn-
over (AICAP) or perforator enhanced transposition flap with
a skin bridge (. Fig. 31.2).

Propeller flap

Pedicled perforator flap

Turnover flap

..      Fig. 31.2  Pedicled perforator

flap types Perforator flap: enchanced transposition

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 386 S. Suominen and M. Kolehmainen
In the lateral thoracic region, perforators and sensate
nerves are in close connection to each other, which results in
an often sensate flap but may also increase the risk of neural-
gia. Thus careful dissection is necessary. Pedicled perforator
flaps are more prone to vasospasm than microvascular perfo-
rator flaps, which is a relative contraindication for the use of
this method in immediate breast reconstructions, especially
for morbid patients after neoadjuvant chemotherapy. However,
due to minimal donor site problems, these flaps are versatile
options for elderly women with shoulder problems or patients
with contraindications to microsurgery, e.g. obesity.
Pedicled perforator flaps alone are a good choice in par-
tial reconstructions or shape corrections. In total breast
reconstruction, additional volume with free fat grafting or an
implant is often needed.
31
Thoracodorsal Artery Perforator (TDAP) Flap
The thoracodorsal artery perforator (TDAP) flap can be har-
vested vertically or horizontally. The horizontal skin island is
identical to the skin island of the myocutaneous LD flap and
is sometimes known as the «LD flap without muscle» [32],
except that in the TDAP flap the skin island should be
planned approximately two fingerbreadth anteriorly from the
lateral edge of the LD muscle in order to include the potential
direct cutaneous branch of the thoracodorsal artery to the
flap. The flap dissection proceeds from the posteromedial tip
of the flap in the suprafascial plane to the level of the scapular
tip. The lower edge of the spindle-shaped skin island is
incised to reveal the lateral edge of the LD muscle.
Thoracodorsal perforators are in a row, usually within 2 cm
distance from the muscle edge. Careful dissection proceeds
in the supra- or sub-fascial plane to reveal the perforators. If
both the thoracodorsal and direct cutaneous perforators are
weak, exploration of lateral intercostal perforators is pro-
posed, as they can be stronger in such cases.
Another option is to include the anterior branch of the
intramuscular thoracodorsal vessel and a piece of latissimus
dorsi muscle, about 1–2 × 3–4 cm in size, as part of the flap
and convert the TDAP flap to a muscle sparing LD flap.
The pedicle can be mobilized to the point where posterior
and anterior thoracodorsal branches merge to form a com-
mon trunk, which gives the pedicle a length of about 4–6 cm
and enables a later LD muscle flap to be harvested on its ped-
icle of the posterior branch. A pedicle length of 15 cm is pos-
sible, if mobilization proceeds up to axillary vessels [37–39].
 ateral Intercostal Artery Perforator
L the deep epigastric vessels can be dissected without sacrifice
(LICAP) Flap
The lateral intercostal artery perforator (LICAP) flap is a per-
forator flap based on the lateral intercostal perforator vessels.
Based on this perforator, a long horizontal skin and subcuta-
neous flap, running towards the back or anteriorly, can be
harvested as a propeller flap. In the majority of cases, even
very long flaps, «hemithoracic propeller flaps», reaching
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almost from the spine to sternum of over 40 cm long, can be
harvested successfully, if the perforator is strong [33, 34].
 nterior Intercostal Artery Perforator
A
(ICAP) Flap
Anterior intercostal perforators are small and numerous, the
largest situating near the midline. The skin flap is designed
along the inframammary fold, and the flap can be harvested on
a row of several small perforators as a turnover flap. This design
is preferable if the inferior pole is low. In cases of medial volume
deficit, an AICAP flap, based on a single medial perforator, as a
propeller or a perforator enhanced transposition flap gives the
needed effect without lowering of the inframammary crease.
Internal Mammary Perforator (IMAP) Flap
The lower pole of the contralateral breast can be used as an
internal mammary perforator-based propeller flap to recon-
struct a breast, if there is a need for reduction mammoplasty.
It is a refreshed old method from the early times of breast can-
cer surgery [13, 33, 34, 40]. In order to gain success with this
method, the quality of breast tissue and skin should be good.
Increased cancer risk of the contralateral breast is a contrain-
dication to this method, and the aesthetic result of the healthy
breast should not be compromised. Transplantation of the
nipple-areola complex is often necessary. The skin overlying
the xiphoid process should be preserved if possible, to respect
aesthetic units [35, 36, 40, 41].
31.3.4 Microvascular Flaps
Lower Abdominal Flaps
The skin and subcutaneous tissue of the lower abdomen pro-
vide an excellent donor site where the tissue quality mimics
that of the breast. This elliptical or w-shaped flap between the
umbilicus and the suprapubic crease can be raised on several
different pedicles according to the technical expertise of the
surgeon and the patient’s vascular anatomy.
Although Hartrampf popularized this flap in the 1980s as
the pedicled TRAM (transverse myocutaneous rectus
abdominis myocutaneous) flap [42], it had already been
described as a free flap by Holmström in 1979 [43]. A pedi-
cled TRAM is based on the superior epigastric system, a free
TRAM on the deep epigastric vessels, which are the domi-
nant supplier to this skin and subcutaneous fat paddle [44]. A
further development came by Koshima [45] who showed that
of the rectus abdominis muscle as a perforator flap, and Allen
was the first to use this concept in breast reconstruction and
called it the DIEP (deep inferior epigastric perforator) flap
[46]. He also popularized the idea of Grotting from 1991 to
further minimize the donor site morbidity by raising the
same flap as a SIEA (superficial inferior epigastric artery) flap
on the superficial inferior epigastric vessels [47, 48].
Specific Autologous Flap Techniques
Pedicled TRAM
The pedicled version of the abdominal flap remains a work-
horse flap for surgeons and centres that do not have the
facilities for free tissue transfer. The flap is raised on the supe-
rior epigastric vessels that run through the rectus abdominis
muscle. Sacrificing the entire width of the muscle makes dis-
section safe and easy but can result in abdominal bulging or
hernia formation. This risk can be lessened by including only
a strip of the muscle, but as the motor nerves run horizon-
tally through the muscle, the preservation of motor function
requires more delicate intramuscular dissection. Comparative
studies have shown that the donor site defect is similar to that
of a muscle sparing free TRAM [49]. In a USA nationwide
study of more than 21,000 patients, pedicled TRAM flaps had
more pulmonary complications, pneumonia and pulmonary
embolisms, but free TRAM patients had more wound com-
plications, longer hospital stay and higher overall cost [50].
In a study by Macadam and colleagues, the pedicled TRAM
had more partial failures and fat necrosis than free TRAMs
or DIEPS, which is not surprising as the superior epigastric is
not the dominant supplier to this flap [44, 51].
Free TRAM
Nahabedian and colleagues classified the free TRAM flap
according to the degree of muscle sacrifice:
55 MS-0, inclusion of the full width of the muscle
55 MS-,1 preservation of the lateral third of the muscle
55 MS-2, preservation of both medial and lateral thirds
55 MS-3, preservation of all of the muscle as in a DIEP
flap [52]
Naturally, inclusion of a piece of the whole width of the mus-
cle makes the elevation simpler and safer, but the donor site is
equivalent to that of a pedicled TRAM and muscle continuity
is lost. Unfortunately comparative studies of the donor site
have shown that even if the muscle sparing techniques lessen
the abdominal wall donor problems, bulging and hernias still
remain a risk [53]. This is probably due to the long fascial
opening and splitting of the muscle which damages several
segmental nerves, thus denervating the spared muscle.
DIEP
A true benefit for the donor site came from the development
of the DIEP flap, as the perforating vessels are dissected
through the muscle to reveal the main pedicle within the
muscle belly which is carefully dissected free. It is possible to
preserve all, or almost all, of the segmental nerves, and thus
the remaining muscle will remain functional. Ideally only
one perforator, situated in the middle of the flap, is chosen or
several perforators in the same row. Studies have indicated
that although the flap lives on one perforator alone, less fat
necrosis occurs if two to three perforators are included, pos-
sibly due to enhanced venous return [54]. However, a rough
dissection of several perforators on different sides of the
rares1geo@gmail.com
387 31
muscle can result in a muscle defect equivalent to that of a
muscle sparing (MS) TRAM, and thus it has been difficult to
show the donor site benefit of a DIEP over a MS-TRAM. Ideally
only a 4–6 cm vertical fascial opening is done to expose the
perforator and dissect it through the muscle. If a full length
pedicle is needed, one can perform a transverse appendec-
tomy type of incision at a lower level to expose the deep epi-
gastric vessels.
Preoperative assessment of the anatomy of the DIEA per-
forators helps in planning the operation and in choosing the
best perforator. This is best done by performing a CT angio-
gram of the lower abdomen, but also MRI angiography has
been used [55]. This technology not only provides accurate
mapping of the vessels but helps to determine which
perforator(s) has the shortest intramuscular course and larg-
est calibre. It shows if the deep epigastric has one or two main
trunks and if two nearby perforators can be harvested with-
out muscle sacrifice or not. The perforators can of course also
be mapped by a handheld Doppler, but this does not reveal
their quality or intramuscular course.
A 5-year follow-up study of patients who had undergone
the four different methods to raise this abdominal flap
showed that DIEP patients had significantly less donor site
problems than pedicled TRAM patients, but outcomes did
not differ much between TRAM and MS-TRAM techniques
[51] (. Fig. 31.3).
SIEA
Allen presented the idea of raising the lower abdominal flap
with the superficial vessels, without muscle sacrifice [48].
These vessels can be exposed by undermining at the level of
Scarpa’s fascia in the groin. The vein can be followed to its
origin inside the subcutaneous tissue, and the artery runs
..      Fig. 31.3  Two flap reconstructions in the same patient, delayed
reconstruction with DIEP and immediate reconstruction with TMG
 388 S. Suominen and M. Kolehmainen

below it but the origin of the artery is usually 2–3 cm more
cranially sited and often merges with the superficial circum-
flex artery. It is wise to follow both pedicles under the fascia
until their entry into the femoral vessels to achieve appropri-
ate diameter and length. The artery is more prone to spasm,
and before making the final decision to use this pedicle, it is
wise to clamp all DIEA perforators and make sure that the
flap is sufficiently vascularized. The SIEA pedicle is usable in
only about 10% of the population and is safest when har-
vested from the axial side only. It is advisable to judge the
vascularity preoperatively by either CT or MRI angiography.
Although this technique results in a perfect donor site, it
is unfortunately not without problems. The vessel anatomy is
variable, and the artery small, and consequently there are
higher flap loss and complication rates compared to DIEP or
31 TRAM flaps. Park and colleagues reported their experience
of 145 SIEA flaps over an 8-year period, and 80% had arterial
problems in the initial operation, with a flap loss rate of 4.8%
[56]. A recent Dutch study confirmed that SIEA flaps do have
a higher revision and flap loss rate compared to DIEP flaps
[57]; however they have a place in bilateral breast reconstruc-
of the gracilis muscle posteriorly. No harvest between the
skin and gracilis muscle is performed. The subcutaneous fas-
cia is opened on top of the gracilis; the muscle is bluntly dis-
sected free from the surrounding structures until its
tendinous insertion, which is divided under palpation con-
trol. The secondary pedicle to the SFA is clipped, if possible.
The primary pedicles, the medial circumflex femoral vessels,
are clipped from side branches and dissected separately until
they meet the deep femoral vessels. Additional access lateral
to the adductor longus muscle may be used to reveal the deep
femoral vessels properly. The motor branch from the obtura-
tor nerve is cut and the origin of the muscle divided.
Pedicle vessels are clipped along the femoral vessels and
anastomosed either to the internal mammary or thoracodor-
sal vessels. The breast is shaped, trying to position the skin
island in its cranial and medial part and hiding the muscle
below the central part of the breast, as muscle atrophy may
create a depression in the skin envelope.
The TMG/TUG flap is often the same size as half of the
DIEP flap, which makes the method versatile especially in
bilateral or immediate breast reconstructions (. Fig.  31.4).  

tions and in combined lymph node transfer where the bene- Even slim patients tend to have subcutaneous fat in the
fits outweigh the higher risk. medial thigh, even when the lower abdomen lacks volume.
Donor site scars are inconspicuous, the medial part of the
Thigh Flaps scar most frequently descending. Scar tension in the gracilis
The upper thigh is a versatile donor site for several flaps suit- donor site and posterior thigh numbness are often temporary.
able to breast reconstruction. The transverse myocutaneous Seroma formation and secondary wound healing are rela-
gracilis (TMG, . Fig.  31.3)/transverse upper gracilis (TUG)
  tively common problems, but lower limb lymphedema is rare.
flap and profunda artery perforator (PAP) flap are the most
popular flaps. Also the lateral thigh is an optional donor site in
breast reconstruction: anterolateral thigh (ALT) and tensor
fasciae latae (TFL) flaps may be used for some patients [58–62].

Transverse Myocutaneous Gracilis (TMG), i.e.

Transverse Upper Gracilis (TUG) Flap
Although the gracilis muscle flap and gracilis myocutaneous
flap with a vertical skin island have been used in reconstruc-
tive surgery for a long time [63], the recent use of a ­horizontal
orientation of the gracilis skin angiosome was only described
in the 1990s [64]. At the beginning of this millennium, this
flap, with its near invisible donor site, was introduced as a
new breast reconstruction method, the transverse upper
gracilis flap [65] and soon popularized as the transverse
myocutaneous gracilis flap [66].
A spindle-shaped skin island is marked on the proximal
thigh, with the upper edge sited along the inguinal-­
infragluteal crease and the height defined by grasping a tissue
fold. The anterior tip is marked medial to the femoral vessels
and posterior to the lateral tip of the gluteal fold. The patient
is positioned in a supine position with the legs elevated and
abducted as for gynaecological surgery. The skin is incised,
and the maximal amount of subcutaneous fat is included in
the flap and dissection proceeds suprafascially towards both
ends of the skin paddle. The fascia is incised above along the
adductor longus muscle anteriorly and on the posterior edge ..      Fig. 31.4  Two flap donor sites in the same patient: DIEP and TMG

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Specific Autologous Flap Techniques
Profunda Artery Perforator (PAP) Flap
In 2010, the profunda artery perforator (PAP) flap was intro-
duced as an alternative flap option in the upper thigh [67]. As
a perforator flap, only skin and subcutaneous fat supplied by
the (usually 9 cm long) direct skin perforators arising from
the deep femoral vessels are harvested for the flap. Identical
skin and subcutaneous tissue flaps can be based on either the
TMG or PAP pedicle, but often the PAP flap skin island lies
more posteriorly. Benefits of the PAP flap compared to the
TMG flap is that muscle is not sacrificed and the pedicle is
longer. The disadvantages are that the TMG flap is easier to
harvest in the supine/gynaecological position, the vascular
pedicle is more predictable and the average volume of the
flap is greater [68–71]. Both TMG and PAP flaps are rela-
tively small flaps, on average under 400 g, which has inspired
some surgeons to use two flaps stacked to reconstruct one
breast [68, 71–73].
Gluteal and Lumbar Flaps
S-GAP
The superior gluteal artery perforator flap is an alternative for
the more pear-shaped patient and is often regarded as the
microsurgeons’ second choice if the abdomen is unavailable
[74, 75]. Traditionally the skin island is placed in the middle
of the buttocks, in a triangle between the coccyx, iliac crest
and greater trochanter, but a more superior placement
(LSGAP) yields a more aesthetically pleasing donor scar.
However, this positioning also makes perforator harvest
more demanding as they can be found in the proximal third
to the middle third of the line between the posterior iliac
crest and the greater trochanter [76]. In a Northern European
population, it is rare to find patients with enough volume in
this donor site.
I-GAP
The inferior gluteal artery perforator flap was also popular-
ized by the group of Allen, as an alternative in women with a
pear-shaped body and large buttocks [74]. This flap, however,
has never gained much popularity and was largely aban-
doned due to the potential donor deficit to both sensation
and contour [77]. However, several groups have recently
advocated its use as an extension of a thigh flap (TMG or
PAP) [68, 78]. The patient should be properly informed about
the donor site defect with the scar, flattening of the buttock
and decreased sensation, before decision making.
Lumbar Artery Perforator Flap
The lumbar artery perforator flap is a novel option in breast
reconstruction. First described by Kato and colleagues as a
perforator-based pedicled flap, its microsurgical transfer
to the breast was reported by De Weerd and colleagues in
2003, but only popularized more than 10 years later by van
Landuyt who has reported the largest clinical experience
[79–81].
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389 31
It is based on a constant row of perforating branches of
the lumbar arteries which arise from the posterior wall of the
aorta at the level of the four upper lumbar vertebrae. The per-
forators have connections to several other vascular systems,
for example, the S-Gap pedicle, and the flap areas overlap. In
a computer tomography angiogram study, Hamdi and col-
leagues found that in 60% of patients, the dominant perfora-
tor was the third and in 30% the fourth [82]. As the perforators
are constant, a CT angiogram is not necessary, but marking
the perforators to the skin preoperatively with a handheld
Doppler can be helpful.
The fat pad between the iliac spine and the lowest rib, the
«love handle», is harvested. Either an oblique scar mimicking
the tension lines of the back or a curved horizontal scar can
be planned. The skin incisions continue as tapered fat har-
vest, but care must be taken not to take too much, as gluteal
fat is easily available. The width of the skin island is deter-
mined by a pinch test and fat harvest planned to allow a
direct tensionless closure.
The flap is harvested in a lateral decubitus position,
allowing a two-team approach in even an immediate recon-
struction setting. Most authors prefer to use the internal
mammary vessels as recipients, and although they can be
prepared during flap harvest, anastomosis is usually post-
poned until the donor site is closed and the patient turned
and re-draped. Due to the shortness of the pedicle, vein
grafts are recommended. Our preference is to use the thora-
codorsal vessels as recipients, the anastomosis can then be
performed while the donor site is closed, and then the
patient is turned on her back only for the final positioning of
the flap. Vein grafts are usually not necessary due to the lon-
ger recipient vessels.
This flap is often the only voluminous donor site in thin
patients and has its place in the armamentarium of a breast
reconstructive surgeon. However, the small calibre and short-
ness of the vessels make this flap technically demanding, and
it is not a flap for the beginner.
31.3.5 Bilateral Reconstruction
An increasing number of women are being identified as car-
riers of high-risk breast cancer genes, and many are request-
ing risk-reducing surgery to both breasts. Unlike breast
cancer patients, these women have healthy breasts, which
makes breast reconstruction more challenging, as even
minor complications worsen their previously excellent qual-
ity of life. In principle all methods are available for recon-
struction.
Prophylactic cases are usually bilateral, patients may be
young and often without sufficient autologous tissue to per-
mit breast reconstruction. Implants provide a good tempo-
rary alternative, but some patients opt for a more permanent
result with autologous reconstruction, which may be supple-
mented with lipofilling.
 390 S. Suominen and M. Kolehmainen
31
..      Fig. 31.5  Three team approach in bilateral breast reconstruction with thigh flaps
The inner thigh flaps (TMG/PAP) have proved to be a
useful donor site for autologous tissue, as flap harvest is
quick, allowing a multi-team (even 3–4 teams, . Fig. 31.5.)  
approach in the gynaecological position, and one thigh flap is
often more or at least equivalent to half of the DIEP flap. The
upper back (LD, ms-LD or TDAP flap alone or with an
implant) is another versatile flap donor site.
31.4 Conclusions
Autologous tissue is the optimal choice when aiming for
breast reconstruction which will be durable throughout the
patients’ lifetime. Subcutaneous fat resembles a fatty breast
by appearance, feel, softness and laxity. It changes shape as
the woman gains or loses weight and ages naturally.
All breasts are different in size and form and so are all
women; body types vary from apple to pear, from tall to short
and from chubby to slim. To cater for all needs, a reconstruc-
tive surgeon must have a large armamentarium of methods
to choose from. The patient of the twentieth century expects
and deserves individualized treatment.
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reconstruction. Ann Plast Surg. 1991;27:351–4.
48. Allen RJ, Heitland AS.  Superficial inferior Epigastric artery flap for
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51. Macadam SA, Zhong T, Weichman K, Papsdorf M, Lennox PA, et  al.
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reconstruction methods. Plast Reconstr Surg. 2016;137(3):758–71.
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cussion 476–7.
53. Suominen S, Tervahartiala P, von Smitten K, Asko-Seljavaara S. Mag-
netic resonance imaging of the TRAM flap donor site. Ann Plast
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54. Grover R, Nelson JA, Fischer JP, Kovach SJ, Serletti JM, Wu LC. The
impact of perforator number on deep inferior epigastric perforator
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55. Masia J, Clavero JA, Larrañaga J, Vives L, Pons G. Preoperative plan-
ning of the abdominal perforator flap with multidetector row com-
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56. Park JE, Shenaq DS, Silva AK, Mhlaba JM, Song DH.  Breast recon-
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after urgent microvascular revision of free DIEP, SIEA and SGAP flaps
for autologous breast reconstruction. J Plast Reconstr Aesthet Surg.
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58. Wei F-C, Suominen S, Cheng M-H, Celik N, Lai Y-L.  Anterolateral
thigh flap for postmastectomy breast reconstruction. Plast Reconstr
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31 tion using bilateral anterolateral thigh flaps: a case report. Ann Plast
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the free lumbar artery perforator flap for breast reconstruction. J
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 393 32

Goldilocks Procedure
Fiona MacNeill

32.1 Overview – 395

32.2 Advantages – 395

32.3 Disadvantages – 395

32.4 History – 395

32.5 Background – 395

32.5.1 De-epithelialised Dermal Flaps in Plastic Surgery – 396
32.5.2 De-epithelialised Dermal Flaps in Implant
Breast Reconstruction Surgery – 397

32.6 Indications for the Goldilocks Approach – 397

32.6.1 Women Not Suitable for Standard Breast
Reconstruction (Obese, Comorbidities, Older) – 397

32.7 Patient Selection – 397

32.7.1 Large Ptotic Breasts – 397

32.8 Contraindications – 397

32.8.1 Previous Breast Radiotherapy – 397
32.8.2 Oncology – 397

32.9 Nipple Areola Complex Preservation – 398

32.10 Surgical Technique – 398

32.10.1 Presurgery Marking – 398
32.10.2 Surgery – 398

32.11 Complications – 399

32.12 Limiting Complications by Maintaining Flap Vascularity – 399

32.13 Aesthetic Outcomes – 399

32.14 Radiotherapy – 399

32.15 Symmetrising Surgery – 399

32.16 Second-Stage Surgery – 399

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_32

rares1geo@gmail.com
32.17 Postmastectomy Imaging – 400

32.18 Costs – 400

32.19 Future – 400

32.20 Conclusion – 400

References – 400

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Goldilocks Procedure
32.1 Overview
The Goldilocks procedure describes a mastectomy per-
formed through Wise pattern skin incisions: the redundant
lower pole skin and subcutaneous tissue, usually discarded
as part of a mastectomy, is preserved, de-epithelialised and
then rolled up to create a breast mound around which the
superior pole skin flaps are draped (pre- and post-opera-
tive photographs are shown in . Figs. 32.1, 32.2, 32.3, and
 
32.4).
32.2 Advantages
55 Suitable for women not usually considered for breast
reconstruction because of the combination of:
55Surgical risk factors (obesity, age, comorbidities)
55Larger breasts requiring a complex reconstructive plan
55 Relatively simple and safe one-stage autologous breast
reconstruction with no donor site morbidity or implants
55 May tolerate postmastectomy radiotherapy (RT) (similar
to a conserved breast)
32.3 Disadvantages
55 Limited applicability:
55Not suitable for small- to moderate-sized breasts with
limited ptosis
55Can only be performed at the time of mastectomy
55 Requires meticulous surgical technique to prevent
dermal flap fat necrosis and wound healing problems
55 Difficult to get an aesthetic outcome comparable to other
autologous or implant-based techniques
..      Fig. 32.1 Preoperative
photographs of an ideal
candidate for a Goldilocks
procedure with large, highly
ptotic breasts following weight
loss surgery. Scars from 42cm 41cm
laparoscopic bariatric surgery are
highlighted
Bariatric surgery
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395 32
32.4 History
This technique of breast reconstruction after mastectomy
was first described in 1960 [1], then fully described as the
Goldilocks procedure in 32 breast cancer patients (50
breasts), by Drs Heather Richardson and Grace Ma in 2012
[2]. They proposed that this relatively simple autologous
(local flap) breast reconstruction technique could allow
women who may otherwise not be good candidates for more
conventional reconstruction techniques (usually because of
age, obesity, comorbidities, etc.) to undergo a breast recon-
struction. Dr. Tomoko Ogawa has described a small series of
five obese Japanese women with variable aesthetic outcomes
[3], and Dr. Schwartz from the USA has described a
Goldilocks procedure with a free nipple graft [4].
Richardson and Ma were the first to use the term
«Goldilocks» procedure. The name was inspired by a popular
twentieth-century English language fairy tale character [5]
who found herself in the house of Mummy, Daddy and Baby
bear, she tasted porridge that was too hot and too cold then lay
in beds that were too soft and too hard: finally she chose Baby
bears’ porridge and bed because they were «just right».
Correspondingly, the Goldilocks mastectomy represents a
«just right», comprise between the extremes of breast amputa-
tion with no reconstruction or complex reconstruction.
32.5 Background
There is little published on the Goldilocks procedure, but
technically it has evolved from well-established aesthetic and
reconstructive techniques and there is an extensive literature
base describing a variety of potential uses of de-epithelialised
dermal flaps to remodel or reconstruct the breast.
 396 F. MacNeill

32.5.1  e-epithelialised Dermal Flaps

D
in Plastic Surgery

Reduction mammoplasty for severe breast hypertrophy

(macromastia) or gigantomastia (where 1–2 kg of tissue may
be removed per breast) is a technically challenging proce-
dure. The long pedicle required to preserve the nipple areolar
complex (NAC) may increase the risk of nipple necrosis so
the standard approach is simple breast amputation through a
Wise pattern incision with free NAC grafting onto a de-­
epithelised dermal bed [6]. However as with the Goldilocks
procedure, this technique results in a flat wide breast with
minimal projection. A number of modifications have been
described to preserve sufficient dermoglandular tissue on a
standard pedicle around which the skin flaps can be draped
to allow a more projected breast mound [7, 8].
..      Fig. 32.2  Intraoperative photograph showing very large inferior Kollias and colleagues [9] in Australia have described the
32 de-epithelialised skin flap after folding to create the breast mound,
prior to re-draping with the superior skin flaps and ultimately
breast amputation/inferior pedicle mound technique for
reducing the contralateral breast in women with breast hyper-
placement of the free nipple graft
trophy when the index breast has been removed for cancer.

..      Fig. 32.3  Early (2 weeks)

post-operative photograph after
goldilocks procedure. A Wise
pattern mastectomy has been
performed and the inferior skin
flap de-epithelialised and folded
to provide the new breast
mound. The superior skin flap has
been closed, and free nipple
grafting has been performed

..      Fig. 32.4  Six months

post-operative photographs

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Goldilocks Procedure
32.5.2  e-epithelialised Dermal Flaps
D 86 years, the Goldilocks procedure may offer the opportunity
in Implant Breast Reconstruction
Surgery
Following mastectomy and implant reconstruction through a
Wise pattern incision, the lower pole de-epithelised dermal
flap can provide implant support and coverage similar to that
described for acellular dermal matrices (ADMs) and meshes
[10, 11]. As the dermal flap is a living autologous tissue, it has
advantages over manufactured meshes or acellular animal
derived dermal matrices (ADM). The vascularised flap lies
behind the vulnerable «T» junction (angle of sorrow) so pro-
tecting the implant if there is any T junction dieback [12].
For subpectoral implant reconstruction, the dermal flap can
be sutured to the lower border of the elevated pectoralis
major, or alternatively it may be sutured to the anterior sur-
face of pectoralis major for prepectoral implant placement
[13]. The dermal flap can also be used in combination with
an ADM or meshes if required.
32.6 Indications for the Goldilocks
Approach
32.6.1  omen Not Suitable for Standard
W mound. A large breast with limited ptosis and a limited infra-
Breast Reconstruction (Obese,
Comorbidities, Older)
The Goldilocks approach can be considered for women who
are not suitable for standard breast reconstruction techniques
and would otherwise have a simple mastectomy with no
reconstruction. The mastectomy can be oncologically indi-
cated or a woman’s preference to manage her cancer, or it
may be for risk reduction in high penetrance gene carriers or
those with a high-risk family history.
Reconstruction may not be possible or recommended
because of a range of patient factors that might restrict recon-
struction choices (e.g. a large body habitus with large breasts
may not be suitable for implants, and the corresponding obe-
sity may contraindicate a DIEP) or because the risks of pro-
longed time on the operating table, anaesthesia and
post-operative recovery is unacceptable for whatever reason.
Usually women deemed not suitable for breast recon-
struction are older with multiple comorbidities such as dia-
betes, hypertension and smoking, often compounded by
obesity (BMI  >  30). Richardson and Ma commented that
such women automatically exclude themselves from recon-
struction as clinicians are usually focused on simplifying the
treatment process to minimise risk and the need for multiple
interventions and complex follow-up.
As life expectancy continues to increase in the EU [14]
where the average life expectancy of a woman in Spain is now
rares1geo@gmail.com
397 32
of reconstruction to older women who may not wish to
undergo more major autologous procedures and for whom
implants are not age appropriate. Older women also tend to
exclude themselves from reconstruction often because of its
perceived risks and complexities [15].
32.7 Patient Selection
32.7.1 Large Ptotic Breasts
Patient selection is crucial to the success of this approach.
The Goldilocks technique is essentially an extreme reduction
mammoplasty: so to create enough volume to give any sem-
blance of a breast shape, patients require ample skin and sub-
cutaneous adiposity between the inframammary fold and
nipple.
A successful Goldilocks procedure requires the combina-
tion of obesity and a large breast (macromastia) with grade 3
or 4 ptosis (Regnault’s classification [16]. The definition of
macromastia is variable and not standardised, but in short
there has to be sufficient lower pole skin and adiposity to give
a volume that will create an aesthetically acceptable breast
mammary fold (IMF) to NAC distance or a very ptotic but
involuted thin breast will have insufficient lower pole der-
mal/subcutaneous fat to create a convincing breast mound.
32.8 Contraindications
32.8.1 Previous Breast Radiotherapy
Previous breast RT may compromise the vascularity of the
lower pole tissue and increase the risk of post-operative
wound healing problems and fat necrosis of the dermal flap.
In the Richardson and Ma paper, two women had undergone
previous RT.
The poorly informed patient with high aesthetic ideals.
32.8.2 Oncology
The Goldilocks procedure is contraindicated in the following
circumstances:
55 Whenever skin sparing mastectomy is not considered
oncologically safe (e.g. inflammatory cancers).
55 Large inferior pole tumours or tumours with inferior
pole skin involvement. In this situation alternative
dermal flaps can be considered, for example, a superior
medial pedicle dermal flap
 398 F. MacNeill
32.9 Nipple Areola Complex Preservation
The NAC can only be preserved if oncologically safe to do so
and is the patient’s preference. The original 2012 series of
Richardson and Ma did not preserve the NAC, but a 2015
case report by Schwartz has indicated it is feasible at the time
of mastectomy and reconstruction.
Immediate use of the original NAC has the benefit of lim-
iting the need for second-stage surgery in these high-risk
women. In aesthetic surgery for macromastia, the NAC has
been successfully preserved on a variety of pedicles, for
example, a thin superomedial dermal pedicle that can be
rotated into position.
If the NAC pedicle is too long/thin to maintain viabil-
ity, then it is safer to harvest the NAC as a full thickness
graft and store in a saline-soaked gauze swab until the end
of the procedure at which point it can be sutured to a de-
32 epithelised dermal bed as a free nipple graft as described by
Schwartz (iv).
32.10 Surgical Technique
32.10.1 Presurgery Marking
A presurgery Wise pattern mark-up with the patient stand-
ing is essential. The surgeons’ preferred Wise pattern mark-
ing can be employed using standard reduction mammoplasty
principles. Marking the desired nipple height is even more 5. Reconstruction
important for a Goldilocks procedure than a standard mam-
moplasty as once the considerable weight of the breast has
been removed the skin envelope retracts: even in older
patients there is considerable skin elasticity, and this can
result in the NAC being too high. Marking the new nipple
height at 24–26  cm is safe and can always be adjusted on-­
table if required. The new NAC position can be drawn in or
more safely left to the end of the procedure to allow for skin
reshaping and adjustments.
32.10.2 Surgery
There are a number of different skin sparing mastectomy and
dermal flap reconstruction techniques that may be adapted
to the patients’ requirements and reflect the surgeons’ exper-
tise and preference. The below is simply a guide.
1. De-epithelialisation
It is easier to de-epithelialise before the breast is removed.
All the skin inside the Wise pattern marking is de-­
epithelised. The dermal flap will run inferior to the NAC
down to the IMF, and the length will vary from patient to
patient. Not all de-epithelialised tissue may be required
for the reconstruction, but this can be assessed and refined 6. NAC position
during the reconstruction. A neo-NAC can be created by The most appropriate position for the NAC can be deter-
leaving a disc of skin at the appropriate position on the
dermal flap, but the positioning can be difficult to predict.
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2. Nipple areola complex
The NAC can be left on the breast if to be removed,
retained on a pedicle or taken as a full thickness graft.
3. Mastectomy
Mastectomy is carried out through either a circumareo-
lar, small elliptical incision around the NAC or a
standard Wise pattern mastectomy. The plane of
dissection is along the superficial fascia «oncological
plane» (Rusby) to remove as much breast tissue as
possible. «Thick» flaps, retaining obvious breast glandu-
lar tissue to increase flap volume to facilitate breast
reconstruction is not acceptable. However equally great
care must be taken to retain as much of the subcutane-
ous fat as is possible and not to over-dissect into the
subcutaneous fat or beyond the breast anatomical
boundaries: this is especially important for the lower
skin flap where the thickness of the flaps will naturally
increase towards the IMF.
4. Axilla
Axillary surgery can be easily performed through the lat-
eral Wise pattern scars. A separate axillary incision risks
compromising the vascularity of the lateral mastectomy
skins flaps. Retraction of the lateral flaps is required to
facilitate access to the axilla, but this must be careful and
gentle. Every effort must be made to retain any perfora-
tors from the axilla/chest wall that may supply the lateral
breast skin envelope.
1. The whole of the lower pole de-­epithelialised dermal
flap can be used: wrapping the lateral one-third and
medial one-third behind the central one-third, suturing
dermis to dermis then curling the flap into a mound
positioned over the meridian and suturing to the upper
limits of the superior mastectomy flap dissection.
2. Alternatively the central two-third of the lower pole
de-epithelialised dermal flap can be released from the
medial and lateral de-epithelised triangles and curled
around itself to create a central mound then positioned
as above. The de-epithelised triangles (usually removed
in a traditional mammoplasty) can be removed if not
required, left in situ and «folded» into the breast cavity
at closure or if vascularity is excellent, released as small
secondary flaps to provide extra volume and projec-
tion, especially medially and centrally.
3. The superior skin flaps are then draped around the new
breast mound and adjusted (with further de-epithelisa-
tion along the vertical and less commonly horizontal
limbs) so the skin sits snugly (but not tightly) over the
mound. The de-­epithelised tissue between the vertical
limbs of the superior mastectomy flap can also be
inverted to give more central volume and projection.
mined on the new mound, a 5  cm diameter circular of
dermis de-epithelised and the NAC secured using a
Goldilocks Procedure
s­ tandard technique. Alternatively a nipple can be recon-
structed from redundant vertical limb skin using a range
of techniques (see 7 Chap. 33).
 
7. Closure
Closure must be relaxed with no tension to allow rapid
wound healing especially at the T junction.
32.11 Complications
In this high-risk group of women, there are potentially a wide
range of surgical and non-surgical complications. The main
surgical risk is breast skin envelope necrosis with poor wound
healing and flap ischemia with fat necrosis, leaving a hard
distorted breast. The Richardson and Ma series had no sec-
ond surgeries to manage complications and an impressively
low risk of complications with only one seroma, three cases
of cellulitis and one of fat necrosis.
32.12  imiting Complications by
L indicated on standard postmastectomy radiotherapy criteria
Maintaining Flap Vascularity
Maintaining the vascularity of the inferior pole dermal flap is
crucial in preventing ischemia and fat necrosis which either
forms a hard indurated mass or leaks dead and dying fat for
months finally resulting in a hard and distorted breast. There
are a few basic principles to ensure good flap vascularity:
55 Skin envelope incisions must be minimised to maintain
continuity of the subdermal vascular plexus.
55 The dermal flap should be maintained on a broader base
than for a standard reduction mammoplasty so it will
support more length. In view of this the 2:1 (length:width)
rule for safe flap vascularity is less important.
55 If the flap looks compromised trim length back to
healthy bleeding tissue.
55Meticulous dissection in the correct planes to
preserve the subdermal vascular plexus.
55Maintain natural flap thickness especially peripherally
around the breast base and towards the IMF. This
should give skin envelope flaps that are thicker at the
base and thinner towards the NAC.
The Goldilocks technique takes advantage of the fact that the
dermal flap is naturally thinner and more malleable at the NAC
end and broader and thicker towards the base of the breast.
32.13 Aesthetic Outcomes
This depends on appropriate patient selection and meticu-
lous surgery to preserve the redundant subcutaneous tissue
to ensure sufficient dermal flap volume to create a pleasing
mound with proportionate volume and projection.
It also depends on the ability of the surgeon to sculpt the
dermal flap and de-epithelised tissues and match and shape
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399 32
the skin flaps to the new mound volume. It can be very diffi-
cult to achieve a good medial fullness and cleavage.
A Goldilocks’ procedure will generally result in a smaller,
flatter less-projected breast with a more modest aesthetic
outcome than could be expected from standard breast recon-
struction. Consequently patient expectations must be man-
aged by thorough preoperative counselling with clear
explanations of the likely outcomes as well as honest photo-
graphs. The Richardson and Ma paper is well illustrated with
a range of outcomes. The very honest illustrated paper from
Japan demonstrates why the technique is not suited to women
with small non-ptotic breasts.
32.14 Radiotherapy
A Goldilocks procedure is not breast conservation but a com-
bined mastectomy and reconstruction where the breast glan-
dular tissue has been removed using standard mastectomy
techniques. Consequently radiotherapy is only required if
(large, high-risk cancers, younger women, see 7 Chap. 41).
If postmastectomy RT is indicated, the new breast mound
should tolerate radiotherapy in a manner similar to a fatty
breast that has undergone conservation. Only five of the
Richardson/Ma breasts underwent RT so it is difficult to
draw any meaningful conclusions. However there is increas-
ing evidence that well-vascularised free DIEP flaps tolerate
RT well [17], so it is reasonable to assume this may also apply
to the Goldilocks well-vascularised pedicled dermal flaps.
32.15 Symmetrising Surgery
Women suitable for the Goldilocks procedure usually have
ptotic, generous breasts, so a unilateral therapeutic Goldilocks
procedure will result in significant asymmetry. This can be
managed with an external prosthesis in the bra, simultaneous
or delayed contralateral symmetrising reduction mammo-
plasty or a bilateral Goldilocks procedure. In the original
series of Richardson and Ma of the 32 women, 28 underwent
simultaneous procedures: 18 bilateral Goldilocks procedures
(the majority for bilateral breast cancer) and 10 reduction
mammoplasty.
32.16 Second-Stage Surgery
The objective of the Goldilocks procedure is to facilitate a one-
stage breast reconstruction in high-risk women who are not
good candidates for second-stage or repeat surgeries; however
further aesthetic enhancements such as nipple reconstruction,
fat transfer and scar and skin envelope adjustment may be
possible and reasonable if the patient is fit and willing. Implant
augmentation would need to be approached with caution but
in theory would be feasible.
 400 F. MacNeill
32.17 Postmastectomy Imaging
The new breast does not require imaging surveillance unless
significant amounts of breast tissue have been retained to
bulk out the flap – this is to be discouraged and may be tech-
nically challenging to interpret. Any new lumps must not be
assumed to be fat necrosis so must be treated as potential
cancer recurrence and investigated thoroughly with imaging
and biopsies if indicated.
32.18 Costs
This is a relatively simple procedure with minimal additional
costs above those of a mastectomy. Good patient selection
and meticulous surgery should minimise complication-­
associated costs. Symmetrising surgery, nipple reconstruc-
32 tion and other second-stage surgery may be required, but
this is likely to be less frequent than for women who undergo
standard reconstruction, especially implant-based recon-
struction.
32.19 Future
Breast reconstruction is now well embedded in patient-­
focused breast cancer literature, and the discussion is
expected by patients when mastectomy is required. Obesity
is increasing as are the numbers of women over 65 years.
This relatively simple autologous breast reconstruction
technique is potentially underutilised both for the higher-
risk women as described above and also in a wider group of
women currently offered implants and more complex
autologous procedures. The indications and costings need
refining.
32.20 Conclusion
The Goldilocks procedure is a relatively simple one-stage autol-
ogous reconstruction technique suitable for a highly selected
group of women otherwise not suited to breast reconstruction.
It can be challenging to achieve an acceptable cosmetic out-
come, and the risk of complications is potentially high.
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References
1. Hirsch HA, Kaser O, lkle FA. Atlas of gynaecological surgery: includ-
ing breast surgery and related urologic and intestinal surgical oper-
ations. 1st ed. Stuttgart: Theime Medical Publishers; 1960. p. 447.
2. Richardson H, Ma G.  The goldilocks mastectomy. Int J Surg.
2012;10:522e526.
3. Ogawa T. Goldilocks mastectomy for obese Japanese females with
breast ptosis. Asian J Surg. 2015;38:232e235.
4. Schwartz J-CD, Skowronski PP. Total single-stage autologous breast
reconstruction with free nipple grafts. PRS Global Open. 2016;3(12):
e587.
5. Opie I, Opie P. The classic fairy tales. Oxford: Oxford University Press;
(1992) [1974]. isbn:0-19-211559-6.
6. Thorek M. Possibilities in the reconstruction of the human form. NY
Med J. 1922;116:572.
7. Koger KE, Sunde D, Press BH, et  al. Reduction mammaplasty for
gigantomastia using inferiorly based pedicle and free nipple trans-
plantation. Ann Plast Surg. 1994;33:561–4.
8. Gorgu M, Ayhan M, Aytug Z, Aksungur E, Demirdover C. Maximizing
breast projection with combined free nipple graft reduction mam-
maplasty and back-folded dermaglandular inferior pedicle. Breast J.
2007;13(3):226–32.
9. Green M, Aspinall S, Kollias J.  Safety and efficacy of contra-lateral
breast reduction for women with mammary hypertrophy undergo-
ing mastectomy for breast cancer. Breast. 2009;18(5):276–8.
doi:10.1016/j.breast.2009.09.007. Epub 2009 Oct 21.
10. Nava MB, Cortinovis U, Ottolenghi J, Riggio E, Pennati A, Catanuto
G, Greco M, Rovere GQ. Skin-reducing mastectomy. Plast Reconstr
Surg 2006;118(3):603–10; discussion 611–3.
11. Goyal A, Wu JM, Chandran VP, Reed MWR.  Outcome after autolo-
gous dermal sling-assisted immediate breast reconstruction. Br J
Surg. 2011;98(9):1267–72.
12. Derderian CA, Karp NS, Choi M. Wise pattern breast reconstruction:
modification using alloderm and a vascularized dermal-­
subcutaneous pedicle. Ann Plast Surg. 2009;62:528e32.
13. Caputo GG, Marchetti A, Dalla Pozza E, Vigato E, Domenici L, Cigna
E, Governa M.  Skin-reduction breast reconstructions with Prepec-
toral implant Plast Reconstr Surg 2016;137(6):1702–5. doi: 10.1097/
PRS.0000000000002227. PMID:27219226.
14. http://ec.europa.eu/eurostat/statistics-explained/index.php/
Mortality_and_life_expectancy_statistics
15. Walton L, Ommen K, Audisio RA.  Breast reconstruction in elderly
women breast cancer: a review. Cancer Treat Rev. 2011;37:353e7.
16. Regnault P. Breast ptosis. Definition and treatment. Clin Plast Surg.
1976;3(2):193–203. PMID:1261176.
17. Taghizadeh R, Moustaki M, Harris S, Roblin P, Farhadi J.  Does post-­
mastectomy radiotherapy affect the outcome and prevalence of
complications in immediate DIEP breast reconstruction? A prospec-
tive cohort study. J Plast Reconstr Aesthet Surg. 2015;68(10):1379–85.
doi:10.1016/j.bjps.2015.06.003. Epub 2015 Jun 12. PMID:26210234.
18. Robertson SA, Rusby JE, Cutress RI. Determinants of optimal mas-
tectomy skin flap thickness. Br J Surg 2014;101(8):899-911. doi:
10.1002/bjs.9470. Epub 2014 Mar 24. Review. PMID: 2466461.
 401 33

Nipple Reconstruction
Valentina Lefemine and Kelvin F. Gomez

33.1 Introduction – 402

33.2 Indication for NAC Reconstruction – 402

33.3 Marking – 402

33.4 Local Flaps – 403

33.4.1 Skate Flaps – 403
33.4.2 Star Flap – 403
33.4.3 CV Flap – 403
33.4.4 S-Flap – 403
33.4.5 Local Flaps with Augmentation – 407
33.4.6 Nipple Sharing (Composite Nipple Graft) – 408

33.5 Areolar Reconstruction – 408

33.6 Alternative to NAC Reconstruction – 409

33.6.1 Prosthetics – 410
33.6.2 Temporary Nipple Tattoos – 410

References – 410

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_33

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 402 V. Lefemine and K.F. Gomez
Overview
5 Recreation of the nipple-areola complex is associated
with improved patient satisfaction and a better accep-
tance of body image.
5 Determining the new NAC position can be challenging,
and nipple reconstruction can potentially emphasize the
asymmetry between the breasts.
5 There are a multitude of surgical techniques for nipple-
areola complex reconstruction with no significant differ-
ence in either overall outcomes or complication rates.
5 There are now several alternatives to nipple reconstruc-
tion including nipple-areolar prostheses, temporary nip-
ple tattoos and 3D tattoos.
33.1 Introduction
The gradual acceptance of skin-sparing mastectomy as an
oncologically safe procedure in an ever-growing group of
patients has transformed the surgical management of breast
33 cancer [1]. A nipple-sparing mastectomy (NSM) should be
regarded as the most extreme form of a skin-sparing mastec-
tomy [2, 3]. There are no absolute criteria to govern patient
selection, and indications for NSM are constantly expanding
[4–6]. Factors that pose an increased risk of occult nipple
involvement are larger tumour size, multicentricity, shorter
tumour to nipple distance (1.5–2.5 cm are variably quoted as
appropriate), an extensive in situ component, lymphovascu-
lar invasion and axillary lymph node involvement [7]. There
is emerging evidence that [8, 9] a negative retroareolar
biopsy at the time of surgery is the most important marker of
oncological safety. Other strategies include intraoperative
frozen section, which is not always reliable [10]. Absolute
contraindications to nipple preservation include direct
tumour extension into the nipple clinically or on imaging,
Paget’s disease of the nipple and inflammatory breast cancer.
In some instances, nipple preservation is technically difficult
in the presence of large ptotic breasts, in women who have
had previous breast reduction surgery and in women for
whom there is a high risk of nipple necrosis after surgery
(smokers, diabetics, arteriopaths, obesity). In addition, some
mastectomy scar patterns are associated with a higher risk
than others [11].
Whilst differing units may vary in how their patients are
selected for NSM, these decisions should be made within a
multidisciplinary forum after review of risk factors. These
issues are discussed more fully in chapter (7 Chap. 17).
 
33.2 Indication for NAC Reconstruction
Nipple reconstruction represents the final leg of the patient
journey; it is the «finishing touch» that will make a breast out
of the mound that has been created. There is evidence [12]
that recreation of the NAC is associated with improved
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patient satisfaction and a better acceptance of body image.
Indications for NAC reconstruction include patients post-
mastectomy with breast reconstruction and patients who
have undergone oncoplastic breast conserving surgery (e.g.
therapeutic mammoplasty or central excision) where the
NAC has had to be sacrificed for oncological reasons or has
been lost due to postoperative complications and congenital
or developmental abnormalities such as athelia or amastia
and post-traumatic deformities.
Judicious patient selection is by far the most important
consideration when deciding how to proceed with a NAC
reconstruction. The site, size, shape and colour of the native
NAC, the type of underlying breast reconstruction, the
planned adjuvant or neoadjuvant treatment modalities and
all previous scars have to be taken into consideration. It is
indeed useful to note that poorly located scars can prohibit
the use of certain flap techniques due to potential disruption
of the blood supply.
Timing of the NAC reconstruction is a crucial factor in
determining the final aesthetic result. Nipple-areolar recon-
struction can be performed at the same time as the breast
reconstruction but should ideally be postponed for
3–6 months until after the final reconstructive operation, to
allow the reconstructed breast to settle into its final shape
and position. An operation performed too early may result in
asymmetric placement of the neo-nipple.
33.3 Marking
Determining the new NAC position can be challenging. The
ideal position should create an equilateral triangle with the
sternal notch and the contralateral nipple, and this rule
should be followed if the nipple-inframammary fold distance
is similar between the breasts. However, this is not always the
case and ultimately the patient might have to choose whether
the new nipple is placed in a position which is right for the
shape and volume of the reconstructed breast but potentially
asymmetrical or placed eccentrically on the reconstructed
breast but to match the NAC position on the contralateral
side. Most patients will prefer the former [13], in which case
the neo-nipple should be placed at the point of maximum
convexity and projection on the breast mound. It is essential
that the nipple position is checked by the patient, in front of
a mirror. The use of a round adhesive label to help the patients
visualize the new nipple may be helpful in deciding on the
optimal position.
Nipple reconstruction can potentially emphasize the
asymmetry between breasts in women with a unilateral
breast reconstruction. In the natural contralateral breast, the
NAC position will most likely change with time, whilst the
reconstructed breast tends to be less mobile and generally
resistant to the change of shape due to ageing. Good sym-
metry might not last long, and the patient needs to be aware
of this.
Nipple Reconstruction
33.4 Local Flaps
Numerous surgical techniques for NAC reconstruction have
been developed over many years. Good long-term projec-
tion is an ongoing challenge for the surgeon. The neo-nipple
projection is dependent on the thickness of the dermis as
well as the quantity and quality of subcutaneous tissue avail-
able for harvesting. Therefore, the thick dermis of a latissi-
mus dorsi flap will serve the purpose much better than a
thin, stretched skin flap overlying an implant-based recon-
struction. Regardless of the method of skin flap used, loss of
projection of the reconstructed nipple should always be
anticipated. It has been suggested [14] that an overcorrec-
tion of between 25% and 50% of the final desired result
should be built in to planning the procedure.
Central or island-based flaps have not survived the test
of time and have been largely abandoned [15] due to poor
cosmetic outcomes. Subdermal flaps are currently the most
utilised method. There are a multitude of flap designs
reported in the literature with no significant difference in
either overall outcomes or complication rates. We describe
some of the most commonly used flaps below; there are
numerous other flap designs which are nicely reviewed by
Sisti and colleagues [16].
33.4.1 Skate Flaps
Skate flaps were amongst the first techniques described. In its
original design, the large donor site required a skin graft for
the areola reconstruction, whilst subsequent modifications
allowed for primary closure of the donor site. Skate flaps
(. Fig. 33.1) should be considered in patients with an autolo-
gous breast reconstruction, whereas in an implant recon-
struction there might be not enough subcutaneous tissue or
skin laxity to allow this design.
Once the position of the neo-nipple is established, the
flap is sketched with a width three times the diameter of the
contralateral nipple and twice its height.
The wings of the skate are harvested as a partial thick-
ness flap, whilst the central part of the flap is elevated to
include subcutaneous tissue which will ensure both good
vascularization to the flap and provide bulk to the neo-
nipple.
The lateral edges of the wings are then sutured together
and wrapped around the belly of the composite part of the
flap. When the donor site is being closed primarily, care
must be taken not to apply any tension to the closure as
this will result in late loss of nipple projection and flatten
the breast at this site. If primary closure cannot be achieved
without tension, it should not be forced, but instead a
small full thickness skin graft is used to cover the exposed
dermis.
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403 33
33.4.2 Star Flap
The star flap (. Fig. 33.2), designed by Anton and Hartrampf
[17], is a modification of the skate flap. Three arms are drawn
from the base of the flap at 90° from each other to resemble a
star. The arms are raised as a full thickness flap towards the
base with some subcutaneous tissue to preserve the blood
supply. The central vascular core is left intact, and the lateral
arms are wrapped around the central core to create the lateral
walls of the nipple and provide its projection. Finally, the cen-
tral arm is used as a covering cap. The donor site is closed
primarily without tension preferably using absorbable sutures.
33.4.3 CV Flap
The C-V flap (. Fig. 33.3), which evolved from the skate flap,
consists of a central C flap and two lateral V flaps. The flap is
drawn around the chosen site for the new nipple. The base of
the V flaps provides the projection of the neo-nipple, whilst
the width of the C flap will be equivalent to the final nipple
diameter. As the flap is elevated, care must be taken not to
divide the base of the C flap as this will impair the blood sup-
ply to the whole flap. The V flaps and the distal end of the C
flap should include the subdermal vascular plexus and some
fatty tissue but are left rather thin, whilst more subcutaneous
tissue is left centrally to create the bulk of the nipple.
The donor sites of the V flaps are then closed primarily. This
will allow the donor site of the C flap to close in and provide a
semicircular edge where the new nipple will be sutured into.
The V flaps are then overlapped onto each other whilst
the C flap provides the covering cap.
Good results are obtained with 4/0 monofilament absorb-
able sutures to create these flaps and 3/0 absorbable sutures
for the closure of the V flap donor sites (. Fig. 33.7a).
Several minor modifications to this technique are
described in the literature, a common one being a fish tail
flap where the two lateral flaps are more angulated rather
than being diametrically opposite to each other.
33.4.4 S-Flap
In cases where the ideal new nipple position lies within the
site of a scar, S-flaps (. Fig.  33.4) have proved very useful.
Two equal-sized flaps with opposing bases are drawn at each
side of the scar. The length and base widths of the flaps will
determine both the diameter and projection of the nipple.
The flaps are then elevated with some subcutaneous tissue
and the tips of each flap opposed and sutured together. The
donor sites are then closed primarily. In Cronin’s original
description [18], a full thickness skin graft was used to cover
both the neo-nipple and areola; however the advent of tattoo-
ing has made this requirement obsolete.
 404 V. Lefemine and K.F. Gomez

Skate flap marking and raising

a b

A
B
Body
Wing Wing

33
Skin marking Flap elevation

c d

A B

Suture joining A to B to C Primary closure of donor site

..      Fig. 33.1  a Skate flap marking up. b Flap raising: the bilateral which is at the margin of the dermal defect where the base of the
dermal wings are thin peripherally and thicker at the base; the central nipple will fall. d The wings of the skate are sutured together around
body of the flap includes a substantial amount of soft tissue. c The tips the central belly of the flap. Primary closure of donor sites
A and B of the wings are brought together and sutured to point C,

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Nipple Reconstruction
405 33
Star flap marking and raising

a b

Skin marking Flap elevation

c d

Lateral arms sutured together Central arm is covering cap

..      Fig. 33.2  a Star flap marking up. b The three arms of the star are core and sutured together. d The central arm is used as covering cap.
raised full thickness towards the base; the central part has substantial Primary closure of donor sites
subcutaneous tissue. c The lateral arms are wrapped around the central

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 406 V. Lefemine and K.F. Gomez

C-V flap marking and raising

a b

A C

Marking Raising of the flap

33
c d

B
B
C
C
A
A

D
D

A + C overlapped Lateral donor sites closed.

Lower edge of A will close onto D

e
B

B sutured as covering cap

..      Fig. 33.3  a C-V flap marking up. b Elevation of the flap: lateral arms overlapped and sutured together. d Primary closure of the donor site will
and distal central arm left thin; more subcutaneous tissue is raised make D to close in to provide the base of the new nipple. Lower border
centrally to create the bulk of the nipple. c Lateral arms A and C of A is sutured to the donor site D. e B is sutured in as covering cap

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Nipple Reconstruction
407 33

S flap marking and raising

a b

A A
B
Scar
B

Flap marking – cut along Join A to B

marking

Close donor site

primarily

..      Fig. 33.4  a S flap marking and elevation. b Flaps A and B sutured together to form the new nipple. c Primary closure of donor site

33.4.5 Local Flaps with Augmentation
Surgeons have always battled to recreate a nipple that will
continue to keep its shape and projection with time. At the
time of surgery, the nipple can be augmented by inserting
within the flap autologous, allogeneic or synthetic filler mate-
rials – alone or in combination. There is no strong evidence
to support one type of filler over another [19]. Recognized
autologous grafts include auricular or costal cartilages, bone,
fat and dermal grafts. The use of synthetic materials (e.g. sili-
cone, polyurethane, polytetrafluoroethylene) poses the risk
of foreign body reactions, migration and possibly extrusion
[20] but allow for sustained nipple projection.
Acellular dermal matrices have been reported [21] to pro-
vide good long-term nipple projection with low rates of com-
plications but do impose a significant financial burden. The
patient’s own dermis may also be used as an internal de-­
epithelialised graft.

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 408 V. Lefemine and K.F. Gomez

33.4.6  ipple Sharing (Composite Nipple

N a
Contralateral nipple sharing
Graft) Distal graft from donor nipple

The contralateral nipple is the obvious choice for a donor site Composite
as it provides a perfect match in terms of colour and texture graft
but has the major disadvantage of interfering with a perfectly Donor
normal contralateral nipple. Composite nipple grafts are nipple
indicated in women who have large, projecting nipples and
would welcome a nipple reduction. It can also be used in
patients whose breast reconstruction is obtained by tissue
expansion, meaning that there is very little skin laxity and
subcutaneous tissue left to recreate a nipple of adequate size
and projection. Excision of graft
Patients who do not fit either of these criteria tend to be
reluctant to sacrifice a well-formed and functioning nipple,
b
especially when considering the potential side effects such as
scarring, chronic pain, loss of sensation and partial loss of
the lactiferous ducts which might result in breast-feeding
impairment.
If the projection of the donor nipple is larger than its
33 diameter, the use of the lower half (. Fig. 33.5) of the nipple
 
Needle
as the graft is optimal. The inferior edge of the donor site is
then folded and sutured onto the areola. Alternatively, the
composite graft can be taken from the distal part (. Fig. 33.6)  

Contralateral nipple sharing

Inferior graft from donor nipple
Donor site closed with purse
a string or interrupted stiches

Composite Donor ..      Fig. 33.6  a Distal half of the nipple used as composite graft. b The
graft nipple donor site is closed with a purse string or interrupted stiches

of the donor nipple which is then closed with either a purse-­

string suture or by simply opposing the edges.
The recipient site of the neo-nipple is de-epithelialised
with a size 15 blade and the graft sutured in place with either
continuous or interrupted 4.0 monofilament absorbable
Excision of graft
sutures.
The graft dressing should be left undisturbed for 5–7 days
b to allow it to revascularise and adhere.

33.5 Areolar Reconstruction

Current areola reconstruction techniques range from simple

Remaining donor nipple turned
down and sutured
..      Fig. 33.5  a Lower half of the nipple used as composite graft. b The
donor nipple is folded inferiorly and sutured to the areola
areolar tattooing to more complex skin grafting procedures
or a combination of both. In the past, reconstruction of the
areola almost always involved skin grafts from various body
sites that were selected on the basis of pigmentation. The
most common donor sites were the labia minora or majora,
inguinoperineal skin, upper inner thigh and retroauricular
area. Skin graft can be harvested from non-specific area such
as skin folds from mastectomy and abdominal scars, albeit
nonpigmented.

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Nipple Reconstruction
a b
..      Fig. 33.7  a Nipple reconstruction with C-V flap. b Nipple prosthesis. c Trays of nipple prostheses showing available colours. d 3D nipple-
areolar tattoo (Courtesy of Maria Jones, Advanced nurse practitioner, Royal Glamorgan Hospital)
Areolar grafting is now largely obsolete due to the dra-
matic recent improvement and wider availability of tattooing
techniques.
Intradermal tattooing may be used as an adjunct to any
NAC reconstruction technique and can be performed before
or after surgical reconstruction depending on the surgeon’s
preference. Post-nipple reconstruction tattooing helps to
correct discrepancies in size, shape and colour and helps
achieve the best possible match with the contralateral NAC.
NAC tattooing is relatively cheap, does not require a
general anaesthesia and has a low complication rate [22] in
terms of allergic reactions or infections but has the disad-
vantage of fading with time and requiring occasional reap-
plication. A mirror image of the existing areola is drawn on
the reconstructed side and the pigment colour chosen to
match the contralateral side. It is desirable to involve the
patient in the choice of colour prior to tattooing. A brush of
colour close to the existing nipple can help in the selection
of the appropriate pigment. The procedure is performed in
a sterile setting. The area to be tattooed is infiltrated with a
mixture of local anaesthetic and epinephrine to minimize
bleeding and a size 4–6 needle brush used to embed the
pigment. Several passes are usually required with regular
wiping off of the excess surface pigment after each pass for
better appreciation of the depth of embedded colour. Care
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409 33
must be taken not to place the pigment too superficially as
this will result in pigment extrusion and sloughing or force
it too deeply which will result in macrophage processing
and removal, with early pigment fading. The colour of the
neo-areola at the end of the procedure must be noticeably
darker than the contralateral areola to account for the inev-
itable loss of pigment over time. The advent of three-
dimensional (3-D) tattooing has created a very valid
alternative to surgical nipple-areola reconstruction. 3-D
tattoos recreate the impression of depth on a two-­
dimensional surface [23] allowing for superb cosmetic
results (. Fig.  33.7d), arguably as good, if not better than
the surgical methods described.
There is also increasing interest in more artistic tattoos
over the breasts in lieu of a formal nipple tattoo (. Fig. 33.8).
Many of these are extremely attractive and popular with some
women.
33.6 Alternative to NAC Reconstruction
There are now several alternatives to nipple reconstruction
which might be preferable for the patient who does not wish
to endure any more surgery or who is worried about develop-
ing future asymmetry.
 410 V. Lefemine and K.F. Gomez
..      Fig. 33.8  Bilateral reduction pattern mastectomy and reconstruc-
tion for risk reduction with artistic breast and nipple tattoos
33.6.1 Prosthetics
10. Petit JY, Veronesi U, Orecchia R, Rey P, Martella S, Didier F, et al. Nip-
Ready-made nipple-areolar prostheses (. Fig.  33.7b) have
 
been around for some 20 years, come in a variety of shades
33 and sizes (. Fig. 33.7c) and have a high patient satisfaction
rate [24]. Custom-made prostheses are also available. They
are created on the impression of the natural nipple and,
although more expensive, give a perfect match with the con-
tralateral NAC. The silicone-based material used for mod-
ern nipple prostheses is extremely realistic in simulating soft
tissue.
The prosthesis is attached to the breast with a medical
adhesive which is waterproof and strong enough for most
day-to-day activities. Once attached, the prosthesis can stay
in place for up to 3 months. Nipple prostheses, if well looked
after, have a lifespan of between 2 and 3 years.
33.6.2 Temporary Nipple Tattoos
Temporary nipple tattoos or NAC transfers have become
more popular recently. There is a variety of affordable, ready-­
made tattoos that can also be customised for a higher price.
The tattoo transfer is applied directly onto the skin and then
dampened to allow the pattern to be imprinted. These tem-
porary tattoos usually last for about a week or two and can be
easily removed by rubbing them with alcohol. Some patients
will use them as a temporary measure whilst awaiting a for-
mal NAC reconstruction or definitive tattooing, whilst others
prefer them as a long-term option to avoid the constraints of
more definitive techniques.
References
1. Carlson GW.  Technical advances in skin sparing mastectomy. Int J
Surg Oncol. 2011;2011:Article ID 396901:7 p. doi:10.1155/2011/396901.
2. Cunnick GH, Mokbel K.  Skin-sparing mastectomy. Am J Surg.
2004;188(1):78–84.
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3. Wijayanayagam A, Kumar AS, Foster RD, Esserman LJ.  Optimizing
the total skin-sparing mastectomy. Arch Surg. 2008;143(1):38–45.
4. De La Cruz L, Moody AM, Tappy EE, Blankenship SA, Hecht EM. Over-
all survival, disease-free survival, local recurrence, and nipple-areo-
lar recurrence in the setting of nipple-sparing mastectomy: a
meta-analysis and systematic review. Ann Surg Oncol.
2015;22:3241–9.
5. Krajewski AC, Boughey JC, Degnim AC, et al. Expanded indications
and improved outcomes for nipple-sparing mastectomy over time.
Ann Surg Oncol. 2015;22:3317–23.
6. Huang NS, Wu J. Nipple-sparing mastectomy in breast cancer: from
an oncologic safety perspective. Chin Med J. 2015;128:2256–61.
7. Vyas JJ, Chinoy RF, Vaidya JS.  Prediction of nipple and areola
involvement in breast cancer. Eur J Surg Oncol. 1998;24:15–6.
8. Adam H, Bygdeson M, de Boniface J. The oncological safety of nip-
ple-sparing mastectomy – a Swedish matched cohort study. Eur J
Surg Oncol. 2014;40(10):1209–15.
9. Ryu JM, Nam SJ, Kim SW, Lee SK, Bae SY, Yi HW. At all. feasibility of
nipple-sparing mastectomy with immediate breast reconstruction
in breast cancer patients with tumor-nipple distance less than
2.0 cm. World J Surg. 2016;40(8):2028–35.
ple sparing mastectomy with nipple areola intraoperative radio-
therapy: one thousand and one cases of a five years experience at
the European institute of oncology of Milan (EIO). Breast Cancer Res
Treat. 2009;117(2):333–8.
11. Endara M, Chen D, Verma K, Nahabedian MY, Spear SL. Breast recon-
struction following nipple-sparing mastectomy: a systematic
review of the literature with pooled analysis. Plast Reconstr Surg.
2013;132(5):1043–54.
12. Momoh AO, Colakoglu S, de Blacam C, Yueh JH, Lin SJ, Tobias AM,
et al. The impact of nipple reconstruction on patient satisfaction in
breast reconstruction. Ann Plast Surg. 2012;69(4):389–93.
13. Bostwick J, Jones G.  Nipple-areolar reconstruction. In: Bostwick’s
plastic & reconstructive breast surgery, vol. 2. 3rd ed. St. Louis: Qual-
ity Medical Pub; 2010. p. 1664–5. 2.
14. Nimboriboonporn A, Chuthapisith S. Nipple-areola complex recon-
struction. Gland Surg. 2014;3:35–42.
15. Spear SL.  Nipple-areola reconstruction. In: Surgery of the breast:
principles and art, vol. 1. 2nd ed. Philadelphia: Lippincott Williams &
Wilkins; 2006. p. 894. 1.
16. Sisti A, Grimaldi L, Tassinari J, Cuomo R, Fortezza L, Bocchiotti MA,
et al. Nipple-areola complex reconstruction techniques: a literature
review. Eur J Surg Oncol. 2016;42(4):441–65.
17. Anton LE, Hartrampf CR. Nipple reconstruction with local flaps: star
and wrap flaps. Perspect Plast Surg. 1991;5(1):67–78.
18. Cronin ED, Humphreys DH, Ruiz-Razura A.  Nipple reconstruction:
the S flap. Plast Reconstr Surg. 1988;81:783–7.
19. Winocour S, Saksena A, Oh C, Wu PS, Laungani A, Baltzer H, Saint-­
Cyr M.  A systematic review of comparison of autologous, alloge-
neic, and synthetic augmentation grafts in nipple reconstruction.
Plast Reconstr Surg. 2016;137(1):14e–23e.
20. Jankau J, Jaskiewicz J, Ankiewicz A. A new method for using a sili-
cone rod for permanent nipple projection after breast reconstruc-
tion procedures. Breast. 2011;20:124–8.
21. Hwang K, Hwang JH, Park JH, Kim DJ, Shin YH. Experimental study
of autologous cartilage, acellular cadaveric dermis, lyophilized
bovine pericardium, and irradiated bovine tendon: applicability to
nasal tip plasty. J Craniofac Surg. 2007;18:551–8.
22. Becker H.  Nipple-areola reconstruction using intradermal tattoo.
Plast Reconstr Surg. 1988;81:450–3.
23. Halvorson EG, Cormican M, West ME, Myers V. Three-dimensional
nipple-areola tattooing: a new technique with superior results.
Plast Reconstr Surg. 2014;133:1073–5.
24. Janes S.  Custom-made nipple prosthesis: a long-term satisfaction
survey. J Can Res Ther. 2005;1:111–3.
 411 34

Complications of Breast
Surgery and Their Management
Michalis Kontos and Christos Markopoulos

34.1 Introduction – 412

34.2 Bleeding and Haematoma – 413

34.3 Surgical Infections – 414

34.4 Neuropathic Pain and Muscle Weakness

Due to Nerve Damage – 414

34.5 Seroma – 416

34.6 Cording and Range of Movement of the Shoulder – 416

34.7 Delayed Wound Healing and Wound Dehiscence – 417

34.8 Lymphoedema of the Breast and Associated Infections – 418

34.9 Necrosis of Mastectomy Skin Flaps, Oncoplastic Conserving

Surgery Flaps and Necrosis of the Nipple – 418

34.10 Surgical Complications Associated with Breast

Reconstruction – 419

34.11 Deep Vein Thrombosis (DVT) and Pulmonary

Embolism (PE) – 419

34.12 Allergy and Reaction to Medications – 420

34.13 Conclusion – 420

References – 420

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_34

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 412 M. Kontos and C. Markopoulos

Key Points
55 Breast surgery-specific complications can
compromise quality of life, increase costs and
delay administration of adjuvant treatment.
55 They are related to the division of blood vessels,
nerves and lymphatics.
55 Seroma formation is the most common complica-
tion of breast surgery.
55 Most severe complications of axillary surgery are
arm lymphoedema, compromise of shoulder
movement and neuropathic pain.
55 Age, obesity, smoking, diabetes and other severe
comorbidities are the most significant risk factors
for the majority of complications.
55 When oncoplastic techniques are involved,
complications may also include ischaemia and
necrosis of the flaps or the nipple.
55 Deep vein thrombosis, pulmonary embolism and
reaction to medications are the most severe
general complications which may rarely happen
in breast cancer surgery.
34
..      Fig. 34.1  Affected range of motion of right shoulder after full
34.1 Introduction axillary clearance

Complications of breast surgery are very rarely life-threaten-
ing but can significantly compromise quality of life, and, in
regard to breast cancer patients, they can delay administra-
tion of adjuvant treatment with potentially detrimental
effects on survival. These patients might require longer hos-
pitalisation, repeat surgery, more clinic visits and dressing
changes and have an adverse psychological impact.
Complications are usually the result of the following:
1. Division or injury of vessels providing blood supply either
to the tissues neighbouring the surgical area or to tissues
that are used as flaps for reconstruction. Therefore, the
creation of dermal flaps, as, for example, in skin sparing
mastectomy, may result in a compromise in their blood
supply, especially if flaps are long and thin. This is also
the case with the raising of cutaneous (dermal), myocu-
taneous or other types of flaps from neighbouring or
3. Disruption of lymphatics. Lymphoedema of the ipsilateral
arm or breast is a well-recognised complication of
axillary surgery and is caused by disruption of lymphatic
flow from the arm or breast and may also be caused or
worsened by radiotherapy to the breast or axilla.
4. Contamination with skin flora. Although breast surgical
procedures are regarded as «clean», infections can occur,
usually due to the proximity of the surgical field to the
skin, the surgical handling of the tissues, the use of tissue
flaps and artificial implants for reconstruction and the
high fat content (a fragile and poorly vascularised tissue)
of the mammary gland.
5. Formation of scar tissue in surgical cavities or unsightly
skin scars. Formation of connective tissue in the axillary
cavity after complete clearance can contribute to
impaired shoulder mobility (. Fig. 34.1). Poor-quality

distant areas, as, for example, in latissimus dorsi skin suturing, delayed wound healing and dehiscence
reconstruction or therapeutic mammaplasties. A typical may also cause ugly scars.
complication secondary to compromised blood supply is 6. Accumulation of «tissue fluid» in the surgical cavity
nipple necrosis, sometimes seen after nipple sparing (seroma). It is not entirely clear whether seroma is a
mastectomy or therapeutic mammaplasty. result of lymphatic leakage or of tissue exudate, due to
2. Division of nerves. Some nerve damage might inevitably surgical trauma or both [1].
be expected in breast and axillary surgery, for example,
the sacrifice of intercostal brachial nerves (which are the Factors associated with an increased risk of postoperative
cutaneous branches of the intercostal nerves running complications include:
across the axillary cavity mediolaterally) during full 55 Age
axillary clearance. There are, however, specific nerves 55 Obesity
which must be spared, as their damage leads to severe 55 Smoking
chronic sequelae, for example, «winging of the scapula» 55 Excessive use of alcohol or recreational drugs
after damage to the long thoracic nerve of Bell. 55 Diabetes

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Complications of Breast Surgery and Their Management
..      Table 34.1  The Clavien-Dindo simplified classification of
surgical complications
Grade I Any deviation from the normal postoperative
course that can be treated with simple medications
(antiemetics, antipyretics, analgesics, electrolytes,
physiotherapy)
Grade II Requiring pharmacological treatment other than
the above and/or blood transfusion
Grade III Requiring surgical intervention
Grade IV Life-threatening complications with organ dysfunc-
tion and/or need for ICU management
Grade V Death
55 Chronic renal failure or chronic obstructive pulmonary
disease
55 Atherosclerosis and cardio-vascular disease
55 Autoimmune and connective tissue disorders
55 Preoperative chemotherapy
55 History of irradiation to the chest wall
55 Previous surgical procedures on the breast
Breast surgery complications may vary in severity, from
severe to mild. Life-threatening complications are very rare.
Seroma, infections requiring antibiotic treatment only, par-
tial flap or nipple necrosis, limited bleeding and delayed
wound healing are classified as mild. Severe complications
are those requiring hospitalisation, repeat surgery, blood
transfusion, total or extensive flap or nipple necrosis and
implant removal.
As with all surgical complications, classification of sever-
ity is helpful for undertaking high-quality audits and research.
A number of such systems are in use. The most popular is the
Clavien-Dindo system, which is very simple to use and mod-
ifiable for any complication or disease site (. Table 34.1) [2].
 
More complex is the Common Terminology Criteria for
Adverse Events (CTCAE, V 4.0) system which is much more
research specific but requires reference to specific criteria for
each complication and is not as easy to use [3].
34.2 Bleeding and Haematoma
The breast has a rich network of small arteries. Usually these
arteries are branches of the internal mammary artery, the
intercostal arteries, the lateral thoracic artery and the thora-
coacromial artery. Some of these vessels can be missed dur-
ing the stage of haemostasis as they tend to retract inside the
bulk of the pectoralis major muscle and may cause significant
postoperative bleeding. Furthermore, the tributaries of the
axillary vein require special attention during axillary node
clearance, as failure to identify and ligate these may result in
significant bleeding as well as further injury to the vein dur-
ing attempts to achieve haemostasis. Finally, in cases of pre-
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413 34
operative chemotherapy, the involved and previously matted
axillary lymph nodes tend to regress and can mislead the
surgeon into believing that planes along vessels have been
maintained; thus in the effort to dissect them, it is possible to
cause injury to the axillary vein or other large vessels.
The frequency of postoperative bleeding is difficult to
estimate, as small haematomas of minimal clinical signifi-
cance are common. In contrast, significant haemorrhage and
large, expanding haematomas which require blood transfu-
sion and/or surgical intervention are unusual. The incidence
of haematoma after breast surgery without reconstruction is
reported to be between 2% and 10%. It is possible that more
complex procedures that involve reconstruction or interven-
tion to the contralateral breast have a higher risk of bleeding
[4, 5]. The early use of a good quality brassiere, which applies
mild but steady pressure to the breast, may reduce this risk in
cases of conservation. Areas that can also bleed are the donor
areas of the back (latissimus dorsi (LD)) or the lower abdo-
men (transverse rectus abdominis myocutaneous (TRAM)
and deep inferior epigastric flaps (DIEP)) when reconstruc-
tion with autologous tissues has been carried out [5, 6]. If a
submuscular implant is used, the vessels between the chest
wall and pectoralis major muscle also need attention.
Anticoagulant therapies are associated with an increased
risk of postoperative haemorrhage and must be managed
appropriately. Non-steroidal anti-inflammatory drugs
(NSAIDs) are associated with a slightly increased risk of
postoperative bleeding, and it is advisable (but not essential)
that they are discontinued a week before complex proce-
dures. The risk with most NSAIDs is not great; however more
recent agents inhibiting platelet function such as clopidogrel
do carry a greater risk, and discontinuation is strongly
advised before routine surgery. Warfarin must likewise be
discontinued prior to surgery to allow the internationally
normalise ratio (INR) to fall to 1.5 or less. Depending on the
indication for warfarin, a bridging anticoagulant protocol to
cover the perioperative period may be required. Low molec-
ular weight heparin (LMWH) for the prevention or treat-
ment of deep vein thrombosis (DVT) or atrial fibrillation
complications may increase the risk of bleeding, especially if
given at therapeutic rather than prophylactic doses and again
should be stopped before surgery. It is worth mentioning
that, although considerable blood loss into the drain may
occur, drains often fail to drain haemorrhage due to clot for-
mation in the surgical cavity or within their lumen. In these
cases extensive bruising and oedema of the breast or chest
wall are usually visible [7, 8].
Reoperation is indicated in cases of large, expanding hae-
matomas – especially when painful or at risk of causing wound
dehiscence – or where hypotensive shock is present (rare) or
blood transfusion is required. Often there is no visible bleeding
vessel and haematoma evacuation is adequate; however, it is
wise to ensure normotensive anaesthesia before closure in case
the bleeding vessel is pressure sensitive. Meticulous washing
and haemostasis facilitate healing, improve cosmesis, reduce
postoperative pain and prevent delay of adjuvant treatment.
 414 M. Kontos and C. Markopoulos
The decision to reoperate to control bleeding must be taken
earlier if reconstruction has taken place, as haematomas can
affect the blood supply to vascular pedicles or increase the risk
of infection.
34.3 Surgical Infections
These are usually caused by skin flora, most commonly
Staphylococcus. The incidence varies among studies from 10%
to 20% [9, 10]. Autologous or silicone implant-based recon-
structions do not seem to be associated with higher rates of
infection, but the consequences are considerably more sig-
nificant. The use of acellular dermal matrices for reconstruc-
tion is however associated with a higher infection risk [11].
Risk factors for infections include age, obesity, diabetes,
smoking and recent chemotherapy. Hypertension, ASA score
3 or 4, a history of previous breast surgery, haematoma and
lengthy or bilateral procedures have also been reported to
increase the risk [12–14].
Radiotherapy given after silicone implant-based recon-
struction increases the risk of infection (as well as the risk of
34 other local complications such as skin necrosis, wound
dehiscence and capsule contracture) significantly and inde-
pendently of other risk factors (. Fig. 34.2) [15–18].
 
Surgical infections may be prevented with antibiotic pro-
phylaxis, simple penicillins or cephalosporins are often used
but gentamycin may also be added when reconstruction is
taking place. Some surgeons prefer to administer antibiotic
prophylaxis even in the absence of risk factors, by giving a
single dose intraoperatively or covering for 24  h. Notably,
antibiotics have not been proven to be more effective if given
for more than 2 days [14, 19].
Treatment of surgical infections must be given in a timely
manner to prevent delay to adjuvant therapies. Simple cellu-
litis is treated with antibiotics against skin flora on an outpa-
tient basis. Infective collections should be drained surgically
by inserting a drain in the cavity through which lavage can be
..      Fig. 34.2  Inflammation and wound break down after mastectomy
with immediate silicon based reconstruction followed by radiotherapy
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..      Fig. 34.3  Bacterial infection after delayed breast reconstruction
presenting with erythema and local sensitivity. The implant was
removed
done. Small abscesses after conservation surgery may be
treated with needle aspirations that may have to be repeated
several times; in this way, reoperation is avoided but recovery
may be slightly delayed.
Infections related to silicone implants or tissue expanders
are much more difficult to treat. If the implant comes into
contact with infected material, its removal may be the only
option (. Fig. 34.3). Needless to say that any other artificial
materials used for the reconstruction may have to be removed
too (ADMs and meshes). Meticulous wash out and use of
drains for a few days are also mandatory. Rates of implant
loss due to infection vary in published literature between 0%
and 2% [20, 21]. Repeated attempts for reconstruction should
then be delayed until all infection has been effectively treated
and scarring has matured (a few months). In such cases,
reimplantation is associated with a high rate of further infec-
tion of up to 50%, and a flap-based, fully autologous tech-
nique may be safer. Recently there have been reports of
implant-based reconstruction salvage after cavity wash out,
implant exchange and antibiotic use. Implant salvage rates
can exceed 50% in these series and depends mainly on the
severity of the infection [22–24].
34.4  europathic Pain and Muscle
N
Weakness Due to Nerve Damage
A percentage of patients who undergo breast surgery will
develop persistent chronic postoperative pain. This may occur
after any surgical procedure to varying degrees, but breast
surgery seems to be one of the most common causes with an
incidence of up to 60%. It may affect the breast, the chest wall
and the arm, especially its upper inner surface. The pain can
feel like burning, cold or paraesthesia and may be associated
with a trigger point, but there may be no other symptoms or
signs indicative of a problem. The pain can occasionally be
severe and necessitate treatment with serotonin reuptake
Complications of Breast Surgery and Their Management
inhibitors such as pregabalin or gabapentin. Common anal-
gesics are not usually very effective. Some improvement may
be gained by low-dose antidepressant therapy such as ami-
tryptyline. In cases where there is a definite trigger point,
focal injection with local anaesthetic and steroids may help.
Risk factors for neuropathic pain are young age, breast con-
servation, radiotherapy, chemotherapy, depression and axil-
lary surgery, especially full axillary clearance [25, 26].
Dysaesthesia and/or paraesthesia can also affect the sur-
gical area due to damage to sensory nerves. Specifically,
injury to the intercostal brachial nerves, which run across the
axillary cavity from medial to lateral, will result in persistent
paraesthesia along the upper inner surface of the arm. Efforts
to save these nerves during surgery are often ineffective or
even cause worse symptoms, probably due to their inevitable
injury or devascularisation [27].
Paraesthesia of the nipple is common, especially after
procedures which involve significant undermining of the
nipple-areola complex. The symptom tends to improve with
time, but impaired sensitivity is not uncommon and patients
should be warned in advance. Thus, nipple numbness persists
in 35% of patients 2 years after an inverted-T breast reduction
and in 21.5% after inferior pedicle procedures [28, 29]. For
415 34
Similarly, sacrifice of the medial and lateral pectoral
nerves, which innervate the pectoralis muscles, results in
muscle weakness and atrophy. These nerves can be injured
during insertion of submuscular implants or an intermuscu-
lar approach to the apical axillary nodes.
The most significant nerve to injure during axillary proce-
dures is undoubtedly the long thoracic nerve (of Bell). This
nerve arises from the anterior rami of the fifth, sixth and sev-
enth cervical nerves; then it descends behind the brachial
plexus and the axillary vessels, along the lateral surface of the
serratus anterior. It must be identified and preserved during
axillary node clearance. It can be usually found on the outer
surface of the serratus anterior, relatively close to the axillary
vein. When all the axillary tissue is detached from the lateral
thoracic wall, the nerve is pulled towards the specimen side,
and the surgeon can identify it as a cordlike structure running
in a cranio-caudal direction. Another area where it can be
damaged is higher up, where it crosses the axillary vein, during
the dissection of levels 2 and 3 of the axillary lymphatic tissue.
The most typical symptom of long thoracic nerve damage
is projection of the scapula backwards, either spontaneously
or when pressure is applied with the ipsilateral arm on a hard
surface (winged scapula) (. Fig.  34.4). Pain, weakness  –

patients receiving surgical treatment for recurrent periareolar especially when the arm is flexed – and medial displacement
infections, permanent loss of nipple sensation is the norm.
The cords of the brachial plexus lie cephalad to the axillary
vein, relatively protected from direct surgical trauma during
axillary procedures. Injury, however, is possible, usually due to
prolonged abduction of the ipsilateral arm of more than 90°
intraoperatively. When the cords or branches of the plexus are
injured, symptoms may include muscle weakness or total
paralysis. Because a complete division of a nerve is highly
unlikely – and neurapraxia much more likely than severance –
symptoms usually subside with time. Early physiotherapy,
steroids and vitamin B complex supplements are included in
the treatment. When neuropathic pain is also present, it can be
treated with antiepileptics, antidepressants or common opioid
or non-opioid analgesics [30–34]. Risk factors for neurological
symptoms are preoperative chemotherapy  – which is fre-
quently neurotoxic, obesity and lengthy surgical procedures. It
is rare for early breast cancer-affected axillary nodes to directly
invade the nerves or vessels requiring their sacrifice except in
cases of very obviously advanced disease where neoadjuvant
therapies are preferable to surgery in the first instance.
Division of the thoracodorsal bundle must be avoided
unless directly invaded by the tumour, a condition which is
rarely seen. Deprivation of the LD muscle from its nerve stim-
uli results in muscle weakness and difficulty in medial rotation,
adduction, extension and hyper extension of the arm. Sacrifice
of the arterial supply to the LD precludes breast reconstruction
with this muscle. It is worth mentioning, however, that because
the movements of the shoulder are the result of groups of
muscles working in combination, LD muscle weakness or even
its complete absence from its natural position has minimal
impact on most daily activities with a few exceptions; this
explains why the use of this muscle in breast reconstruction
carries an almost negligible risk of significant disability. ..      Fig. 34.4  Winged scapula after full axillary clearance

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 416 M. Kontos and C. Markopoulos
of the scapula are common too. It seems that this complica-
tion is more frequent than generally believed, reaching
10–30% in some reports. With time, however, it tends to
resolve, as the nerve injury is often only temporary (neura-
praxia) and rectifies itself without treatment. Eventually, less
than 3% of patients who undergo full axillary clearance will
end up with permanent symptoms. Generally speaking, a
«winged scapula» is treated with physiotherapy and ortho-
paedic braces if necessary. If symptoms persist for more than
a few months, surgical treatment may be indicated and
includes muscle or tendon transfers or fixation of the scapula
to the rib cage [35–37].
A different group of nerve injuries may result at the donor
sites of autologous tissue reconstruction. The most common
relevant complication is weakness of the anterior abdominal
wall after DIEP or TRAM flap reconstructions due to divi-
sion of the nerves entering the rectus abdominis muscle
through its lateral edge. Thus, even if the muscle remains in
situ, the bulging of its most inferior part or even the develop-
ment of a true hernia is not uncommon.
34 34.5 Seroma
Seroma is the collection of serous fluid within the surgical
cavity after excision of part or all of the breast or axillary tis-
sue. Usually these are the spaces between the muscular floor
and the skin after mastectomy or conservation surgery and
the axillary cavity after full nodal clearance. The pathophysi-
ology of seroma formation is not entirely clear but is a very
common condition occurring in up to 80% of cases [38]. It is
often considered not a true complication but an inevitable
consequence of surgery. Its clinical significance is usually
minor, but it may cause concerns to the patient and require
repeated drainage.
The symptoms of seroma formation are subtle. There may
be discomfort or a vague sensation of heaviness. Occasionally,
serous collections may leak through the skin (usually
through the suture line), causing anxiety to the patient.
Rarely seromas can cause significant pain, delayed healing,
wound dehiscence, infection and compromise of the range of
movement of the shoulder. Seromas increase the risk of
infections during adjuvant chemotherapy and might cause
difficulty to the planning of radiotherapy treatment. Seromas
associated with ADM reconstructions may reduce the speed
of vascularisation of the ADM and so increase the risk of
infection. For this reason prolonged drainage is advised
[39–42].
It has been suggested that serous collections at the surgical
site are related to the division of lymphatic vessels and leakage
of lymphatic fluid. However, it is known that the composition
of seroma changes after a few days, eventually becoming an
exudate. Diathermy causes thermal injury to the surrounding
tissue, which responds with fluid production [1].
rares1geo@gmail.com
Due to the high frequency of this complication, there
have been several suggestions on how to prevent it. Ultrasonic
scissors, pressure dressings, tacking with sutures, avoidance
of electrocautery, application of agents to the surgical cavity
which are supposed to facilitate the adherence of its walls to
each other and eliminate dead space and the restriction of
arm use in the first few days have all been suggested, but tri-
als have not been convincing, usually presenting mixed
results (. Table 34.2) [43–86]. The use of drains may reduce
the size of seroma, and surgeons tend to keep them in situ
from 1 day to 1 week or even longer especially when recon-
struction has taken place [87–89]. The treatment of seroma is
simple and consists of transcutaneous needle aspiration
which may have to be repeated several times. Sometimes the
seroma persists for several months and a reoperation is
needed.
Risk factors for seroma formation are age, obesity, use of
electrocautery, size of the tumour, size of the breast, full axil-
lary clearance and number of lymph nodes removed [90–95].
Seroma formation after silicone implant-based recon-
struction needs special attention. Generally speaking, drains
tend to be left in place for longer and are removed when out-
put is less than 20–40 mls per day. This gives time for some
healing to take place as well as stabilisation of the surgical
cavity. The presence of a large seroma may cause an anatomi-
cally shaped implant to rotate or shift position if permitted to
occur. However prolonged use of drains may increase the
risk of infections. In the case of seroma formation around a
silicone implant or a tissue expander, aspiration and drainage
may be done under aseptic ultrasound guidance if it becomes
tense or uncomfortable.
34.6  ording and Range of Movement
C
of the Shoulder
It is well established that surgical procedures involving axil-
lary node clearance or, to a lesser degree, sentinel node biopsy
may affect the range of motion of the shoulder. This compli-
cation was underestimated in the past, and the advice given
to patients used to be that the movements of the ipsilateral
arm should be kept to a minimum for days or weeks in order
to minimise the risk of seroma formation. Today, patients
start abducting and flexing the arm early in the postoperative
period, and with the exception of a few elderly patients this
complication is rare. Moreover, the widespread use of senti-
nel node biopsy which reduces axillary scaring also contrib-
utes towards the better results. Physiotherapy before and
after surgery is helpful and often routinely offered in many
units to reduce this complication [96, 97].
The range of the motion of the shoulder can be impaired
in up to 25% of patients following axillary node clearance
(. Fig.  34.1). However, with time and physiotherapy rates
can considerably improve [98, 99]. It is preferable to provide
Complications of Breast Surgery and Their Management
417 34

..      Table 34.2  Methods used to reduce postoperative seroma

Technique Reference Comment

investigated

Harmonic energy Iovino et al. [43]
He et al. [44]
Böhm et al. [45]
Kozomara et al. [46]
Galatius et al. [47]
Kontos et al. [48]
Yilmaz et al. [49]
Deo et al. [50]
Khan et al. [51]
Rohaizak et al. [52]
Ribeiro et al. [53]
In some published trials, the use of harmonic energy has been shown to reduce
postoperative seroma and/or duration of drainage after breast cancer surgery,
especially when compared to monopolar electrocautery. However there is a large
number of publications supporting that the use of harmonic scalpel is not
beneficial and also more expensive. Meta-analyses results are also mixed [54–56].
Even in publications with results favourable for harmonic scalpel, drains were
invariably used, and postoperative aspirations of serous collections were
probably less but still necessary

Fibrin glue Sanders et al. [57] Despite the evidence from animal models that fibrin sealant reduces postopera-
Kulber et al. [58] tive seroma, clinical applications gave variable results. A relevant meta-analysis
Butler CE [59] concludes that there is no benefit from its use [67]
Jain et al. [60]
Cipolla et al. [61]
Gilly et al. [62]
Moore et al. [63]
Vaxman et al. [64]
Mustonen et al. [65]
Ulusoy et al. [66]

Tacking sutures Purushotham et al. [68]
Purushotham et al. [69]
Classe et al. [70]
Schuijtvlot et al. [71]
Ouldamer et al. [72]
Ten Wolde et al. [73]
Ouldamer et al. [72]
van Bastelaar et al. [74]
Sakkary MA [75]
There have been numerable reports on techniques of mechanical suturing of the
mastectomy or/and axillary lymphadenectomy flaps to the underlying muscular
structures. The mechanism is to reduce dead space, accelerate healing and
possibly avoid using drains. Different results have been reported although there
must be at least some degree of benefit from the technique. A relevant literature
review [76] also suggests that closure of the dead space by flap fixation with
sutures reduces seroma formation and the number of aspiration

Pressure dressing Chen et al. [77]
O’Hea et al. [78]
Kontos et al. [79]
External pressure to the area of mastectomy with special garments or dressings is
based on the idea of elimination of the dead space and keeping the mastectomy
flaps in constant contact with the chest wall to facilitate adherence. Again only
one a trial reports good results, and even then many patients underwent extra
clinic visits and repeated aspirations

Restriction of arm Chen et al. [80]
use Abe et al. [81]
Jansen et al. [82]
Petrek et al. [83]
Knight et al. [84]
Schutz et al. [85]
The restriction of the use of the ipsilateral arm after breast cancer surgery aims to
fast local healing and elimination of the surgical cavity. The restriction has been
applied for a variable period of time, sometimes until drain removal. The
published results, however, are very diverse, and a relevant review concluded that
although there may be a degree of benefit with regard to seroma formation, safe
conclusions regarding the shoulder long-term function cannot be made [86]

pre-­emptive physiotherapy and exercise advice than to treat
the problem after it is established. It is obvious that nerve
damage, especially to the long thoracic nerve of Bell, signifi-
cant neuropathic pain and radiotherapy to the axilla worsen
the problem. Finally, it is worth noting that severe impair-
ment of the range of motion of the shoulder complicates
adjuvant radiotherapy setup and planning.
A specific type of scarring in the axilla is the formation of
elongated fibrous cords which may occur in 5–10% of cases.
These can extend outside the axillary area and reach the
elbow or even the forearm. They cause significant deteriora-
tion of the range of the movements of the shoulder and may
take weeks or months to resolve. Physiotherapy is of para-
mount importance to achieve their resolution.
34.7  elayed Wound Healing and Wound
D
Dehiscence
Delayed healing of a surgical incision is not uncommon in
breast surgery. Its severity can vary from simple delay of the
healing process to actual failure of the suture line and true

rares1geo@gmail.com
 418 M. Kontos and C. Markopoulos
dehiscence. Tissue necrosis is not a prerequisite; loss of the
ability of tissues to heal in a timely manner is enough to cause
this complication.
It is difficult to estimate the actual frequency of delayed
healing, as it has not been agreed upon what constitutes a
delay and because often a simple and short delay has no fur-
ther implications. In cases when there is necrosis of the
underlying tissues (e.g. fat necrosis), there is an increased
risk of infection. Often, additional interrupted sutures and
thorough local asepsis buy time for the healing process to be
completed. Good surgical technique and avoidance of isch-
aemic tissue flaps prevent this complication. A history of
radiotherapy or surgical procedures in the area, recent che-
motherapy, smoking, poorly controlled diabetes and older
age seem to be of the most common risk factors. Specifically
for smoking, this should be stopped at least a month before
surgery in order to minimise its adverse effects on the tissues
locally [6, 100, 101]. This is of critical importance for com-
plex flap-based procedures such as mastopexy, autologous
free or pedicled flaps and implant-based procedures where
smoking increases the risk of complications several fold in
most series [102, 103].
34 Extensive tissue manipulation, which often takes place in
oncoplastic and reconstructive surgery, can result in damage
to the blood supply of the flaps. Good surgical technique,
adequate training and a thorough understanding of the blood
supply of flaps are necessary in order to avoid these compli-
cations, although anatomic variants mean that they are occa-
sionally inevitable.
If silicone implant-based reconstruction has taken place,
the prevention of wound complications is of paramount
importance. The underlying pectoralis major muscle often
protects the implant from exposure in case of wound dehis-
cence; however, if the incision is placed at the inferior aspect
of the reconstructed breast, it is possible that a wound break
down will leave the implant or the ADM exposed and vulner-
able to infections. Practically speaking, it is difficult to avoid
implant and ADM removal if they become visible though a
dehisced suture line, as they are usually already infected.
Certain incision types are more prone to a risk of wound
breakdown and should be used with caution in high-risk
cases. High-risk mastectomy incisions for skin or nipple
necrosis include the wise pattern or mastopexy incisions and
periareolar incisions. Indicatively, after nipple sparing mas-
tectomy and immediate reconstruction, nipple necrosis has
been reported at 8–10% for periareolar/circumareolar and
mastopexy incisions, 18% for inframammary and as high as
82% for transareolar incisions [104].
34.8 Lymphoedema of the Breast
and Associated Infections
After breast conserving surgery – especially if it involves axil-
lary node clearance and radiotherapy – it is possible for the
remaining breast to develop lymphoedema presenting with
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the typical appearance of peau d’orange. The breast has an
oedematous and often erythematous appearance, giving the
impression of a bacterial infection. Skin oedema and peau
d’orange are typical, and often the condition recurs repeat-
edly. The appearance of the breast can also resemble inflam-
matory cancer recurrence. For this reason, mammography,
MRI and biopsy of the most severely affected area of the skin
or parenchyma may be appropriate to rule this out [105].
Microbiology samples are usually negative. Lymphoedema of
the breast is reported in up to 5% of conservation cases.
Almost always it occurs within the first year postoperatively,
and it can persist for more than 6 months or even be perma-
nent. It seems that damage to the lymphatic system as a result
of excisions in the upper outer quadrant, axillary node clear-
ance, radiotherapy and postoperative haematomas can cause
this condition [106]. It is also more common in patients with
large breasts, with a large volume of resected tissue, with arm
lymphoedema and with more than one breast biopsy or
seroma aspiration. Resolution may require physiotherapy
and lymphatic massage techniques to encourage alternate
lymphatic drainage channels to open up [107]. The use of a
well-fitted brassiere which supports and gently compresses
the breast tissue can drain the oedema from the breast and
potentially prevent infection. If infection is present, antibiot-
ics can be used. Extremely rarely and only as the very last
resort, mastectomy can be discussed when infectious epi-
sodes are frequent and severe and antibiotic therapy is practi-
cally continuous.
34.9  ecrosis of Mastectomy Skin Flaps,
N
Oncoplastic Conserving Surgery Flaps
and Necrosis of the Nipple
Excision of the underlying breast tissue with preservation of
the overlying skin or/and the nipple results in a significant
decrease in the blood supply to these structures. This is the
case because the skin and nipple receive part of their blood
supply from the subdermal vascular plexus and part from the
underlying breast tissue: the latter is lost during surgery and
the former may be damaged if the dissection or handling of
the flaps is suboptimal. It is also known that the longer and
thinner a flap is, the more risk of compromise to its blood
supply.
In a routine simple mastectomy, the two skin flaps left to
cover the defect after the excision of the breast tissue are
relatively short and well vascularised, and therefore necro-
sis is rare. In contrast when the skin and/or the nipple is
preserved, as part of an immediate reconstruction proce-
dure, the skin flaps tend to be longer and thinner, especially
in the area of the nipple/areola complex. This means that
delayed healing and necrosis are more common. Some
degree of skin or nipple necrosis occurs in 5–10% of cases
and total nipple loss in 1–2% (210). Epidermolysis, i.e. isch-
aemia of the superficial skin layers only, is more frequent
than full necrosis, is self-­limiting and does not leave a scar
Complications of Breast Surgery and Their Management
[108, 109]. In case of full thickness skin or nipple necrosis,
the affected tissue must be excised after sufficient time is
given for demarcation. Often, during the initial phase, the
area at risk looks more extensive than what it will eventu-
ally end up being, so patience whilst demarcation occurs is
important.
Specifically in oncoplastic breast conservation proce-
dures, the risk of necrosis maybe smaller when a dermoglan-
dular rather than a purely glandular (parenchymal) flap is
considered. This risk is reported less than 2% in most relevant
reports [110].
The generally accepted risk factors for ischaemia or necro-
sis are the same as those for delayed healing and wound dehis-
cence as they share the same pathophysiological aetiology.
34.10  urgical Complications Associated
S and Pulmonary Embolism (PE)
with Breast Reconstruction
An increasing percentage of patients who undergo mastec-
tomy opt for reconstruction. Breast reconstruction tech-
niques can be surgically challenging and carry the risk of
significant complications. Some of them have already been
mentioned. In this section necrosis of free or pedicled flaps
used in reconstruction and donor site morbidity will be
briefly discussed.
Ischaemic necrosis of the flaps used in reconstruction can
be partial or total and lead to failure of the procedure. The
most frequent reconstruction techniques are the free or ped-
icled flaps which involve the transverse rectus abdominis
muscle (TRAM or DIEP), the LD muscle, the superior gluteal
artery perforators (SGAP) and the transverse upper gracilis
(TUG) muscle. Partial necrosis can occur in up to 10% of
cases but is less in high volume centres (2–3%) [111, 112].
Vascular diseases and atherosclerosis, diabetes, obesity, bilat-
eral procedures and use of the superficial inferior epigastric
artery are proven risk factors. Smoking is also a significant
risk factor for ischaemic complications, and smoking cessa-
tion 3–4 weeks prior to the procedure is mandatory. Pedicled
LD reconstruction seems to be sufficiently robust with low
rates of such adverse events, but even so, smoking cessation is
strongly advised [111, 113].
When ischaemic necrosis is diagnosed, affected tissue
must be removed surgically. Sometimes a short delay before
debridement will allow sufficient demarcation of the necrotic
tissues and more accurate estimation of the extent of the
damage. Often more than one surgical procedure is neces-
sary. The primary aim is excision of the non-viable tissue and
achievement of skin coverage as soon as possible. A second
attempt at reconstruction can be made later when the area is
sterile again and the scarring has matured. It is obvious that
if this complication occurs after an immediate reconstruc-
tion, timely treatment and avoidance of adjuvant treatment
delays are of the utmost importance [114, 115].
With regard to the donor area, delayed or suboptimal
healing due to tension on the suture line is neither infrequent
rares1geo@gmail.com
419 34
nor negligible. Moreover, when the transverse abdominis
muscle is moved away from its natural location, the anterior
abdominal wall weakens, and the probability of hernia devel-
opment is higher. In some cases there is no true protruding of
an organ subcutaneously but a «bulging» of the abdominal
wall due to its weakness and the pressure from inside. In
order to avoid this complication, the use of meshes is com-
mon practice, but some morbidity occurs in 10% of cases.
Needless to say that reconstructions that maintain the muscle
in its original location and preserve its innervation (DIEP)
have significantly lower rates of hernias or abdominal wall
weakness, at around 5%, i.e. less than non-muscle sparing
procedures (TRAM) [116, 117].
34.11 Deep Vein Thrombosis (DVT)
It is established that malignancy and prolonged bed rest
increase the probability of DVT and PE.  This is a life-­
threatening condition, and therefore all patients at risk for
DVT must be identified and prophylaxis instituted. Early
ambulation, use of compression stockings in the peri- and
postoperative period, use of intraoperative pneumatic com-
pression devices and administration of low molecular
weight heparins (LMWH) are frequently used as prevention
methods.
Specifically for breast cancer patients who undergo sur-
gery, there is no overall consensus on which subgroups will
require DVT prophylaxis, and guidelines can vary between
centres [7]. However, the majority of breast procedures are of
low or intermediate complexity, and early discharge from
hospital is the norm. Furthermore, operable breast cancer is
not regarded as such a significant risk factor for DVT risk in
the way other malignancies are [118–121]. For these reasons,
patients who undergo simple breast procedures have mini-
mal risk for thromboembolism  – often less than 1%  – and
early mobilisation, compression stockings and pneumatic
compression devices are usually sufficient unless other risk
factors are present [118–120].
There are certainly groups of patients with a higher risk of
DVT than usual. These are the lengthier procedures such as
reconstructions (especially autologous) and complex masto-
pexy cases. Specifically for the time-consuming reconstruc-
tions, the risk of thromboembolism can be as high as 15%
without LMWH prophylaxis [122]. The Caprini score has
been created for the estimation of the risk and can be used in
the decision on LMWH administration [123–125].
In conclusion, the majority of patients who have breast
surgery do not need DVT prophylaxis other than early
ambulation, use of compression stockings and pneumatic
compression devices intraoperatively. The group of patients
who have one or more risk factors for DVT or undergo
lengthy surgical procedures such as immediate reconstruc-
tions (especially autologous) or complex mammaplasties
should be treated with LMWH as a precaution.
 420 M. Kontos and C. Markopoulos
..      Fig. 34.5  Skin necrosis after methylene blue injection for sentinel
node biopsy. The patient had undergone nipple excision and Grisotti’s
oncoplastic local reconstruction
34.12 Allergy and Reaction to Medications
34 Patients who undergo breast surgery are exposed to risks
associated with the administration of medications, blood or
blood products, which may be allergenic. Here, only medica-
tions that are given intraoperatively by the surgeons will be
discussed.
Regarding the blue dye used for the identification of the
sentinel node – often Patent Blue V – allergic reactions can
occur up to 1  h after injection in up to 2% of the patients.
Allergy can be anything from haemodynamic instability and
shock to skin-restricted symptoms, such as blue hives
(. Fig.  34.5). Corticosteroids, antihistamines, fluid adjust-
ment and possibly adrenaline are used. The patients will have
to remain under close surveillance for a few hours before
discharge.
When methylene blue is used for the sentinel node
biopsy, allergic reactions are even rarer. A more frequent side
effect is skin necrosis which can be partial or full thickness
(. Fig. 34.6).
Both dyes can affect oximetry readings, and the anaesthe-
tist should be advised accordingly beforehand. Finally, their
use is contraindicated during pregnancy as its effect on the
embryo is not known.
The radioisotope Tc 99 m which is used in sentinel node
biopsy has minimal side effects. There is no need for protec-
tion against radiation for operating room personnel, and it has
been reported to be safe even in pregnant patients [126, 127].
Regarding local anaesthetics, which are used for local
anaesthesia or postoperative analgesia, their side effects are
more common in patients with a history of myocardial
infarction, heart failure and liver diseases. Cardiovascular
complications (about 2%) include hypotension, bradycardia
and cardiac arrest. Allergic reactions vary from true shock to
skin manifestations only. Neurologic and psychiatric com-
plications can also occur but are uncommon after local
injection.
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..      Fig. 34.6  Blue hives after Patent V injection for sentinel node
biopsy
34.13 Conclusion
Breast surgery is generally very safe with a mortality rate of
less than 1% [128]. Serious complications are uncommon but
may have a significant impact on quality of life and delay
commencement of adjuvant therapies. Risk factors are well
described for most complications, and patients should be
warned about these risks during preoperative counselling.
Breast surgical procedures must be carried out by specialist
teams who help to keep the complication rates low but also
treat them effectively and in a timely fashion whenever they
occur.
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 425 V

Adjuvant Therapy for

Early Breast Cancer
Contents

Chapter 35 Adjuvant Endocrine Therapy – 427

Manuela Rabaglio and Monica Castiglione

Chapter 36 Adjuvant Chemotherapy – 439

Giuseppe Curigliano, Angela Esposito, and Carmen Criscitiello

Chapter 37 Adjuvant Molecular Therapies in Breast Cancer – 447

A. Prove, L.-A. Teuwen, and Luc Dirix

Chapter 38 Primary Systemic Therapy for Breast Cancer – 453

Cornelia Liedtke and Hans-Christian Kolberg

Chapter 39 Radiotherapy for Breast Cancer – 463

Barbara Alicja Jereczek-Fossa, Maria Cristina Leonardi,
and Samantha Dicuonzo

rares1geo@gmail.com
 427 35

Adjuvant Endocrine Therapy

Manuela Rabaglio and Monica Castiglione

35.1 Introduction – 428

35.2 Definition of Menopause – 428

35.3 Endocrine Treatment in Premenopausal Women – 428

35.4 Endocrine Treatment in Postmenopausal Women – 432

35.5 Conclusion – 435

References – 435

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_35

rares1geo@gmail.com
 428 M. Rabaglio and M. Castiglione
35.1 Introduction
Endocrine manipulation of breast cancer was under investi-
gation as an experimental treatment modality as far back as
the end of the nineteenth century. The relationship between
ovarian function and breast cancer became evident when
Thomas William Nunn first reported the case of a woman
with breast cancer, whose disease regressed 6 months after
her menstruation ceased [1]. In 1896, George Beatson [2]
reported the outcome of bilateral oophorectomy in three
patients with advanced breast cancer, and, one year later,
Stanley Boyd described the result of this procedure for three
further patients, performed the first oophorectomy as adju-
vant therapy and published a paper on his first five cases [3].
In the following years Beatson, Boyd and other surgeons
reported several cases of regression of breast cancer in
patients undergoing bilateral oophorectomy. Two decades
later early observations about the efficacy of ovarian irradia-
tion were published [4] despite the fact that no one under-
stood the underlying mechanism of this effect. Estrogen
receptors on breast cancer specimens were first described in
1962 by Jensen and Jacobson [5]. In the past, these receptors
were measured with binding assays, but in modern practice
immunohistochemistry is the preferred method [6, 7]. The
35 response to endocrine manipulation is clearly recognized to
be dependent on the expression of estrogen and progester-
one receptors [8]. Most breast cancers express estrogen
receptors (ERs), progesterone receptors (PRs) or both: 80%
in postmenopausal patients and at least 30–50% in pre-
menopausal patients [9]. The aim of adjuvant endocrine
treatment is to suppress the growth-stimulating effect of
estrogen on breast cancer cells. The level of suppression dif-
fers substantially depending on the menopausal status of the
patient.
35.2 Definition of Menopause
According to the definition of menopause used by the
National Comprehensive Cancer Network [10], women of
60 years or older are considered postmenopausal by default.
Women younger than 60  years are considered postmeno-
pausal if they have undergone bilateral oophorectomy or if
they have not had any menstrual periods for 12 months in
the absence of tamoxifen, chemotherapy or ovarian suppres-
sion. For women with breast cancer who were premeno-
pausal before treatment, in particular chemotherapy,
amenorrhea is not a reliable indicator of postmenopausal
status and has to be verified biochemically. This is usually
confirmed by assessing levels of estrogen, progesterone,
luteinizing hormone and follicle-­stimulating hormone. The
former two are very low and the latter elevated once meno-
pause is established.
rares1geo@gmail.com
35.3 Endocrine Treatment
in Premenopausal Women
The production of estrogen in premenopausal women occurs
mainly in the ovaries; therefore, the first adjuvant treatment
used in this setting was bilateral oophorectomy. Its routine
use in early breast cancer treatment was introduced about
50 years after the first description of its use in the advanced
setting [2]. The introduction in the 1980s of ovarian function
suppression (OFS) using luteinizing hormone-releasing hor-
mone (LHRH) analogs added a further reversible therapeutic
option with similar results to bilateral surgical oophorectomy
[11]. The efficacy of OFS has been compared either alone ver-
sus chemotherapy or in combination with chemotherapy or
endocrine therapy, in particular tamoxifen. An earlier meta-
analysis [12] demonstrated that adjuvant treatment with
ovarian function suppression alone reduced the absolute
recurrence rate by 4.3% and increased absolute overall sur-
vival in women aged 50  years or less by 3.2%. Conversely,
several prospective studies conducted in the 1990s, and a
subsequent meta-analysis, failed to demonstrate significant
improvement in outcomes with the use of ovarian suppres-
sion when added to other adjuvant systemic therapies, such
as chemotherapy or tamoxifen [13, 14].
The selective estrogen receptor modulator tamoxifen is
used in premenopausal women to reduce the effect of estro-
gen on hormone-sensitive breast cancer cells. The Oxford
meta-analysis [15] showed that the favourable effect of
5 years of tamoxifen treatment on recurrence rate and mor-
tality was similar across all age groups, independently from
the menopausal status, and was not jeopardized by prior use
of chemotherapy. Five years of adjuvant treatment with
tamoxifen also resulted in a significant proportional reduc-
tion of the incidence of contralateral breast cancer by almost
50% [16]. The IBCSG13–93 trial [17], in which 1246 pre-
menopausal women with node-positive breast cancer were
randomized to receive anthracycline-based adjuvant chemo-
therapy with or without sequential tamoxifen, showed after a
median follow-up of 7 years a significantly improved disease-­
free survival in women receiving tamoxifen. Women who
became amenorrhoeic after chemotherapy had a significantly
better outcome independently of the use of tamoxifen.
Prolonged administration of tamoxifen until 10  years was
investigated in the ATLAS and aTTom trials and resulted in
further survival benefit, independently of menopausal status.
In the ATLAS trial, the cumulative risk of death from breast
cancer 15 years after diagnosis among women on tamoxifen
for 10  years was 12.2% vs. 15% in women who stopped
tamoxifen at 5 years, an absolute difference of 2.8% [18]. The
ASCO Guidelines were thereafter accordingly updated and
recommended consideration of extension of tamoxifen ther-
apy to 10  years [19] in women remaining premenopausal
after 5 years of adjuvant tamoxifen (. Table 35.1).
Adjuvant Endocrine Therapy
429 35

..      Table 35.1  Tamoxifen alone and with chemotherapy

Study Patient population Treatment Results

NATO (N = 605) Nodal positive, premenopausal; T × 2 years (N = 300) Better PFS and OS with T
[64] nodal positive or negative, vs.
postmenopausal No treatment (N = 305)

NSABP B-14 Nodal negative, T × 5 years T > placebo DFS 83% vs. 77%;
(N = 2644) ≤49 years and ≥50 years vs. Tam decreased RR 44%;
[65] Placebo no OS difference

NSABP B-14 Nodal negative T × 5 more years (N = 593) No DFS/OS difference at

Tam > 5 years ≤49 years and ≥50 years vs. 4 years;
(N = 1172) (after 5 years T) Placebo (N = 579) T < placebo at 7 years
[66]

Scottish trial Nodal negative, premenopausal T × 5 years adjuvant (N = 667) T > no treatment
(N = 1323) and postmenopausal vs. DFS/RFS
[67] T after relapse (N = 656) No impact on OS

Scottish trial Nodal negative (after 5 years T) T (N = 173) No difference except increase
Tam beyond 5 years vs. in endometrial cancer with
(N = 342) No further therapy (N = 169) T > 5 years
[68, 69]

GROCTA trial Nodal positive, premenopausal T × 5 years No difference in DFS/OS

(N = 504) (N = 237) vs. between Tam and chemo in
[70] CMF × 6, E × 4 premenopausal women, except
vs. an excess of locoregional
CMF × 6, E × 4, T x 5 years recurrences with T

GABG study Nodal positive CMF × 6 CMF > T for DFS/OS

(N = 331) < 50 years vs.
[71] T × 5 years

ECOG study Nodal positive Chemotherapy T > no treatment after

(N = 533) ER positive and ER negative vs. chemotherapy
[72] chemotherapy, T X 5–10 years

IBCSG 13–93 Nodal positive, pre- and AC × 4, CMF × 3, T × 5 year T > no treatment for DFS
(N = 1246) perimenopausal vs.
[17] AC × 4, CMF × 3, no treatment

Abbreviations: N number; CMF cyclophosphamide/methotrexate/fluorouracil, AC doxorubicin/ cyclophosphamide, E epi-doxorubicin, G

goserelin, E exemestane, OFS ovarian function suppression, OA ovarian ablation, T tamoxifen, HRs hormone receptors, ERs estrogen
receptors, NATO Nolvadex Adjuvant Trial Organization, NSABP National Surgical Adjuvant Breast and Bowel Project, GROCTA Gruppo di
Ricerca per la Ormono-Terapia Adiuvante (Italian breast cancer adjuvant chemo-hormone therapy cooperative group), GABG Gynecologi-
cal Adjuvant Breast Group, ECOG Eastern Cooperative Oncology Group, IBCSG International Breast Cancer Study Group, PFS progression-
free survival, OS overall survival, DFS disease-free survival, RR relapse rate, RFS relapse-­free survival

Side effects of tamoxifen  Tamoxifen treatment in premeno-
pausal women is associated with a variety of symptoms, includ-
ing vasomotor symptoms, vaginal complaints (dryness, itching
and discharge), decrease of libido, amenorrhea, insomnia and
mood disturbances, leading to significant restriction in the
quality of life [15]. The small absolute increase in the incidence
of thromboembolic events and uterine cancer are both seen
mostly in women older than 55 years.
The role of AIs in combination with OFS has been assessed
in the ABCSG12 trial as well as in the SOFT and TEXT trials.
The ABCSG12 trial was a randomized, controlled, open-­
label, two-by-two factorial, multi-centre trial. It recruited
1803 premenopausal women with endocrine-sensitive early
breast cancer receiving the LHRH antagonist (goserelin) and
compared the efficacy and safety of anastrozole and tamoxi-
fen with or without zoledronic acid for 3  years [20]. At a
median follow-up of 62  months (range 0–114.4  months),
overall no difference was detected in disease-free survival
between women receiving A or T (HR 1.08, 95% CI 0.81–
1.44; p = 0.591), but those on anastrozole had inferior overall
survival (46 vs. 27 deaths; HR 1.75, 95% CI 1.08–2.83;
p = 0.02). The addition of zoledronic acid improved disease-­
free survival (HR 0.68, 95% CI 0.51–0.91; p = 0.009).
The recently reported Suppression of Ovarian Function
(SOFT) trial was designed to evaluate whether OFS in
­combination with either tamoxifen or an AI (exemestane)

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 430 M. Rabaglio and M. Castiglione

added benefit compared to tamoxifen alone in premeno-
pausal women with hormone-sensitive early breast cancer
receiving endocrine treatment alone or who remained pre-
menopausal after adjuvant chemotherapy. In women, who
remained premenopausal after adjuvant chemotherapy, add-
ing OFS to tamoxifen resulted in an absolute increase in
5-year breast cancer-free survival of 4.5%. The benefit was
even greater when comparing tamoxifen alone versus
exemestane plus OFS, with a 5-year absolute increase in
breast cancer-free and distant recurrence-free survival of
7.7% and 4.2%, respectively [21]. No OS data have been pro-
vided so far.
The TEXT trial randomized premenopausal women
receiving OFS to exemestane or tamoxifen. In contrast to the
ABCSG12 trial, women randomized to the AI and OFS arm
had significantly better disease-free survival compared to the
tamoxifen and OFS arm (HR, 0.72). Overall survival between
the groups was not significantly different (HR, 1.14) [22].
Based on these results, an expert panel of the American
Society of Clinical Oncology (ASCO) recently published an
update of the clinical guidelines on the use of OFS in premeno-
pausal women with hormone-sensitive early breast cancer
[23]. These guidelines are in line with the recommendations
of the St. Gallen Consensus Conference 2015 [24]:
55 The Panel recommends that higher-risk patients should
receive ovarian suppression in addition to adjuvant
endocrine therapy, whereas lower-risk patients should
not.
55 Women with stage II or stage III breast cancers who
would ordinarily be advised to receive adjuvant chemo-
therapy should receive ovarian suppression in addition
to endocrine therapy.
55 Women with stage I or II breast cancers at higher risk of
recurrence, who might consider chemotherapy, may also
be offered ovarian suppression in addition to endocrine
therapy.
55 Women with stage I breast cancers not warranting
chemotherapy should receive endocrine therapy but not
receive ovarian suppression.
55 Women with node-negative cancers 1 cm or less (T1a,
T1b) should receive endocrine therapy but not receive
ovarian suppression (. Table 35.2).

..      Table 35.2  Ovarian suppression studies

35 Study Patient population Treatment Results

Ovarian ablation vs. chemotherapy

Scottish trial (N = 332) Nodal positive CMF × 6–8 cycles No difference in event-free or

[73] vs. OS
Goserelin x 2 years Goserelin better in HR+
CMF better in HR-

Scandinavian study (N = 732) Nodal positive or T > 5 cm CMF × 9 cycles No difference

[74] vs.
Ovarian irradiation

TABLE study (N = 589) Nodal positive CMF × 6 cycles No difference

[75] vs.
Leuprorelin x 2 years

ZEBRA study (N = 1640) Nodal positive CMF × 6 cycles No difference for HR+
[76] vs. CMF better for HR-
Goserelin × 2 years

Ovarian ablation + chemotherapy

INT0101 study (N = 1503) Nodal negative CAF × 6 Better TTR/DFS with CAFGT
[77] vs. No diff OS
CAF × 6 + G x 5 years CAFG better for <40 yrs.?
vs.
CAF × 6 + GT x 5 years

ZIPP trial (N = 2648) Stage I/II T × 2 years G better for DFS/OS

43% of enrolled patients also vs.
received chemotherapy G × 2 years
[78] vs.
TG × 2 years
vs.
No hormonal treatment

IBCSG 11–93 (N = 174) Nodal positive AC × 4 + OA/OS + T × 5 years No difference

[79] vs.
OA/OS + T × 5 years

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Adjuvant Endocrine Therapy
431 35

..      Table 35.2 (continued)

Study Patient population Treatment Results

IBCSG VIII (N = 1063) Stage I/II, nodal negative G × 2 years CMF > G in HR- patients
[80] vs. CMF = G in ER+ patients
CMF × 6
vs.
CMF × 6, Z × 1.5 years

Arriagada et al. (N = 926) Nodal positive, high grade Chemo No difference overall
[81] 63% HR+ vs. Lower recurrence <40, ER+
77% received anthracycline-based chemo + OA/OFS
chemo

Ovarian ablation + tamoxifen

INT0142 (N = 350) Nodal negative T × 5 years No difference

closed early due to poor vs.
accrual [82] OA + T × 5 years

Vietnamese (N = 709) Stage I/II OA + T Better DFS/OS with OA + T

[83] vs.
observation

GROCTA (N = 244) Nodal positive G + T No difference

[84] vs.
CMF × 6

FASG06 (N = 333) Nodal positive Triptorelin x 3 years + T No difference

[85] vs.
FEC × 6

French (N = 162) Nodal positive OA + T No difference

[86] vs.
FAC

ABC (OAS) (N = 2144) Stage I/II/III T ± chemo + OA/OFS No difference

[13] vs.
T ± chemo

ABCSG5 (N = 1045) Stage I/II G x 3 years + T × 5 years Better DFS with G + T
[87] vs. No difference in OS
CMF × 6

Ovarian ablation + tamoxifen vs. AIs

ABCSG12 Premenopausal G + A No difference in DSF

[20, 56] Stage I/II/III vs.
G + A + Z
vs.
G + T
vs.
G + T + Z

IBSCG 24–02/BIG 2–02: SOFT Premenopausal T No difference in DSF

[21] No adjuvant chemotherapy or vs.
premenopausal after adjuvant OFS + T
chemotherapy vs.
OFS + E

IBSCG 25–02/BIG 3–02: TEXT Premenopausal women with HR+ OFS + T In the combined analysis SOFT/
[22] tumours who require OS with or vs. TEXT: DSF better for OFS + E
without chemotherapy from the OFS + E
start of adjuvant therapy

Abbreviations: N number, CMF cyclophosphamide/methotrexate/fluorouracil, AC doxorubicin/cyclophosphamide, FAC fluorouracil/doxorubi-

cin/cyclophosphamide, FEC fluorouracil/epi-doxorubicin/cyclophosphamide, CAF cyclophosphamide/doxorubicin/fluorouracil, G goserelin, E
exemestane, OFS ovarian function suppression, OA ovarian ablation, T tamoxifen, Z zoledronic acid, HRs hormone receptors, ERs estrogen
receptors, IBCSG International Breast Cancer Study Group, TABLE Takeda Adjuvant Breast Cancer Study with Leuprorelin Acetate, ZEBRA
Zoladex Early Breast Cancer Research Association, ZIPP zoladex in premenopausal patients, GROCTA Gynecological Adjuvant Breast Group,
FASG French Adjuvant Study Group, ABC Adjuvant Breast Cancer (Ovarian Ablation Suppression), ABCSG Adjuvant Breast Cancer Study Group

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 432 M. Rabaglio and M. Castiglione
Side effects of OFS  The main side effects of OFS are due to
estrogen deprivation leading to premature menopause and
include hot flashes, sweats, weight gain and decreased libido as
well as sleep disturbances, mood alterations and bone loss. In
the Nurse’s Health Study, bilateral oophorectomy was associ-
ated with a significant increase in all-cause mortality [25], but
this effect was seen only in women who underwent oophorec-
tomy due to benign disease. The risk of cardiovascular disease
and stroke may also be increased after OFS: A meta-analysis of
18 studies found a significantly increased risk of cardiovascular
disease in women who underwent bilateral oophorectomy
compared with premenopausal women of the same age (RR
2.62, 95% CI, 2.05–3.35) [26]. The addition of tamoxifen or an
AI to OFS may intensify postmenopausal symptoms and mus-
culoskeletal side effects as reported in the quality of life (QoL)
sub-studies of the SOFT and TEXT trials, but differences in
symptom-specific QoL were less pronounced for patients with
prior chemotherapy [27, 28]. Furthermore, the addition of OFS
to oral adjuvant endocrine therapy seems not to affect cogni-
tive function in a clinically meaningful way after one year of
treatment [29].
35.4 Endocrine Treatment
in Postmenopausal Women
35
Due to cessation of hormone production by the ovaries, the
level of circulating estrogen after the menopause is substan-
tially lower than in the premenopausal women. For thera-
peutic purposes, the effect of estrogen on hormone-sensitive
breast cancer cells can be additionally reduced with selective
estrogen receptor modulators (SERMs) like tamoxifen [30]
or with selective estrogen receptor downregulators (SERDs)
like fulvestrant [31]. Alternatively the level of circulating
estrogen can be lowered with the use of aromatase inhibitors
(AIs) [32]. These drugs block the extragonadal transforma-
tion of androgen to estrogen, in particular in the adrenal
glands and in several other tissues. In postmenopausal
women, this aromatization is the primary source of estrogen.
Tamoxifen is a SERM with a predominantly antagonistic
effect on the ERs in breast tissue, a partial agonistic effect in
bone, the cardiovascular system and the CNS and an agonis-
tic effect on the uterus, liver and vaginal mucosa. For more
than 30 years, tamoxifen has been the drug of choice in the
treatment of hormone-sensitive breast cancer, leading to a
reduction in disease recurrence and in contralateral breast
cancer of about 50% and of mortality by around 30% [12, 16].
In early breast cancer, treatment with tamoxifen for 5 years
reduces the recurrence rate by about half during treatment
and by about one-third in the subsequent 5 years and reduces
breast cancer mortality by almost one-third throughout the
first 15 years [15]. Extending tamoxifen treatment to 10 years
induces a further mortality reduction during years 10 to 14
[18, 33] by about 20%.
rares1geo@gmail.com
In the concomitant administration of tamoxifen and che-
motherapy in postmenopausal women, tamoxifen seems to
diminish the efficacy of anthracycline-based chemotherapy
[34, 35], and it should be avoided. Few or no data are avail-
able for the interaction of tamoxifen with other treatments
like taxanes, trastuzumab or radiotherapy [36].
The conversion of tamoxifen to the active metabolite
endoxifen is dependent on the activity of cytochrome P450
2D6 (CYP2D6). During the last decades, several studies have
reported on the potential association between CYP2D6 poly-
morphism and tamoxifen treatment outcomes, with highly
inconsistent results [37, 38]. The recently published ASCO
Guidelines about the use of biomarkers to guide decisions on
adjuvant systemic therapy couldn’t support the use of
CYP2D6 polymorphism to decide which patients may bene-
fit from tamoxifen [39]. Association between vasomotor or
musculoskeletal symptoms, metabolism and outcome has
been extensively reported. Poor or intermediate metabolism
phenotypes seem to be associated with tamoxifen-induced
hot flushes but not with inferior outcomes in term of disease-­
free survival [40]. On the other hand, patients reporting
arthralgia/myalgia symptoms may have favourable disease-­
free survival and breast cancer-free interval [41].
Side effects of tamoxifen  Thromboembolic events, in par-
ticular deep vein thrombosis and pulmonary embolism, as well
as the increased incidence of cerebrovascular accidents repre-
sent the more severe side effects of tamoxifen. Tamoxifen use
can also lead to hot flushes, vaginal discharge and sexual dys-
function [42]. An increased risk of endometrial cancer
(. Fig. 35.1) seems to be more frequent in women over 55 years
of age [15]. Recent data reported cognitive function distur-
bance at least in the short term after treatment initiation [43],
with women showing greater degrees of reduction of psycho-
motor and motor speed in patients treated with AIs compared
with patients taking tamoxifen.
A recently published meta-analysis using individual data
from almost 32000 postmenopausal women with hormone-­
sensitive early breast cancer participating in clinical trials
showed that 5 years of aromatase inhibitor treatment reduces
the relative recurrence rates by about 30% compared with
5  years of tamoxifen during the treatment phase, but not
thereafter. Five years of an aromatase inhibitor reduces
10-year breast cancer mortality rates by about 15% if com-
pared with 5 years of tamoxifen and by about 40% (propor-
tionately) if compared with no endocrine treatment at all
[44]. In particular in trials comparing 5 years of tamoxifen
versus AI treatment (n  =  9885), AIs reduced breast cancer
recurrence during years 0 to 1 (RR 0.64, 95% CI 0.52–0.78)
and years 2 to 4 (RR 0.80, 95% CI 0.68–0.93) and lowered
breast cancer mortality (RR 0.85, 95% CI 0.75–0.96). Five
years of AI also reduce the incidence of contralateral breast
by about 1.5% in ten years if compared with 5 years of tamox-
ifen (incidence rate of 2.1% for AI versus 4.7% for tamoxi-
Adjuvant Endocrine Therapy
433 35

ENDOMETRIAL CANCER INCIDENCE ENDOMETRIAL CANCER INCIDENCE ENDOMETRIAL CANCER INCIDENCE

Entry age < 55 Entry age 55–69 Entry age 70+
5280 women 22593 women 9164 women
Endometrial cancer incidence

Endometrial cancer incidence

Endometrial cancer incidence

50 50 50
5–y gain 0.2% [95% CI–0.1 to 0.6] 10–y gain 0.7% [95% CI–0.4 to 1.2] 10–y gain 14% [95% CI–0.3 to 2.1]
40 Logrank 2p = 0.07 40 Logrank 2p < 0.00001 40 Logrank 2p = 0.0005

30 30 30

20 20 20
% % %
95% CI Tam +/– AI 95% CI Tam +/– AI 95% CI Tam +/– AI
10 0.3% 10 1.2% 10 1.8%
0.1% 0.4% 0.4%
0.3% AI +/– Tam 0.5% AI +/– Tam 0.8% AI +/– Tam
0.1% 0.1% 0.2%
0 0 0
0 5 9 years 0 5 10 years 0 5 10 years
Event rates (% / year) and logrank analyses Event rates (% / year) and logrank analyses Event rates (% / year) and logrank analyses
Allocation Years 0 – 4 Years 5+ Allocation Years 0 – 4 Years 5 – 9 Years 10+ Allocation Years 0 – 4 Years 5 – 9 Years 10+
AI +/– Tam 0.03 (2/6942) 0.02 (1/5860) AI +/– Tam 0.04 (10 / 27683) 0.04 (9 / 23636) 0.08 (2 / 2370) AI +/– Tam 0.07 (8 / 12261) 0.06 (5 / 8133) 0.0 (0/721)
Tam +/– AI 0.06 (4/6750) 0.09 (5/5628) Tam +/– AI 0.11 (31 / 27580) 0.15 (34 / 22964) 0.18 (3 / 2166) Tam +/– AI 0.16(18 / 10991) 0.15 (12 / 8068) 0.0 (0/741)
Rate ratio, from 0.48 [CI 0-10 –2.38] 0.25 [CI 0.05 –1.22] Rate ratio, from 0.35 [CI 0-19 –0.66] 0.30 [CI 0.17 –0.57] 0.45 [CI 0.09 –2.23] Rate ratio, from 0.44 [CI 0-21 –0.95] 0.39 [CI 0.15 –1.00]
(O-E)/v –1.1 / 1.5 –2.1 / 1.5 (O-E)/v –10.6 / 10.2 –12.7 / 10.7 –1.2 / 1.5 (O-E)/v –5.3 / 6.5 –4.0 / 4.2

..      Fig. 35.1  Endometrial cancer incidence (Reprinted from Ref. [44], Commons Attribution License CC BY. 7 http://www.thelancet.com/  

Copyright © Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). pdfs/journals/lancet/PIIS0140-6736(15)61074-1.pdf)

Open-access article distributed under the terms of the Creative

fen). In trials comparing a five-year course of tamoxifen [CI], 93 to 96) with letrozole and 91% (95% CI; 89 to 93) with
versus 2–3 years of tamoxifen followed by an AI to complete placebo [48] (. Table 35.3).  

5 years of endocrine treatment (n = 11,798), the switch to an

AI resulted in a reduced breast cancer recurrence rate during Side effects of AIs  AIs are associated with a higher risk of
years 2–4 (RR 0.56, 95% CI 0.46–0.67) and fewer deaths from osteoporosis, fractures, cardiovascular risk and hypercholes-
breast cancer (RR 0.84, 95% CI 0.72–0.96) as well as an terolemia but with a lower risk of thromboembolic events and
­absolute reduction of contralateral breast cancer incidence endometrial cancer when compared to tamoxifen [44, 49].
by 0.8%. Finally, in trials, which compared 5 years of AI alone Furthermore, AIs are associated with musculoskeletal symp-
versus 2–3 years of tamoxifen followed by an AI, the treat- toms and may reactivate ovarian function [50–54].
ment with an AI alone resulted in a lower recurrence rate Because of the increased risk of bone loss, patients should
during years 0 to 1 (RR 0.74, 95% CI 0.62–0.89) and similar be encouraged to have adequate calcium and vitamin D3
recurrence rates in years 2 to 4 (RR 0.99, 95% CI 0.85–1.15) intake [55]. The prophylactic use of bisphosphonates may be
as well as a trend towards reduced breast cancer mortality discussed in women taking AIs, although the treatment is not
(RR 0.89, 95% CI 0.78–1.03) but no relevant reduction in reimbursed in all countries. A prolongation of DFS and breast
contralateral breast cancer (0.3%) . cancer-specific survival has been reported [56]. The use of
In the same meta-analysis, the sequence of AI followed by bisphosphonates decreases the risk of skeletal events (frac-
tamoxifen as investigated in the BIG 1–98 trial [45–47] was tures) in patients with treatment-induced osteoporosis [57].
not included. In the BIG 1–98 trial, 8000 women were ran- The enzyme aromatase is encoded by the gene CYP19A1,
domized to receive 5  years of tamoxifen or letrozole or a which is a complex gene with many variants. Some polymor-
sequential treatment with 2.5 years of tamoxifen followed by phisms have been related to abnormal activity of aromatase,
2.5 years of letrozole or vice versa. Monotherapy with letro- breast cancer risk as well as aromatase inhibitor-associated
zole showed a better outcome compared with tamoxifen arthralgia and bone mineral density [58]. A meta-analysis
alone, but there was no significant difference between based on a systematic review of the literature revealed asso-
sequential therapies with only 2.5 years of AI and letrozole ciations between CYP19A1 polymorphisms and clinical out-
alone for 5 years. comes as well as adverse events in breast cancer patients
Recently data about extended endocrine treatment with receiving AIs, although its role for the daily use has not yet
an AI has been published. A total of 1918 patients were ran- been established [59].
domly assigned to receive letrozole (959 patients) or placebo Recent reports showed that the impairment of the cogni-
(959 patients) after 4.5 to 6  years of AI [72]. The 5-year tive function during treatment with AIs may be less marked
disease-­free survival rate was 95% (95% confidence interval than that seen in women taking tamoxifen [60–62].

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 434 M. Rabaglio and M. Castiglione

..      Table 35.3  Tamoxifen vs. Aromatase Inhibitor Studies

Study Patient population Treatment Results

ATAC (N = 9366) ER positive or Tamoxifen versus anastrozole versus Anastrozole better PFS than
[88, 89] unknown combination for 5 years tamoxifen or combination

BIG1–98 (N = 8010) HR positive Tamoxifen 5 years versus letrozole
[45–47] 5 years versus tamoxifen 2–3 years +
letrozole to complete 5 years versus
letrozole 2–3 years + tamoxifen to
complete 5 years
Letrozole better PFS than tamoxifen
upfront, but no significant difference
between the sequential therapies

NCIC-CTG MA17 (N = 5187) ER positive After 5 years tamoxifen: letrozole Letrozole better PFS than placebo
[46, 90, 91] versus placebo for 5 years Longer OS with letrozole for
node-positive patients

NCIC-CTG MA17R ER positive After 4.5 to 6 years of AI: letrozole Extended letrozole better PFS than
(N = 1918) versus placebo for another 5 years placebo
[48]

IES (N = 4247) ER positive or After 2–3 years tamoxifen: exemestane Better PFS after switch to exemes-
[92, 93] unknown versus tamoxifen to complete 5 years tane
Borderline better for switch after
exemestane

ABCSG + ARNO 95 ER positive After 2 years tamoxifen: anastrozole Better PFS after switch to anastrozole
(N = 3224) versus tamoxifen to complete 5 years Longer OS after switch after
[94, 95] anastrozole in the ARNO 95 trial

ITA (N = 448) Node positive After 2–3 years tamoxifen: anastrozole Better PFS after switch to anastrozole
35 [96] ER positive versus tamoxifen to complete 5 years Longer OS after switch after
anastrozole

Hormonal Adjuvant Treatment HR positive Tamoxifen 2 years and then letrozole Effect on BMD and hormonal
Bone Effects (HOBOE) (N = 227) 3 years changes (no data about efficacy)
[97, 98] versus
letrozole 5 years
versus
letrozole + zoledronic acid 5 years

Preoperative arimidex
Compared with tamoxifen
(PROACT) (N = 451)
[99]
Tumour ≥3 cm Anastrozole 12 weeks preoperative Anastrozole better PFS than
then anastrozole 5 years postoperative tamoxifen
versus
tamoxifen 12 weeks preoperative and
then tamoxifen 5 years postoperative

TEAM (N = 9532) Any node / tumour Exemestane 5 years Exemestane alone or after tamoxifen
[100] >3 cm / Grade versus better PFS than tamoxifen alone
III > 1 cm tamoxifen 5 years
versus
tamoxifen 2.5–3 years and then
exemestane 5 years

AREAS (N = 706) Stage I-IIIB; HR Tamoxifen 1–4 years and then Better PFS after switch to anastrozole
[101] positive tamoxifen 5 years
versus
tamoxifen × 1–4 years and then
anastrozole 5 years

University of Siena Exemestane HR positive Tamoxifen 5 years Effect on BMD and hormonal
Trial (N = 70) versus changes (no data about efficacy)
[102] tamoxifen 2–3 years and then
exemestane 5 years

Abbreviations: N number, ATAC arimidex, tamoxifen, alone or in combination, BIG Breast International Group, NCIC-CTG National Cancer
Institute of Canada Clinical Trials Group, IES Intergroup Exemestane Study, ABCSG Austrian Breast and Colorectal Cancer Study Group,
ARNO German Adjuvant Breast Cancer Group, ITA Italian tamoxifen anastrozole, AERAS Arimidex Extended Adjuvant Randomized Study,
TEAM Tamoxifen and Exemestane Adjuvant Multicenter, HRs hormone receptors, ERs estrogen receptors, BMD bone mineral density

rares1geo@gmail.com
Adjuvant Endocrine Therapy
..      Fig. 35.2 Algorithm
endocrine treatment
Premenopausal
HR positive
breast cancer
Postmenopausal
35.5 Conclusion
Adjuvant endocrine treatment is mandatory in women with
hormone-responsive breast cancer. The choice of compound,
combination with other drugs or treatment modalities (i.e.
OFS, chemotherapy or targeted treatments) and duration of
the treatment are however dependent on several factors like
menopausal status, risk factors for recurrence as well as
patient preferences and co-morbidities.
For premenopausal women with hormone receptor-
positive breast cancer and remaining premenopausal after
chemotherapy, OFS in combination with tamoxifen or AIs
may be considered in higher-risk patients. If OFS is
included, the optimal duration of such therapy should be
5 years. Extended endocrine therapy with tamoxifen for a
total of 10  years should be discussed for premenopausal
patients initially node-positive or with other adverse
pathology [24].
For postmenopausal women with hormone receptor-­
positive breast cancer, the use of AI therapy at some point
during adjuvant treatment, either as upfront therapy or as
sequential treatment after tamoxifen, is recommended (pos-
sibly with the exception of lowest-risk patients in whom
tamoxifen alone may be sufficient) [19, 24, 63] (. Fig. 35.2).
rares1geo@gmail.com
435 35
High Risk OFS + TAM or AI
Low Risk TAM 5-10 years
AI 5-10 years
TAM 2-3 years AI 2-3 years
AI 2-3 years TAM 2-3 years
TAM 5-10 years
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 439 36

Adjuvant Chemotherapy
Giuseppe Curigliano, Angela Esposito, and Carmen Criscitiello

36.1 Introduction – 440

36.2 Endocrine-Responsive Breast Cancer – 440

36.3 Luminal A – 441

36.4 Luminal B – 441

36.5 HER2 Positive – 441

36.6 Triple Negative – 442

36.7 Predictive Tools for Chemotherapy Response – 442

36.8 Conclusions – 443

References – 443

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_36

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 440 G. Curigliano et al.
36.1 Introduction
Adjuvant chemotherapy is a treatment for supposed micro-
metastatic disease. It aims at reducing the subsequent risk of
relapse and death after primary breast cancer. In the past
35 years, several chemotherapy regimens have been used in
the adjuvant setting. The three chemotherapy regimens that
have proved to improve most breast cancer outcome are (1)
cyclophosphamide, methotrexate and 5-fluorouracil (CMF)
regimen, (2) the anthracycline-based regimens and (3) the
taxane-based regimens [1–3]. According to the results of the
meta-­analysis conducted by the Early Breast Cancer Trialists’
Collaborative Group (EBCTCG), adjuvant chemotherapy
decreased the annual relative risk of relapse and mortality by
23% and 17%, respectively. [1]. The assessment of biological
features of the disease is crucial to select the best treatment
option for patients with early breast cancer. Conventionally,
the selection of the most active adjuvant regimen for patients
with breast cancer was based on stage rather than on biology.
Nevertheless, breast cancer can no longer be considered as a
single disease, as several breast cancer subtypes have been
defined by genetic array tools [4, 5]. Traditional clinical-
pathological features are routinely used for approximations
to this classification [6]. Immunohistochemical markers such
as estrogen receptor (ER), progesterone receptor (PgR) and
human epidermal growth factor receptor 2 (HER2) play a
key role in defining the clinicopathological surrogate defini-
36 tions of subtypes, with – accordingly – different risk factors,
natural histories and sensitivity to systemic therapies [7–9].
In the present chapter, we will attempt to address the issue of
selecting the most appropriate cytotoxic regimen for adju-
vant therapy according to the different subgroups of breast
cancer, namely, endocrine-responsive (luminal A and lumi-
nal B), HER2-positive and triple-negative breast cancer.
36.2 Endocrine-Responsive Breast Cancer
Luminal breast cancers, which represent the most frequent
subtypes of breast cancer, include tumours expressing
ER. They are defined as a group of tumours with a great het-
erogeneity in histology, natural history, molecular signatures
and response to treatments [10, 11]. According to their differ-
ent gene expression profiles, two main ER-positive breast can-
cer subtypes are recognized, specifically luminal A and
luminal B [4, 12, 13]. As compared to the luminal A subtype,
the luminal B subtype is characterized by lower expression of
ER levels, lower or no expression of PR [14] and a higher pro-
liferation index [15]. Also, it is thought that luminal B tumours
derive greater benefit from chemotherapy than luminal A
tumours [5, 16, 17]. One of the most remarkable and chal-
lenging questions is whether (some) luminal breast cancer
patients could be spared adjuvant chemotherapy. In this con-
text important and innovative trials have tried to address this
question by using genomic tools. In women with early-stage
breast cancer, the 70-gene signature test (MammaPrint) has
been shown to improve prediction of clinical outcome. The
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recently published phase 3 MINDACT trial was designed to
offer prospective evidence of the clinical utility of using the
70-gene signature in addition to standard clinical-pathologi-
cal criteria to select patients for adjuvant chemotherapy [18].
This trial randomized 6693 women with early-stage breast
cancer and evaluated both the genomic risk (using the
70-gene signature) and the clinical risk (using a modified ver-
sion of Adjuvant! Online) [18]. Women at low clinical and
genomic risk did not receive chemotherapy, while those at
high clinical and genomic risk did. In patients with discor-
dant risk results, either the genomic risk or the clinical risk
was used to decide the use of chemotherapy. Women at high
clinical risk and low genomic risk for recurrence who were
spared chemotherapy based on the 70-gene signature had a
5-year rate of survival without distant metastasis of 94.7%
(95% confidence interval, 92.5–96.2), and that was 1.5 per-
centage points lower than the rate with chemotherapy. The
subset of patients who had estrogen receptor-positive, human
epidermal growth factor receptor 2-negative and either node-
negative or node-positive disease had similar rates of survival
without distant metastasis. These results tell us that about
46% of women with breast cancer who are at high clinical risk
might not need chemotherapy [18].
The Trial Assigning Individualized Options for Treatment
(Rx), or TAILORx, aims at examining whether genes that are
frequently associated with risk of recurrence can be used to
assign patients with early-stage breast cancer to the most
proper and effective treatment [19]. TAILORx seeks to
incorporate a molecular profiling test (the 21-gene assay
(Oncotype DX Recurrence Score, Genomic Health)) into
clinical decision making, thus sparing women needless
treatment when chemotherapy is not likely to be of signifi-
cant benefit. This study involved more than 10,000 women
recently diagnosed with hormone receptor-positive, HER2-­
negative, axillary node-negative breast cancer with tumours
of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in
the greatest dimension but with tumours at intermediate or
high grade) who were considered to be candidates to adju-
vant chemotherapy according to clinicopathologic features
[19]. Patients were categorized into three recurrence risk
groups according to their score calculated by the 21-gene
assay. Women in the lowest-risk group were allocated to
receive hormone therapy, women in the intermediate-risk
group were randomized to receive either hormone therapy
alone or hormone therapy plus adjuvant chemotherapy and
women in the highest-risk group were allocated to receive
hormone therapy plus adjuvant chemotherapy. In September
2015, Sparano and colleagues published results from an
analysis of the women in the lowest-risk group. 1626 women
(15.9%) had a recurrence score of 0–10 and were assigned to
receive endocrine therapy alone. Among patients with hor-
mone receptor-positive, HER2-negative, axillary node-­
negative breast cancer that had a favourable gene expression
profile and who would have been considered suitable to
adjuvant chemotherapy according to clinicopathologic fea-
tures, the rates of recurrence at 5 years with endocrine ther-
apy alone were very low [19]. The 5-year rate of invasive
Adjuvant Chemotherapy
441 36
disease-­free survival was 93.8% (95% confidence interval 36.4 Luminal B
[CI], 92.4 to 94.9), the rate of freedom from recurrence of
breast cancer at a distant site was 99.3% (95% CI, 98.7 to Luminal B tumours are characterized by higher proliferation
99.6), the rate of freedom from recurrence of breast cancer at rates and an increased risk of relapse when compared to
a distant or local-regional site was 98.7% (95% CI, 97.9 to patients with luminal A tumours. Hence, the addition of che-
99.2) and the rate of overall survival was 98.0% (95% CI, 97.1 motherapy to endocrine treatment is indicated for the major-
to 98.6) [19]. ity of these patients. The benefit of chemoendocrine therapies
compared to endocrine therapies alone was clear in several
trials [8, 23]. Particularly, data from a large meta-analysis of
36.3 Luminal A patients with ER-positive tumours from the Early Breast
Cancer Trialists’ Collaborative Group (EBCTCG) reported
The majority of luminal A tumours have an outstanding that proportional risk reductions from chemotherapy were
prognosis with endocrine therapy alone. In this subset the slightly affected by age, nodal status, tumour size or differen-
use of chemotherapy is much discussed, particularly in node-­ tiation, estrogen receptor status or tamoxifen use [24]. For
negative disease. The International Breast Cancer Study patients with luminal B subtype cancers, the majority of the
Group (IBCSG) trial IX for postmenopausal women and the St. Gallen panellists considered the use of chemotherapy.
IBCSG trial VIII for premenopausal patients [8, 20–22] com- Normally, chemotherapy regimens should comprise anthra-
pared three or six courses of adjuvant cyclophosphamide, cyclines and taxanes. The optimal adjuvant chemotherapy
methotrexate and fluorouracil (CMF) with or without endo- duration is not established yet, but a duration of 4–6 months
crine therapy versus endocrine therapy alone. In these stud- is considered to be reasonable [10].
ies, chemotherapy showed no benefit in ER-positive/
HER2- negative breast cancer patients (hazard ratio [HR]
0.90; 95% CI, 0.74–1.11) in the subset of ER-positive, HER2-­ 36.5 HER2 Positive
negative and low-Ki67 tumours, which corresponds to the
proxy definition of luminal A disease [22]. Moreover, the About 15% of breast cancer presents with HER2 overexpres-
results of the retrospective analysis of the NSABP B-20 trial sion/amplification. This feature is associated with a poor
(which compared tamoxifen only versus MF  +  T versus prognosis [25] and remains the main predictive biomarker
CMF + T in women with ER+ cancer and found both overall for the use of the humanized monoclonal antibody trastu-
and disease-free survival advantage in both chemotherapy zumab and other anti-HER2 drugs [26, 27]. Since 2005, the
arms versus tam alone) showed that patients with ER-­ adjuvant treatment of this breast cancer subtype has drasti-
positive/node-negative breast cancer and with a low RS by cally changed with the publications of the findings from the
Oncotype DX treated with tamoxifen did not benefit from first-generation adjuvant trials combining trastuzumab with
the addition of CMF chemotherapy [23]. Nowadays, there chemotherapy, either concomitantly or sequentially [28–31].
are controversies regarding the therapeutic approach to opti- Additionally, HER2 amplification is associated with greater
mally treat luminal A disease with a large tumour burden sensitivity to chemotherapy, including anthracyclines [32–
(e.g. nodal involvement). Usually nodal involvement is sup- 34] and taxanes [35–37]. Actually the most relevant issue is
posed to require the use of adjuvant chemotherapy, despite whether or not to include an anthracycline in the adjuvant
the fact that the good outcome of luminal A disease with treatment of HER2+ breast cancers, particularly in view of
endocrine therapy alone and its relative chemoresistance [8, the risk of cardiotoxicity which is increased with sequential
23] induce consideration that these tumours should be cured trastuzumab therapy [38]. An interesting discovery is that
according to biology rather than stage. This clinical topic is HER2 and topoisomerase IIa (TOPO2A) gene coamplifica-
actually explored in the RxPONDER trial which studies if tion is associated with high sensitivity to anthracycline-based
patients with ER+/ HER 2 negative breast cancer, RS  ≤  25 chemotherapy [39]. According to these data, the BCIRG
and with involvement of one to three axillary nodes may be (Breast Cancer International Research Group) [40] retro-
spared adjuvant chemotherapy [19]. Results from this trial spectively looked at the predictive value of TOPO2A gene
should help addressing whether favourable tumour biology amplification in patients with HER2-overexpressing breast
is more significant than unfavourable tumour stage when cancer in a randomized trial, which compared anthracycline-­
making adjuvant therapy decisions. Up to now, according to taxane-­based chemotherapy with taxane only-based chemo-
the St. Gallen consensus, in patients with luminal A-like dis- therapy. The investigation confirmed a greater benefit for
ease, chemotherapy could be added to endocrine therapy on anthracyclines in patients with HER2+/TOPO2A-amplified
the basis of tumour burden and risk assessment. The St. disease. Nonetheless, the predictive value of TOPO2A gene
Gallen panellists did not specify a preferred chemotherapy amplification has not been independently validated and
regimen for these patients and expressed the view that any of chromosome 17 polysomy may be the more influential pre-
the standard regimens, including the first- and second-­ dictor [41]. To date, there are insufficient proofs for modify-
generation regimens (CMF, Adriamycin plus cyclophospha- ing chemotherapy regimens on the basis of TOPO2A
mide (AC), Taxotere plus cyclophosphamide (TC)), could be expression, HER2 status or chromosome 17 copy number. So
considered [10]. far, for patients with HER2-positive disease, the standard

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 442 G. Curigliano et al.
adjuvant treatment is trastuzumab plus chemotherapy, which
should include a taxane and an anthracycline according to
the St. Gallen guidelines [10].
36.6 Triple Negative
Triple-negative breast cancers (TNBCs), defined by their lack
of immunohistochemical staining for ER and PgR and lack of
overexpression or amplification of HER2/neu, are character-
ized by their aggressive clinical course and poor prognosis
[12, 42]. Lacking specific targeted therapy, chemotherapy
with standard cytotoxic agents is the only systemic treatment
option approved for these patients. There is no robust evi-
dence to advice use, or avoidance, of specific chemotherapy
agents in the TNBC subset. Several studies have demon-
strated a broad chemosensitivity for these tumours, mainly
in the neoadjuvant setting [17, 43–45]. In these trials, TNBCs
revealed higher response rates (RR) than other BC subtypes
but showed a poor overall survival rate. The TNBC subtype is
associated with a paradox: despite a subgroup of patients
who are very chemosensitive, the whole subgroup shows
poor disease-free and overall survival. This paradox was
emphasized by a neoadjuvant analysis in which TNBC
patients achieving pCR had an excellent outcome (3-year
overall survival 94% vs. 98% for non-TNBC), while TNBC
patients not achieving a pCR had a high probability of sys-
36 temic relapse (63% vs. 76%, respectively) and death (74% vs.
89%, respectively) within 3 years of primary diagnosis [43].
The elucidation of this behaviour could be found in the fact
that within the TNBCs exists a subgroup with intrinsic che-
moresistance. Thus, the identification of specific biomarkers
could be useful to recognize patients at different responsivity
to chemotherapy and to develop new therapeutic approaches.
Chemotherapy benefit in TNBC could be related to its
high proliferative rate and  – to some extent  – intersection
with BRCA1 mutation-related breast cancers. BRCA1 is
involved in homologous recombination, a cellular process of
double-strand DNA break repair, and in the cell cycle arrest
necessary for DNA damage repair. Loss or inactivation of
BRCA1 may induce peculiar susceptibility to DNA damag-
ing agents, such as platinum derivatives, and relative resis-
tance to mitotic spindle poison, like taxanes and vinca
alkaloids [46]. Nevertheless, data on the role of platinums in
TNBC are still limited and controversial. At the 2013 San
Antonio Breast Cancer Symposium, the preliminary results
of the CALGB/Alliance 40,603 study were reported. In this
trial, patients were randomly assigned in a 2 × 2 schema to
receive weekly paclitaxel for 12 courses plus dose-dense
anthracycline/cyclophosphamide with or without the addi-
tion of biweekly bevacizumab for nine cycles or the addition
of carboplatin every 3 weeks for four cycles. The addition of
carboplatin to the neoadjuvant regimen significantly aug-
mented the rate of pathologic complete response in patients
with triple-negative breast cancer [47]. In contrast, the
results from the neoadjuvant trial GEICAM/2006–03
showed that the addition of carboplatin to conventional
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chemotherapy (epirubicin plus cyclophosphamide followed
by docetaxel) in basal-like breast cancer patients did not
increase efficacy [48].
Potential biological bases for taxane sensitivity in TNBC
are the high tumour proliferative rate and the presence of
aberrant p53 in about 50% of TNBC [49]. Data about the role
of taxanes in the TNBC population come from retrospective
subgroup analyses of randomized trials. Some trials reported
a favourable impact of taxanes on the prognosis of TNBC
[35, 50–52], while others did not show any additional benefit
from taxane therapy in this population [53, 54]. Preclinical
and clinical data regarding the efficacy of anthracyclines in
TNBC are limited and contradictory. A meta-analysis of ran-
domized trials comparing anthracycline-based regimens ver-
sus CMF reported that TNBC patients have a 23% reduction
in the risk of recurrence with the use of anthracyclines [55].
Conversely, a retrospective analysis from the MA.5, which
compared CMF versus CEF, revealed an almost significantly
(P  =  0.06) higher disease-free survival (DFS) for basal-like
breast cancer receiving CMF (5y–DFS: CMF  =  0.71;
CEF = 0.51) [56].
The activity of alkylating agents in TNBC is hard to mea-
sure. Retrospective studies suggest that TNBC may have par-
ticular sensitivity to alkylating agents. Among these, a study
by Colleoni and colleagues reported that classical CMF had
greatest benefit in patients with triple-negative to node-­
negative breast cancer [22]. Regarding the choice of the adju-
vant chemotherapy regimen in this subtype, the St. Gallen
panel strongly endorsed both anthracyclines and taxanes and
did not believe that platinum or regimens emphasizing alkyl-
ating agents were specifically required [10].
36.7 Predictive Tools for Chemotherapy
Response
Thus far, tools to personalize chemotherapy use in breast can-
cer are lacking and biomarker studies for chemotherapy ben-
efit have been disappointing. Because of breast cancer
heterogeneity, individual biomarkers are unlikely to be useful
in aiding in the current clinical management decision-­making
process. Multiple parameters can influence response to che-
motherapy but none has been endorsed into clinical use
because of their inability to predict response to treatment.
A biomarker frequently investigated is p53, which is a
transcription factor that mediates antiproliferative mecha-
nisms in response to various forms of cellular stresses, in par-
ticular DNA damage [57]. As a predictive biomarker for
treatment response, the role of p53 remains unclear. Preclinical
studies suggested p53-dependent anthracycline-induced
apoptosis and p53-independent taxane activity [58, 59].
Still, dedicated clinical research has not defined a predic-
tive role for p53 mutations. In the past, many reports have
retrospectively evaluated the role of p53 in subgroups from
biologically unselected breast cancer trials. However, the
clinical data were contradictory and inconclusive, and no
robust predictive correlation was demonstrated [60–64]. The
Adjuvant Chemotherapy
only study designed to prospectively evaluate the predictive
role of p53 was the neoadjuvant phase III EORTC 10994/BIG
00–01 trial [65]. In this study, although p53 status was prog-
nostic for overall survival, it was found to be not predictive of
sensitivity to taxanes. In the retrospective exploratory analy-
sis performed on samples collected in the context of the pro-
spective BIG 02–98 randomized phase III clinical trial, it was
found that p53 mutations had no value in predicting response
to docetaxel therapy in node-positive breast cancer patients
[66]. These findings exemplify how a single biomarker may
be inadequate to predict treatment response to chemother-
apy. Actually p53 should be considered as a surrogate mea-
sure for cellular capacity for apoptosis and cell proliferation
control rather than as a drug target.
TOPO2A, the molecular target of anthracyclines, has also
been extensively investigated. The association of TOPO2A
status with anthracycline efficacy, in patients with HER2-­
amplified tumours, has been addressed by many studies, but
the reported results are conflicting, and the use of TOPO2A
as a predictive factor is actually an issue of dispute [67–74].
Actually, while some studies showed a lack of association
between TOPO2A expression and responsiveness to anthra-
cyclines [67], others demonstrated TOPO2A overexpression
as being associated with higher response rates in patients
treated with anthracycline combinations [71–73] but also
with shortened survival [72]. The definitive answer after
years of disagreement seems to come by the meta-analysis by
Di Leo and colleagues showing that patients with HER2 non-­
amplified or TOPO2A normal tumours gain some additional
benefit from treatment with anthracyclines. Therefore, there
is no evidence for the use of anthracyclines only in patients
with HER2-amplified or TOPO2A-aberrated tumours [55].
The prediction of treatment efficacy according to one gene
only might denote an incomplete approach, and other bio-
logical factors, such as stromal activation and markers of
immune response, might have a role in predicting the respon-
siveness to anthracyclines [69]. In the era of personalized
medicine, a multifactorial approach should be taken and
should be the challenge of the future.
36.8 Conclusions
Precise tools to optimally select patients and regimens for
adjuvant chemotherapy in early breast cancer are missing.
There is a need for biomarker discovery that could help iden-
tify patients who are more likely to benefit from chemother-
apy. Research that aims at understanding the complexity of
resistance to chemotherapy agents and the way in which
resistance can be overcome are essential. Appreciation of
additional diversity in biology and treatment sensitivity
within the breast cancer intrinsic subtypes requires new
approaches to personalize as much as possible the treatment
and maximize efficacy. To achieve this goal, it is fundamen-
tal to identify the functional biological targets, the cell path-
way functions, the intra-tumoural biological heterogeneity
and influential host features, mostly the host stroma and
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443 36
immune defences contained in the tumour microenviron-
ment. We believe that in the near future, breast cancer treat-
ment will be more tailored to both the individual and the
tumour. There will be more investment in trials in the neo-
adjuvant setting in order to identify active drugs for further
clinical development and to find biomarkers of response.
Another potential approach for the future will be the use of
gene expression arrays. Specific gene expression signatures
have been proposed to predict response to selected chemo-
therapies [75, 76]. Another strategy might be the develop-
ment of in vitro drug assays, in which short-term cultures of
breast cancer-­derived cell suspensions are subjected to a
number of cytotoxic drugs in vitro. Among these, the micro-
plate adenosine triphosphate (ATP)-based tumour chemo-
sensitivity assay (ATP-TCA) has gained particular interest
for ex vivo chemosensitivity testing of native non-haemato-
logical tumours [77] although such assays are currently only
for use within a trial setting at present. It has been postulated
that the most effective drug in  vitro would also result in a
superior response in vivo. The contemporary understanding
of the molecular biology of breast cancer presents an
extremely complex portrait of disease. Based on this infor-
mation, considerable efforts will be made to identify bio-
markers that will be able to predict the response to a specific
treatment while minimizing the risk of unnecessary side
effects.
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 447 37

Adjuvant Molecular Therapies

in Breast Cancer
A. Prove, L.-A. Teuwen, and L. Dirix

37.1 Introduction – 448

37.2 Endocrine Treatment – 448

37.3 Vascular Endothelial Growth Factor

(VEGF)-Directed ­Treatment – 448

37.4 HER2-Directed Treatment – 449

37.4.1 Concurrent or Sequential HER2 Blockade – 449
37.4.2 Role of Dual Adjuvant HER2 Blockade – 449
37.4.3 Role of Dual Adjuvant VEGF/HER2 Inhibition – 450
37.4.4 Role of Extended HER2 Blockade – 450
37.4.5 De-escalating Regimens – 450
37.4.6 Efficacy in Small HER2 Tumours – 451

37.5 Conclusion – 451

References – 451

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_37

rares1geo@gmail.com
 448 A. Prove et al.
37.1 Introduction
Adjuvant therapies (radiotherapy, chemotherapy, endocrine
and targeted agents) in patients with localised cancer are
aimed at the elimination of putatively present micrometa-
static disease. The underlying concept being that this mini-
mal amount of disease is more amenable to definitive
eradication as compared to macroscopic disease. The history
of adjuvant therapy in breast cancer originated with the
introduction of combination chemotherapy with CMF
(cyclophosphamide, methotrexate, 5-fluorouracil) in the
1970s by the Milan group [1]. Initially this was introduced
for patients with node-positive disease. Subsequently its ben-
efit was also demonstrated in unselected patients with breast
cancer without nodal involvement. Although the use of
anthracyclines was also pioneered by the same Milan group,
the introduction of adjuvant Adriamycin was established by
the NSABP group [2]. These developments were paralleled
by the use of adjuvant endocrine interventions. These ini-
tially included the use of oophorectomy and tamoxifen [3, 4].
It took until the adjuvant meta-analysis in 1998 by the Early
Breast Cancer Trialists’ Collaborative Group (EBCTCG) to
definitively make the point that tamoxifen was only effective
in patients with oestrogen receptor (ER)-positive breast can-
cer [4]. Criteria such as tumour (T)-stage, the presence of
nodal disease, age, menopausal status and ER expression
were henceforth used to tailor adjuvant therapy.
The reproducible identification of intrinsic breast cancer
subtypes by genome-wide expression profiling studies and
37 their validated prognostic significance led to gradual changes
in adjuvant therapy guidelines [5–8]. Most notably, the con-
version of these expression-based intrinsic subtypes into
clinically defined subtypes (albeit an imperfect translation),
based on routine immunohistochemical methods, modu-
lated the selection of different adjuvant options according to
these subtypes. The availability of multigene tests, including
both prognostic and predictive assays, will further tailor and
in general limit the use of adjuvant chemotherapy in patients
with ER-positive disease and potentially might enable selec-
tive extension of the duration of endocrine agents in charac-
terised subgroups [9–11].
37.2 Endocrine Treatment
Current adjuvant endocrine regimens and their indications
are discussed separately (7 Chap. 35). In summary, tamoxi-
 
fen for at least 5 years and for up to 10 years remains the
standard of care for all premenopausal patients with ER and/
or progesterone receptor (PgR)-positive breast cancer [12].
The combination of ovarian suppression and tamoxifen or an
aromatase inhibitor (AI) should be strongly considered in
those premenopausal patients with high-risk disease [13]. In
postmenopausal patients with endocrine sensitive disease, 5
years of an aromatase inhibitor (AI) reduces 10-year breast
cancer mortality rates by 15% compared with 5 years of
rares1geo@gmail.com
tamoxifen [14]. Even longer continued use of an AI for up to
10 years even after a preceding 5 years of tamoxifen is effec-
tive in increasing further disease-free survival [14].
37.3  ascular Endothelial Growth Factor
V
(VEGF)-Directed ­Treatment
Extensive preclinical work has established angiogenesis, the
sprouting of new blood vessels originating from a preexisting
vasculature, as one of the hallmarks of cancer [15–17].
Understanding of these pathways has progressed since the
early days of angiogenesis research. Angiogenesis was once
suggested to be a universal prerequisite for any tumour
growth and thus a potentially universal target in patients with
growing cancers. It has now been shown to be more relevant
in some tumours than in others. Most angiogenesis inhibitors
target, or at least co-target, the VEGF-VEGF receptor type 2
(VEGF-R2) pathway. The efficacy of VEGF-­directed therapy
is clearly successful in increasing overall survival (OS) in
patients with advanced clear cell renal cancer and metastatic
colorectal cancer, either as a single agent or in combination
with chemotherapy, respectively. However, in both these dis-
eases, anti-VEGF strategies have failed to demonstrate any
benefit in the adjuvant setting. In metastatic breast cancer, the
addition of bevacizumab to different types of chemotherapy,
used in first- or later lines of treatment, resulted in significant
gains in response rate (RR): in significant but modest gains in
progression-free survival (PFS) but without a convincing
influence on overall survival (OS) [18, 19]. Similarly, in the
neoadjuvant setting, the addition of bevacizumab to standard
chemotherapy in general results in an increase in the rate of
pathological complete response (pCR), although data are
somewhat conflicting. Different studies have investigated the
efficacy of adding bevacizumab to standard adjuvant therapy,
according to clinically defined breast cancer subtypes. The
use of an angiogenesis inhibitor in the adjuvant setting has a
number of clear rationales: preclinical synergy with different
cytotoxics (notably with taxanes), synergy with anti-HER2
agents, the increase in response rates in metastatic disease,
the immunomodulating properties of VEGF and the concept
of angiogenesis inhibition as means to induce and/or sustain
tumour dormancy. Three large randomised phase III studies
investigated the adjuvant value of bevacizumab in the three
different breast cancer subgroups.
In the largest study ever in triple-negative breast cancer,
the Beatrice trial, 1290 patients were randomised to receive
chemotherapy alone and 1301 to receive bevacizumab plus
chemotherapy [20]. Most patients received an anthracycline-­
containing therapy, and 63% had node-negative disease. The
3-year invasive disease-free survival (IDFS) was 82·7% with
chemotherapy alone and 83·7% with the combination. No
difference in OS was observed.
In the Eastern Cooperative Oncology Group E5103 study,
4994 patients with HER2-negative breast cancer were assigned
to one of three treatment arms [21]. In addition to doxorubi-
Adjuvant Molecular Therapies in Breast Cancer
cin and cyclophosphamide followed by weekly paclitaxel,
patients received either placebo (Arm A), or bevacizumab
during chemo (Arm B) or bevacizumab during chemo fol-
lowed by bevacizumab monotherapy for ten cycles (Arm C).
The primary endpoint was invasive disease-free survival
(IDFS). Nearly two out of three patients had ER+ disease
(64%). With a median follow-up of 47.5 months, the 5-yr
IDFS (95%CI) was not different between these three regi-
mens, respectively, 77% (70.9%–81.2%), 76% (71.5%–79.8%)
and 80% (77%–82.5%).
Finally, in the BETH study, 3509 women with HER2-­
positive breast cancer who were either node-positive or high-­
risk node-negative (41%) were included [22]. Patients were
enrolled in one of two chemotherapy regimens: six cycles of
docetaxel/carboplatin plus trastuzumab (TCH) with or with-
out bevacizumab or an anthracycline-based regimen involv-
ing three cycles of docetaxel plus trastuzumab given with or
without bevacizumab followed by three cycles of
5-­fluorouracil, epirubicin and cyclophosphamide (FEC). In
both regimens, patients continued trastuzumab with or with-
out bevacizumab after chemotherapy to complete 1 year of
targeted therapy. Bevacizumab added to adjuvant chemo-
therapy plus trastuzumab had no effect on IDFS. At a median
follow-up of 38 months, IDFS rates were 92% for both groups
of the TCH cohort. A secondary endpoint compared IDFS in
patients in the anthracycline-based vs the TCH-based
cohorts and also found no significant differences between the
regimens, whether with or without bevacizumab.
These studies have ended the discussion on a possible role
for bevacizumab in the adjuvant setting in patients with
breast cancer.
37.4 HER2-Directed Treatment
The HER2-positive subgroup of breast cancer is defined by
increased expression and/or amplification of the HER2 gene.
Consensus criteria of what is to be considered HER2-positive
disease is defined by the most recent American Society of
Clinical Oncology/College of American Pathologists (ASCO-­
CAP) guidelines [23]. These criteria have changed somewhat
over time. Some discussion remains regarding borderline
cases and heterogeneity. In general, some 15–20% of patients
presenting with primary localised breast cancer belong to
this subgroup. Some 50–60% of these patients also express
the ER and/or the PgR in their tumours.
The introduction of trastuzumab combined with chemo-
therapy in first-line treatment of HER2-positive metastatic
breast cancer resulted in a clinically significant survival ben-
efit. This gain in OS was observed with the combination of
trastuzumab with either anthracyclines or paclitaxel [24].
This impressive improvement was however accompanied by
the emergence of cardiac toxic effects of trastuzumab, most
notably if used in combination with anthracyclines.
Different randomised trials have investigated the benefit
of at least 1 year of trastuzumab combined with standard
rares1geo@gmail.com
449 37
adjuvant chemotherapy. Positive interim analyses were first
reported in 2005 [25, 26]. Other studies have investigated dif-
ferent durations of trastuzumab and the combined neoadju-
vant and adjuvant use of trastuzumab.
The HERA trial and the NCCTG N9831 studies used
sequential trastuzumab in at least one study arm, starting the
antibody after the end of chemotherapy [25, 26]. The BCIRG
006 trial asked the question of the efficacy of a non-­
anthracycline/trastuzumab combination as one of the exper-
imental arms [27].
In the initial analysis, outcomes were reported with
median follow-up of between 24 and 36 months. The range of
benefit in DFS in favour of trastuzumab resulted in hazard
ratios (HR) of between 0.48 and 0.67 (p < 0.0001), and the
range in benefit in OS was between 0.59 and 0.67 (p = NS to
p = 0.015). Absolute improvements in DFS ranged from 6%
to 11%. With longer follow-up of these trials (8-year median
follow-up from HERA and from the combined analyses of
NSABP B-31 and NCCTG N9831 and 10 years for BCIRG
006), there continues to be statistically and clinically signifi-
cant improvements in DFS and OS [28–30]. The magnitude
of benefit appears to have somewhat decreased over time as
more events (both relapses and deaths) occur, but absolute
gains in OS are larger now than in earlier analyses. The selec-
tive crossover of some of the patients initially randomly
assigned to the no trastuzumab arm will have mitigated some
of the initial differences. However, relapses unfortunately
continue to occur at a relatively constant rate over time in the
trastuzumab-treated arms. Overall, in the combined NSABP
B-31 and NCCTG N9831 data, an estimated improvement in
10-year DFS of 40% (HR 0.60, CI 0.53 to 0.68, p <.001) and
an increase of 10-year OS from 75.2% to 84% (HR0.63, CI
0.54 to 0.73, p < .001) has been shown [30]. These improve-
ments were observed in all subgroups, suggesting a benefit
irrespective of tumour size, hormone receptor status, nodal
status or patient age. Similarly for the HERA trial, with a
median follow-up of 8 years, and despite a crossover in half
of the patients, a significant improvement in DFS and OS was
observed with HRs of 0.76 for both DFS and OS.
37.4.1  oncurrent or Sequential HER2
C
Blockade
The analysis of the sequential versus concurrent trastuzumab
arms of the in NCCTG N9831 trial suggested a positive risk
to benefit ratio for the concurrent paclitaxel and trastuzumab
regimen. This resulted in the concurrent regimen as being
the standard of care treatment [31].
37.4.2 Role of Dual Adjuvant HER2 Blockade
The first attempt to escalate the degree of HER2 inhibition
consisted in the implementation of dual HER2 blockade by
the addition of lapatinib (a reversible tyrosine kinase i­ nhibitor
 450 A. Prove et al.
of HER1 and HER2) to trastuzumab. This attempt was first
tested in the neoadjuvant setting in the NeoALTTO trial. The
dual blockade of HER2 translated into a near doubling of the
pathological complete response rate (pCR) [32]. Unfortunately,
in the four-arm adjuvant ALTTO trial, the arm with the dual
HER2 inhibition failed to improve on the standard trastu-
zumab arm [33]. Adding lapatinib to adjuvant trastuzumab
either in sequence or in combination failed to improve DFS
but added toxicity. There has been much discussion about
why the results of NeoALTTO failed to translate into clinical
benefit in the ALTTO trial. But similar findings were made in
the NSABP B-41 randomised trial of neoadjuvant therapy in
operable, HER2-positive breast cancer where the addition of
lapatinib, whilst increasing the pCR rate, failed to make a dif-
ference to DFS or OS [34].
Following the impressive results of dual HER2 inhibition
with trastuzumab and pertuzumab in the Cleopatra study,
clinical assessment of the adjuvant performance of the com-
bined trastuzumab/pertuzumab regimen is ongoing in the
APHINITY trial, which compares trastuzumab/pertuzumab
and chemotherapy vs trastuzumab and chemotherapy for
adjuvant treatment. At present there is no role for dual HER2
inhibition in the adjuvant setting.
37.4.3  ole of Dual Adjuvant VEGF/HER2
R benefits be obtained with a shorter duration of trastuzumab
Inhibition
In spite of a sound preclinical rationale, negative results were
37 reported for the addition of bevacizumab to adjuvant trastu-
zumab treatment within the context of the BETH study [22].
37.4.4 Role of Extended HER2 Blockade
The HERA trial was a three-arm study comparing observa-
tion to 1 or 2 years of adjuvant trastuzumab after the end of
standard chemotherapy. In the comparison between 1 and 2
years of consecutive trastuzumab, the hazard ratio between
both arms was 0.99 (0.85 to 1.14, p  =  0.86) [35]. Although
this study was also negative for both the ER+ and the ER-
subgroups, there was a temporary and not statistically sig-
nificant separation of the curves in favour of 2 years of
trastuzumab in the ER-negative cohort, which is indicative of
an increased short-term risk of relapse in the control group,
who did not receive any adjuvant therapy during that time.
The conclusion of the HERA extension arm remains that
increasing the duration of trastuzumab beyond 1 year after
chemotherapy is not an effective strategy.
In the ExteNET study, 2840 patients, who had completed
up to 2 years of the standard therapy of 1 year of adjuvant
trastuzumab, were randomised between observation and
daily intake of 240 mg of neratinib, on oral irreversible HER1,
HER2, and HER4 inhibitors [36]. The patient population
enrolled in ExteNET had a higher risk of recurrence com-
pared with the HERA patients. Neratinib is an oral agent
with significant activity in the metastatic setting both in
rares1geo@gmail.com
trastuzumab pretreated and unpretreated patients [37]. Its
main toxicity is diarrhoea. Grade 3 diarrhoea occurred in
40% of the patients in the neratinib arm of ExteNET. This led
to dose reductions in 26% of patients and drug discontinua-
tion in 17%. An intensive loperamide prophylaxis schedule
has since been shown to decrease the incidence of grade 3
diarrhoea to below 20%.
At 2 years after enrollment, 70/1420 invasive disease
events occurred in the neratinib arm versus 109/1420 in the
placebo arm. The absolute reduction in IDFS at 2 years was
2.3%. Apparently, the benefit of extended HER2 inhibition
was nearly exclusively limited to the ER-positive subgroup.
This is surprising as in HERA the non-significant numerical
benefit was limited to the ER-negative subgroup, and simi-
larly in all neoadjuvant studies, pCR rates were invariably
higher in the ER-negative subgroup.
Nonetheless, the ExteNET study demonstrates that con-
tinued HER2 inhibition with a non-cross-resistant agent
after disease control with primary chemotherapy and trastu-
zumab is able to improve DFS.
37.4.5 De-escalating Regimens
If longer use of trastuzumab is not better, could the same
therapy? This question begged to be addressed, not only
because of the lack of improvement with 2 years of trastu-
zumab in HERA but also because of the excellent results
obtained in the FinHER study [38]. In this smaller adjuvant
trial, patients with HER2-positive breast cancer received only
9 weeks of trastuzumab with an HR of 0.57 for the trastu-
zumab comparison. A direct randomised comparison of 6
versus 12 months of trastuzumab was undertaken by the
PHARE investigators, and the results for 3380 patients at 42.5
months of median follow-up showed overall that 6 months of
trastuzumab could not be shown to be non-inferior to 12
months of therapy (HR 1.28, 95% CI 1.05–1.56, p = 0.29 for a
non-inferiority bar set at a HR of 1.15) [39]. In the PHARE
trial, patients were stratified according to concomitant or
sequential use of adjuvant trastuzumab. Patients with ER-­
negative tumours treated with 6 months of sequential trastu-
zumab chemotherapy had significantly shorter DFS than did
patients with ER-negative tumours treated with 12 months of
sequential trastuzumab following chemotherapy (HR 1.57,
95% CI 1.08–2.28). In patients with ER-negative tumours
who received concomitant chemotherapy and trastuzumab,
the estimate of 6 versus 12 months of trastuzumab seemed
the most compatible with the non-inferiority hypothesis (HR
1.10, 95% CI 0.73–1.65) [40].
Mavroudis and colleagues reported on a randomised
study by the Hellenic Oncology Research Group (HORG)
comparing 6 versus 12 months of adjuvant trastuzumab [41].
The drug administration in this study, both for the chemo-
therapy and for the trastuzumab, was dose-dense, i.e. on a 2
weekly basis for both. A total of 481 patients were randomised
to receive 12 months or 6 months of adjuvant trastuzumab.
Adjuvant Molecular Therapies in Breast Cancer
The null hypothesis for this trial was that 6 months of adju-
vant trastuzumab is not inferior to 12-month treatment in
terms of 3-year DFS. The non-inferiority hazard ratio (HR)
margin of 1.53 was derived from an estimated absolute differ-
ence in 3-year DFS of 8%, based on an expected DFS in the
12-month group of 85%. After a median follow-up of 47 and
51 months, 17 (7.1%) and 28 (11.7%) patients had experi-
enced disease recurrence (p = 0.08) in the 12- and 6-month
groups, respectively. The 3-year DFS was 95.7% versus 93.3%
numerically in favour of the 12-month treatment group (HR
= 1.57; 95% CI 0.86–2.10; p = 0.137).
Further studies are investigating the duration question,
but for now, 1year of trastuzumab remains the unchallenged
standard of care.
37.4.6 Efficacy in Small HER2 Tumours
Trastuzumab combined with chemotherapy is the standard
adjuvant treatment in patients with HER-2-positive tumours
and a diameter of >1cm or positive lymph nodes based on the
results the six adjuvant studies. Does this benefit persist in
patients with smaller tumours, expected to have a lower a
priori risk of recurrence ? A meta-analysis was performed on
the efficacy of trastuzumab in the subgroup of patients with
HER2-positive disease and a T1 primary tumour [42]. Of
note only a small minority of these patients had node-­
negative disease, and most of these were enrolled in the
HERA trial, which used a sequential trastuzumab design. In
total 4220 patients had T1 tumours with the overwhelming
majority being classified as T1c (80% of HR+ group, and 82%
of the HR group had a T1c tumour). In the HR+ group (n
=2263), treatment with trastuzumab decreased the cumula-
tive incidence of a DFS event at 8 years from 24.3% to 17.3%,
with a decrease in cumulative incidence of death from 11.6%
to 7.8% or an absolute gain in OS of 3.8%. In the 1975 HR
patients, treatment with trastuzumab decreased DFS events
at 8 years from 33.5% to 24.0% or an absolute gain of 9.4%.
The overall survival at 8 years increased by 8.8%.
Clearly this type of analysis does not answer the question
of a potential benefit of trastuzumab for those patients with a
T1a/T1b and node-negative HER2-positive primary breast
cancer. Overall it is estimated that 6–10% of the small node-­
negative breast tumours are HER2-positive, and there is con-
flicting evidence from numerous retrospective studies for an
inferior outcome in these patients with recurrence being esti-
mated from 5 up to 30% after 5–10 years of follow-up [43,
44]. The prospective single arm adjuvant paclitaxel and
trastuzumab trial (APT) enrolled 410 patients with HER2-­
positive, node-negative disease with a tumour size of up to
3  cm [45]. Only 8.9% had a T2 tumour, and 49.4% had a
tumour up to 1 cm in diameter, and 67% of enrolled patients
had hormone receptor-positive disease. The 3-year rate of
IDFS was 98.7% (CI 97.6 to 99.8). Only two patients devel-
oped distant recurrence. These results were obtained with a
relative low toxicity cost; 13 patients (3.2%) had at least one
episode of grade 3 neuropathy and two patients suffered from
rares1geo@gmail.com
451 37
symptomatic congestive heart failure (0.5%). This study dem-
onstrates that the APT regimen is both safe and results in
excellent DFS. It represents a viable option for patients with
HER2-overexpressing T1a and T1b tumours. A comparative
trial is randomising patients with stage I ­ HER2-­ positive
breast cancer between this APT-regimen and T-DM1.
37.5 Conclusion
We still lack an effective adjuvant targeted agent for those
patients with the highest risk of recurrence, the patients with
triple-negative breast cancer. In contrast the improvement
obtained with 1 year of trastuzumab to be initiated concomi-
tant with taxane chemotherapy remains impressive. One year
of trastuzumab given concurrently with a taxane and in gen-
eral following an anthracycline combination is the preferred
standard of care in all patients with node-positive or T1c
HER2-positive primary breast cancer. As an alternative, the
non-anthracycline-containing regimen, the TCH regimen
from BCIRG006, is an acceptable and safe choice. The role of
neratinib is an additional option to improve DFS further.
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 453 38

Primary Systemic Therapy

for Breast Cancer
Cornelia Liedtke and Hans-Christian Kolberg

38.1 The Principle of Primary Systemic (Neoadjuvant, Induction)

Therapy for Operable Breast Cancer – 454

38.2 The Prognostic Relevance of Pathological

Complete Emission (pCR) – 455

38.3 Regimens in Neoadjuvant Therapy – 455

38.3.1 Neoadjuvant Endocrine Approaches – 455
38.3.2 General Considerations Regarding Primary Systemic
Chemotherapy Regimens – 456
38.3.3 Choice of Therapy Regimens in HER2-­Positive Breast Cancer – 457
38.3.4 Choice of Therapy Regimens in Patients
with HER2-Negative Breast Cancer – 458

38.4 Predictive Markers for the Benefit of Primary

Systemic Therapy – 459
38.4.1 Tumour-Infiltrating Lymphocytes (TILs) – 459
38.4.2 Individual Molecular Biomarkers of Resistance – 459
38.4.3 Tumour Cell Proliferation – 459
38.4.4 BRCA Status – 460

38.5 Future Concepts in Primary Systemic Therapy

for Breast Cancer – 460
38.5.1 Tailoring Therapy Based on Neoadjuvant Therapy Response – 460
38.5.2 Window of Opportunity Trials – 460

38.6 Conclusion – 460

References – 461

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_38

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 454 C. Liedtke and H.-C. Kolberg
38.1  he Principle of Primary Systemic
T ..      Table 38.1  Arguments pro and contra primary systemic
(Neoadjuvant, Induction) Therapy
for Operable Breast Cancer
Breast cancer is a malignancy with a comparably long natural
history with mortality basically caused by distant metastases
and not by local disease. Therefore, even aggressive local
therapy alone may be insufficient to achieve long-term sur-
vival in those cases where micrometastases are already pres-
ent at the time of diagnosis. In 1975, follow-up data revealed
that only 25% of patients with lymph node involvement sur-
vived beyond 10  years after diagnosis despite ultraradical
surgery [1]. This led to the first trials comparing chemother-
apy versus no chemotherapy [2] and tamoxifen versus no
adjuvant endocrine therapy [3] yielding significant survival
benefits in both cases. In a mouse model (using a highly
aggressive mouse mammary adenocarcinoma strain),
Adriamycin caused a complete remission in over 80% of the
mice when given before surgery [4]. In the early 1980s, the
first non-randomized studies evaluated the benefit of pri-
mary systemic therapy in humans. Although these studies
were very heterogeneous, showed varying breast conserva-
tion rates (from 24% to 88%) and examined response and
rates of pathological complete remission (pCR) as the only
endpoints, they were still a «proof of concept» for the neoad-
juvant approach in a time when a tumour size of larger than
3 cm was an indication for a mastectomy [5–7].
In 1998, the first dataset comparing preoperative and
postoperative chemotherapy was published (NSABP-B18). A
total of 1523 patients were randomized to four cycles of AC
administered preoperatively versus postoperatively. The sur-
38 vival variables showed no difference, whereas the rate of
breast-conserving therapy was significantly higher in the
neoadjuvant arm. Achieving a pathologic complete remis-
sion was associated with a better overall prognosis [8]. In the
subsequent NSABP trial, the NSABP-B27 study, patients
were randomized into three arms: four cycles of preoperative
AC versus the same schedule with the addition of four cycles
of docetaxel versus four cycles of preoperative AC followed
by four cycles of docetaxel after surgery. As expected both
arms with four cycles of AC preoperatively yielded similar
pCR rates (12.9% versus 14.4%), whereas the arm containing
AC followed by docetaxel in the preoperative setting was sig-
nificantly superior with a pCR rate of 26.1%. A significant
survival benefit with DFS and OS superior by about 20% was
observed for the patients achieving a pCR [9].
In recent years neoadjuvant therapy has become a stan-
dard of care not only for inoperable or locally advanced cases
but also for smaller operable tumours. It is an option for all
patients where systemic therapy is definitely indicated at the
time of diagnosis with the goal of improving disease-free and
overall survival [10]. The improvement in rates of breast con-
servation surgery with primary systemic therapy should not
be forgotten but has become a secondary goal particularly in
the era of oncoplastic surgery. The cytotoxic regimens used
in the neoadjuvant setting in routine clinical practice are the
same as used for adjuvant therapy. This implies that the indi-
rares1geo@gmail.com
therapy
Pro Contra
In vivo sensitivity testing Fear of patients to leave
the tumour in place
Strong prognostic value of pCR Discrepancy in grading for
core biopsy and definite
specimen: risk of
overtreatment
Higher rate of breast-conserving Discrepancy between
surgery/higher rate of operabil- clinical and pathological
ity/improved cosmetic outcome nodal status: risk of
undertreatment
Therapy monitoring possible Prognostic value of pCR
not demonstrated for all
subtypes and regimens
Psychologic effect of tumour Lack of guidelines for
shrinking progressive disease under
neoadjuvant therapy
Post-neoadjuvant concepts in
case of non-pCR
cation for primary systemic therapy comprising chemother-
apy should be restricted to cases where the need for
chemotherapy is certain. The neoadjuvant approach carries
the potential for response-guided treatment because of its
efficacy at in vivo sensitivity testing, which may increase the
rate of breast-conserving surgeries. In addition, especially in
triple-negative cases, primary systemic therapy provides time
for genetic testing which may have consequences for subse-
quent surgical management. A choice of arguments for and
against primary systemic therapy is presented in . Table 38.1.
Many patients such as those with, for example, non-­
inflammatory HR-positive and HER2-negative, low prolifer-
ative index breast cancer have no indication for chemotherapy
due to a low expected relative and absolute treatment benefit
and thus are not candidates for neoadjuvant chemotherapy.
In cases of high tumour burden, they may benefit from pri-
mary endocrine therapy in order to perform breast-­
conserving surgery. In contrast, high-risk HR-positive/
HER2-negative patients with tumours showing a high prolif-
eration rate, high tumour burden in the breast and/or axilla
or further risk factors such as grade 3 or high-risk classifica-
tion based on a multigene assay may benefit from cytotoxic
therapy and are therefore also candidates for neoadjuvant
chemotherapy. The use of chemotherapy in HER2-positive
and triple-negative breast cancer is common clinical practice.
A lack of expression of oestrogen and progesterone receptors
with or without overexpression of HER2  in combination
with high proliferative activity, high tumour grade, high
expression of Ki-67 or high genomic grade index is the main
predictors for response to neoadjuvant therapy [11, 12].
Other predictors with a lower impact are age, non-lobular
tumour type or early clinical response [13].
Primary Systemic Therapy for Breast Cancer
The indications for primary systemic therapy (irrespec-
tive of whether the recommended therapy is combination
chemotherapy, an antibody-containing regimen or endo-
crine therapy) are easily summarized:
55 Inflammatory breast cancer
55 Inoperable breast cancer
55 To facilitate breast conservation surgery
55 If the same systemic therapy would also be indicated
in the adjuvant setting
55 If adjuvant chemotherapy is likely to be advised and
complex surgery is planned which may otherwise delay
systemic therapy
55 If adjuvant chemotherapy is likely to be advised and the
results of gene testing are awaited which may affect
subsequent treatment decisions
455 38
the heterogeneity of response. Consequently, optimized
quantification of chemotherapy response has been suggested,
for instance, by the use of semi-quantitative scoring systems
such as the Residual Cancer Burden (RCB) [18] which com-
bines histopathological tumour diameter, tumour cellularity,
the number of axillary lymph node metastases and the diam-
eter of axillary lymph node metastases by the use of a math-
ematical model to convert these into a single parameter that
reflects the extent of chemotherapy response on a scale of
0–3. A value of 0 corresponds to a pCR. These values have
been shown to correlate significantly with the prognosis of
the patient in a semi-quantitative matter. Although the RCB
score is used primarily in the USA, the use of this parameter
can also be seen to be extending into Europe; however, this is
largely in the context of clinical trials at present.

Women must be counselled about the success or failure rate

of PST in facilitating BCS if this is the aim, and a pretreat- 38.3 Regimens in Neoadjuvant Therapy
ment MRI should be done to ensure unifocality if this is the
aim. During and after PST, imaging with MRI to assess 38.3.1 Neoadjuvant Endocrine Approaches
response may be useful to monitor response and guide sub-
sequent therapy. In some cases a complete pathological and Although some physicians feel that primary endocrine ther-
imaging response may occur, and in women wishing breast apy is mainly used in older postmenopausal women with
conservation therapy, it is important that a marker clip is comorbidities in order to achieve operability in large tumours
placed in the tumour to facilitate subsequent tumour local- or to avoid surgery at all in cases of severe risks for operative
ization. complications, basically all patients with endocrine respon-
Following completion of primary systemic chemother- sive tumours and favourable risk factors such as ER/PR sen-
apy, surgery should take place between 4 and 6 weeks later to sitivity, low nuclear grade or low Ki-67 [19] are candidates for
allow leucocyte counts to recover. a primary endocrine approach due to the low expected
response rates to neoadjuvant chemotherapy [20]. In clinical
practice this approach is rarely chosen for fit patients with
38.2 The Prognostic Relevance of good operability that are usually treated with endocrine ther-
Pathological Complete Emission (pCR) apy after surgery.
In general the endocrine regimen should be chosen
Numerous studies have shown that achieving a histopatho- according to the adjuvant data on endocrine therapy, but it is
logical complete remission represents an independent prog- also helpful to look at the literature specifically looking at
nostic parameter in the preoperative setting and therefore primary endocrine therapy.
may serve as a surrogate marker for long-term survival of In analogy to adjuvant studies, comparisons in the neo-
breast cancer [14, 15]. However, there is variability regarding adjuvant setting have demonstrated the superiority of aroma-
both the probability and the prognostic validity of achieving a tase inhibitors over tamoxifen [21, 22]. Direct comparisons
pCR among the distinct intrinsic breast cancer subtypes: of letrozole, anastrozole and exemestane have shown similar
while pCR is an important outcome parameter among efficacy for all three drugs [23].
patients with high-risk breast cancer subtypes (such as triple-­ The optimal duration of neoadjuvant endocrine therapy
negative breast cancer (TNBC) or HER-positive/hormone is unclear. Many patients are treated preoperatively for
receptor (HR)-negative breast cancer), other breast cancer 4–6 months in clinical practice although 37% of patients may
subtypes (such as low-risk hormone receptor positive (lumi- achieve maximal response only after 6–12 months [24].
nal A)) may have a favourable prognosis even in cases where For the reasons discussed above regarding which patients
there is residual tumour at the time of surgery. Nevertheless, are candidates for neoadjuvant endocrine therapy, direct
achievement of a pCR is considered to be a relevant endpoint comparisons with neoadjuvant chemotherapy are rare. The
for regulatory authorities as the Food and Drug Administration few data indicating that in selected cases neoadjuvant endo-
in granting approval for new agents. crine therapy and neoadjuvant chemotherapy have the same
Another matter of debate is the optimal definition of response rates [25] reflect the fact that most patients in the
pCR: at present there is debate about whether residual DCIS chemotherapy arms should not have received neoadjuvant
should be included in the definition of pCR [15, 16] and chemotherapy because of the favourable characteristics of
whether nodal response should be considered [17]. their tumours: simply put, the biology of disease likely to
Finally, the simple dichotomy of chemotherapy response respond to endocrine therapy is less likely to respond to che-
(i.e. pCR vs. any residual tumour) may not accurately reflect motherapy and vice versa.

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456 C. Liedtke and H.-C. Kolberg

..      Table 38.2  Clinical trials investigating neoadjuvant endocrine therapy combined with agents targeting endocrine resistance

Trial number and Phase Arms Duration Primary endpoints

planned recruitment

PI3K inhibitor

NCT02273973N = 330 Phase II Arm A: taselisib + letrozole 16 weeks pCR

Arm B: placebo + letrozole

NCT01923168N = 360 Phase II Arm A: BYL719 + letrozole 24 weeks pCR

Arm B: buparlisib + letrozole
Arm C: placebo + letrozole

AKT inhibitor

NCT01776008N = 87 Phase II MK-2206 + anastrozole; goserelin acetate if Maximum four cycles pCR based on Ki-67
premenopausal of 28 days each values

CDK4/6 inhibitor

NCT01723774N = 29 Phase II PD0332991 + anastrozole + goserelin Maximum four Complete cell cycle

acetate if premenopausal cycles of 28 days arrest (CCCA) based
each on Ki-67 values

NCT0229801N = 306 Phase II Arm A: letrozole 14 weeks Change in Ki-67

Arm B: letrozole (2 weeks) and then values, cCR
letrozole + palbociclib (12 weeks)
Arm C: palbociclib (2 weeks) and then
letrozole + palbociclib (12 weeks)
Arm D: letrozole + palbociclib

NCT02400567N = 132 Phase II Arm A: chemotherapy (FEC-Doc) 18 weeks Residual cancer

Arm B: letrozole + palbociclib (12 weeks) burden

Ki-67 may represent a potential biomarker for use
among patients undergoing primary endocrine therapy. In
the IMPACT trial, Ki-67 measurements after 2  weeks of
38 endocrine therapy were able to predict recurrence free
survival [26]. The POETIC trial, which recruited 4000
Studies are evaluating combinations of endocrine therapy
with agents targeting endocrine resistance such as PI3K
inhibitors, AKT inhibitors and CDK4/CDK6 inhibitors in the
neoadjuvant setting. Several trials investigating this approach
are currently recruiting (. Table 38.2) [29].

patients until April 2014, was designed to test the signifi-

cance of 2-week Ki-67 measurements during endocrine
therapy as a prognostic marker for survival variables.
However, results from this trial are not available yet [27].
Similarly, a 3-week approach regarding Ki-67 re-biopsy is
investigated by the ADAPT trial. Pre- and postmenopausal
patients with less than four positive lymph nodes are
receiving 3 weeks of endocrine induction therapy accord-
ing to guidelines. Risk of recurrence is furthermore
assessed using the recurrence score: patients with a recur-
rence score of 11 or lower are treated with postoperative
endocrine therapy alone; patients with a recurrence score
of 26 or higher will receive neoadjuvant chemotherapy. In
the group of patients considered to carry an intermediate
risk of recurrence (i.e. recurrence scores 12–25), further
therapy is decided based upon Ki-67 measurements fol-
lowing 3 weeks of endocrine therapy: patients with a Ki-67
higher than 10% after 3 weeks of endocrine induction
therapy are classified as nonresponders and will receive
neoadjuvant chemotherapy, whereas in cases of a drop of
Ki-67 below 10%, patients are operated on and will stay on
endocrine therapy according to guidelines [28]. This trial
is also still recruiting patients.
38.3.2  eneral Considerations Regarding
G
Primary Systemic Chemotherapy
Regimens
Usually, neoadjuvant treatment regimens consist of combina-
tion chemotherapy regimens containing both taxanes and
anthracyclines sequentially or simultaneously. However,
anthracycline-free chemotherapy regimens may be ­considered
a valuable alternative. It is suggested to use those chemother-
apy regimens that would have been applied in the adjuvant
setting rather than primary systemic setting. Response con-
trol during PST is important and is usually carried out by
ultrasound evaluation every 6 weeks. However, data regard-
ing an adjustment of the treatment regimen during the course
of therapy in case of lack of sufficient response is insufficient
despite the fact that there is data suggesting that patients with
hormone receptor-positive breast cancer might benefit from
switching to a non-cross-resistant regimen [30]. It is a com-
mon practice that patients not responding to PST and dem-
onstrating tumour progression should stop treatment and
immediately undergo adequate local therapy.

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Primary Systemic Therapy for Breast Cancer
457 38
38.3.3  hoice of Therapy Regimens in HER2-­ increase pCR rates significantly if added to trastuzumab [32].
C
Positive Breast Cancer The increase in pCR, however, did not translate into a signifi-
cant improvement of disease-free survival in a clinical trial
Choice of neoadjuvant therapy is largely decided upon based using lapatinib and trastuzumab as part of an adjuvant treat-
on established combinations of chemotherapy with trastu- ment regimen (Adjuvant Lapatinib and/or Trastuzumab
zumab or dual HER2 blockade. There is a large body of evi- Treatment Optimisation (ALTTO) Trial [33]). Therefore, lapa-
dence suggesting that the poor prognosis associated with tinib is not acknowledged as an optimal combination partner
HER2 overexpression/amplification is counterbalanced by for trastuzumab in the potentially curative setting.
the high probability of benefit from HER2-directed thera- In contrast, data regarding the HER2 dimerization inhib-
pies: in the neoadjuvant setting, the addition of the anti-­ itor pertuzumab seem to be more promising as findings from
HER2-­directed antibody trastuzumab to chemotherapy is the neoadjuvant NeoSphere trial suggest [34]: Gianni and
associated with a significant increase of pCR in several large-­ colleagues reported results obtained from 417 patients with
scale clinical trials leading to its approval as part of primary HER2-positive breast cancer with a tumour size larger than
systemic therapy among patients with HER2-positive breast 2 cm who were randomized to four 12-week treatment arms:
cancer (see . Table 38.3).
 
trastuzumab/docetaxel, pertuzumab/trastuzumab/docetaxel,
Since the development of trastuzumab, several novel agents pertuzumab/trastuzumab and pertuzumab/docetaxel. The
have been evaluated for the use among patients with HER2- authors observed a significant increase in the rate of pCR by
positive breast cancer mainly in the primary systemic therapy the addition of pertuzumab to trastuzumab and docetaxel
setting. There is a large body of evidence suggesting that the (45.8% versus 29.0%). In the subgroup of patients with
small molecule lapatinib is inferior to trastuzumab with regard HER2-positive/HR-negative breast cancers, the pCR rate
to rates of pCR as part of a combination regimen [31], but may achieved by the use of dual HER2 blockade in combination

..      Table 38.3  pCR rates of combined HER2-directed therapies in the neoadjuvant setting

NeoSphere (n = 417) pCR (ypT0)

Trastuzumab + docetaxel 29.0%

Pertuzumab + trastuzumab + docetaxel 45.8%

Pertuzumab + trastuzumab 16.8%

Pertuzumab + docetaxel 24.0%

Neo-ALTTO (n = 455) pCR (ypT0/is ypN0)

Trastuzumab → trastuzumab + paclitaxel 29.5%

Lapatinib → lapatinib + paclitaxel 24.7%

Trastuzumab/lapatinib → trastuzumab/lapatinib + paclitaxel 51.3%

TRYPHaena (n = 225) pCR (ypT0/is) pCR (ypT0 and ypN0)

FEC + pertuzumab + trastuzumab × 3 → pertuzumab + trastuzumab + docetaxel × 3 61.6% 50.7%

FEC × 3 → pertuzumab + trastuzumab + docetaxel × 3 57.3% 45.3%

Docetaxel/Carboplatin + trastuzumab + pertuzumab × 6 66.2% 51.9%

GeparQuinto (n = 620) pCR (ypT0 and ypN0)

Epirubicin + cyclophosphamide + trastuzumab → docetaxel + trastuzumab 30.3%

Epirubicin + cyclophosphamide + lapatinib → docetaxel + lapatinib 22.7%

GeparSixto (n = 137) pCR (ypT0 and ypN0)

Weekly paclitaxel + non-pegylated liposomal doxorubicin + trastuzumab + lapatinib × 18 36.8%

Weekly paclitaxel + non-pegylated liposomal doxorubicin + trastuzumab + lapatinib × 32.8%

18 + carboplatin

GeparSepto (n = 1.200) pCR (ypT0 and ypN0)

Weekly nab-paclitaxel × 12 → 4 × EC + trastuzumab + pertuzumab 74.6%

Weekly paclitaxel × 12 → 4 × EC + trastuzumab + pertuzumab 66.7%

rares1geo@gmail.com
 458 C. Liedtke and H.-C. Kolberg
with docetaxel was as high as 63.2%. Of note, among patients
in the chemotherapy-free arm, dual HER2 blockade alone
resulted in an impressive pCR rate of 16.8%.
Consequently, pertuzumab has received a label extension
for the primary systemic setting in combination with trastu-
zumab and is registered in many countries as part of a stan-
dard neoadjuvant chemotherapy regimen. There is still,
however, an ongoing debate as to whether this improvement
in pCR will also translate into an improvement of prognosis.
Survival analyses from the NeoSphere trials suggest a signifi-
cant benefit regarding 3-year DFS (85 vs. 92%, HR 0.60 (95%
CI 0.28–1.27)) [35]; however, data from the corresponding
adjuvant Aphinity trials have not been reported yet.
38.3.4  hoice of Therapy Regimens
C German Breast Group (GBG) [45]) showed an increase
in Patients with HER2-Negative
Breast Cancer
Choice of chemotherapy regimen among patients with HER2-
negative breast cancer is largely independent of hormone
receptor expression status. Sequential or simultaneous combi-
nation chemotherapy containing both anthracyclines and tax-
anes has long been regarded as the standard primary systemic
chemotherapy approach. Adjuvant studies have suggested
benefit from the application of dose-dense chemotherapy if
metastatic disease is diagnosed in more than three axillary
lymph nodes [36] as well as in patients with TNBC [37].
Despite these data being limited largely to the adjuvant
setting, dose-dense chemotherapy is increasingly applied in
the primary systemic therapy setting as well in case of high
axillary tumour burden and other high-risk features.
38 Despite patients with TNBC carrying an overall unfa-
vourable prognosis, they are also characterized by an
increased chance of response to neoadjuvant chemotherapy,
which is reflected by increased rates of pCR [12]. This phe-
nomenon is often referred to as the «triple-negative paradox»
in the literature [38].
Given the importance of pCR as a prognostic parameter
among patients with TNBC, there is an urgent need to opti-
mize the efficacy of primary systemic chemotherapy and
thereby improve prognosis among patients with TNBC. This
may be achieved by the following considerations:
55 Optimization of chemotherapy scheduling (i.e. through
dose-dense/dose-intensified regimens) [39]
55 Use of additional agents in combination with standard
combination chemotherapy regimens
55 Development of novel targeted agents for patients with
TNBC
55 Identification of biomarkers for response to neoadjuvant
chemotherapy in TNBC to allow for treatment individu-
alization
rares1geo@gmail.com
Several studies have aimed at increasing chemotherapy effi-
cacy through addition of novel agents such as capecitabine
[40, 41] or eribulin [42]. However, solid data and validation
studies are lacking despite the fact that subgroup analyses
showed a significant benefit in TN breast cancer subgroups
by these approaches. In contrast, there is an accumulating
body of evidence suggesting that platinum salts should be
added to anthracycline/taxane chemotherapy in case of
triple-­negative breast cancer.
While historical data has suggested for several years that
platinum-containing chemotherapy may be particularly ben-
eficial to patients with TNBC [43, 44], prospective evidence
was lacking until the publication of two important neoadju-
vant clinical trials:
The first study (GeparSixto (NCT01426880) by the
regarding the primary study endpoint (i.e. pCR defined as
ypT0 ypN0) from 36.9% (58 of 157 patients, 95% CI 29.4–
44.5) to 53.2% (84 of 158 patients, 95% CI 54.4–60.9)
(p  =  0.005) through the addition of carboplatin to an
anthracycline/taxane chemotherapy regimen. In addition
to this, the addition of carboplatin not only led to an
increase in pCR but resulted in an improved prognosis
among patients with TNBC: after a median follow-up of
3 years, disease-free survival for patients assigned to carbo-
platin was 85.5% compared with 76.1% for patients assigned
no carboplatin [46].
The second study (CALGB/ALLIANCE-40603
(NCT00861705) by the Cancer and Leukemia Group B
(CALGB) [47]) analysed the use of carboplatin (and beva-
cizumab) among patients with TNBC in addition to a
sequential anthracycline/taxane chemotherapy regimen
and demonstrated an increase in the pCR rate from 41% to
54% (p = 0.0018). Given that hematologic toxicity and par-
ticularly serious adverse events were less common in asso-
ciation with the sequential regimen, it is regarded by many
as representing a more feasible regimen in daily clinical
management of patients with TNBC. In contrast to the sur-
vival analyses derived from GeparSixto trial, survival anal-
ysis of CALGB-­40603 regarding the secondary endpoints
of event-free (EFS) and overall survival (OS) suggested an
insignificant effect with hazard ratios of 0.84 (95% CI 0.58–
1.22, P  =  0.36) and 1.15 (95% CI 0.74–1.79, P  =  0.53),
respectively [48].
Overall, two distinct scenarios regarding the future use of
carboplatin among patients with TNBC seem imaginable:
55 Use of platinum salts to increase efficacy at the cost of
increased toxicity (i.e. therapy intensification)
55 Use of platinum salts to improve the therapeutic index
through improvement of treatment tolerability (i.e.
therapy de-escalation by replacing taxanes or more
importantly anthracyclines) (See . Fig. 38.1.)
Primary Systemic Therapy for Breast Cancer
459 38
crine resistance and resistance against endocrine therapy.
Integrating new principles Recently, results of a pooled analysis of four different clinical
in neoadjuvant therapy (e.g. trials (GeparQuattro/GeparQuinto, GeparSixto, Neo-­
platinum salts, combined
ALTTO, CHERLOB) were presented analysing the associa-
targeted therapies,
biologicals etc.) tion between PIK3CA mutation status and neoadjuvant
therapy response (i.e. pCR rates) among patients with HER2-­
positive breast cancer undergoing HER2-targeted agents.
Results of this analysis suggest that in fact the presence of
Intensification of therapy: Deescalation of therapy:
PIK3CA mutations in HER2+ breast cancer predicts for a
higher toxicity less toxicity
higher eff icacy equivalent efficacy significantly lower rate of pCR: within the subgroup of
patients with hormone receptor-positive breast cancer,
patients with PIK3CA mutations had a pCR rate of only 7.6%
compared to 24.2% among patients with PIK3CA wild-type
..      Fig. 38.1  Different modern approaches in primary systemic status (p < 0.001). In contrast, no difference in pCR (27.2%
therapy for breast cancer
vs. 36.4%) according to PIK3CAmutation status was observed
among patients with HER2-positive/HR-negative breast can-
cer (p = 0.125).
38.4  redictive Markers for the Benefit
P
of Primary Systemic Therapy
38.4.3 Tumour Cell Proliferation
There are a large number of biomarkers that have been sug-
gested to predict an improved chance of benefit from primary The significance of expression of the proliferation marker
systemic chemotherapy (i.e. associated with an increased Ki-67  in particular in the differentiation of luminal breast
chance of pCR). Currently, there are four parameters that are cancer subtypes (luminal A vs. luminal B) is a matter of
of particular interest: intense discussion. It is an acknowledged fact that hormone
55 The presence of tumour-infiltrating lymphocytes receptor-positive breast cancer with an increased expres-
55 Individual biomarkers sion of Ki-67 (luminal B subtype) shows a poorer prognosis
55 Parameters reflecting tumour cell proliferation but a higher probability of responding to neoadjuvant che-
55 BRCA mutation status motherapy.
Denkert and colleagues examined the association
between the expression of the proliferation marker Ki-67 and
38.4.1 Tumour-Infiltrating Lymphocytes the response to neoadjuvant chemotherapy as well as disease
(TILs) prognosis in individual breast cancer subtypes [50]. Patients
were stratified based on Ki-67 expression in three groups
There is a high level of evidence suggesting that the presence with cutoff values of lower than 15%, 15–35% and higher
of tumour-infiltrating lymphocytes (TILs) is able to reliably than 35%, respectively. Ki-67 was found to be of different
predict treatment response. This parameter seems to be par- prognostic and predictive values among different breast can-
ticularly relevant among high-risk breast cancer subtypes cer subtypes.
such as TNBC and HER2-positive disease. However, there is For patients with TNBC, a significant correlation between
uncertainty as to whether TILs may predict a subtype-­specific expression of Ki-67 and the pCR rate could be demonstrated.
effect or are rather associated with overall chemotherapy-­ The pCR rates for Ki-67 expression of ≤15%, 15–35% and
sensitivity. Furthermore, before this biomarker justifies intro- ≥35% were 15%, 22% and 38% (p = 0.003). However, no sig-
duction into daily clinical routine, hurdles such as lack of nificant differences regarding overall survival probabilities
standardization in analysis of TILs have to be overcome [49]. were observed. KI-67 was similarly associated with pCR
among patients with HR-positive/HER2-negative breast can-
cer (p  <  0.0005); no significant association with pCR was
38.4.2 Individual Molecular Biomarkers observed among patients with hormone receptor-positive/
of Resistance HER2-positive breast cancer and patients with hormone
receptor-negative/HER2-positive breast cancer. The only
The phosphatidylinositol-4,5-bisphosphate 3-kinase, cata- breast cancer subtype in which Ki-67 expression was associ-
lytic subunit alpha (PIK3CA) is a class I PI 3-kinase catalytic ated with OS was hormone receptor-positive/HER2-negative
subunit. It has repeatedly suggested mediating both endo- breast cancer.

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 460 C. Liedtke and H.-C. Kolberg
38.4.4 BRCA Status
Both in  vitro and preclinical analyses suggest a particular
sensitivity of BRCA1-associated breast cancers against plati-
num salts [51]. Between 10 and 20% of patients with TNBC
carry a BRCA1 mutation. Furthermore, TNBC carries many
histological and molecular features that are commonly found
among hereditary breast cancers. This has triggered an
intense (and yet ongoing) debate as to whether either diagno-
sis of TNBC or rather diagnosis of hereditary breast cancer
(regardless of molecular subtype) seem to represent the opti-
mal predictive factor for use of platinum salts as part of a
neoadjuvant treatment regimen.
Analyses derived from patients in the metastatic setting
suggest a particular sensitivity to carboplatin in first-line
monochemotherapy among patients with metastatic TNBC
(response rates 68% vs. 33%, p = 0.03) [52]. In contrast, in the
curative setting, results obtained in translational analyses of
the GeparSixto study did not confirm a predictive associa-
tion between BRCA1 mutations and carboplatin efficacy
among patients with TNBC [53]. Therefore, use of platinum
salts may be considered in patients with TNBC irrespective
of BRCA1 mutation status.
38.5  uture Concepts in Primary Systemic
F investigates whether patients with hormone receptor-­positive
Therapy for Breast Cancer
Primary systemic therapy clinical trials are of (increasing)
interest given the utility of pCR as an early response param-
eter and strictly defined endpoint. In fact, a significant (and
clinically relevant) increase in pCR (i.e. through the addi-
38 tion of a novel therapeutic substance) is an accepted param-
eter for (provisional) licencing of these agents in the curative
setting.
38.5.1 Tailoring Therapy Based
on Neoadjuvant Therapy Response
In contrast, patients that do not derive substantial benefit
from primary systemic therapy multi-agent approaches and
are left with residual cancer at the time of surgery represent a
particular challenge to the treating physician. For these
patients, additional/alternative treatment approaches are
urgently warranted. Post-neoadjuvant treatment options
might represent an issue for these patients that are commonly
left with a particularly unfavourable prognosis (particularly in
case of extensive residual disease or even disease progression
on therapy). Options are somewhat limited for these patients.
Recent analyses (Japan) suggest that post-­neoadjuvant use of
capecitabine might become an option for patients with TNBC
and residual tumour following preoperative chemotherapy
[54]. Current clinical trial concepts focus on the introduction
of new substances, such as selective inhibitors of cyclin-
rares1geo@gmail.com
dependent kinases (CDK) 4 and 6  in hormone receptor-
negative cancers (i.e. Penelope B, NCT01864746) or trastu-
zumab-DM1 (TDM1) among patients with HER2-positive
disease (Katherine, NCT01772472) and olaparib in BRCA1−/
BRCA2-positive patients (OLYMPIA study, neoadjuvant
cohort).
On the other hand, achievement of a pCR mirroring
highly responsive disease might also justify reduction of
treatment intensity such as cessation of trastuzumab therapy
in the post-neoadjuvant setting. Unfortunately, at present
there are insufficient data available to justify this. Studies that
will investigate such treatment concepts are still recruiting or
in preparation.
38.5.2 Window of Opportunity Trials
Other studies use the primary systemic therapy time window
to assess the biological response of tumour cells to a few week
period of therapy in an aim to enable modification of the
treatment regime by determining tumour cell proliferation
before and after the intervention. The Adjuvant Dynamic
Marker-Adjusted Personalized Therapy Trial (ADAPT, opti-
mizing risk assessment and therapy response prediction in
early breast cancer) of the West German Study Group (WSG)
breast cancer and a significant decrease in Ki-67 expression
during a 3-week endocrine therapy schedule may be safely
spared adjuvant chemotherapy (7 http://www.­wsg-online.­
com). Comparable study concepts for patients with other
breast cancer subtypes (such as HER2-positive or triple-­
negative tumours) are ongoing.
38.6 Conclusion
Primary systemic therapy is an exciting area of clinical prac-
tice and active research. It has many potential values in treat-
ment personalization, enhanced surgical and oncological
outcomes and given us a greater understanding of disease
biology and response rates. It also has a role in prediction of
prognosis. Understanding of these issues is vital in modern
multidisciplinary cancer care.
Key Messages
55 Patients whose indication for adjuvant chemo-
therapy is obvious at the time of diagnosis are
candidates for neoadjuvant chemotherapy.
55 Chemotherapy regimens commonly equal those
used in the adjuvant setting.
55 For patients with triple-negative breast cancer,
the addition of carboplatin to anthracycline
taxane chemotherapy increases response rates
and potentially survival.
Primary Systemic Therapy for Breast Cancer
461 38
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 463 39

Radiotherapy for Breast Cancer

Barbara Alicja Jereczek-Fossa, Maria Cristina Leonardi,
and Samantha Dicuonzo

39.1 Introduction – 464

39.2 Contraindications to Radiotherapy – 464

39.3 Adjuvant Radiation Therapy After Breast-

Conserving Surgery – 465
39.3.1 Radiotherapy to the Whole Breast and Tumour Bed (Boost) – 465
39.3.2 Radiotherapy to the Whole Breast, Tumour Bed
and Regional Nodes – 467

39.4 Adjuvant Radiation Therapy After Mastectomy – 468

39.4.1 Radiation Therapy to the Chest Wall – 468
39.4.2 Loco-Regional Radiation Therapy (Chest Wall
and Regional Nodes) – 469

39.5 Radiation Treatment Planning and Delivery – 470

39.6 Toxicity – 473

39.7 Breast Reconstruction and Radiotherapy – 477

References – 479

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_39

rares1geo@gmail.com
 464 B.A. Jereczek-Fossa et al.

39.1 Introduction greater target dose homogeneity and sparing of normal tissue
can be accomplished; these strategies help to minimize the
Early breast cancer is commonly treated with breast-­ side effects related to radiation [15].
conserving surgery (BCS) followed by radiation therapy to A shorter course of breast irradiation treatment with higher
the residual mammary gland. Numerous randomized trials dose per fraction (hypofractionation), instead of the conven-
have demonstrated that the long-term survival rate among tional scheme of 5–6  weeks, is now known to give excellent
patients treated with breast-conserving therapy (BCT) is results compared to standard regimes. Hypofractionation is a
equivalent to those who undergo mastectomy, the standard valid option from a biological point of view as breast cancer
surgical treatment until the 1970s [1–6]. Based on prelimi- cells are more sensitive to higher doses per fraction. It is also
nary data from these trials, the US National Institutes of advantageous both for patients and radiotherapy centres as it
Health (NIH) published a consensus statement in 1991, reduces overall treatment times, increases patient compliance
claiming that BCT is an «appropriate method of primary and reduces waiting lists and treatment costs [16, 17].
therapy for the majority of women with stage I and II breast Finally, the increasing use of oncoplastic surgery may
cancer and is preferable because it provides survival rates make radiotherapy planning more «challenging» but does
equivalent to those of total mastectomy and axillary dissec- not represent a contraindication to its application. It is impor-
tion while preserving the breast» [7]. tant that the surgeon and radiation oncologist work closely
Whole-breast irradiation (WBI) reduces local relapse and together to ensure the treatment is appropriately targeted.
has been shown to reduce breast cancer-specific mortality, In the present chapter, we discuss the role of radiation
especially in high-risk patients [8]. In the future this gain therapy for early breast cancer treatment (including manage-
might be even larger as we acquire data from more recent ment of cT3N1M0 disease whose management is often simi-
trials using more effective and safer radiotherapy techniques lar to stage I and II breast cancer) [18].
(only studies started before the year 2000 were included in
the recent Early Breast Cancer Trialist’s meta-analysis on
BCT). Randomized trials have also demonstrated a decrease 39.2 Contraindications to Radiotherapy
in in-breast recurrences with application of additional radia-
tion dose (boost) to the tumour bed [9, 10]. In the treatment of early breast cancer, it is important to con-
BCT is not appropriate for every case of early breast can- sider both general and specific contraindications to radiation
cer and mastectomy may be required or preferred by the therapy (. Table 39.1).  

patient. Mastectomy is required if radiotherapy is contraindi- The patient’s ability to access a radiotherapy centre in rela-
cated, in cases of an unfavourable ratio between tumour size tion to their general physical and psychological performance
and breast size that would result in an unsatisfactory cos- status and their logistical situation should be assessed before
metic effect (although such instances are now less common conservative surgery is planned. It should be kept in mind
due to oncoplastic surgery and primary systemic therapy), that some neurological or orthopaedic conditions such as
multicentric breast cancer and inflammatory breast cancer. severe upper limb functional limitations or n ­ eurodegenerative
39 When an early breast cancer fulfills the criteria for BCS disorders like Parkinson’s disease can compromise the setup
except for size, preoperative systemic therapy can be a rea- and ability to safely deliver the radiation treatment.
sonable option to avoid mastectomy.
In high-risk patients, including those with four or more
positive axillary lymph nodes (ALNs) or involved resection ..      Table 39.1  General and specific contraindications to
radiation therapy
margins where further surgery is not possible, radiation
therapy to the chest wall may be necessary following mastec- General Patient’s inability to access a radiotherapy centre
tomy [11–13]. Neurological/orthopaedic conditions (upper limb
In particular clinical situations, the radiotherapy volume functional limitations, inability to keep still, etc.)
may also include regional (infraclavicular region, supracla- Severe lung disease
vicular area, axilla) and internal mammary lymph nodes [14]. Severe cardiac disease for left-sided breast tumours
Germline TP53 mutations (Li-Fraumeni syndrome)
For patients receiving primary systemic therapy, admin-
istration of radiation therapy should be made based on pre-­ Specific
chemotherapy tumour characteristics. Absolute Pregnancy
Patient’s inability to maintain stable treatment
The main goal of radiation therapy is to eliminate any position
residual tumour cells while minimizing damage to adjacent Active connective tissue diseases (systemic lupus
tissues: this is achieved with dose fractionation that enables erythematosus, dermatomyositis and scleroderma)
healthy cells to repair sublethal damage, as opposed to the Relative Quiescent connective tissue diseases (systemic
tumour cells which are unable to repair radiation-induced lupus erythematosus, dermatomyositis and
damage. Modern technologies allow safe administration of scleroderma)
Very large breast volume
radiation therapy. Thanks to computed tomography (CT)-
Previous thoracic irradiation
based treatment planning, linear accelerators and new tech- Genetic predisposition to breast cancer
niques such as intensity-modulated radiation therapy (IMRT),

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Radiotherapy for Breast Cancer
Specific contraindications to radiation treatment are tra-
ditionally divided into absolute and relative.
55 Pregnancy is an absolute contraindication to breast
radiotherapy for its teratogenic risk (abortion, malfor-
mations, growth retardation and radiation-induced
cancers). Before starting treatment, it is mandatory to
ensure that women of childbearing age are not pregnant,
and pregnancy must be prevented during the radio-
therapy course. When a breast cancer diagnosis occurs
during pregnancy, conservative surgery may be consid-
ered, and radiotherapy is usually postponed until after
delivery, although the delay of the commencement of
WBI might have some impact on efficacy. However, the
possibility of receiving chemotherapy during pregnancy,
as of the end of first trimester, may play a role on local
control (see 7 Chap. 42) [19].
55 Patients’ inability to maintain a stable treatment position
(advanced Parkinson’s disease, advanced essential
tremor, etc.) is an absolute contraindication because it
prevents the correct execution of radiation treatment.
55 Li-Fraumeni syndrome is an absolute contraindication
because, in these patients, ionizing radiation exposure
increases the incidence of second malignancies.
55 Relative contraindications are shown below:
55 Connective tissue diseases involving the skin such as
systemic lupus erythematosus, dermatomyositis and
scleroderma, if quiescent, represent a relative contraindi-
cation and, if active, might be an absolute contraindica-
tion because of the amplification of reported toxicity.
Rheumatoid arthritis is not considered a contraindica-
tion to radiation therapy. Moreover, new radiotherapy
approaches, such as partial-breast irradiation, which
reduces the irradiated volume, could be promising to
improve the feasibility and tolerability of radiotherapy in
patients with connective tissue diseases and will prob-
ably help to overcome the unresolved concerns about
radiotherapy indications for patients with connective
tissue diseases [20].
55 Severe lung disease with impaired respiratory capacity [21].
55 Severe cardiac disease for left-sided breast cancers [22].
55 The irradiation of very large breasts can be difficult due
to the difficulty in reproducing the setup of dose delivery
and the inhomogeneity of dose distribution, with a
possible negative impact on post-treatment cosmesis. In
these particular situations, radiation in the prone
position or lateral decubitus position or, in selected
patients, accelerated partial-breast irradiation (APBI)
might be considered [23].
55 Previous thoracic irradiation, although not an absolute
contraindication, should be assessed with caution and
may be considered for PMRT or treatment of recurrent
disease. The previous radiotherapy details (technique,
volumes, dose and fractionation) and the interval
between previous irradiation and the new planned
treatment must be carefully evaluated before re-­
irradiation is undertaken. In case of re-irradiation, lower
rares1geo@gmail.com
465 39
doses and smaller volumes are employed in order to
limit normal tissue injury [24].
55 Women with a known genetic predisposition to develop
cancers should be handled with care because of the
increased risk of radiation-induced cancers (e.g. carriers
of germline mutations in genes involved in the DNA
damage repair pathway) [25].
The involvement of the multidisciplinary team evaluating the
feasibility of radiotherapy is crucial in the assessment of the
appropriateness of BCT for each individual patient.
39.3  djuvant Radiation Therapy After
A
Breast-Conserving Surgery
39.3.1  adiotherapy to the Whole Breast
R
and Tumour Bed (Boost)
Radiation therapy to the whole breast following BCS is widely
accepted as a standard of care for women with early-stage
invasive breast cancer.
Long-term results from numerous randomized con-
trolled trials have confirmed overall survival equivalence
between BCT and mastectomy for early-stage invasive breast
cancer (. Table 39.2).
In 1995, the Early Breast Cancer Trialists’ Collaborative
Group (EBCTCG) meta-analysis showed that in the nine tri-
als of mastectomy versus BCS plus radiotherapy, there was no
apparent difference in overall mortality (22.9% versus 22.9%)
and local recurrences (6.2% with mastectomy as compared
with 5.9% with breast conservation) [26]. Although these tri-
als varied in inclusion criteria and in surgical technique and
radiotherapeutic and systemic treatment protocols, they
showed that BCT can be applied safely in patients with early
breast cancer.
In modern practice, 5- and 10-year actuarial local recur-
rence rates of less than 5% are not uncommon with results
near to 0% in some series, as in the ELIOT trial (0.4% in the
external beam radiotherapy group after a medium follow-up
of 5.8  years). The enormous improvement in surgery and
radiotherapy techniques and systemic therapy with more
effective cytotoxic, endocrine and targeted treatments, and
higher-quality surgical procedures with much more diligent
attention to achieving clear margins, has undoubtedly con-
tributed to this reduction in  local failure rates after BCT
when compared to the historic trials [27, 28].
In addition to the randomized trials comparing breast
conservation with mastectomy, different randomized trials
have compared conservative surgery alone with conservative
surgery and radiation, in order to investigate whether radia-
tion following BCS can be omitted. The majority of random-
ized trials have demonstrated that radiation therapy following
BCS lowers the local relapse rates by at least half and is asso-
ciated with acceptable toxicity and morbidity [29]. The
impact of radiation following BCS on breast cancer mortality
 466 B.A. Jereczek-Fossa et al.

..      Table 39.2  Overall survival from randomized controlled trials comparing breast-conserving therapy with mastectomy

Study and period of Pts (n) Follow-­up (years) Treatment Pts (n) Overall survival
accrual Type

Veronesi et al. [1] 701 20 (median) BCT 352 59% at 20 years

(National Cancer Institute
of Milano) 1973–80 RM 349 59% at 20 years (p = 1.0)

Fisher et al. [2] 1851 20 (mean) BCT 628 46% at 20 years

(NSABP B-06) 1976–84
TM 589 47% at 20 years (p = 0.57)

Poggi et al. [3] 237 18.4 (median) BCT 121 54% at 20 years
(U.S. National Cancer
Institute) 1979–87 MRM 116 58% at 20 years (p = 0.67)

Arriagada et al. [4] 179 22 (mean) BCT 88 65% at 10 years

(Institut Gustave–Roussy)
1972–79 MRM 91 67% at 10 years (p = 0.16)

Blichert–Toft et al. [5] 731 19.6 (median) BCT 367 57.8% at 20 years
(DBCG-­82TM) 1983–89
MRM 364 50.6% at 20 years (p = 0.20)

Litière et al. [6] 868 13.4 (median) BCT 448 51.6% at 15 years
(EORTC 10801) 1980–86
MRM 420 53.6% at 15 years (p = 0.225)

Pts patients, BCT breast-conserving therapy, RM radical mastectomy, TM total mastectomy, RR relative risk, MRM modified radical mastectomy

or overall survival, however, has been the subject of ongoing concerns, many clinicians and patients would only consider
debate until very recently. This issue has been clarified by the the avoidance of radiation or the use of APBI in the context
EBCTCG in three large meta-analyses published in 1995, in of a clinical trial [8, 30] (see 7 Chap. 44).
 

2005 and finally in 2011 [8, 11, 26].
In its recent quinquennial meta-analysis update pub-
lished in 2011, the EBCTCG included 17 randomized studies
39 comparing adjuvant radiotherapy versus no radiotherapy fol-
lowing BCS. A total of 10,801 patients with pT1–pT2 tumours
were recorded, the majority of whom (n = 7287) were node
negative, 1050 node positive and 2464 nodal status unknown.
The analysis not only reported significant 10-year absolute
risk reduction of any (loco-regional or distant) first recur-
rence by 15.7% with radiotherapy following BCS but showed
also that radiotherapy reduced the breast cancer death rate by
about one-sixth. Overall, radiotherapy reduced the 15-year
risk of breast cancer death from 25.2% to 21.4% (absolute
reduction 3.8%, 2p = 0.00005) [8].
Given the impact of radiation on both local control and
breast cancer-specific survival, the standard of care for the
majority of patients with invasive breast cancers undergoing
BCS is the use of radiation following BCS, and the avoidance
of radiation therapy outside the context of a clinical trial
must be approached cautiously.
There are, however, subsets of patients who are at lower
risk of recurrence, for whom the absolute benefit might be
clinically not meaningful. A common and clinically relevant
example of this is in women over age 70 with hormone
receptor-­positive tumours, where observation following BCS
is considered an acceptable option. However, given these
The tumour bed is the area at highest risk for tumour cell
contamination, and a number of randomized trials have
investigated the effect of an additional dose of radiation to
the tumour bed (known as boost) after the administration of
WBI.
The European Organisation for Research and Treatment
of Cancer (EORTC) has undertaken the 22,881–10,882
(boost versus no boost) trial in order to clarify whether this
strategy has any merit or adverse effects [10, 31, 32]. In 5318
patients with a microscopically clear resection margin after
surgery to the primary tumour, an additional dose of RT to
the tumour bed nearly halved the annual odds of local recur-
rence (hazard ratio, 0.59), with a 10-year actuarial rate of
local recurrence of 10.2% in the «no boost» group and 6.2%
in the «boost» group (p < 0.0001). In the latest publication of
this trial, with a median follow-up of 17.2  years, ipsilateral
breast tumour recurrence had increased in both treatment
groups (possibly as a consequence of development of second
primaries): 16.4% for the «no boost» group and 12% for the
«boost» group. However, the relative benefit of boost for local
control remained statistically significant with an HR for an
ipsilateral breast tumour recurrence as a first event of 0.65
(p < 0,0001).
Overall, boost did not improve overall survival which was
81.7% for both arms after 10 years of follow-up and 61.1% in
the «no boost» group versus 59.7% in the «boost» group after

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Radiotherapy for Breast Cancer
20  years; the failure of improved local control to increase
overall survival has been hypothesized by the authors to
derive from successful salvage mastectomy treatment for
these breast recurrences.
Boost RT is associated with an increase in breast fibrosis;
although not significant at 5 years, at 10- or 20-year follow-­up,
the extra boost dose has been shown to increase rates of mod-
erate or severe fibrosis from 13% to 28% and from 15% to
30.4%, respectively. For this complication, the boost dose was
not the sole factor that affected the cosmetic outcome nega-
tively (other factors included the location of the primary
tumour in the lower quadrants, the volume of breast tissue
excised, administration of systemic therapy, breast infection or
hematoma in the postoperative period and clinical T2 stage).
As early analyses found the largest clinical benefit from
boost in younger patients (40  years old or younger), the
authors tried to determine whether the effect of an additional
radiation dose depended on age. The 2015 analysis confirmed
that patients’ age was strongly correlated with the absolute
risk of ipsilateral breast tumour recurrence: 20-year cumula-
tive incidence ranged from 34.5% for patients 35  years or
younger to 11.1% for patients older than 60  years, and the
reduction of risk by giving a boost dose was significant for
the younger age groups (for age ≤ 40 years, p = 0.003 and, for
age 41–50 years, p = 0.007) [10, 31, 32].
Based on this landmark phase III trial, administration of
a boost dose following WBI is strongly indicated especially if
patients have high-risk factors for recurrence, such as
age  <  50  years old, pathologically involved ALN, lympho-­
vascular invasion and/or a close or positive resection margin.
For the older women, its routine use is less clear, but, in
patients over 60 years of age with small, node-negative, hor-
mone receptor-positive tumours, omission of a boost may be
reasonable [10, 33].
39.3.2   adiotherapy to the Whole Breast,
R grade and nodal ratio >20–25%. So, in the presence of two or
Tumour Bed and Regional Nodes
Regional node irradiation (RNI) should be considered in the
following circumstances:
55 In cases with more than three ALN metastases, it is
recommended.
55 In the case of one to three positive ALNs, it should be
considered, especially when additional risk factors are
present.
RNI includes the infra- and supraclavicular region and any
part of axillary bed at risk. A number of radiotherapy centres
include the internal mammary chain, irrespective of known
neoplastic involvement. In 2016 the NCCN guidelines were
extended to include the elective irradiation of internal mam-
mary nodes, in light of recent publications.
Supported by similarities in tumour biology, most of the
data available on RNI in patients treated with BCS were
extrapolated from studies of patients undergoing mastec-
tomy, in particular from three remarkable randomized clini-
rares1geo@gmail.com
467 39
cal trials conducted by Overgaard and Ragaz. Furthermore,
the historical recommendation to treat only in cases with
more than three positive nodes was made despite the fact that
these trials showed a benefit in survival for all node-positive
patients [34–36].
Vicini and colleagues first demonstrated a statistically sig-
nificant reduction in the rate of regional nodal failure in patients
with more than three positive lymph nodes treated with BCT
and RNI. The authors stated that, combining their study with
the available literature, the data were «sufficient to support the
inclusion of at least the supraclavicular fossa and level III ALN
in patients with four or more positive nodes because of a statis-
tically significant reduction in the rate of regional nodal failure
with a relatively mild increase in toxicity» [37].
In 2011, the previously mentioned meta-analysis from
the EBCTCG reported a 10-year improvement in the rate of
any first recurrence of 21.7% in patients with four or more
positive nodes who received adjuvant radiation therapy after
BCS [8].
Currently RNI, in cases with more than three positive
nodes, is recommended by all national and international
guidelines [18, 38, 39].
However, some authors suggest that RNI, in particular
RT to the supraclavicular fossa, even in patients with more
than three positive nodes, cannot be routinely justified if the
intent is to improve survival [40].
The need for RNI in cases of one to three positive nodes
is currently an issue of intense debate.
Many studies published in recent years, mostly retrospec-
tive, have investigated this question. Despite the heterogene-
ity of these trials in the number of patients, analysis period,
adjuvant systemic therapy regimes and radiotherapy vol-
umes, these studies all emphasized the importance of differ-
ent risk factors for local relapse, nodal relapse and distant
metastases such as young age, tumour size, negative hor-
monal receptors, extensive intraductal component, high
more of these risk factors, RNI should be considered [41–43].
Ideally, treatment recommendations should be made on
the basis of well-designed phase III clinical trials. To date, the
MA.20 and EORTC 22922/10925, two large randomized
clinical trials with 85% and 43.1% of included patients having
one to three positive ALNs, respectively, have been published
as full papers. Both studies have stressed the need of RNI
after BCS regardless of the number of positive lymph nodes,
but they have not demonstrated any significant impact on OS
from RNI.
The sites of nodes needed to be treated with the intent of
improving OS and DFS remain unknown (the EORTC trial
included internal mammary and medial supraclavicular
lymph nodes; in the MA.20 trial, the internal mammary
lymph nodes with the supraclavicular and ALNs were irradi-
ated) [44, 45].
However, they both showed that RNI improves DFS, and
distant DFS, without adding substantial toxicity; the EORTC
trial also reported a small but significant benefit with respect
to death from breast cancer (. Table 39.3).
 468 B.A. Jereczek-Fossa et al.

..      Table 39.3  Results from MA.20, EORTC 22922/10925 and French trials

MA.20 [44] (median follow- EORTC 22922/10925^ [45] (median French trial [63] (median follow-
­up = 9.5 years) follow-up = 10.9 years) ­up = 11.3 years)

WBI WBI + RNI WBI WBI + RNI PMRT PMRT + RNI

(916 pts) (916 pts) (2002 pts) (2002 pts) (662 pts) (672 pts)

DFS 77% 82% 69.1% 72.1% 49.9% 53.2%

p = 0.01a p = 0.04a p = 0.35

Isolated LR DFS 92.2% 95.2% – – – –

p = 0.09a

Distant DFS 82.4% 86.3% 75% 78% – –

p = 0.03a p = 0.02a

OS 81.8% 82.8% 80.7% 82.3% 59.3% 62.6%

p = 0.38 p = 0.06 p = 0.8

BC mortality 12.3% 10.3% 14.4% 12.5% – –

p = 0.11 p = 0.02a

WBI whole-breast irradiation, RNI regional node irradiation, PMRT post-mastectomy radiotherapy, pts. patients, DFS disease-free survival, LR
loco-regional, OS overall survival, BC breast cancer
aSignificant; ^ 76.1% of patients treated with BCS; 23.9% of patients treated with mastectomy

Due to this ongoing uncertainty, RNI in cases with one to
three positive ALNs should be discussed in a multidisci-
plinary team meeting and then discussed with the patient.
The indication for radiotherapy to the axilla is generally
restricted to patients with recurrent disease, or if ALNs are
clinically involved and no axillary dissection is possible or
planned, despite the EORTC 10981–22,023 AMAROS trial,
where patients with clinical T1–T2 N0 primary breast cancer
were randomly assigned to axillary radiotherapy or axillary
lymph node dissection, it showed that, for patients with a
39 positive sentinel lymph node, either modality provides excel-
lent and comparable axillary control. Moreover, the rates of
lymphoedema were lower in patients treated with axillary
radiotherapy than in those treated with axillary lymph node
dissection [46].
39.4  djuvant Radiation Therapy After
A risk categories for local relapse. These include lympho-­
Mastectomy
After mastectomy for early breast cancer, radiation therapy
for clinical stages I–II and T3N1M0 breast cancer depends
on tumour size, ALN involvement and the state of the surgi-
cal margins. General indications for post-mastectomy radia-
tion therapy (PMRT) are listed below:
55 Tumour >5 cm
55 Four or more positive ALNs (PMRT is mandatory)
55 One to three ALNs (PMRT is recommended)
55 Positive surgical margins when further surgery is not
possible
55 Chest wall/skin infiltration (T4a, T4b, T4c)
55 Inflammatory cancer (T4d)
55 Pectoral muscle invasion
Generally, radiation therapy to the chest wall only is recom-
mended in the case of T3 N0 tumours, positive surgical mar-
gins or pectoral muscle invasion; in the remaining situations,
PMRT includes chest wall and regional lymph nodes.
39.4.1 Radiation Therapy to the Chest Wall
There is strong evidence that tumour size greater than 5 cm,
as a sole negative feature, is a risk factor for loco-regional
recurrence (LRR), so chest wall irradiation is traditionally
recommended for these patients, but there is controversy
concerning the real need for PMRT for pT3N0M0 breast
cancer due to low recurrence rates after a median follow-up
time of 10 years or more [12, 47, 48].
A comprehensive review of studies including T3  N0
patients was performed indicating the main risk factors and
vascular invasion, blood vessel invasion, positive lymph node
ratio > 20%, close resection margins <3 mm, grade 3, young
age/premenopausal status, extracapsular nodal invasion,
negative hormone receptor status and invasive lobular can-
cer. These high-risk factors help to identify T3  N0 patients
who will benefit from PMRT [49].
Positive and close surgical margin status is generally
believed to be associated with high LRR risks, but there are
few available studies examining this issue in the post-­
mastectomy setting and even fewer analyses focusing on the
specific role of PMRT in these patients [50, 51]. In spite of
this, chest wall irradiation is recommended in patients with
positive surgical margins (if there is no option for further
surgery) and should be considered for women with a close
resection margin and one or more additional risk factors

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Radiotherapy for Breast Cancer
(age  ≤50  years, T2 tumour size, grade 3, lympho-vascular
invasion, triple-negative disease) [18, 51, 52].
39.4.2 Loco-Regional Radiation Therapy
(Chest Wall and Regional Nodes)
Regarding nodal status, historically PMRT to the chest wall
and regional lymph nodes has been delivered in the case of
four or more positive nodes at axillary dissection [47, 53–56].
The background for this indication was the general assump-
tion that only patients with very high risk of LRR will benefit
from postoperative radiotherapy in terms of survival and, as
expressed in the National Institutes of Health consensus
report 2000, «….the high-risk group includes women with
four or more positive nodes» [57].
Three well-conducted randomized trials have shown that,
for node-positive breast cancer patients unselected for the
number of lymph nodes involved, irradiation of the chest wall
and regional lymph nodes after mastectomy and ALN dissec-
tion improves DFS and OS in addition to loco-regional con-
trol [34–36]. In the DBCG 82b trial (1708 high-risk
premenopausal patients), the 10-year loco-regional recur-
rence rate was 9% in PMRT + chemotherapy patients in con-
trast to 32% in patients treated with chemotherapy alone, and
the corresponding survival rates were 54% and 45%, respec-
tively, in favour of PMRT + chemotherapy (p  <  0.001). The
DBCG 82c trial (1375 high-risk postmenopausal patients)
showed a 10-year loco-regional recurrence rate of 8% in
PMRT + tamoxifen patients compared to 35% in tamoxifen-
only patients with the corresponding 10-year survival rates of
45% and 36%, respectively, in favour of PMRT + tamoxifen
(p = 0.03). Remarkably, there has been an ongoing debate on
whether or not PMRT should be given to patients with one to
three positive ALN. In a subgroup analysis of the Danish tri-
als, the addition of radiation therapy resulted in a substantial
reduction in the 15-year LR failure rate from 27% to 4%
(p < 0.001) and from 51% to 10% (p < 0.001), in patients with
one to three versus four or more axillary positive nodes,
respectively. The 15-year survival benefit after radiation ther-
apy was equally pronounced in both groups (57% versus 48%,
p = 0.03, and 21% versus 12%, p = 0.03). As PMRT improved
the outcome to the same extent in the two groups, the authors
suggested considering a «modification of the current guide-
lines for indications for post-mastectomy irradiation» [34, 35,
58]. Finally, Ragaz and colleagues (318 premenopausal high-
risk patients, PMRT + CMF versus CMF without PMRT)
observed that after a median follow-up of 15 years, there was
a significant absolute improvement of 20% in local relapse free
survival (p < 0.003) with a corresponding 8% improvement in
survival rates (54% versus 46%, p = 0.07). The 20-year results
of this trial confirmed previous analyses showing that the
impact of radiation therapy for all survival outcomes in the
subgroup with one to three nodes involved was similar to the
subgroup with four or more nodes involved and both groups
had a risk reduction of the same order of magnitude [36, 59].
rares1geo@gmail.com
469 39
The recently published update of the EBCTCG meta-­
analysis should bring the debate about patients with one to
three positive ALN to an end, since it unequivocally demon-
strated that these patients receive the same survival benefit
from PMRT as patients with more than three involved lymph
nodes. In 1314 patients with pN+ (one to three nodes), the
risk for local recurrence at 10 years was significantly reduced
from 20.3% to 3.8%, and breast cancer mortality decreased
significantly by 7.9% after 20 years; in comparison, the risk
for local recurrence in 1772 patients with pN+ (four or more)
at 10 years was significantly reduced from 32.1% to 13.0%,
and breast cancer mortality was also reduced by 9.3% at
20 years. Importantly, after mastectomy and axillary dissec-
tion, radiotherapy reduced both recurrence and breast can-
cer mortality in the women with one to three positive lymph
nodes even when systemic therapy was given [13].
Despite these results, routine use of PMRT in the case of
less than four ALNs is not yet the standard of care, and con-
sequently its general use in patients with tumours <5 cm is
based on the presence of other prognostic risk factors
(age < 40–45, tumour diameter > 3.5 cm, ER and PgR nega-
tivity, lympho-vascular invasion, grade 3 or a positive lymph
node ratio > 20%) [60–62].
The results of the Medical Research Council Selective Use
of Postoperative Radiotherapy After Mastectomy (SUPREMO)
trial, a randomized phase III trial assessing the role of irradia-
tion in women with intermediate-risk breast cancer following
mastectomy, will help determine the real impact of PMRT in
this subgroup of patients in terms of loco-regional control
and overall survival, but it will take years before a definitive
answer is obtained [63].
The role of irradiation of internal mammary nodes
(IMNs) remains unclear as a French trial failed to demon-
strate a survival benefit for IMN irradiation in patients with
positive axillary nodes (pN+) or central/medial tumours
with or without pN+, and the EORTC 22922/10925 (23.9%
of the entire population were treated with mastectomy) can-
not determine whether internal mammary irradiation or
medial supraclavicular irradiation contributed more to the
outcome [64].
On the other hand, the results from the Danish population-­
based study in which patients with left-sided node-positive
breast cancer underwent only medial supraclavicular irradia-
tion, whereas patients with right-sided node-­positive breast
cancer underwent both internal mammary and medial supra-
clavicular irradiation, support the role of including the inter-
nal mammary chain in the success of regional nodal radiation
therapy (the study included patients treated both with
lumpectomy and mastectomy) with a benefit on overall
­survival [65].
In the meantime, the use of PMRT in patients with early-­
stage breast cancer should be considered a valuable option,
and its recommendation should be individualized according
to patient and tumour features.
In . Table  39.4 general indications for radiotherapy in
early breast cancer are summarized.
 470 B.A. Jereczek-Fossa et al.
..      Table 39.4  Summaries of general indications for radiotherapy in early breast cancer (see the text for more details)
Indications
After breast-conserving surgery
(radiation therapy to the residual mammary paren-
chyma ± regional nodes)
After mastectomy, positive axillary nodes (radiation
therapy to chest wall and regional nodes)
After mastectomy, negative axillary nodes (radiation
therapy to chest wall ± regional nodes)
39.5 Radiation Treatment Planning
and Delivery
It is important to individualize radiation therapy delivery,
and CT-based treatment planning is mandatory to delineate
target volumes and adjacent organs at risk.
According to the indications reported in the previous
paragraphs, volumes of interest of radiation treatments are
listed below:
55 After BCS: the target includes the residual mammary
gland (the skin should not be included unless it is
affected by the disease), the site of the primary tumour
(boost) and drain sites when indicated.
55 After mastectomy: the target includes the ipsilateral
chest wall (skin and rib plane), mastectomy scar and
drain sites when indicated.
39 55 Supraclavicular and infraclavicular nodes: the term
supraclavicular is synonymous with inferior deep
cervical nodes according to the AJCC classification of
the head and neck region. The term infraclavicular
nodes is synonymous with apical or level III axillary
nodes.
55 Internal mammary nodes: the target volume should be
restricted to the ipsilateral side and usually should not
extend below the third or fourth intercostal space
(. Fig. 39.1).
55 Axillary nodes (ALNs): the ALNs are divided into level I
(low axilla) and level II (mid-axilla). Level III (apical
axilla) corresponds to the infraclavicular nodes.
For node identification, the corresponding arteries and
veins can be used as a surrogate for nodal location (as the
nodes themselves are not usually visible on planning imag-
ing). Accurate knowledge of radiological anatomy is
required for delineation of targets mentioned above; how-
ever, contouring is a process prone to errors and inter- and
intra-­operator variability. In particular, the tumour bed is
subject to topographical uncertainties; consequently, many
authors recommend the use of surgical clips to mark the
rares1geo@gmail.com
Notes
Should be performed in almost all subset
No subsets are identified which can safely avoid radiation therapy
Benefit is minimal in older women with T1 N0 ER+ breast cancer
Add radiation therapy on regional nodes in the case of more than three
positive axillary nodes (it should be considered in the case of 1–3 positive
axillary nodes)
Mandatory in the presence of four or more positive axillary lymph nodes
Recommended for patients with one to three axillary lymph nodes involved
Recommended for tumour size >5 cm
Recommended for positive surgical margins
To consider in the case of close margins and other risk factors
lumpectomy site [66]. Moreover, several anatomically based
guidelines have been published for definition of the plan-
ning target volume and organs at risk like the heart and lung
[39, 67–69].
For planning and treatment, the patients lie in the supine
position with one or both arms in abduction (>90°) on a
breast board. Prone positioning may be tried to further
reduce the dose to adjacent normal tissues.
Different techniques can be used to deliver radiation
treatment: homogeneity in dose distribution is usually
achieved by a conformally shaped tangential wedge field tech-
nique, mostly with photons at energies of 4–8 MV (. Fig. 39.2).  
For chest wall irradiation, single electron beam field of appro-
priate energy may be an alternative allowing for better sparing
of underlying tissues. Intensity-modulated radiotherapy
(IMRT) allows for better dose conformation and reduction of
the dose to the surrounding organs. This may allow for wider
implementation of hypofractionated schedules or a concomi-
tant boost approach (see below). For larger breasts or for
patients with difficult anatomical variants (i.e., funnel chest,
pectus excavatum), IMRT or the use of active breathing con-
trol may be appropriate to fulfill the minimum homogeneity
criteria and to spare radiation to the lungs and to cardiac
structures (for left-sided tumours), respectively [70, 71].
The dose-volume histogram (DVH) is a graphical repre-
sentation of the dose that is received by normal tissues and
target volumes within a radiation therapy plan (. Fig. 39.3).
Correct treatment delivery has to be documented with
verification of daily setup consistency. Several imaging
modalities are available (electronic portal imaging device,
cone beam CT, etc.). The choice of modality of imaging, fre-
quency (daily, weekly, etc.) and working mode (online/offline
verification) is not yet standardized and depends on the tech-
nique and institutional workflow [72].
Four randomized clinical trials have investigated hypo-
fractionated WBI schedules (39–42.9 Gy in single fractions
of 2.6–3.3  Gy) compared to standard 50  Gy in single frac-
tions of 2 Gy. These studies with 10-year follow-up reported
that local tumour control and breast cosmesis were similar
Radiotherapy for Breast Cancer
471 39
..      Fig. 39.1  Transverse view of a
treatment plan for whole-breast
RT with simultaneous integrated
boost and internal mammary
chain irradiation. The green colour
corresponds to 95% of the
prescribed dose to the breast and
internal mammary nodes, the
orange colour to 95% of the boost
dose, the blue colour to 25% of
the boost dose (Tomotherapy®
Treatment Planning System)

..      Fig. 39.2  Transverse view of a

treatment plan for whole-breast
RT with a conformally shaped
tangential fields techniques
(relation between colours and
prescribed dose is shown on the
left of the figure; ML medial-
lateral, LM lateral-medial)

with a hypofractionated regimen compared with 50 Gy in 25
fractions over 5 weeks (. Table 39.5) [16, 17, 73, 74].
 
Based on convenience and data from trials, in many
countries, short-course radiation therapy is now considered
the «gold standard» for adjuvant breast cancer radiotherapy
[75, 76].
The conventional post-mastectomy RT dose is
45–50.4 Gy, given in 1.8–2.0 Gy fractions. Although there is
no high-­quality evidence that hypofractionation has similar
efficacy and safety as conventionally fractionated radiation
treatment for early breast cancer, the large British Columbia
randomized controlled trial demonstrated an overall sur-
vival benefit of PMRT with a hypofractionated schedule
(37.5 Gy in 16 fractions), and retrospective studies showed
that short courses of radiotherapy are as effective as conven-
tional radiotherapy in the post-mastectomy setting [36, 77].
Moreover, a small percentage of post-mastectomy patients
were included in the START A and B trials. A randomized
controlled trial would be necessary to more completely
assess the acute and long-term toxicity of post-mastectomy
hypofractionated radiotherapy compared with standard
fractionation.
In many cases WBI includes delivering higher dose to the
tumour bed (boost). Typical boost doses are 10–16 Gy at 2 Gy
per fraction. External beam photons and electrons, interstitial
and endoluminal brachytherapy and intraoperative radio-
therapy with electrons are used for boost treatment. IORT
with electrons has been demonstrated to be the method

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 472 B.A. Jereczek-Fossa et al.

..      Fig. 39.3  An example of a
dose-volume histogram: dose
distribution (horizontal axis) is
related to organ volume (vertical
axis); every structure corresponds
to a different colour (red, boost;
pink, breast; green, ipsilateral
lung; violet, heart; dark green,
contralateral breast) (Tomo-
therapy® Treatment Planning
System)

delivering the most uniform dose distribution within a given

..      Table 39.5  Characteristics and outcomes of randomized target volume. The different boost techniques have no
hypofractionation trials
­significant impact on the oncologic outcome. For IORT with
Dose Number 10-­year 10-year electrons, long-term follow-up data are available, indicating
comparisons of local cosmesis (% excellent local tumour control rates in every risk group.
(Gy/fraction/ patients control with good/ Usually intraoperative treatments precede WBI, while in the
wk) (%) excellent or external beam treatment, the boost dose is administered after
«no event»)
the end of WBI. In recent years, IMRT allows the integration
Owen [73] of the boost dose simultaneously with whole-breast irradia-
(RMH/GOC trial) tion (simultaneously integrated boost, SIB), when the patients
receive two different dose levels per fraction at the same time
Control 50/25/5 470 87.0 28.8
(. Fig. 39.4) [78, 79].
 

Arm 1 39/13/5 466 85.2 42 The total dose for regional node irradiation (RNI) should
39 Arm 2 42.9/13/5 474 90.4 25.6 be in the range of 45 Gy–50 Gy using conventional fraction-
ation protocols (5  ×  1.8–2.0  Gy/week). At present there is
Bentzen, 2008 [16]
insufficient evidence for hypofractionation in this setting. In
(START trial A)
randomized studies investigating hypofractionation, 79% of
Control 50/25/5 749 92.6 72.9 the patients were node negative, and only a minority of
Arm 1 39/13/5 737 91.2 78.4 patients were treated with RNI (Canadian study, none;
START A, 13%; START B, 7%). However, in the institutions
Arm 2 41.6/13/5 750 93.7 71.8
where hypofractionation for whole-breast radiotherapy is
Bentzen, 2008 [17] commonly used, such fractionation is applied also to the
(START trial B) treatment of the regional nodes [75].
Control 50/25/5 1105 94.5 68.8 Accelerated partial-breast irradiation (APBI), for patients
at a lower risk for local recurrence, has been explored as an
Arm 1 40/15/3 1110 95.7 73.8
alternative modality. It appears advantageous in terms of
Whelan [74] time- and cost-saving and normal tissue-sparing. APBI refers
(Canadian trial) to the irradiation of a smaller breast volume over a shorter
Control 50/25/5 612 93.0 71.3 time interval, covering the tumour bed with a limited margin
of normal tissue, a single intraoperative fraction or postop-
Arm 1 42.5/16/3.5 622 94.0 69.8
erative radiation therapy over 1–3  weeks administered by
RMH/GOC Royal Marsden Hospital and Gloucestershire brachytherapy or external beam. The use of APBI is not the
Oncology Centre, START Standardisation of Breast Radiotherapy, standard of care, and recommendations from GEC-ESTRO
wk. week (. Table 39.6) and ASTRO may help to define the inclusion
 

criteria for APBI [80, 81].

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Radiotherapy for Breast Cancer
473 39
..      Fig. 39.4  Transverse view of a
treatment plan for whole-breast
irradiation with simultaneous
integrated boost. Colour green
corresponds to 95% of the
prescribed dose to the breast,
colour orange to 95% of the
boost dose, colour blue to 25% of
boost dose (Tomotherapy®
Treatment Planning System)

Several techniques can be used for delivering APBI 39.6 Toxicity

including multicatheter brachytherapy (. Fig. 39.5), intra-
 

cavitary balloon brachytherapy, external beam radiother-
apy and intraoperative radiotherapy (IORT). IORT is a
technique allowing the administration of radiation at the
time of surgery, feasible due to the availability of mobile
linear accelerators (. Fig.  39.6). There are several poten-
tial advantages of IORT: reduction of radiation treatment
time, no treatment delay for patients who must undergo
chemotherapy, direct visualization of the tumour bed
with a reduction of the risk of missing the tumour bed
target and the potential to shield surrounding organs.
Two large randomized controlled trials about IORT have
been completed: the Targeted Intraoperative Radiotherapy
Alone (TARGIT-A) trial and the Electron Intra-operative
Therapy (ELIOT) trial. Based on the current evidence,
IORT may be considered in patients who fall into GEC-
ESTRO low-risk and ASTRO approved low-risk categories
within an agreed protocol or a clinical trial as local recur-
rence rates are somewhat higher than with conventional
WBI (. Table 39.7) [82].
In . Table 39.8 available results from closed phase III tri-
als on APBI with other techniques are summarized [83–89].
Radiotherapy after BCS or mastectomy can be associated
with acute and late toxicity, but it is usually a well-tolerated
treatment. Incidence and severity depend on many factors,
linked both to treatment modality and individual patient
sensitivity. Toxicity can be scored using different scales such
as the RTOG-EORTC, the LENT-SOMA or the CTCAE tox-
icity scoring systems [90–92].
Treatment-related factors comprise total dose, dose per
fraction, irradiated volume, dose inhomogeneity, irradia-
tion technique, timing of chemo- or hormonal therapy, type
of the surgery and postsurgical complications. Factors
related to the patient include age; comorbidities like diabe-
tes mellitus, arterial hypertension, cardiovascular disease
and connective tissue disease; lifestyle habits (tobacco
smoking, alcohol intake); body mass index; and genetic sus-
ceptibility [93, 94].
Radiation-induced toxicity mainly affects the skin, lungs,
heart and lymph node drainage. Acute radiation-induced skin
reactions are often characterized by swelling, redness, pigmen-
tation and dry or moist desquamation (less frequent), which
could result in pain, burning and itching (. Fig.  39.7a–c).

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 474 B.A. Jereczek-Fossa et al.

..      Table 39.6  GEC-ESTRO recommendations on patient selection for accelerated partial-breast irradiation

Characteristic Low-risk group – good Intermediate-risk group – pos- High-risk group – contraindica-
candidates for APBI sible candidates for APBI tion for APBI

Patient age >50 years 40–50 years ≤40 years

Histology Invasive ductal, mucinous, Invasive ductal or lobular, –

tubular, medullary and colloid mucinous, tubular, medullary
and colloid

ILC Not allowed Allowed –

Associated LCIS Allowed Allowed –

DCIS Not allowed Allowed –

Histologic grade Any Any –

Tumour size pT1–pT2 (≤30 mm) pT1–pT2 (≤30 mm) pT2 (>30 mm), pT3, pT4

Surgical margins Negative (≥2 mm) Negative, but close (<2 mm) Positive

Multicentricity Unicentric Unicentric Multicentric

Multifocality Unifocal Multifocal (limited within 2 cm of Multifocal (>2 cm from the index
the index lesion) lesion)

EIC Not allowed Not allowed Present

LVI Not allowed Not allowed Present

ER, PR status Any Any –

Nodal status pN0 (by SLNB or ALND) pN1mi, pN1a (by ALND) pNx; ≥pN2a (four or more
positive nodes)

Neoadjuvant chemother- Not allowed Not allowed If used

apy

From Polgár et al. (Ref. [80] with permission from Elsevier)

APBI accelerated partial-breast irradiation, ILC invasive lobular carcinoma, LCIS lobular carcinoma in situ, DCIS ductal carcinoma in situ, EIC
extensive intraductal component, LVI lympho-­vascular invasion, ER oestrogen receptor, PR progesterone receptor

39
..      Fig. 39.5  Interstitial brachytherapy for accelerated partial-­breast
radiotherapy: implantation of flexible applicators attached to the skin
with buttons; the tumour bed has previously been measured by
ultrasound
Long-term effects include breast pain, fibrosis or induration,
lymphedema and discoloration or telangiectasiae of the skin.
Despite the high number of trials in this field, there is only
limited data suggesting the effectiveness of any single interven-
tion for reducing radiation-induced skin reactions [95].
There is increasing interest in reducing treatment-related
complications with advanced technologies. IMRT, which
allows the delivery of a more homogeneous dose of radiation
across the breast, limiting the «hot spots» (areas receiving
excessive dose), has been proven to reduce the incidence of
skin telangiectasia and moist desquamation and improve
overall cosmesis [96, 97].
Cardiac toxicity is thought to be principally associated
with vascular damage, in particular to microvessels and to
the left anterior descending (LAD) artery, which runs along
the anterolateral heart border and is often within or close to
the radiotherapy tangential fields used to treat the breast or
chest wall in patients with left-sided disease [98]. Historic
data have shown increases in cardiac mortality following

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Radiotherapy for Breast Cancer
475 39

..      Fig. 39.6  IORT technique. After the removal of the tumour bearing
breast quadrant, an aluminium-lead shielding disc is placed posterior
to the parenchyma to protect the thoracic wall, the heart and the lung;
the anatomy of the breast is temporally restored by suturing the
glandular tissue together, taking care to correctly expose the clinical
target volume. A metallic ring with atraumatic hooks is used to hold
open the skin. The applicator is placed and connected to the head of
the treatment machine (hard docking, shown in the figure), the beam
parameters needed to deliver the prescribed dose using an electron
beam of appropriate energy are calculated and the patient is treated
(beam on time is less than 2 min, and the entire procedure lasts about
15–20 min). After irradiation, all the materials are removed, and
cosmetic reconstruction of the breast is performed

..      Table 39.7  Summaries of characteristics of patients and ..      Table 39.7 (continued)

results of the TARGIT-A and ELIOT phase III trials
TARGIT-A (3451 ELIOT (1305
TARGIT-A (3451 ELIOT (1305 patients) patients)
patients) patients)
G3 15 23
Ages eligible (years) ≥ 45 ≥ 48 and <75 ER-positive (% of 90 92
Inclusion criteria Unifocal IDC ≤ 3.5 cm, Unifocal IDC patients)
N0-N1, M0 and No. of positive nodes (% of patients)
ILC < 2.5 cm
  0 82 73
Exclusion criteria ILC, EIC ≥ 25% DCIS, LCIS
  1–3 15 21
Median follow-up 2.4 5.8
(years)   ≥ 3 4 6

Tumour size (% of patients) Dose (Gy) 20 21

< 1 cm 36 66 Local recurrence (%) 3.3 4.4

1–2 cm 50 18 Overall survival (%) 96.1 96.8

> 2 cm 14 16 From Esposito et al. [82] with permission from John Wiley and
Sones
Tumour grade (% of patients) TARGIT Targeted Intraoperative Radiotherapy, ELIOT Electron
Intra-operative Radiation Therapy, IDC invasive ductal cancer,
G1 33 25
ILC invasive lobular cancer, EIC extensive intraductal compo-
G2 52 52 nent, DCIS ductal carcinoma in situ, LCIS lobular carcinoma in
situ, ER oestrogen receptor

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 476 B.A. Jereczek-Fossa et al.

..      Table 39.8  List of available results from closed phase III trials on accelerated partial breast irradiation

Trial (enrolment N pts F-up APBI WBRT LR rate OS rate

period) [years] APBI vs WBRT APBI vs WBRT
Dose fractionation Dose fraction- (p-value) (p-value)
ation

Christie Hospital 708 8 40–42.5 Gy/8 fr 40 Gy in 15 fr 25% vs. 13% 73% vs. 72%
(1982–1987) (p < 0.0001) (no significant
[82] differences)

Cookridge Hospital 174 8 50 Gy in 20 fr 40 Gy in 15 fr 12% vs. 4% 70% vs. 73%
(1986–1990 closed) + (p = 0.07) (p = 0.7474)
[83] Boost (max 15 Gy
in 5 fr)

BUDAPEST 258 10.2 36.4 Gy in 7 fr 50 Gy in 25 fr 5.9% vs. 5.1% 79.7% vs. 82.1%
(1998–2004) or (p = 0.77) (p = 0.73)
[84] 42–50 Gy in 25 fr

GEC-ESTRO 1184 6.6 32 Gy in 8 fr 50–50.4 Gy in 1.44% vs. 0.92% 97.3% vs. 95.6%
(2004–2009) or 30.3 Gy in 7 fr 25–28 fr (p = 0.42) (p = 0.11)
[85] or +
50 Gy Boost (10 Gy in 5
fr)

Hospital de la 102 5 37.5 Gy in 10 fr 48 Gy in 24 fr 0% vs. 0% Similar

Esperanza (–) +
[86] Optional boost
10 Gy

IMPORT LOW 2018 5.7 Test 2: 40 Gy in 15 Tangential fields Test 2: 0.5% vs. 1.1% NA
(2006–2010) fr (control) and 0.2%
[87] (test1)

Florence University 520 5 30 Gy in 5 50 Gy in 25 fr 1.5% vs. 1.4% 99.4% vs. 96.6%
(2005–2013) non-consecutive fr + (p = 0.86) (p = 0.057)
[88] (over 2 weeks) Boost (electrons)
10 Gy in 5 fr with

APBI: accelerated partial breast irradiation; WBRT: whole breast radiation therapy, NA data not available

39
adjuvant radiation treatment for left-sided breast cancer [11,
99, 100]. In the aforementioned 2005 meta-analysis from the
EBCTCG, the ratio of non-breast cancer deaths in irradiated
versus nonirradiated patients was 1.12. This excess mortality
was multifactorial, but due in large part to an increased risk
of cardiac death, with a ratio of 1.27 when compared to
patients not undergoing radiotherapy [11]. Darby and col-
leagues showed that a mean heart dose increase of 1 Gy was
associated with a relative percentage increase in cardiac
events of 7% without an established threshold dose below
which no cardiac effect was observed [99].
These findings refer to radiation therapy regimes used in
the past that are vastly different from the radiation therapy
delivered today. A recent analysis of the long-term risk of
breast cancer-related cardiac toxicity by treatment era sug-
gests that improvements in radiotherapy planning and deliv-
ery have been translated into reductions in toxicity [101].
Technologic advances help radiation oncologists and physi-
cists to optimally spare cardiac structures, by using, for
instance, optimization of beam angles, active breathing
modalities, prone breast positioning, partial-breast treat-
ment, IMRT and proton beam radiotherapy.
Lung toxicity is strictly correlated with the dose delivered
and the volume irradiated, in particular with the mean dose to
the lungs [102], and presents as subacute radiation pneumoni-
tis and lung fibrosis. Often asymptomatic, the subacute radia-
tion pneumonitis may sometimes present with coughing,
fever and modest dyspnea; it generally occurs 4–12 weeks after
the end of radiotherapy, and only a limited number of patients
need medical treatment. Lung fibrosis is observed approxi-
mately 6–12 months after the end of radiotherapy, and it can-
not be differentiated from other chronic lung diseases. The
reported incidence of radiation pneumonitis, including also
radiological changes, ranges from 1% to 80%. This wide range
of incidence rates across studies is due to variations in simula-
tion techniques, treatment schedules and fields, total dose, use
of photons/electrons and various scoring systems [103, 104].
Modern radiotherapy with strict adherence to dose constraints
and increased attention to the safety of treatments have led to
lower rates of pneumonitis, even when extended irradiation
fields are designed to include regional lymph nodes. In the

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Radiotherapy for Breast Cancer
a
b The retrospective SEER analysis, including 182,057 5-year
c usually not available in cancer registry studies. Furthermore,
..      Fig. 39.7  a–c Bright erythema at the end of radiation therapy
course. a This toxicity is rare and quickly resolves, as documented in the
other two images; b the same patient after a month (no toxicity is
observed) and c after a year (faint hyperpigmentation is present in the
upper outer and inner quadrants)
recently published MA.20 trial, grade 2 pneumonitis (symp-
tomatic, requiring medical intervention) occurred in 0.2% of
patients randomized to WBI and in 1.3% of patients random-
ized to receive additional radiation to the regional lymph
nodes, while no patient had pneumonitis of grade 3 or greater.
rares1geo@gmail.com
477 39
Lymphedema of the arm can occur in about 20–30% of
long survivors [105]. The risk of lymphedema is most strongly
correlated with the extent of axillary dissection [106] and
adjuvant nodal irradiation. After adjuvant irradiation of only
the mammary gland or chest wall, the risk of lymphedema is
about 1.8–3% (as high as after surgery alone), whereas in the
case of extension of radiation fields to regional lymph nodes,
the risk increases to 8.9% [11, 107, 108]. Irradiation of the
axillary region increases the incidence of lymphedema by
between 25% and 54% [109, 110].
Informed consent, patient counselling and prevention
strategies are of paramount importance in women receiving
regional node irradiation (RNI) and in those undergoing
axillary dissection; moreover, nomograms have been
designed to predict the risk of lymphedema after axillary dis-
section, and their use should be considered [111].
survivors of loco-regional invasive breast cancer which were
analysed with a median follow-up of 13  years, showed the
absolute estimated excess of secondary malignancy after
breast irradiation of about 5% for the contralateral breast and
6% for other cancers [111]. Importantly, the majority of sec-
ond solid cancers in breast cancer survivors were not related
to radiotherapy but to the other factors (lifestyle, obesity,
etc.) underlining the importance of counselling after breast
cancer treatment [111]. In this systematic evaluation, there
was evidence of a small, but significantly increased, risk of
lung cancer and other cancers in high-dose regions after
breast-conserving surgery (RR = 1.38), higher for ipsilateral
than contralateral lung cancer (1.54 vs. 1.18). Information on
other potential confounding factors such as smoking was
in general, radiation-related risks were lower among women
treated in more recent years [112].
Angiosarcoma of the breast is increasingly seen following
breast RT, usually with a lag time of 5–15 years. This is a very
rare malignancy being seen in 1 per 1000 women but is very
aggressive, with a poor prognosis (see 7 Chap. 46).
All these risks are greatly outweighed by the benefit of
primary disease treatment.
39.7  reast Reconstruction and
B
Radiotherapy
Clear evidence regarding the optimal integration of breast
reconstruction (BR) and PMRT is still lacking across the lit-
erature. BR can be carried out using autologous tissue or an
implant, and either option can be performed immediately
after mastectomy or delayed [113]. A number of factors
related to stage of disease, patient characteristics and physi-
cian expertise can influence the choice of the type of BR, and
the importance of a multidisciplinary approach must be
highlighted [114, 115].
Cost-effectiveness, positive psychological impact, improved
ability to retain much of the breast skin envelope and/or the
nipple, enhanced cosmesis and lower morbidity due to operat-
 478 B.A. Jereczek-Fossa et al.
ing on nonirradiated tissues, all favour the use of immediate
BR, while fewer technical difficulties in designing radiotherapy
fields and in delivering the proper dose to the target volumes
encourage the choice of delayed BR [116–118]. In fact, in case
of immediate BR, the altered shape of the reconstructed breast
may lead to underdosage of the target volumes or to excess
irradiation of the adjacent healthy structures [119, 120].
With the increasing use of sophisticated techniques such
as IMRT, most of these technical challenges can be solved,
achieving satisfactory treatment plans even in patients with
unfavourable anatomies (e.g. funnel chest) or those in need
of internal mammary chain irradiation [121]. Moreover,
IMRT decreases the incidence of complications due to the
improved dose homogeneity [122].
Conventional RT doses in the literature are the same as
those applied for PMRT. The literature on hypofractionation
is scarce in the presence of BR because of concerns about side
effects. Whitfield and colleagues reported on the use of a
3-week schedule (40 Gy in 15 fractions over 3 weeks), with a
rate of severe capsular contraction of 19.5% at 4 years, com-
parable to the conventional 5-week schedule [123].
The most common radiation-related complications after
autologous BR were fat necrosis, flap loss, fibrosis and con-
tracture. A recent review performed by Kelley and colleagues
showed that BR with autologous tissue can be safely carried
out both before and after PMRT. In fact, pooled complication
rates between flaps irradiated before or after BR were not sta-
tistically different with regard to flap loss, wound complica-
tions, infection, hematoma, seroma and fat necrosis, all of
them ranging from 1% to 13%. Other systematic reviews
confirmed these findings. In the review conducted by Berbers
and colleagues while the overall complication rate was simi-
lar, flap fibrosis appeared less frequently if autologous BR was
carried out after radiotherapy (2.7%, 95% CI 8.4–13%) than
39 if carried out before irradiation (36%, 95% CI 17.1–54.9%)
[124–127].
Long-term complications of BR with implants in situ
include infection, pain, skin necrosis or inadequate healing,
implant explantation, fibrosis and progressive asymmetry,
implant rupture and capsular contracture, which is increased
by several folds when implants are irradiated. The risk of
complications is high irrespective of the timing of recon-
struction: pooled data from the study conducted by Momoh
and colleagues on implant reconstruction showed similar
rates of mild and severe capsular contraction (25% and 32%)
and implant failure (19% and 20%) in patients exposed to
radiotherapy before or after BR.  The review performed by
Berbers and colleagues found that the total complication rate
was significantly higher for implant reconstruction if
­performed after radiotherapy (48.7%, 95% CI 38.8%–58.6%)
than if performed before irradiation (19.6%, 95% CI 0.9–
38.3%) [127, 128]. Kronowitz and colleagues reported on a
two-stage approach the so-called delayed-immediate BR. The
first stage consists in placing a saline-filled tissue expander
which is deflated in cases where irradiation is necessary or
otherwise replaced with a definitive prosthesis [129].
rares1geo@gmail.com
A subgroup analysis in the context of a systematic review
conducted by El-Sabawi and colleagues revealed that radio-
therapy to the tissue expander carried a higher risk of failure
than radiotherapy to the permanent implant (18.8% vs 14.7%,
p 0.006) [125]. In the case of expanders, radiotherapy must
commence once full expansion is achieved, and the tissue
expander should be kept at a constant volume during irradia-
tion [130].
Concerns upon the metallic port of the expander remain
theoretical. Dosimetric studies showed an increased dose
due to the scattering of secondary electrons only very close to
the metallic port, which is unlikely to worsen toxicity [131].
Focal underdosage, caused by the metallic port attenuating
the radiation beam to the tissue which lies in its direct
shadow, is considered clinically negligible [132].
In the case of planned PMRT, the reconstruction choice
generally favours autologous BR.  A systematic review on
more than 5000 patients showed that reconstruction failure
occurred in 16.8% in implant-based reconstructions and
1.6% in autologous BR with PMRT. Regarding complication
rates, a significantly higher incidence of infection (13.5% vs.
5.8%), flap necrosis (10.5% vs. 5%), reoperation (37% vs.
16.6%) and total complications (41.3% vs 30.9%) was noted
in implant-based BR compared to autologous BR. The meta-­
analysis performed by Schaverien and colleagues focusing on
autologous BR showed no significant differences in total
complication rates (33.9% vs. 28.6%) and surgical revision
(18.3% vs. 16.1%) in the radiotherapy group compared to
nonirradiated patients, while fat necrosis was higher in the
radiotherapy group (23.8% vs. 8.5%, p 0.006) [126–130].
Regarding BR with tissue expanders/permanent prosthe-
ses (TE/PI), a meta-analysis clearly showed that immediate
BR using implants in patients who are likely to be candidates
for PMRT is associated with an increased risk of postopera-
tive complications [133].
The combined use of an autologous flap and an implant
did not completely protect from complications, but immedi-
ate BR patients on whom this technique is used might gain
more than a threefold lower rate of capsular contracture than
with implant alone BR (6.8% versus 25%) [134].
zz Reconstruction in Previously Irradiated Fields
Patients who are candidates for BR after having received pre-
vious radiotherapy to the chest wall may be exposed to an
increased risk of complications, due to the vascular distress
of the recipient vessels and the stiffness of the skin and sub-
cutaneous tissues. BR with TE/PI alone is considered a rela-
tive contraindication because of the risk of bone deformity
and rib fractures, poor cosmetic outcomes and implant fail-
ure as discussed above [135].
A recent meta-analysis on the impact of prereconstruc-
tion radiotherapy on the outcome of reconstruction modali-
ties showed that autologous flap BR and the combination of
flaps and implants were the best options in previously irradi-
ated patients. In fact, implant reconstruction had signifi-
cantly increased risks for all kinds of complications compared
to non-radiotherapy-treated patients. The risk of capsular
Radiotherapy for Breast Cancer
contracture increased significantly (RR 3.32) with a trend
towards increased surgical revisions (RR 1.67) and recon-
13. Early Breast Cancer Trialists’ Collaborative Group; McGale P, Taylor C,
struction failure (RR, 2.58; 95% CI, 1.86–3.57) compared to
the nonirradiated group. Autologous tissue reconstruction
and a combination flap and implant showed a 92% and 72%
decreased risk of reconstruction failure, respectively, com-
pared with that of prosthetic reconstruction. In particular
14. Poortmans PM, Struikmans H, Bartelink H. Regional nodal irradiation
autologous tissue BR had the lowest pooled incidence of BR
failure (2.1%), followed by flap + prosthesis (6.9%), while
prosthesis had the highest incidence (33.7%) [136–138].
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131. Moni J, Graves-Ditman M, Cederna P, Griffith K, Krueger EA, Fraass
BA, et al. Dosimetry around metallic ports in tissue expanders in
patients receiving postmastectomy radiation therapy: an ex vivo
evaluation. Med Dosim. 2004 Spring;29(1):49–54.
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132. Damast S, Beal K, Ballangrud A, Losasso TJ, Cordeiro PG, Disa JJ,
et al. Do metallic ports in tissue expanders affect postmastectomy
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133. Barry M, Kell MR. Radiotherapy and breast reconstruction: a meta-
analysis. Breast Cancer Res Treat. 2011;127(1):15–22.
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cations analysis of 266 immediate breast reconstructions. J Plast
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135. Tseng J, Huang AH, Wong MS, Whetzel TP, Stevenson TR. Rib frac-
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136. Lee KT, Mun GHJ.  Prosthetic breast reconstruction in previously
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2006;57(2):134–7.
 485 VI

Breast Cancer in
Special Groups
Contents

Chapter 40 Breast Cancer in Special Groups: Young Women

with Early Breast Cancer – 487
Rossella Graffeo and Olivia Pagani

Chapter 41 Hereditary Breast Cancer – 499

Teresa Ramón y Cajal, Anna Virgili, and Nuria Dueñas

Chapter 42 Breast Cancer in Special Groups: Breast Cancer

in Pregnancy – 511
Matteo Lambertini, Hatem A. Azim Jr,
and Fedro Alessandro Peccatori

Chapter 43 Fertility Preservation in Women

with Breast Cancer – 521
Anna Rachelle Mislang, Matteo Lambertini,
and Laura Biganzoli

Chapter 44 Breast Cancer in Older Patients – 529

Anne Shrestha and Lynda Wyld

Chapter 45 Breast Cancer in the Male Patient – 541

M. Umit Ugurlu and Bahadir M. Gulluoglu

Chapter 46 Sarcoma of the Breast – 551

Erkki Tukiainen and Andrew Lindford

Chapter 47 Desmoid (Aggressive) Fibromatosis of the Breast – 559

Nicholas Eastley, Jaroslaw Krupa, and Robert Ashford

rares1geo@gmail.com
 487 40

Breast Cancer in Special

Groups: Young Women
with Early Breast Cancer
Rossella Graffeo and Olivia Pagani

40.1 Introduction – 488

40.2 Epidemiology and Biology – 488

40.3 Genetic Predisposition and Testing – 488

40.4 Diagnostic Procedures, Staging and Follow-Up – 489

40.5 Treatments – 490

40.5.1 Treatment for Early Breast Cancer – 490
40.5.2 Adjuvant Systemic Treatments – 491

40.6 Fertility and Birth Control – 494

40.7 Pregnancy During and After Breast Cancer – 494

40.8 Psychosocial Issues (Job, Insurance, Family Care) – 495

40.9 Summary and Conclusions – 495

References – 495

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_40

rares1geo@gmail.com
 488 R. Graffeo and O. Pagani
40.1 Introduction
Breast cancer (BC) in young women is a complex disease:
multidisciplinary management is warranted as outlined in
the last Breast Cancer in Young Women consensus recom-
mendations (BCY2) which also identify research priorities in
this field [1].
40.2 Epidemiology and Biology
BC is the most common female cancer with an estimated
age-standardized incidence of 71/100,000 women in 2012
[2]: despite being the most common cause of death in women
worldwide [3], it is associated with one of the highest 5-year
survival rates (81.8%, 95% CI 81.6%– 82.0%) [4]. EUROCARE
estimates that among 114,000 BCs diagnosed in Europe in
women aged 15–99, 5% occur in women aged 15–39, 16% in
women aged 40–49 and almost half (49%) in women aged
50–69 [5]. Young patients are those <40 years at BC diagno-
sis, recognizing their specific issues compared to both older
premenopausal and postmenopausal women. BC incidence
in young women has been stable over the past few decades.
Survival rates are higher in women living in Northern as
compared to Eastern Europe, possibly related to the varying
availability of targeted treatments and combined systemic
approaches [6].
Despite the rarity of the disease, young BC patients are
more likely to die of their disease than older patients (crude
HR = 1.39; CI 1.34 to 1.45) [7]; the 5-year absolute survival
rate for women diagnosed <44 years is 84% compared with
87% for women diagnosed at 45–54 years or older [6]. The
lack of systematic screening and diagnostic delays, both con-
tributing to a later stage at diagnosis, and a more aggressive
disease biology (e.g. increased rate of hormone receptor
(HR)-negative or triple-negative disease) may all contribute
40 to their poor prognosis [8].
Young women tend to have aggressive cancer phenotypes
(high grade, HR negative or triple-negative, high prolifera-
tion rate, extensive lymphovascular invasion, HER2 positive)
[9]. Studies have yet to document age-specific tumour gene
expression, but BC arising at a young age seems to be bio-
logically distinct beyond subtype distribution [10, 11]. Data
are limited and difficult to interpret due to small sample sizes
and heterogeneous cutoffs to separate young and old patients.
Johnson and colleagues recently reported clinico-pathologic
characteristics, expression of 17 selected genes and outcomes
in 778 patients (13% aged <40, 87% aged ≥40): a higher pro-
portion of young women were diagnosed with HER2-
enriched and basal-like BCs compared to older women
(23.3% vs. 17.2% and 41.8% vs. 23%, respectively), whereas
older patients had more luminal A tumours (37.6% vs.
15.5%). The 10-year survival in young and older patients
with luminal A disease was not significantly different (62.5%
vs. 73.2%, respectively), while a significantly inferior survival
was reported in young patients with luminal B (10.0% vs.
51.3%), basal-like (46.5% vs. 54.8%) and HER2-enriched
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tumours (16.7% vs. 50.0%) compared to older patients [12].
On the contrary, a recent National Comprehensive Cancer
Network (NCCN) Breast Cancer Outcome Project analysed
17,575 women with early BC (1916 <40 years of age at diag-
nosis, median follow-up 6.4 years): in women with HER2- or
triple-negative disease, there was no clear increased risk of
BC ­mortality among women ≤40 years compared to women
51–60 years, while in women with luminal A BC, there was a
statistically significant increase in BC death among younger
women [13]. The authors concluded that in women with
luminal disease, young age has a negative prognostic impact
probably due to inadequate therapy, decreased treatment effi-
cacy (different hormonal milieu) and lower treatment adher-
ence. Overall, these data suggest BC in young women is a
biologically different disease which needs to be better under-
stood and studied in specific research programs.
40.3 Genetic Predisposition and Testing
Genetic counselling and testing are an integral component of
the management of women with newly diagnosed BC, par-
ticularly if young.
Family history of breast/ovarian cancer and young age at
diagnosis are both correlated with genetic predisposition.
Approximately 10% of BCs are associated with mutations in
a predisposing gene: most cases are attributable to BRCA1 or
BRCA2 mutations and <1% to mutations in other genes with
a high or moderate penetrance (. Table  40.1) [14, 15].
Several multiplex panels incorporating moderate- and high-­
penetrance genes are now commercially available and
approved in the USA and still under investigation in Europe
as they contain genes for which clinical validity or signifi-
cance is not yet established [16]. Tung and colleagues found
that among 488 sequential BC patients, tested with a panel of
25 predisposition genes in a single institution, 10.7% had a
mutation, 6.1% in BRCA1 and BRCA2 and 4.9% in another
gene (CHEK2, ATM, BRIP, PALB2, PTEN, NBN, RAD51C,
RAD51D, MSH6, PMS2): for BRCA1 and BRCA2, the preva-
lence of deleterious mutations decreased with age at diagno-
sis (12.2%, 3% and 1.8% at ≤45  years, 46–60  years and
≥60 years, respectively), while the frequency of mutations in
other genes was independent of age [14]. As expected, factors
significantly predicting for BRCA mutations were younger
age at diagnosis, Ashkenazi Jewish heritage, triple-negative
phenotype, high histologic grade and family history. No fac-
tor predicting for mutations in non-BRCA genes was identi-
fied, possibly because of the small number of patients in these
cohorts [14].
Eccles and colleagues studied 591 patients with HER2+
BC diagnosed at ≤40 years and found that overall the inci-
dence of predisposing mutations was low in the absence of a
family history. Deleterious TP53 mutations in these patients
were more frequent than BRCA mutations, suggesting that
clinicians should consider this possibility in this specific
population, particularly when BRCA testing is negative [17].
TP53 germline mutations may also be identified among
Breast Cancer in Special Groups: Young Women with Early Breast Cancer
489 40
start discussing RRSO in BRCA1 carriers between 35 and
..      Table 40.1  Cancer susceptibility genes other than BRCA1
and BRCA2
40 years of age, upon completion of childbearing [20, 21].The
PROSE multicentre prospective cohort study evaluated the
Gene Pen- Risk category References effect of RRSO on mortality in 2482 BRCA carriers: the
etrance ­surgical cohort had a lower all-cause, BC-specific and ovar-
ian cancer-specific mortality [22]. Overall, RRSO can
Breast genes
decrease BC risk by 40–70%, ovarian or fallopian tube cancer
ATM Moderate Higher than general Easton DF risk by 80%–90% and overall mortality [23]. No data are
population available in BRCA-mutated BC patients: new studies are
BARD1 Moderate Higher than general Couch FJ needed to evaluate the impact of RRSO in this setting and
population properly counsel patients (see 7 Chap. 7, for more detailed
 

CDH1 High High Pharoah PD

discussion).
Another important consequence of genetic testing in the
CHEK2 Moderate Higher than general Easton DF clinical management of young BC patients derives from
population
development of poly ADP-ribose polymerase inhibitors
NBN Moderate Higher than general Easton DF (PARPi) in BRCA carriers and the recent FDA approval in
population metastatic ovarian cancer [24]. This new class of drugs is
PALB2 Moderate High Easton DF under active development also in BRCA-mutated BC
patients, and phase III studies are ongoing both in the meta-
PTEN High High Tan MH
static and early disease settings [25]. The identification of
STK11 High High Hearle N somatic (i.e. in tumour tissue) BRCA mutations in sporadic
TP53 High High Easton DF BC can further expand the indications of PARPi beyond
germline mutation carriers. Meric-Bernstam and colleagues
Other genes
reported that the relative frequency of somatic versus germ-
CDKN2A Moderate Higher than general de Snoo FA line variants differs according to the involved gene (patho-
population genic TP53 mutations are more likely somatic; pathogenic
CDK4 Moderate Higher than general somatic BRCA1 and BRCA2 mutations are relatively rare)
population [26]. Recently, olaparib has been approved in Europe in
relapsed ovarian cancer patients with BRCA1 and BRCA2
APC Moderate Higher than general Goldgar DE
population germline or somatic mutations [27]. In BC, given the techni-
cal challenges of somatic genetic testing, the uncertain clini-
BMPR1A Moderate Higher than general
cal consequences of such findings and the lack of available
population
therapeutic consequences, clear-cut patient information and
EPCAM High High Win AK consent procedures need to be implemented and investigated
MLH1 High High Win AK before its routine application.
MSH2 High High Win AK

MSH6 High High Tung N 40.4  iagnostic Procedures, Staging

MUTYH Higher than general Out AA
population
PMS2 High High Tung N
i­ndividuals without the «typical» Li-Fraumeni syndrome
(LFS) family histories due to de novo mutations [18], mosa-
icism, incomplete family history information or variable
penetrance of TP53 germline mutations. Based on these data,
the addition of TP53 to BRCA testing should be considered
in young BC patients [19].
Genetic counselling and testing can change both primary
surgical management (mastectomy vs. breast conserving; see
below) and subsequent follow-up (radiologic surveillance,
risk-reducing surgery). Risk-reducing mastectomy (RRM)
and salpingo-oophorectomy (RRSO) have been shown to be
effective preventive measures in healthy mutation carriers,
and the NCCN 2017 guidelines recommend in particular to
D
and Follow-Up
Breast density in young women often limits the diagnostic
accuracy of mammography in asymptomatic patients, but
additional routine screening with tomosynthesis or ultra-
sound has not yet been proven to be beneficial: the prelimi-
nary results of the ASTOUND trial in 3.231 women suggest
that ultrasound has better incremental BC detection than
tomosynthesis [28], but these results might be overtaken by
the forthcoming introduction of tomosynthesis as a routine
screening modality in many countries. Digital breast tomo-
synthesis was approved by the FDA in 2011 based on its
improved detection of breast lesions especially in women
with non-fatty breasts. The additional benefit of breast MRI is
still controversial, but the lack of evidence on improved out-
comes speaks against its routine use, irrespective of age [29].
MRI is indicated as an adjunct to mammography in the set-
ting of equivocal mammography/ultrasound, in pathologic
axillary nodes with an unknown primary tumour and in

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 490 R. Graffeo and O. Pagani

monitoring the response to neoadjuvant chemotherapy [30,
31] (see 7 Chap. 21 ‘Breast Surgery After Primary Systemic
 
Therapy’).
MRI in addition to mammograpy is recommended in
high-risk women, in particular BRCA carriers, and annual
MRI screening is indicated in women with history of chest
radiation for Hodgkin disease [32].
Systemic staging in young BC patients is not substantially
different than in older patients. For patients with stage I/II
disease, routine systemic imaging is not recommended in the
absence of signs or symptoms suggestive of metastatic dis-
ease; in patients with T3 N1–3 or symptomatic disease, addi-
tional testing should be considered. Post-therapy follow-up
should include regular physical examination every
4–6 months and annual breast imaging for at least the first
5 years. In the absence of clinical signs-symptoms suggestive
of recurrent disease, additional investigations are not recom-
mended as no impact on survival or ability to palliate recur-
rent disease has been described [1, 33].
[42]. No long-term survival data are yet available, and there-
fore platinum agents should not be routinely incorporated
into neoadjuvant regimens. Limited data are available for
neoadjuvant endocrine therapy (ovarian function suppres-
sion (OFS) plus tamoxifen or aromatase inhibitors (AIs)) in
young patients. An International Breast Cancer Study Group
(IBCSG) randomized phase II trial (IBCSG 41–13 TREND)
is evaluating the efficacy of the luteinizing hormone-­releasing
hormone (LHRH) antagonist degarelix versus triptorelin as
neoadjuvant treatment in premenopausal patients receiving
letrozole. In the absence of definitive data, neoadjuvant
endocrine therapy should not be routinely recommended for
young women outside of clinical trials however.
The management of patients with significant residual dis-
ease after preoperative treatment is challenging. Clinical tri-
als with novel agents/approaches are needed to define the
best loco-regional and ≪adjuvant≫ medical treatments in
this difficult disease setting.
Adequate time for genetic counselling and testing should
be allocated during the preoperative period.

40.5 Treatments Surgery

Young patients with early BC routinely undergo primary
40.5.1 Treatment for Early Breast Cancer breast (breast conserving or mastectomy) and axillary sur-
gery (sentinel node biopsy or axillary dissection) with or
Neoadjuvant Treatment without loco-regional radiotherapy. Margin assessment is
BC in young women tends to be diagnosed more often at particularly relevant for young patients undergoing breast
locally advanced stages than in older individuals [8], and conservation as young age is a well-known independent risk
consequently young patients often require and benefit from factor for increased local recurrence (LR) [43]. In 2,233 con-
preoperative systemic therapies [34]. A pooled analysis of secutive BC patients who underwent BCT, the risk of LR was
individual data from eight randomized trials of the German associated with younger age (HR for age > 50 = 0.56; p = 0.01),
Breast Group showed that young women (n  =  1.453) were non-luminal A subtype (HR for luminal B  =  2.64,
more likely to achieve a pCR after neoadjuvant chemother- HER2  =  5.42, TNBC  =  4.32; p  <  0.001 each) and higher
apy, especially in HR+/HER2- and triple-negative disease regional nodal involvement, the latter both representing the
(20.9% in women under 40 vs. 17.7% in women 40–49 years most frequent biology and staging characteristics in young
vs. 13.7% in women ≥50 years; p < 0.001) [35, 36]. Age was women [44]. In the recently published POSH prospective
40 also independently prognostic for survival in HR+/HER2- cohort study of 3,024 BC patients aged 18–40 years, the LR
disease, with women <40 years without a pCR having a worse rate was higher in patients treated with BCS as compared to
disease-free survival (DFS) compared to their counterparts mastectomy at 5 and 10 years (5.3% vs. 2.6%, p < 0.001, and
achieving a pCR. Despite a higher local relapse rate after neo- 11.7% vs. 4.9%, p < 0.001, respectively), but distant metasta-
adjuvant chemotherapy and breast conservation, no long-­ ses and deaths were lower for BCS when adequate postsurgi-
term significant adverse survival impact in young women has cal radiotherapy, stage at diagnosis and margin width were
been demonstrated [37] as prognosis in patients most likely considered [45]. In addition, a recent registry-based study
to benefit from neoadjuvant strategies (triple-negative and [46] and meta-analysis confirmed no difference in overall
HER2+) is mainly driven by systemic recurrences [38]. survival (OS) among young BC patients undergoing mastec-
The indications for (inoperable or locally advanced tomy or breast conservation [47]. When mastectomy is indi-
tumours especially in BC subtypes associated with high cated or desired by a patient, limited data are available on the
chances of response) and strategy of preoperative therapy survival impact of contralateral RRM, even in mutation car-
need to be discussed and planned in a multidisciplinary team riers. A recent meta-analysis found neither an absolute
and do not differ according to age [39]. reduction in the risk of distant metastases nor an improve-
The preoperative therapeutic options include chemother- ment in OS associated with contralateral RRM in patients at
apy (the same regimens as recommended in the adjuvant set- increased genetic risk, despite the decrease in contralateral
ting) and HER2-targeted therapy (dual anti-HER2 blockade BC incidence [48] (for additional details, see 7 Chap. 7,  

with trastuzumab and pertuzumab combined with chemo- ‘Risk-Reducing Surgery’).

therapy, if available) [40]. Improved pCR rates among triple-­ The indications for and techniques of axillary and breast/
negative disease were shown with the incorporation of oncoplastic surgery are identical to other age groups (see
platinum agents [41], especially in BRCA mutation carriers 7 Chaps. 17, 18, 19, 23 and 24). Patients who have one or two
 

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Breast Cancer in Special Groups: Young Women with Early Breast Cancer
pathologically involved sentinel nodes may not require a
complete axillary dissection [49].
When mastectomy is indicated, skin- and nipple-sparing
techniques with immediate breast reconstruction should be
preferred if technically possible, oncologically appropriate
and desired by the patient [50]. The indications for postmas-
tectomy loco-regional radiotherapy should not discourage
immediate reconstruction when modern radiotherapy tech-
niques are applied, but women should be made aware of the
risks of adverse outcomes and inferior long-term cosmesis in
such cases.
Radiotherapy
Given the higher local recurrence risk seen in younger
women, a boost to the site of excision has to be routinely
delivered in young patients treated with breast conservation,
and partial breast irradiation is contraindicated outside a
clinical trial. Postmastectomy radiotherapy and internal
mammary chain irradiation should continue to be discussed
on an individual basis, as in older women, and based on ini-
tial staging if neoadjuvant treatment is given. Hypo-­
fractionated abbreviated regimens with higher doses/
fractions are becoming more widely used in premenopausal
women with satisfactory safety and cosmetic outcomes [51].
While waiting for long-term data, this approach should be
proposed on a case-by-case basis.
40.5.2 Adjuvant Systemic Treatments
Adjuvant treatment recommendations are based on the indi-
vidual risk of relapse, the predicted sensitivity to a specific
therapy and the patient’s preferences. Treatments have to be
tailored, irrespective of age, according to tumour subtype
(defined by grade, vascular invasion, proliferation rate, HR
and HER2 expression) and stage. The genomic profile of the
tumour (luminal A and B, basal-like, HER2+) [52] may add
prognostic information to the classic clinico-pathologic fac-
tors, helping in selecting patients likely to benefit from differ-
ent adjuvant treatments. Young women are nevertheless
under-represented in the retrospective studies evaluating the
clinical value of these tests. Prospective definitive data from
randomized trials (TAILORx, XPonder, PlanB) are awaited
to assess in particular the benefit of chemotherapy according
to individual tumour gene profiling. In the preliminary
reports of the TAILORx [53] and in the GEICAM 9906 trial
[54], premenopausal patients represented ~5% of the total.
The recent results of the MINDACT study suggest that in
patients at high clinical risk of BC recurrence, defined by the
traditional clinical and pathological factors, the addition of
the 70-gene signature adds relevant information for selecting
which patient might benefit from adjuvant chemotherapy
over endocrine therapy alone. The authors concluded that
chemotherapy could be avoided in patients with high clinical
risk but low genomic risk [55]. Patients aged 35–50  years
nevertheless represented only 28% of the entire population
(women <35 years were <1% of the total). Overall, the evi-
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491 40
dence is limited in this age group due to the rarity of the
­disease, and thus these tests should be used with caution in
young women.
In view of the longer life expectancy of young women, side
effects of adjuvant treatments need to be carefully balanced
against benefits, and long-term morbidity should be moni-
tored (e.g. cardiovascular, bone health, cognitive impairment
and premature menopause). In particular, the impact on fer-
tility and the available preservation measures should always
be discussed with patients as early as possible when planning
a treatment strategy (see Fertility and Birth Control below).
Endocrine Therapy
Oophorectomy was the first endocrine treatment used in
young women with advanced BC in 1896 [56]. From 1995
tamoxifen, a selective estrogen receptor modulator (SERM),
was recognized as an effective adjuvant treatment for patients
with HR+ BC. The Early Breast Cancer Trialist’ Collaborative
Group (EBCTCG) meta-analysis of all randomized trials of
adjuvant tamoxifen showed that 2 to 5 years of treatment have
similar efficacy in all age groups, including patients <40 years
[57]. However, young HR+ patients showed a constantly high
risk of long-term relapse and a worse 10-year BC-specific sur-
vival, independent of nodal status, compared to older HR+
patients in a series of 111,993 patients, diagnosed between
1990 and 2003 and included in the SEER database [58]. The
sustained reduction in BC mortality beyond year 10, achieved
by 5 years of tamoxifen, is therefore of particular interest in
younger women. Extended endocrine therapy has not been
specifically studied in young patients. The ATLAS [59] and
aTTom [60] trials show that continuing tamoxifen to 10 years
provides a further reduction in both disease recurrence and
mortality. Premenopausal patients constituted only approxi-
mately 9% of the ATLAS population, and statistical signifi-
cance was not reached in this subgroup, likely because of the
smaller number of events: nevertheless, these results provide
the only available evidence of benefit of extended endocrine
therapy in premenopausal patients and should be discussed
on an individual basis, especially in patients at high risk of
recurrence. The role of aromatase inhibitor (in combination
with OFS) as extended endocrine therapy has been investi-
gated in a phase II single-arm trial (2 years of OFS in combi-
nation with letrozole after at least 4.5 years of tamoxifen). The
study closed after only 16 patients enrolled over 3.5  years,
suggesting young women may not be motivated to undergo
extended therapies and challenging the feasibility of future
studies.
Tamoxifen can induce amenorrhoea and ovarian cysts
and increase estradiol secretion, but ovarian hyperstimula-
tion does not appear to impact on DFS [61, 62].
The benefit of OFS (either temporary by LHRHa or per-
manent by bilateral salpingo-oophorectomy (BSO)) has been
long debated.
The results of the IBCSG SOFT and TEXT trials [63]
(. Fig.  40.1) helped to identify the population of patients
most likely to benefit from adjuvant OFS.  In the non-­
chemotherapy cohort of the SOFT trial (949 patients) (mainly
 492 R. Graffeo and O. Pagani

..      Fig. 40.1  SOFT and TEXT

designs TEXT
Population: Premenopausal women with endocrine-responsive early breast cancer who should
receive OFS from the start of adjuvant thearapy.
Enrollment November 2003 through April 2011
Final accrual: 2672 (revised target: 2639)

R
A
Stratify: N
Tamoxifen + OFS (Triptorelin)
D
Chemo planned O
M
Nodal Status I Exemestane + OFS (Triptorelin)
Z
E

SOFT
Population: Premenopausal women with endocrine-responsive early breast cancer who remain
premenopausal after chemotherapy or after surgery alone.
Enrollment December 2003 through January 2011
Final accrual: 3066 (target: 3000)

R
Stratify: A
N Tamoxifen
Prior chemo D
O Tamoxifen + OFS
Intended OFS
M
Nodal Status I Exemestane + OFS
Z
E

All treatment arms were 5-year durations from randomization.

Tamoxifen 20 mg/day p.o.; Exemestane 25 mg/day p.o.

40 older premenopausal patients at low risk of relapse defined as p < 0.001) [65], with an absolute gain comparable with the
lower-­grade, node-negative, low-proliferating, smaller benefit of AIs in postmenopausal women (. Fig. 40.2). The
 

tumours), >95% of patients remained free from BC at 5 years
irrespective of treatment received (tamoxifen alone, OFS plus
tamoxifen or the AI exemestane). In women at higher risk of
recurrence remaining premenopausal after chemotherapy
(1,084 patients), in particular if <35  years, a significant
improvement in the 5-year BC-free interval (BCFI) was
observed with OFS plus exemestane (85.7%) compared to
OFS plus tamoxifen (82.5%) or tamoxifen alone (78%). In
alignment with the SOFT low-risk cohort data, the Eastern
Cooperative Oncology Group (ECOG) trial 3193 (E-3193)
conducted in 345 low-risk patients (node negative, tumours
<3  cm, no adjuvant chemotherapy) showed no significant
DFS or OS difference, at a median follow-up of 9.9  years,
between tamoxifen and tamoxifen plus OFS, with OS >95%
in both patients’ groups [64].
In the combined SOFT-TEXT analysis (4,690 patients),
OFS plus exemestane significantly improved the 5-year DFS
compared to OFS plus tamoxifen (91.1% vs. 87.3%, HR 0.72;
Austrian Breast and Colorectal Cancer Study Group
(ABCSG) 12 trial also compared OFS plus tamoxifen or the
AI anastrozole in premenopausal patients with early HR+ BC
[66]. The trial did not show any difference in DFS between
arms, but a significantly higher risk of death for anastrozole-­
treated patients was reported at 94.4 months of median fol-
low-­up. This latter finding may at least in part be explained
by both the imbalance in post-relapse AI treatment between
arms (61% vs. 41% of patients in the tamoxifen and anastro-
zole arms, respectively) and differences in outcome between
normal-weight and obese patients (overweight patients
treated with anastrozole had more than a doubling in the risk
of death compared with normal-weight patients). Overall,
the different outcomes between ABCSG 12 and SOFT-TEXT
may be explained by differences in study design and power:
in particular, in the Austrian trial the statistical power was
lower (half the number of events), and the 3-year treatment
duration is no longer standard for oral endocrine therapy.

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Breast Cancer in Special Groups: Young Women with Early Breast Cancer
493 40

5-yr Disease-free
Subgroup No.of Patients No.of Patients with Event Hazard Ration (95% CI)
Survival (%)
Exemestance – Tamoxifen – Exemestance – Tamoxifen – Exemestance– Tamoxifen–
OS OS OS OS OS OS
All patients 2346 2344 216 298 0.72 (0.60–0.85) 91.1 87.3
Cohort
No chemotherapy
TEXT S26 S27 22 40 0.54 (0.32–0.92) 96.1 93.0
SOFT 470 473 20 30 0.68 (0.38–1.19) 95.8 93.1
Chemotherapy
TEXT 806 801 93 130 0.69 (0.53–0.90) 89.8 84.6
SOFT S44 S43 81 98 0.84 (0.62–1.13) 84.3 80.6
Lymph-node status
Negative 1362 1350 70 115 0.60 (0.45–0.81) 95.1 91.6
Positive 984 994 146 183 0.79 (0.64–0.98) 85.6 81.4
0.25 0.50 1.00 2.00 4.00

Exemestance–OS Better Tamoxifen–OS Better

..      Fig. 40.2  Disease-free survival according to treatment group and www.nejm.org/doi/full/10.1056/nejmoa1404037#t=article.

patients’ characteristics (From: Pagani et al. [65]. Copyright © [2014] 7 http://www.nejm.org/doi/full/10.1056/NEJMoa1404037)
 

Massachusetts Medical Society. Reprinted with permission. 7 http://

 

All these data contributed to the most recent treatment Chemotherapy

guidelines (ASCO, St. Gallen, BCY2, NCCN, ESMO) [1, 39,
67, 68], which state higher-risk patients should receive OFS
in addition to oral endocrine therapy and lower-risk patients
should not. The accurate definition of risk is therefore of
paramount importance to tailor treatment in the individual
patient. A continuous, composite measure of recurrence risk
in HER2-negative patients treated in the TEXT-SOFT trials
(4,891 patients) (incorporating age, nodal status, tumour size
and grade, estrogen and progesterone receptor and Ki-67
expression levels) allows better weighing of the relative ben-
efits of OFS, tamoxifen and exemestane. The absolute
improvement in the 5-year BCFI with exemestane plus OFS
versus tamoxifen alone can range from 10–15% in patients
with high recurrence risk to at least 5% in women at interme-
diate risk while being minimal for those at lowest risk [69].
The toxicity profile in TEXT-SOFT was consistent with
the given therapy. In TEXT, musculoskeletal symptoms, sex-
ual complaints (vaginal dryness, decreased libido and dyspa-
reunia), osteoporosis and fractures were more frequent in
patients taking exemestane than tamoxifen where a higher
incidence of sweating, hot flushing and urinary incontinence
was reported [65]. In the SOFT trial, grade ≥ 3 adverse events
were more frequent in patients receiving OFS compared to
those taking tamoxifen alone. Overall, no significant differ-
ences in quality of life (QoL) were observed between treat-
ments, but potential toxicity needs to be incorporated in
individual treatment planning [70, 71]. Young age is a well-
known risk factor for non-adherence/nonpersistence to
endocrine therapy [72]: effective strategies to identify and
manage non-adhering patients are crucial to ensure the best
The impact of adjuvant chemotherapy in premenopausal
women with HR+ disease has been debated and questioned
since the 2007 EBCTCG meta-analysis which showed a ben-
efit of OFS only in the absence of chemotherapy [73]. This
observation raised the hypothesis that temporary or perma-
nent OFS might partly or fully explain the chemotherapy
benefits reported in premenopausal women. Less than 50%
of women <40 years develop amenorrhoea with CMF: mod-
ern anthracycline-taxane-based regimens are unlikely to
cause permanent amenorrhoea in most women <40  years
(and almost none in women <35 years). A joint retrospective
analysis of 9,864 patients treated within trials of chemother-
apy alone from four international cooperative groups
(IBCSG-NSABP-ECOG-SWOG) showed the relative recur-
rence risk was substantially higher for women <35 years with
HR+ disease compared with older patients. This finding was
not observed for patients with HR- tumours, suggesting the
endocrine effects of chemotherapy alone are insufficient for
the younger age group [74, 75]. All randomized trials study-
ing the additional benefit of chemotherapy added to endo-
crine therapy in premenopausal women failed to accrue: the
available indirect evidence [64, 66, 76, 77] of excellent 5- and
10-year outcomes in HR+ premenopausal women (even with
node-positive disease) treated with combined endocrine
therapy alone argues against the universal need for adjuvant
chemotherapy in all premenopausal patients.
When chemotherapy is needed (HR- or high-risk HR+
disease), the choice of regimens (taxane-anthracycline based)
and total duration (4–8 cycles) are the same in pre- and post-
menopausal patients (see 7 Chap. 36 Adjuvant Chemotherapy,

survival opportunities. Curigliano) as the proportional risk reductions with modern

rares1geo@gmail.com
 494 R. Graffeo and O. Pagani

drug combinations are little affected by age [78]. In the
absence of any data favouring one approach over the other,
sequential regimens have at least equal efficacy over combi-
nation regimens and may be better tolerated.
Novel biological treatments (i.e. PARPi) [79] and specific
chemotherapeutic agents (i.e. platinum derivatives) are
increasing as more women delay childbearing for cultural,
educational and professional reasons [87]. Pregnancy-­
associated BCs are predominantly poorly differentiated and
often diagnosed at advanced stages, in particular during lac-
tation [88]. In general, treatment should follow established
recommendations [89] (see also 7 Chap. 42 Breast Cancer in

under evaluation in triple-negative and BRCA mutation car- Pregnancy). Whenever possible, patients should be enrolled
riers and will possibly improve outcomes in these patient in prospective registration studies [90]. Breastfeeding during
populations. treatment (both chemotherapy and endocrine therapy) is not
recommended as most drugs used to treat BC can be excreted
Targeted Therapy in milk [91].
No evidence is available to recommend a specific HER2-­ The decision to become pregnant after BC is very com-
targeted adjuvant regimen and treatment duration in young plex and involves, among other issues, treatment-related
patients with HER+ disease: the benefit of adjuvant trastuzumab transient/permanent infertility and sexual dysfunction.
appears independent of age in all published studies [1, 80]. Preliminary data of the Helping Ourselves Helping Others
(HOHO) study, a US prospective observational study in
young women with BC addressing disease and psychosocial
40.6 Fertility and Birth Control outcomes at diagnosis and during long-term (10 years) fol-
low-­up, showed that concerns about fertility influenced
All young BC patients should be informed about the poten- treatment decisions in 26% of women, 11% of respondents
tial impact of adjuvant therapies on fertility, asked about considered receiving endocrine therapy for <5 years and 13%
their pregnancy desire and referred to fertility specialists as of them thought a future pregnancy would increase their risk
early as possible (i.e. before initiation of any systemic ther- of recurrence [92]. Unpublished preliminary data from the
apy) if indicated, to discuss and plan the most adequate indi- cohort of women followed outside the USA within the IBCSG
vidual fertility preservation procedure. The ASCO [81] and HOHO study (IBCSG 43–09) show that 20% of patients
ESMO [82] guidelines recommend embryo/oocyte cryo- desire children after BC and are willing to take <5 years of
preservation as the most efficient strategies for fertility pres- adjuvant tamoxifen and 9% are concerned that a future preg-
ervation. Short protocols of ovarian stimulation with LHRHa nancy would increase their risk of recurrence. In a popula-
plus tamoxifen or letrozole have proven to be safe also in tion registry study from Norway, Stensheim and colleagues
HR+ patients and only cause a minimal delay in the start of found that, overall, cancer survivors had a lower pregnancy
adjuvant therapy [83]. Ovarian tissue cryopreservation is rate than controls and female BC survivors in particular have
preferred in young women who require urgent cancer treat- a 70% lower chance of becoming pregnant compared with
ments (e.g. neoadjuvant chemotherapy) as this does not need healthy controls [93]. Young BC survivors and their health
ovarian stimulation, is independent of the phase of the men- professionals can be reassured that there is no clear increased
strual cycle and can be rapidly performed. The presence of risk of recurrence from having a biological child after the dis-
malignant cells in the ovaries has been excluded in most ease [94]. In several population retrospective studies and
40 series, but special attention should be paid in BRCA muta- available meta-analyses, the relative risk of death was similar
tion carriers [84]. Ovarian function suppression (OFS) with or even lower for women who became pregnant after BC
LHRHa during chemotherapy has been longly studied with than for those who did not [94–97].
controversial findings: recent data support both the safety Of note, a multicenter, retrospective cohort study of 333
and efficacy of the procedure, but most guidelines suggest patients who became pregnant any time after BC showed, at
discussing it on an individual basis considering it still experi- a median follow-up of 5 years following conception, no dif-
mental [85] (this area is covered in more detail in 7 Chap. 43 ference in DFS between pregnant and non-pregnant patients
 

‘Fertility’). in the HR+ population and in women who became pregnant

An additional topic of discussion includes contraceptive <2 years following diagnosis versus those who became preg-
methods during treatments as chemotherapy, anti-HER2 nant afterwards [98].
therapy and endocrine therapy which are all teratogenic. Based on all this evidence, an IBCSG-coordinated pro-
Exogenous hormonal contraception is generally contraindi- spective trial (POSITIVE-IBCSG 48–14/BIG 8–13) in
cated, and alternative strategies should be considered [86]. women <40 years with HR+ early BC who received at least
18 months but ≤30 months of endocrine therapy is evaluat-
ing the risk of BC relapse associated with a 2-year treatment
40.7 Pregnancy During and After Breast interruption to allow pregnancy and the factors associated
Cancer with pregnancy success.
Current evidence suggests BC survivors who wish to
Pregnancy-associated BC, defined as BC diagnosed during breastfeed should be encouraged and supported. In general,
pregnancy, in the first postpartum year or any time during loco-regional treatment of the breast may affect lactation, and
lactation, is a relatively uncommon event, but the incidence is many patients can therefore only breastfeed from the untreated

rares1geo@gmail.com
Breast Cancer in Special Groups: Young Women with Early Breast Cancer
breast. Women should be reassured about the adequacy of
milk production by a single breast, but adequate prenatal
breastfeeding counselling is needed in these patients [99].
40.8  sychosocial Issues (Job, Insurance,
P vors has increased in recent years partially because survival
Family Care)
Young women facing a BC diagnosis are at increased risk of
psychosocial distress compared with older patients. An
increasing number of young patients experience long-term
survival but their QoL is often compromised by the effects of
multimodality cancer treatments. The risk of premature
menopause, cognitive impairment, late cardiac toxicity, sec-
ond cancers, persistent fatigue and neuropathy, sleep and
mood disturbances and psychosocial consequences needs to
be adequately addressed in this patient population. After a
systematic literature review, Howard-Anderson and col-
leagues highlighted the need for dedicated research on this
specific survivor population, including the evaluation of
baseline personal characteristics (e.g. life expectations and
needs), which could influence the development of tailored
support interventions. A consensus on the ideal measures for
symptom quantification, QoL and other health outcomes
would be valuable to facilitate future research and its inter-
pretation [100]. The EORTC-validated QoL questionnaires
were submitted to 243 consecutive premenopausal, early-­
stage and relapse-free Spanish BC patients who had received
surgery in the previous 5–20 years. Overall, the study showed
a generally satisfactory QoL and moderate future perspective
limitations. Fatigue and social functioning were key factors
influencing both measures, representing a possible focus of
effective interventions [101]. Younger survivors report feel-
ing more isolated, are less satisfied with traditional support
groups and face more challenges transitioning into the survi-
vorship phase of care due to their specific characteristics,
including couple and family relationships and work/finances
[102]. Several reports emphasize that many young women
require dedicated information and additional support when
dealing with children and family care (e.g. meal preparation
and house cleaning) and insurance/job issues and when fac-
ing the impact of their cancer diagnosis on friends, partners
and other family members [103, 104].
Very few psychosocial interventions have been developed
and studied in young women with early BC.  Mindfulness
meditation has emerged as a promising intervention for can-
cer populations and may be a particularly good option for
younger survivors [105, 106]. A small randomized trial sug-
gests that a brief mindfulness intervention may offer short-­
term subjective benefit and improve psychological and
behavioural measures [107]. The Young and Strong study,
launched in 14 US academic institutions and 40 community
sites, will randomize between an educational and supportive
care intervention focusing on issues unique to young BC
patients (e.g. career development, starting/raising a family,
body image) and a physical activity intervention focusing on
developing and/or maintaining a healthy lifestyle (e.g. bene-
rares1geo@gmail.com
495 40
fits of exercise and resources to enhance physical activity
after diagnosis) [108].
Little information is available regarding work problems
after a BC diagnosis, in particular in young women [109].
Overall, research on return to work (RTW) in cancer survi-
rates have globally increased [110]. A Danish national RTW
program will evaluate whether early and tailored occupational
rehabilitation with the active involvement of both patients and
the workplace will enhance and facilitate RTW [111].
Neurocognitive symptoms (e.g. chemo brain defined as
forgetfulness, distractibility and difficulty with word finding
and concentration) are described among young BC survi-
vors, and several investigations are underway [112]. Recent
findings suggest a relationship between both chemotherapy
and endocrine therapy and structural cerebral changes [113].
40.9 Summary and Conclusions
The management of young BC patients is complex. Young
women tend to develop more aggressive BC subtypes and to
be diagnosed at later stages than their older counterparts. In
general, young age should not be the sole reason to prescribe
more aggressive treatments. Mastectomy confers no OS
advantages when compared with breast-conserving treat-
ment followed by modern radiotherapy. The indications for
axillary surgery and the choice of systemic therapies should
be based on individual biological characteristics, stage and
the patient’s comorbidities. Genetic testing (e.g. BRCA1 and
BRCA2, TP53) should be considered early after diagnosis as
it may influence several treatment decisions.
Young BC patients and survivors face different problems
compared with older women including fertility, pregnancy,
late treatment side effects, social difficulties including job
discrimination and childcare. Research programs addressing
all the unanswered questions for the optimal management of
BC in young women should be developed together with pro-
spectively planned subgroup analyses to enhance the statisti-
cal power of completed studies.
In routine clinical practice, the culture of multidisci-
plinary management and care, ideally within a structured
breast unit, should be reinforced to offer any young BC
patient the best individualized approach and to avoid, in par-
ticular, the risk of overtreatment. The role of patient advo-
cacy is also crucial for both dissemination of information,
knowledge and lobbying.
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 499 41

Hereditary Breast Cancer

Teresa Ramón y Cajal, Anna Virgili, and Nuria Dueñas

41.1 Hereditary Breast Cancer Genetic Testing – 500

41.2 Hereditary Breast Cancer Immunophenotype – 501

41.3 Risk-Reducing Strategies for 

BRCA-­Associated Breast Cancer – 501
41.3.1 Risk-Reducing Bilateral Mastectomy in Healthy
BRCA1/BRCA2 Mutation Carriers – 502
41.3.2 Surgical Approach to BC in BRCA Mutation Carriers – 503
41.3.3 Risk-Reducing Bilateral
Salpingo-­Oophorectomy – 503

BRCA1/BRCA2 Mutation-Associated Breast

41.4 
Cancer Systemic Treatment – 504
41.4.1 PARP Inhibitors in BRCA-Associated Tumours – 505
41.4.2 Platinum Analogues as Therapy in BRCA-Associated
Breast Cancer – 505

References – 507

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_41

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500 T. Ramón y Cajal et al.

41.1  ereditary Breast Cancer Genetic

H ..      Table 41.1  Breast cancer susceptibility genes
Testing
Gene Relative Absolute Associated
At least 10% of all breast cancers (BC) BCs occur in individu- risk (Ref.) risk by tumours
70–80 years
als who have germline mutations in high- or moderate-­
of age (%)
penetrance cancer susceptibility genes, which carry a relative
BC risk of >fivefold and two- to fivefold, respectively [1]. BRCA1 11.4 [3] 75 Breast, ovarian
Selection for gene testing based on clinical criteria for carcinoma
hereditary BC is evolving. The last version of the National BRCA2 11.7 [3] 76 Breast, ovarian
Comprehensive Cancer Network recommends BRCA1 and carcinoma
BRCA2 testing after personalized risk assessment and genetic
TP53 4.3–9.3 [4] 75 Sarcoma, breast,
counselling if: adrenocortical
55 An individual comes from a family with a known carcinoma, brain
deleterious mutation.
PTEN 2–5 [5] 39, 43, 49 Breast, thyroid,
55 The woman has a personal history of ovarian cancer
endometrial cancer
(OC).
55 Male BC or BC diagnosed ≤50 years. CDH1 6.6 [6] 53 Diffuse gastric
cancer
55 The woman has a personal history of BC diagnosed
≤50 years with one or more of the following: an addi- STK11 2–4 [7] 45, 18, 57, 11 Breast, ovarian sex
tional BC primary, ≥1 close blood relative with BC cord-stromal
diagnosed at any age, ≥1 close relative with pancreatic tumours, colon,
pancreas,
cancer or Gleason >7 prostate cancer or belong to either
an unknown or limited family history. NF1 2.6 [8] 26 Peripheral nerve
55 The woman has a personal history of triple-negative BC sheath, brain
diagnosed ≤60 years. PALB2 5.3 [9] 45 Pancreas
55 The woman has a personal history at any age with any of
ATM 2.8 [10] 27 Pancreas
the following: ≥1 close relative with BC diagnosed
≤50 years, ≥2 close relatives with BC at any age, ≥1 close CHEK2 3 [11, 12] 29 Lung
relative with OC at any age, ≥2 close relatives with NBN 2.7[13] 29 Breast
pancreatic and/or prostate at any age and 1 close male
RAD51C 1.5–7.8 [14] Breast
blood relative with BC [2].
RAD51D 6.3[15] Ovarian carcinoma
Other hereditary BC forms, such as Cowden or Li-Fraumeni BRIP1 2 [16] Breast
syndromes, have specific clinical diagnosis and testing crite- 3.6–11 [17] Ovarian carcinoma
ria based on either mucocutaneous lesions/multiple gastro-
intestinal hamartomas or a wide tumour spectrum within the
family [2].
While mutations in the BRCA1 and BRCA2 genes account anticipation of high rates of variants of unknown significance
for up to half of germline mutations and have routinely been (VUS) and unexpectedly positive or ambiguous test results.
41 studied for the past 20  years, the development of next-­ The probability of detecting a VUS depends on the number of
generation sequencing technologies and their multiple genes included in the panel and ranges from 40% to 88% [19,
advantages, including time and cost-­effectiveness compared 20]. However, since multigene testing is increasingly used,
to traditional Sanger sequencing, has allowed either the the identification of VUS is expected to decrease over time.
retesting for BRCA1 and BRCA2 gene mutations (if there was Clinical experience with multigene panel testing of indi-
a prior non-informative result from old-­ fashioned tech- viduals who lacked BRCA1/BRCA2 mutations has reported
niques) or the simultaneous analysis of rarer susceptibility deleterious mutation rates of 3–11%, most commonly in
genes such as ATM, CDH1, CHEK2, PALB2, PTEN, STK11, moderate-risk breast and ovarian cancer genes and Lynch
TP53, NBN, RAD51C, RAD51D, BRIP1 and BARD1 syndrome genes [19–21]. The most common mutations
(. Table 41.1) [18]. Despite the lack of evidence on clinical
  belonging to this category were in PALB2 (23%), CHEK2
utility and the absence of established guidelines guidelines (15%) and ATM (15%) genes [19]. Regarding factors that pre-
regarding the management of individuals with mutations in dicted for mutations in genes other than BRCA1/BRCA2, one
moderate-risk genes, these multiplex panels are commer- study did not find any clinical predictors in 1781 patients,
cially available and currently used in clinical practice world- even though the age at first BC diagnosis was slightly lower
wide. Some panels are phenotype-specific, whereas others for BRCA1/BRCA2 mutation carriers compared to those with
cover a broad spectrum of cancers and are marketed for mutations in other BC susceptibility genes [20]. In addition,
expanded pan-cancer genetic risk assessment. These panels the risks associated with some genes could be the result of
require adequate pretest counselling and informed consent in interactions with other genes or environmental ­interactions.

rares1geo@gmail.com
Hereditary Breast Cancer
501 41
Moreover, it is perfectly possible that different mutations most robust pathology-based likelihood ratio estimates for
located in the same gene confer a different risk of hereditary prediction of BRCA1/BRCA2 mutation in women younger
cancer. As a result of these limitations, current internationalthan 70  years [29]. Therefore, an ER-positive phenotype
initiatives are trying to fill in these gaps in genotype-­ negatively predicted BRCA1 mutation status, irrespective of
phenotype correlations, expressivity and penetrance, includ- grade, whereas ER negativity plus histological grade 3 was
ing the Evidence-based Network for the Interpretation of more predictive of positive BRCA1 mutation status in women
Germline Mutant Alleles (ENIGMA), the Prospective 50 years or older. In contrast, ER positivity plus grade 3 mod-
Registry Of MultiPlex Testing (PROMPT) and the Consortium estly predicted BRCA2-positive mutation status irrespective
of Investigators of Modifiers of BRCA1/2 (CIMBA). of age, whereas ER negativity plus histological grade 3
The current version (2.2016) of the NCCN guidelines rec- ­features modestly predicted BRCA2-positive mutation status
ommends performing regular breast magnetic resonance at 50 years or older. Triple-negative tumour status was highly
imaging (MRI) tests in women harbouring germline muta- predictive of BRCA1 mutation status irrespective of age and
tions in ATM, CDH1, CHEK2, PALB2, PTEN, STK11 and modestly predictive of positive BRCA2 mutation status in
TP53 genes based on a >20% risk of BC.  Further, risk-­ women 50 years or older.
reducing mastectomy (RRM) should be considered in CDH1, Less is known on the phenotype of other mutated gene-­
PTEN, TP53 and PALB2 mutation carriers and risk-reducing associated BC.  PALB2-related BC, the third most frequent
salpingo-oophorectomy (RRSO) in MMR, BRIP1, RAD51C cause of hereditary breast cancer, mostly resembles BRCA2-­
and RAD51D mutation carriers [2]. associated tumours [9, 30]. Two recent series of PALB2 muta-
tion carriers have compared PALB2-related and sporadic
BC. Both studies reported that 60–74% of tumours were ER
41.2 Hereditary Breast Cancer positive, and, remarkably, 30–35% of them were ER/PR and
Immunophenotype HER2 negative (triple negative). Moreover, the largest pub-
lished cohort of BC in Li-Fraumeni syndrome to date, in 39
BRCA1 tumours are more likely to be high grade medullary- women with TP53 mutations, found that 63% of the invasive
like subtype with features such as an increased mitotic count, BC and 73% of DCIS were positive for HER2 and more than
lymphocytic infiltrate, pushing margins, trabecular growth three quarters of the tumours were positive for
pattern and necrosis [22–24]. Further, frequent basal-­like ER.  Remarkably, the concurrent expression of the ER and
immunohistochemical markers including a lack of oestrogen HER2 was present in 49% of the tumours [31].
(ER), progesterone receptor (PR) and human epidermal Finally, recent studies on the genomic profiles of heredi-
growth factor receptor-2 and increased tp53, cytokeratin 5/6, tary breast tumours compared with sporadic tumours also
cytokeratin 14, cytokeratin 17 and epidermal growth factor suggest distinct genetic pathways in terms of the regions
would also suggest a BRCA1-related BC.  Gene-­expression altered. Therefore, loss of 4q, 3p and 12q and loss of 11q and
studies have shown the majority of BRCA1-BCs fall into the 13q are recurrently seen in BRCA1 and BRCA2 tumours,
basal-subtype group [25]. Single-cell analyses of temporal respectively [32, 33]. Additionally, one study on comparative
somatic events in BRCA1-BC tissue have revealed loss of genomic hybridization array (CGH) analysis of hereditary
PTEN and TP53 mutations as early events in the development BC biopsies has identified four major different groups
of basal-like and luminal tumours, respectively [26]. according to the type and amount of genomic alterations
Breast cancers arising in BRCA2 mutation carriers tend showing one group with a significantly inferior survival [34].
to be more heterogeneous than those arising in BRCA1 muta- This research has also supported the existence of a subset of
tion carriers. However, sparse studies of detailed tumour sporadic tumours that acquire alterations leading to genomic
pathology information from BRCA2 carriers have revealed instability similarly to BRCA1- and BRCA2-related tumours
that they also exhibit a distinct morphologic and molecular with the potential benefits of targeted therapy through the
phenotype. Regarding expression of the ER, the majority of use of agents that lead to DNA double-strand breaks such as
early studies had concurred with a similar prevalence of ER-­ PARP inhibitors and platinum agents.
positive BRCA2-associated BC compared with sporadic con-
trols [24, 27]. In contrast, recent studies have demonstrated
that BRCA2-associated tumours are predominantly luminal 41.3 Risk-Reducing Strategies for 
B in terms of gene expression, more likely to be ER positive BRCA-­Associated Breast Cancer
and with high histological grade, with reduced tubule forma-
tion, continuous pushing margins and less expression of The main goal of managing hereditary BC is to minimize the
basal cytokeratin 5 and HER2/neu protein overexpression incidence and mortality of a first or a second tumour. Early
compared with sporadic BC [24, 28]. intensive surveillance based on the combination of annual
The knowledge of the histopathological features that are MRI and mammography achieves a high sensitivity (80–94%)
characteristic of hereditary BC may be additionally used to in the detection of BC at an early stage and a promising low
prioritize testing of BRCA1 and BRCA2 mutations in BC mortality rate at 5 years [35, 36]. The contribution of mam-
cases. The most recent initiative using the largest pathology mography to screening accuracy in BRCA1/BRCA2 carriers
datasets accrued by CIMBA and BCAC has obtained the has been recently addressed in a recent individual-­patient

rares1geo@gmail.com
 502 T. Ramón y Cajal et al.
meta-analysis, which found differences according to age and
mutation status. Therefore, whereas in BRCA1 mutation carri-
ers the addition of mammography leads to a 3.9% increase in
sensitivity and a 4% loss of specificity regardless of age, a third
of tumours in BRCA2 mutation carriers younger than 40 years
of age were detected by mammography. These results support
the potential consideration of different screening recommen-
dations according to BRCA1 or BRCA2 mutation status [37].
This issue is discussed in more detail in 7 Chap. 6
 
The portfolio of risk-reducing surgical interventions
includes risk-reducing bilateral mastectomy (RRBM), pro-
phylactic contralateral mastectomy (PCM) and risk-reducing
salpingo-oophorectomy (RRSO). Rates of prophylactic bilat-
eral mastectomy and particularly contralateral mastectomy
have been steadily rising over the past 15 years due to multi-
ple factors, including the increased use of preoperative MRI
and the advances in immediate breast reconstruction.
However, prophylactic surgery is not an inconsequential
decision. Informed consent should be based on the individual
cancer risk evaluation in the setting of comprehensive pretest
and post-test counselling. Moreover, multidisciplinary con-
sultations before surgery are recommended to ensure
informed decision-making by the patient.
41.3.1  isk-Reducing Bilateral Mastectomy
R nipple specimen from one carrier compared with two speci-
in Healthy BRCA1/BRCA2 Mutation
Carriers
Updated reports from retrospective and prospective observa-
tional studies that compared BC outcomes in women who
underwent risk-reducing bilateral mastectomy (RRBM) with
surveillance showed a reduction of 90% or more in the risk of
subsequent breast tumour development and decreased BC
mortality by 81–100% among those women who underwent
surgery [14, 38–41]. In line with previous results, the most
recent prospective study assessing the efficacy of RRBM
compared to surveillance in a cohort of 570 healthy BRCA1/
BRCA2 carriers showed significant reductions in all-cause
41 mortality and BC-specific mortality, although confirmation
in larger cohorts of patients with a longer follow-up is war-
ranted [41].
Due to the possible retention of at-risk tissue in the skin
flaps and below the areola, the classic subcutaneous mastec-
tomy, defined as the complete removal of all breast tissue
while leaving the nipple-areola complex (NAC) intact, has
been replaced by total skin-sparing mastectomy (TSSM), a
more recent and popular technique among surgical oncolo-
gists that preserves the overlying skin over the whole breast
and the NAC and enhances the cosmetic outcome. Recent
studies in average-risk populations have demonstrated simi-
lar oncologic safety of TSSM and simple non-skin-sparing
mastectomy, with a locoregional recurrence rate of 2% at
3  years of follow-up [42], and better cosmetic outcomes.
Ductal tissue beneath the nipple should be excised and sub-
mitted to pathology separately. If DCIS or invasive cancer is
identified, then the NAC should be removed. In women with
rares1geo@gmail.com
a previous diagnosis of BC, factors that have been associated
with nipple involvement are the mammographic distance of
the tumour from the nipple and tumour size. In particular,
when the tumour-nipple distance is less than 2 cm or tumour
size greater than 4 cm, nipple involvement is reported in an
average of 50% of cases. For BRCA1/BRCA2 mutation carri-
ers, the concern is that preservation of the NAC skin may
confer an unacceptable rate of new cancer development.
Available data from two subsets of BRCA1/BRCA2 mutation
carriers within overall cohorts of women undergoing pro-
phylactic and therapeutic nipple-­sparing mastectomy (NSM)
reported no new cancers at a maximum follow-up of
43 months [43, 44]. The outcomes of 413 patients undergo-
ing NSM, including 177 BRCA germline mutation or genetic
variants of uncertain significance, at one single institution
reported unexpected invasive carcinoma in 1.7% and 17% of
prophylactic and therapeutic NSM, respectively [45].
Further, one study compared the oncologic outcome and
tumour involvement of the NAC in 53 carriers treated with
TSSM and immediate reconstruction for prophylactic (26
patients) or therapeutic indications (27 patients) with age-
and stage-matched non-BRCA controls. At a mean follow-
up of 51  months, among patients undergoing prophylactic
surgery, no new cases of invasive cancer were found.
However, one ductal carcinoma in situ was diagnosed in one
mens found in the noncarriers cohort. In patients undergo-
ing TSSM for therapeutic indications, «nipple specimen»
analysis found one invasive and one in situ carcinoma in the
noncarrier cohort. At a mean follow-up of 37.3  months,
there were no local recurrences in the BRCA1−/BRCA2-
positive cohort [42].
Data from the largest study of its kind, presented at the
Annual Meeting of the American Society of Breast Surgeons
2016, supports NSM approach as being safe and effective in
the short term. After a median follow-up of 34 months, none
of the 551 nipple-sparing mastectomies performed prophy-
lactically in 348 BRCA1/BRCA2 mutation carriers developed
BC at any site. Whereas accruing more patients and longer-­
term follow-up will be important to confirm the oncologic
safety of this approach, NSM may be offered to BRCA-­
positive women undergoing risk-reducing mastectomy.
Regarding reconstructive techniques, BRCA1/BRCA2
mutation carriers mainly prefer immediate reconstruction
with breast implants which may relate to their young age,
when autologous donor sites are less likely to be adequate
for bilateral reconstructions. Major surgical complications
such as infection, flap necrosis and loss of reconstruction
occur in about 20% of cases [46]. Psychological effects and
health-­related quality of life have also been addressed in
retrospective [47] and a few prospective studies [48–50]. A
large retrospective study from the Mayo Clinic suggested
that 74% of women had a diminished level of emotional con-
cern of developing BC and 48% of women did not change
their level of satisfaction with their body appearance [47].
Remarkably, one prospective study of 65 Swedish women
questioned at baseline and 1  year postoperatively did not
Hereditary Breast Cancer
detect significant negative effects on anxiety, depression
and quality of life. However, women with RRBM reported
a negative impact on sexual pleasure and body image
although they improved their anxiety and social activities
over time [49].
41.3.2  urgical Approach to BC in BRCA
S had a 3.5-fold increased risk for CBC compared with noncar-
Mutation Carriers
BRCA mutation testing strongly influences surgical decisions
in newly diagnosed BC patients. An ongoing prospective
cohort study, including 897 women aged 40  years and
younger at BC diagnosis, resulted in 30% of women report-
ing that knowledge or concern about genetic risk had influ-
enced their surgical treatment decisions [51]. Moreover, once
a BRCA mutation carrier is diagnosed with BC, she faces the
difficult dilemma to choose between breast-conserving ther-
apy (BCT) followed by radiation therapy, unilateral thera-
peutic mastectomy or unilateral therapeutic mastectomy and
prophylactic contralateral mastectomy. Decision-making
about her optimal local management would depend on her
risk of ipsilateral breast recurrence (IBR), the risk of contra-
lateral BC (CBC), the potential survival benefit of prophylac-
tic mastectomy and the potential factors that modify her risk
of IBR and CBC.
The risk of IBR in BRCA mutation carriers compared
with noncarriers was analysed in a recent meta-analysis [52]
that included ten studies (six cohort and four case-control
studies) and reported pooled rates of IBR of 17.3% and 11%
for carriers and controls, respectively (p value = 0.07). Only
two studies showed a trend for more frequent new primary
cancers in BRCA mutation carriers. Based on a subgroup
analysis according to follow-up, there was no difference in
IBR risk in carriers versus noncarriers in studies with a
median follow-up of less than 7 years. However, studies with
longer median follow-up showed that carriers had a signifi-
cantly higher risk of IBR compared with patients with spo-
radic BC. This finding indicates that radiotherapy in carriers
is as effective as in noncarriers, at least in the short term,
although the persistence of a higher risk for developing a new
primary cancer in the residual breast tissue should be also
taken into account. No difference was found in the IBR risk
between BRCA1 and BRCA2 mutation carriers. Regarding
overall survival (OS) and BC specific survival (BCSS) after
BCT between BRCA mutation carriers and noncarriers, two
studies revealed no differences in OS, and two other studies
found conflicting results in BCSS [52].
The most appropriate surgical management of unilateral
BC in BRCA mutation carriers is addressed in one retrospec-
tive cohort study that compared both approaches: BCT and
mastectomy [53]. Remarkably, despite the higher risk of IBR
following BCT compared with mastectomy observed in this
study (23.5% vs. 5.5%), no differences in BCSS and OS were
detected at 15 years. Most of the IBR in the BCT group con-
sisted of less biologically aggressive new primary cancers
than true recurrences [54]. Based on a moderate level of
rares1geo@gmail.com
503 41
e­ vidence, two factors were protective against IBR, the use of
adjuvant chemotherapy (RR 0.51) and undergoing oopho-
rectomy (RR 0.42).
To answer the question regarding the benefit of bilateral
mastectomy, eleven studies (seven cohort and four case-­
control studies) fulfilled the criteria to be included in the
aforementioned meta-analysis [52]. BRCA mutation carriers
riers, and consistently, bilateral mastectomy reduced the risk
of CBC in carriers. Regarding the differential risk between
both genes, BRCA1 mutation carriers had a higher risk of
CBC compared with BRCA2 mutation carriers (21% for
BRCA1 and 15% for BRCA2 mutation carriers). Risk factors
for CBC among BRCA mutation carriers were investigated in
nine studies. Oophorectomy (RR 0.52), older age at diagnosis
and the use of adjuvant tamoxifen (RR 0.57) were associated
with a decreased risk for CBC. With a low level of evidence,
the protective effect of tamoxifen may be stronger in patients
not undergoing oophorectomy. Evidence did not support the
impact of either adjuvant chemotherapy or radiotherapy on
the risk of CBC [55].
Regarding the outcome of patients with a personal his-
tory of BC who complete CPM compared to high-risk sur-
veillance, two early studies [56, 57] with a limited number of
patients and follow-up found no differences in either BCSS
or OS [57]. However, more recent evidence from two retro-
spective [58, 59] and one prospective observational [41]
studies revealed an improved survival after CPM compared
with unilateral mastectomy. In the first study, from Canada,
despite the differences between the two groups concerning
favourable tumour characteristics and more efficient chemo-
therapy regimens in the CPM group, the 20-year survival was
88% compared with 66% for those patients who chose sur-
veillance [58]. The average time from diagnosis to CPM was
2.3  years. In agreement with these results, a second British
cohort study reported a 10-year OS of 89% in the CPM group
compared to 71% in the non-CPM group [59]. This benefit in
BCSS was consistently found in a prospective Dutch analysis,
especially for patients with low risk of primary BC-specific
mortality such as age < 40, grade 1 or 2, no triple-negative
phenotype and lack of adjuvant chemotherapy.
It is important to note that the discussion for or against
CPM should include the risk of recurrence and metastasis as
well as the risk of OC and consideration of prophylactic bilat-
eral salpingo-oophorectomy.
41.3.3 Risk-Reducing Bilateral
Salpingo-­Oophorectomy
Based on the high risk of ovarian and fallopian tube cancer
and the lack of effective screening tools for these tumours,
current international guidelines recommend healthy
BRCA1/BRCA2 mutation carriers to undergo risk-reucing
bilateral salpingo-oophorectomy (RRBSO) around the age
of 40 upon the completion of their childbearing potential
or individualized based on the age of onset of OC in their
 504 T. Ramón y Cajal et al.

..      Table 41.2  Breast cancer risk reduction after bilateral salpingo-oophorectomy

Authors Design Patients Follow-up HR (95%)

RRSO No RRSO (FU) Total BRCA1 BRCA2

Rebbeck et al. [64] Retrospect/ 43 79 RRSO 9.6 year NR 0.53 NR

prospect FU No RRSO 8.1 year (0.33–0.84)

Rebbeck et al. [65] Retrospect/ 99 142 RRSO 8.2 year 0.47 NR NR

prospect FU No RRSO 8.9 year (0.29–0.77)

Domcheck et al. [66] Prospect matched 155 271 RRSO 3.1 year 0.36 NR NR
cohort No RRSO 2.1 year (0.20–0.67)

Domcheck et al. [38] Prospect 336 1034 3 year 0.54 0.63 0.36
unmatched cohort (0.37–0.79) (0.41–0.96) (0.16–0.82)

Mavaddat et al. [3] Prospect 309 679 3 year 0.62 0.52 0.79
unmatched cohort (0.35–1.09) (0.24–1.13) (0.35–1.8)

Heemskerk-­Gerritsen Retrospect/ 346 476 RRSO 5.5 year 1.09 1.21 0.45

et al. [71] prospect FU No RRSO 3.9 year (0.67–1.77) (0.72–2.06) (0.17–1.66)

family [60]. In addition to the reduction of c­ ancer incidence,
RRBSO also decreases the all-cause mortality, BCSS and
OC-specific mortality according to a meta-analysis of three
prospective studies [61, 62]. The procedure must include the
visual assessment of the abdomen and pelvis, pelvic wash-
ings and total bilateral salpingo-oophorectomy with ligation
of the ovarian artery and vein approximately 2 cm proximal
to the ovary and tube. Both serous tubal intraepithelial and
occult invasive serous carcinomas have been identified in
2–17% of the fallopian tubes of BRCA1−/BRCA2-positive
women undergoing RRBSO. Therefore, meticulous process-
ing of the surgical specimen is mandatory to identify occult
invasive disease and the coexistence of potential precursors
of high-grade serous carcinoma [63]. Based on the recent
hypothesis about serous cancers originating from the fallo-
pian fimbria, bilateral salpingectomy with delayed surgical
menopause is an option that should not be used outside of
41 clinical trials.
Beyond its use for the prevention of gynecologic cancer,
several observational studies have evaluated the effects of
RRBSO on BC risk. Five out of seven observational studies
and one meta-analysis, using different designs and analytical
methods, reported a reduction in the risk of BC of approxi-
mately 50% when the surgery was performed before meno-
pause (. Table 41.2). Among the major studies, three of them
did not find a reduction in the risk of a second primary BC
[3, 71, 67]. Minimizing the potential bias of prior studies, the
most recent analysis could not find a significant reduction in
the risk of second BC after a median follow-up time of
3.2 years. Therefore, when counselling BRCA mutation carri-
ers on a second primary BC risk reduction, caution is war-
ranted until a representative number of patients, specially
BRCA2 mutation carriers, and longer follow-up allow us to
draw any conclusion [71].
41.4  RCA1/BRCA2 Mutation-Associated
B
Breast Cancer Systemic Treatment
Proteins encoded by the BRCA1 and BRCA2 genes are essen-
tial for homologous recombination (HR), the cell’s most effi-
cient and accurate DNA repair pathway for double-strand
DNA breaks [68]. According to the Knudson hypothesis [69]
and as a result of genomic injury, tumours in patients har-
bouring germline BRCA1/BRCA2 mutations suffer a somatic
loss of the second BRCA allele, thus leaving the tumour tissue
with a defective HR repair pathway and in need for alterna-
tive DNA repair methods. Single-strand-based base excision
repair (BER) is a primary backup system for HR loss in
response to BRCA1/BRCA2 mutations [68], and PARP-1
mediates BER by recruiting the scaffolding proteins XRCC1,
DNA ligase III and DNA polymerase ß [70]. In BRCA-­
mutated tumour cells, disruption of both repair pathways
leads to cell death.
Advances in the treatment of hereditary BC and OC have
been based on the common clinical and pathologic features
shared by BRCA mutation-associated tumours, sporadic
poorly differentiated high-grade OC and triple-­negative BC
(TNBC) – referred as «BRCAness» – and the hypothesis that
all these tumours might end up being particularly sensitive to
the same drugs. Clinical trials encompassing all these
tumours have tested either the efficacy and tolerability to
DNA-damaging agents alone or in combination with other
cytotoxic agents or the synthetic lethality approach through
the identification, validation and application of new targets
involved in pathways alternative to HR repair of DNA dam-
age such as poly-ADP ribose polymerase (PARP)-1 and
PARP family members.
Current phase 2–3 clinical trials in hereditary BC are
based on preclinical and a few small retrospective studies

rares1geo@gmail.com
Hereditary Breast Cancer
suggesting that BRCA1−/BRCA2-mutated BC cells exhib-
ited greater chemosensitivity compared with wild-type
BRCA1/BRCA2 cells with regard to agents causing double-
strand DNA breaks such as cisplatin and less sensitivity to
taxanes [72, 73]. In addition, PARP inhibitors (PARPi) were
developed either in combination with other drugs in a
range of solid malignancies [74] or in monotherapy in
tumours predicted to be highly sensitive to PARP inhibition
such as the BRCA mutation-associated breast and ovarian
cancers.
41.4.1  ARP Inhibitors in BRCA-Associated
P similar rates obtained by the cooperative group GeparSixto
Tumours
Earlier evidence from phase 1–2 studies testing five PARPi in
monotherapy (olaparib, veliparib, talazoparib, niraparib and
rucaparib) in BRCA-associated breast and ovarian cancers
demonstrated promising antitumour activity with overall
objective rates ranging from 13% to 57% and clinical benefit
in 63% of BC patients [75–84], which was comparable with
response rates observed in studies of single-agent chemo-
therapy. Additional studies of veliparib as a single agent or in
combination with chemotherapy are currently active [85,
86]. Toxicity profiles appear to be similar to cytotoxic agents
but generally manageable. The most frequent grade 1–2
adverse events are nausea, vomiting, diarrhoea, fatigue,
headache and anaemia (common to all them) reported in
81% of patients and thrombocytopenia in 35% of patients
treated with niraparib [87]. Among grade 3–4 toxicities, nau-
sea, vomiting and haematological toxicity were the most
common dose-limiting adverse events found in the phase 1
trials with olaparib [77, 78].
These data guided the development of phase 1 trials with
other agents and two clinical trials of PARPi in combination
with chemotherapy in the treatment of advanced BC. Based
on preclinical data showing the synergic activity between
veliparib and temozolomide [88], this PARPi has been fur-
ther investigated as part of combination schedules in one
phase 2 with a response rate of 22% and clinical benefit rate
of 50%. Best results in terms of efficacy have been obtained in
other phase 1–2 trials of the combination of a PARPi with
cisplatin [89, 90], carboplatin [83, 91] and topotecan [92]
with a wide range of response rates (25–73%) likely explained
by the differences in inhibitory action on PARP among par-
ticular inhibitors.
Ongoing phase 3 trials in the metastatic setting are com-
paring PARPi monotherapy to single-agent chemotherapy
(physician’s choice) or the combination of chemotherapy
plus PARPi or placebo in BRCA1/BRCA2 mutation carriers
with locally advanced or metastatic BC (. Table  41.3). If
positive, these results will be the basis of applications for the
drug regulatory agencies of PARPi for the treatment of
advanced BC, similarly to their approval of olaparib in
platinum-­sensitive BRCA-associated high-grade serous ovar-
ian, fallopian tube and primary peritoneal cancer.
rares1geo@gmail.com
505 41
In the adjuvant or neoadjuvant settings, one ongoing
phase 3 trial is evaluating the efficacy of olaparib as mainte-
nance therapy after 1 year of the completion of neoadjuvant or
adjuvant chemotherapy and radiotherapy in BRCA-­associated
high-risk primary BC [93]. Preliminary data from a second
phase 2 trial with rucaparib plus cisplatin as adjuvant therapy
for TNBC or BRCA-mutated BC after preoperative chemo-
therapy has showed no improvement in 1-year disease-free
survival (DFS) versus cisplatin [94]. Moreover, the I-SPY2
study assessing the addition of veliparib and carboplatin to
standard neoadjuvant chemotherapy in TNBC observed a
pathologic complete response rate of 52% consistent with
and CALGB 40603 (Alliance) testing the addition of carbopla-
tin to standard neoadjuvant chemotherapy [95–97] with
greater benefit observed in patients with germline BRCA1/
BRCA2 or RAD51 mutations. Further in the neoadjuvant set-
ting, one ongoing randomized phase 3 trial, comparing the
efficacy of the combination of carboplatin and veliparib, car-
boplatin to standard chemotherapy versus standard chemo-
therapy in early stage triple negative BC [98], and an additional
phase 2 study of talazoparib monotherapy in patients with
BRCA-associated BC are currently ongoing [99].
The potential use of PARPi as a chemopreventive drug
has been hypothesized based on results obtained by olaparib
and veliparib delaying BC development in BRCA1-deficient
mice. However, this benefit has to be weighed against the risk
of secondary malignancies (especially myelodysplastic syn-
drome and acute myeloid leukaemia).
41.4.2  latinum Analogues as Therapy
P
in BRCA-Associated Breast Cancer
In line with their ability to induce single- and double-strand
DNA breaks and their activity in BRCA-deficient and basal-­
like BC cell lines, platinum analogues exhibit clinically sig-
nificant antitumour activity in BRCA-associated BC both
alone and in combination with other cytotoxic agents and
PARPi. In a pilot study in 20 BRCA1-mutated carriers with
advanced disease, single-agent cisplatin resulted in first-line
overall response rates of 89% and a progression free survival
median (mPFS) mPFS and mOS of 12 and 30 months, respec-
tively [72]. Other trials have tested both sporadic TNBC and
BRCA-associated BC with consistent high responses
(. Table 41.3). Among them, the TNT/BRCA trial, a phase 3
trial, presented at San Antonio Breast Cancer Symposium
2014, compared carboplatin to docetaxel as first- or second-
line chemotherapy and provided evidence on 43 BRCA1/
BRCA2 mutation carriers who had a greater response (68%
with carboplatin and 33% with docetaxel) and a longer mPFS
with carboplatin (6.8  months compared with 3.1  months)
compared to patients with wild-type BRCA genes. In addi-
tion, two phase 2 and phase 3 trials focussed only on BRCA
mutation carriers in the same ­metastatic setting are currently
testing the combination of paclitaxel-­carboplatin plus velipa-

506 T. Ramón y Cajal et al.

..      Table 41.3  Main studies evaluating platinum-based regimens

Authors Phase N (BRCA) Regimen/results

Studies in the neoadjuvant setting

Inform [100] (NCT01670500) 2 166 Cisplatin 4 cycles and AC q2 weeks or q3 weeks 4 cycles
(ongoing)

PrECOG 0105 [101] 2 80 (19) Carboplatin AUC2-gemcitabine 1000 mg/m2 days 1

and 8 and iniparib 5.6 mg/kg days 1, 4, 8 and 11 q3
weeks 6 cycles
pCR 47% in BRCA carriers

Progect [102] 2 49 (13) Carboplatin AUC6-docetaxel 75 mg/m2 q3 weeks

pCR 77%

GeparSixto [95] 2 315 Paclitaxel 80 mg/m2 non-pegylated liposomal

doxorubicin 20 mg/m2 weekly and bevacizumab
15 mg/kg q3 weeks +/−carboplatin AUC 1.5–2 weekly
times 18 weeks
ypT0N0 53 vs. 37%, p = 0.005

Brightness [86] 3 624 (stratified by BRCA status) Carboplatin Q3 weeks only vs carboplatin-veliparib
(ongoing no recruiting)

Studies in the adjuvant setting

HOCN BRE-0146 [103] 2 128/22 (BRCA1/BRCA2) Cisplatin 75 mg/m2 and rucaparib/placebo

83% DFS at 1 year

Studies in the metastatic setting

Byrski et al. [72] 2 20 (BRCA1) Cisplatin 75 mg/m2 6 cycles

ORR 80%, 9p cCR, 7p pCR,
mPFS 12 m, mOS 30 m

Isakoff et al. [104] (TBCRC 009 2 86/11 (BRCA1/BRCA2) Cisplatin/carboplatin (1–2 lines)
trial) ORR 55%, mPFS 3 m

Tutt et al. [72] (TNT/BRCA trial) 3 400 Carboplatin AUC 6 q3 weeks 6 cycles vs. docetaxel
100 mg/m2 q3 weeks 6 cycles (0–1 line)
ORR 68% vs. 33%, p = 0.03

AbbVie M12–895 [105] 2 255 (BRCA1/BRCA2) Carboplatin-paclitaxel and veliparib/placebo q3 weeks vs.
temozolomide and veliparib
(ongoing no recruiting)

NCT02163694 [106] 3 Carboplatin AUC 6 and paclitaxel and veliparib/placebo

41
rib/placebo versus ­temozolomide plus veliparib [105] and
paclitaxel-carboplatin plus veliparib/placebo [106], respec-
tively.
Trials testing platinum analogues in neoadjuvant therapy
for BRCA mutated and TNBC were based on initial results
from one retrospective and prospective analyses in BRCA1
mutation carriers observing a pCR rate of 61% in those
treated with single-agent cisplatin [107]. Among others, one
q3 weeks (0–2 lines) (ongoing)
in the pCR rate with the addition of carboplatin either in
BRCA/RAD50/RAD51 mutation carriers or BRCA mutation-­
negative patients with family history strongly positive for BC
[96]. Additional trials in the neoadjuvant setting are cur-
rently testing the activity of cisplatin versus the standard
anthracycline-containing regimen AC in carriers or the ben-
efit of adding carboplatin or veliparib-carboplatin to pacli-
taxel in BRCA mutation carriers (. Table 41.3).

phase 2 trial, comparing carboplatin-gemcitabine and inipa-
rib assessing pCR and the ability of a homologous recombi-
nation deficiency assay to predict pCR, observed a pCR of
47% in either mutation carriers or those whose tumours
exhibited HR deficiency [101]. These results support the
impact of platinums in multigenetic factors impairing DNA
repair pathways and are consistent with another randomized
phase 2 trial finding higher pCR rates and larger increments
Finally, research on the potential benefit from cisplatin in
the context of the high risk of recurrence after preoperative
chemotherapy has been recently initiated. One randomized
trial in patients with TNBC or known BRCA mutations who
had residual lymph node involvement or >2 cm invasive dis-
ease after anthracycline or taxane neoadjuvant therapy tested
postoperative cisplatin with or without rucaparib showed no
benefit on DFS at 1 year in an interim analysis [103].

rares1geo@gmail.com
Hereditary Breast Cancer
Despite the encouraging results of both strategies (plati-
num analogues and PARPi) for the treatment of BRCA muta-
15. Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR,
tion carriers BC in the neoadjuvant and metastatic settings,
ongoing trials will address the remaining questions such as
the best platinum analogue and their optimal doses, the util-
ity of PARPi in ER-positive BRCA-associated BC, whether
both approaches should be used sequentially or as a synergic
combination, which is the best schedule, long-term toxicity
and outcomes of PARPi and, finally, the full knowledge of
mechanisms of resistance to both.
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 511 42

Breast Cancer in Special

Groups: Breast Cancer
in Pregnancy
Matteo Lambertini, Hatem A. Azim Jr, and Fedro Alessandro Peccatori

42.1 Introduction – 512

42.2 Diagnosis and Staging – 513

42.3 Local Treatment – 514

42.3.1 Surgical Management – 514
42.3.2 Radiotherapy – 514

42.4 Systemic Treatment – 515

42.4.1 Chemotherapy – 515
42.4.2 Anti-HER2 Agents – 516
42.4.3 Endocrine Therapy – 516
42.4.4 Supportive Care – 516

42.5 Obstetric Care and Long-Term Outcomes of Children

with in Utero Exposure to Anticancer Therapies – 517

42.6 Conclusions – 518

References – 518

Matteo Lambertini acknowledges the support from the European Society for Medical Oncology (ESMO)
for a Translational Research Fellowship at Institut Jules Bordet

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_42

rares1geo@gmail.com
 512 M. Lambertini et al.
42.1 Introduction
Breast cancer represents the most common tumour diag-
nosed in women worldwide and the most frequent malig-
nancy in female patients of reproductive age [1].
Approximately 11% of all breast carcinomas are expected to
be diagnosed every year in women under the age of 45, and
the incidence is even higher in developing countries [2].
Between 1 in 3000 and 1 in 10,000 pregnancies may be com-
plicated by the diagnosis of breast cancer [3]. The definition
of pregnancy-associated breast cancer (PABC) refers to
breast cancer diagnosed during pregnancy or within 1 year
after delivery. However, the purpose of the present chapter is
to focus on the situation in which breast cancer is diagnosed
during pregnancy (BCP). The overall incidence of BCP
ranges between 2.4 and 7.3 per 100,000 pregnancies as
reported in population-based studies [4–7]. Although breast
cancer is one of the most frequently diagnosed malignant
neoplasms among pregnant women, BCP can be considered
a rare condition [8]. However, the issue of BCP may become
more common in the future due to both the current trend of
postponing pregnancy to later in life [9] and evidence sug-
gesting that both the incidence of breast cancer in young
women and the occurrence of BCP are increasing [10, 11].
Breast cancer arising at a young age has potentially unique
biologic features [12]: as shown by gene-expression profiling,
the complexity of this condition seems to go beyond breast can-
cer subtype distribution [13]. Pregnancy may add complexity
to breast cancer biology. The hormonal milieu during preg-
nancy with its growth-promoting effects might theoretically
result in a more aggressive biology of breast cancer [14].
Although some studies have suggested no major differences in
the expression of hormone receptors and HER2 as compared to
non-pregnant age-matched breast cancer patients [15–17], sev-
eral studies have shown that BCP seems to be more commonly
associated with unfavourable tumour biology such as a pre-
dominance of triple-negative breast carcinomas (TNBC) [18–
20]. Recently, a genomic profiling analysis including 54
pregnant and 113 age- and stage-matched non-­pregnant breast
..      Fig. 42.1  Algorithm for the
42 management of women with
breast cancer during pregnancy
First trimester
· Surgery
· Wait second trimester for medical
treatment, if feasible
· Discuss termination if medical treatment
is urgently needed
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cancer patients revealed that BCP is associated with specific
activated signalling pathways (e.g. the serotonin receptor path-
way and G-protein-coupled receptor pathway), high expres-
sion of potentially relevant cancer targets (e.g. PD1/PDL1, SRC,
insulin growth factor and Wnt/β-­catenin, RANK-ligand) and a
low prevalence of tumour-infiltrating lymphocytes [21–23].
The unique biologic features of BCP together with the
more frequent delay in diagnosis leading to more advanced
stage at presentation are possible explanations for the find-
ings that PABC seems to be independently associated with a
poor prognosis. As shown by Azim and colleagues in a meta-­
analysis of 30 retrospective control-matched, population-­
based and hospital-based studies including 3628 PABC cases
and 37,100 controls, PABC patients had a significantly higher
risk of relapse (pooled hazard ratio [pHR] 1.60; 95% confi-
dence intervals [CI], 1.19–2.16) and of death (pooled hazard
ratio [pHR] 1.44; 95% CI, 1.27–1.63) compared to women
with non-pregnancy-related breast cancer [24]. Patients with
breast cancer diagnosed in the immediate postpartum period
showed a clear trend towards inferior outcomes (pHR 1.84;
95% CI, 1.28–2.65) compared to those diagnosed during
pregnancy (pHR 1.29; 95% CI, 0.74–2.24) [24]. Another pos-
sible explanation for these findings is that patients with BCP
could be offered «non-standard» potentially suboptimal, sys-
temic therapies, with a possible negative impact on their
prognosis. As shown in a case-control study, patients with
BCP treated at a single institution (i.e. the University of Texas
M.D. Anderson Cancer Center) who received the same stan-
dard anthracycline-based chemotherapy regimen during
pregnancy (i.e. FAC [5-fluorouracil, doxorubicin and cyclo-
phosphamide]) had clinical outcomes that were no worse
than in non-pregnant patients with breast cancer [16]. Similar
findings were observed in Europe in the largest cohort study
available on this topic: no negative prognostic impact of BCP
was shown for patients who received standard treatments
(including chemotherapy) during pregnancy [17].
These findings highlight the importance of increased
awareness and proper clinical management of BCP
(. Fig. 42.1). Since there are no randomized studies in this
Breast lump during pregnancy
Imaging + core biopsy
Second and third trimesters
· Surgery
· Chemotherapy, if indicated (not to be
administered after week 34 of gestation)
· Wait after delivery for radiotherapy, anti-
HER2 treatment and endocrine therapy, if
indicated
Breast Cancer in Special Groups: Breast Cancer in Pregnancy
setting and due to the relative rarity of BCP, decisions on its
clinical management are largely individualized and based on
limited evidence. However, there have been several impor-
tant contributions in the field in recent years, and specific
guidelines have been developed to help physicians in dealing
with pregnant breast cancer patients [11, 25]. A multidisci-
plinary team (i.e. medical oncologist, surgical oncologist,
psychologist, genetic specialist, obstetrician, neonatologist
and paediatrician) should be involved from the outset [26].
According to major international guidelines, the clinical
513 42
nancy increases breast density, making clinical examinations
and mammography more difficult to evaluate [27–29].
Physicians should be aware about the possibility that a breast
lump in a pregnant patient may be associated with a cancer
diagnosis: in these cases, imaging and pathological examina-
tion should be performed without delay [25]. Histopathological
diagnosis based on core biopsy represents the gold standard
for BCP and should follow standard procedures as in non-­
pregnant patients, but the pathologist needs be informed
about the pregnancy status [11, 25] (. Table 42.1).

management of BCP should be performed in institutions
with adequate expertise in dealing with these patients [25].
42.2 Diagnosis and Staging
BCP generally presents at a more advanced stage at diagnosis
as compared to breast cancer in the general population [26].
The possible delay in diagnosis is related to the fact that preg-
Imaging procedures for diagnosis and staging should aim
to limit exposure to ionizing radiation, and the benefits of
each modality versus the potential risks to the foetus should
always be taken into account [11, 25]. Breast ultrasound as
well as mammography with abdominal shielding can be
safely and effectively performed in pregnant patients [30, 31],
while insufficient data are available about the diagnostic
accuracy and safety of contrast-enhanced breast magnetic
resonance imaging (MRI) which is not recommended for

..      Table 42.1  Recommendations for the treatment of women with breast cancer during pregnancy

Intervention Type of intervention Recommendation

Diagnosis Core biopsy Recommended; the pathologist needs to be informed about the pregnancy
and staging
Mammography with abdominal shielding Recommended

Breast ultrasound Recommended

Contrast-enhanced MRI Not recommended

Chest X-ray with abdominal shielding Recommended, if indicated

Ultrasound for abdomen and pelvis Recommended, if indicated

MRI without gadolinium Possible, if indicated

Computed tomography, bone scan and Not recommended

positron emission tomography

Local Breast-conserving surgery or mastectomy Recommended

treatment
Sentinel lymph node biopsy Possible

Immediate breast reconstruction Tissue expander insertion seems feasible, but limited data are available

Radiotherapy Not recommended

Systemic Chemotherapy Recommended in the second and third trimesters (not to be administered
treatment after week 34 of gestation). Anthracyclines plus cyclophosphamide is the
preferred regimen. Taxanes can be administered (paclitaxel to be
preferred). 5-Fluorouracil and dose-dense regimens are not indicated

Anti-HER2 agents Not recommended

Endocrine therapy Not recommended

5-HT3 antagonist Recommended; ondansetron to be preferred

Corticosteroids Not recommended in the first trimester, can be used in the second and
third trimesters (methylprednisolone to be preferred)

NK1 antagonist Not recommended

G-CSF Not recommended

Abbreviations: MRI magnetic resonance imaging, 5-HT3 antagonist 5 hydroxytryptamine-3 receptor antagonist, NK1 neurokinin 1 receptor
antagonist, G-CSF granulocyte colony-­stimulating factors

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 514 M. Lambertini et al.

BCP [11, 25] (. Table 42.1). Ultrasound represents the pre-

 

..      Table 42.2  Treatment options during the different

ferred imaging modality for staging the abdomen and pelvis, trimesters of pregnancy
and chest X-ray with abdominal shielding can be performed
to stage the chest [25] (. Table  42.1). In the cases of sus-
  First Second Third After
pected bone or brain metastases or if the other imaging pro- trimester trimes- trimester delivery
cedures were inconclusive, MRI without gadolinium can be ter
considered [25] (. Table 42.1). Computed tomography, bone
 
Breast Yes Yes Yes Yes
scan and positron emission tomography should be avoided surgery
during pregnancy [11, 25] (. Table 42.1).
 

Sentinel Yes Yes Yes Yes

As recommended by the Panel of the Second International
lymph node
Consensus Conference on Breast Cancer in Young Women biopsy
(BCY2), genetic counselling should be offered for every
Radiotherapy No No No Yes
young breast cancer patient, especially if there is a family his-
tory of breast carcinoma or a diagnosis of TNBC [32]. The Chemotherapy No Yes Yes Yes
probability of detecting BRCA mutations in patients with (no after
TNBC is approximately 20% [33]. Since women with BCP week 34)
are diagnosed at a young age and the majority of them with a Anti-HER2 No No No Yes
TNBC, genetic counselling may be indicated in many of therapy
these patients. Due to the direct influence on breast cancer Endocrine No No No Yes
management in terms of both local and systemic treatment, therapy
rates of BRCA mutation testing are increasing in young
breast cancer patients and will probably become even more
common in the coming years [34]. For breast cancer patients who undergo mastectomy,
immediate breast reconstruction as compared to no recon-
struction offers the same survival rates and should be offered
42.3 Local Treatment to all patients with the exception of those with inflammatory
breast cancer [32]. In women with BCP, only one series of 13
42.3.1 Surgical Management cases showed the feasibility of tissue expander insertion with
a short operation time and no significant morbidity to both
Surgery can be safely performed at any time during the the patient and the foetus [42]. This surgical technique could
course of gestation, and the surgical approach (i.e. radical vs. be considered in this scenario [11], but patients should be
conservative surgery) should follow the same guidelines as aware about the limited data on this topic (. Table  42.1).  

for non-pregnant cases [11, 25] (. Tables 42.1 and 42.2).

Mastectomy is not mandatory for patients with BCP solely
on the basis of possible delay in the delivery of radiotherapy
[11, 25]. Although the available published data on breast con-
servation are limited, they support the safety and feasibility
of this procedure in pregnant patients [35]. However, patients
diagnosed in the first trimester who desire to conserve the
breast should be informed that a possible increased risk of
local recurrence due to the long delay in postoperative radio-
42 therapy cannot be ruled out [35].
According to the American Society of Clinical Oncology
(ASCO), clinicians should not recommend sentinel lymph
node biopsy (SLNB) in patients with BCP [36]. However,
the use of lymphoscintigraphy with technetium-99 SLNB
has been shown to be safe and feasible during pregnancy
[37–40] (. Tables 42.1 and 42.2). The 1-day protocol is asso-
 
Lengthy autologous flap based procedures should probably
be avoided.
42.3.2 Radiotherapy
The exposure of the foetus to radiation therapy can cause sev-
eral adverse effects (i.e. intrauterine growth restriction, men-
tal retardation, risk of childhood cancer, foetal death) [25].
Although some successful cases of radiotherapy for BCP
with the subsequent birth of healthy children have been
reported, the available data are too limited to draw solid con-
clusions [35]. Despite the fact that the radiation doses needed
for adjuvant breast irradiation should be lower than the
threshold for causing foetal toxic effects, it is preferable to
postpone its use until the postpartum period [25] (. Tables  

ciated with a negligible dose to the foetus (i.e. 0.014 mGy or
less), much lower than the limit established by the United
States (US) National Council on Radiation Protection and
Measurements [41]. Hence, specific guidelines for patients
with BCP suggest that SLNB rather than axillary clearance
should be offered whenever indicated [11, 25]. Blue dye for
mapping should be discouraged in pregnant patients due to
the low but potentially harmful risk of anaphylactic reac-
tion [11, 25].
42.1 and 42.2).
Foetal dosage, radiation field extension and gestational
age are the key factors influencing the risk of radiation-­
induced foetal morbidity [25]. During the first trimester and
the early phase of the second trimester, the distance between
the uterus and the radiation field is quite significant, and
breast radiotherapy is considered feasible by some authors
[43]. Nonetheless, only in case no other adjuvant treatment is
indicated and after careful discussion of each individual case

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Breast Cancer in Special Groups: Breast Cancer in Pregnancy
515 42
in a multidisciplinary team, it can be proposed to patients, Anthracyclines are the most studied chemotherapy com-
keeping in mind that this indication is mainly based on theo- pounds during pregnancy, with more than 400 women with
retical assumptions and very limited experiences [11, 35]. BCP treated with these regimens [52]. Hence, anthracycline-­
based chemotherapy should be considered as the first choice
[11, 25]. In non-pregnant breast cancer patients, the addition
42.4 Systemic Treatment of 5-fluorouracil to anthracycline and cyclophosphamide has
been shown to be associated with no survival benefit but
42.4.1 Chemotherapy increased toxicity [53]; hence, the combination of doxorubi-
cin or epirubicin and cyclophosphamide (i.e. AC or EC)
The indication for the use of chemotherapy in patients with should be considered the preferred option also in women
BCP should follow standard recommendations as in the non-­ with BCP [11, 25] (. Table 42.1). 

pregnant setting and should be based on both tumour biol- Clinical experience with the use of taxanes in patients
ogy and tumour stage; however, in this setting some specific with BCP is more limited. Docetaxel and paclitaxel are sub-
issues should be taken into account including gestational age strates for the placental P-glycoprotein transporter that
at diagnosis, expected date of delivery and the preferences of seems to reduce the amount of drug passing from the pla-
the patient and her family (. Fig. 42.1) [11, 25].
  centa into the foetus [54]. In baboon models, docetaxel
In patients with BCP, chemotherapy is contraindicated administered to the mother was not detected in foetal plasma
during the first trimester of gestation, while it can be safely but only in amniotic fluid and foetal tissues at a very low
administered in the second and third trimesters [11, 25] level; paclitaxel showed transplacental transfer, but the levels
(. Tables 42.1 and 42.2).
  of drug in foetal tissues were very low and were not detected
The first trimester is the period of organogenesis which is in the brain or cerebral spinal fluid [55]. In these models,
characterized by high vulnerability to drugs with the possible both paclitaxel and docetaxel were shown to persist for a long
occurrence of both spontaneous abortions and major con- time in foetal tissues, leading to a low level but long exposure
genital foetal malformations [11, 25]. According to the US [55]. In women with BCP, a systematic review including 50
National Toxicology Program Monograph, the overall rate of pregnancies with exposure to paclitaxel and docetaxel
major malformations following exposure to chemotherapy showed that taxanes were well tolerated during pregnancy
during the first trimester was 14%; some chemotherapeutic with manageable toxicities [56]. Hence, when clinically indi-
agents (i.e. cyclophosphamide and 5-fluorouracil) have been cated, the use of taxanes can be considered during pregnancy
associated with a higher risk of major malformations (18% [11, 25] (. Table 42.1). Due to the better toxicity profile and
 

and 31%, respectively) [44]. Additionally, the exposure to no need for granulocyte colony-stimulating factors (G-CSF)
chemotherapy during the first trimester is associated with a nor premedication with high-dose steroids, weekly paclitaxel
13% rate of spontaneous abortion, similar to the rate in should be preferred in women with BCP [11, 25].
healthy women [44]. Termination of pregnancy is not associ- In patients with higher-risk breast cancer, dose-dense
ated with improved maternal outcome [45]; however, for regimens lead to improved overall and disease-free survival
women with stage IV disease as well as for those with high-­ [57, 58]. In women with BCP, only one small retrospective
risk early-stage breast cancer diagnosed during the first tri- cohort study in ten patients evaluated the feasibility of dose-­
mester, termination of pregnancy can be considered to avoid dense chemotherapy during pregnancy [59]. Although the
delay in the initiation of cytotoxic therapy. study showed no increased risk of foetal or maternal compli-
During the second and third trimesters, the administra- cation, due to both the limited data available and the need of
tion of chemotherapy is associated with an overall 3% rate of G-CSF support, dose-dense chemotherapy should not be
major malformations [44], similar to the prevalence in the used in women with BCP (. Table 42.1).
 

US general population [46]. Chemotherapy exposure during Regarding optimal drug dosing in pregnant patients, cli-
this period is associated with a rate of stillbirths of approxi- nicians should be aware that the pharmacokinetics of some
mately 2% [44], slightly higher than in the US general popu- cytotoxic drugs (e.g. doxorubicin, epirubicin, docetaxel and
lation (0.3–0.4%) [47]. Therefore, it can be concluded that paclitaxel) might be altered during pregnancy [60, 61].
the use of chemotherapy during the second and third trimes- However, the calculation of the correct dose in women with
ters is feasible but can be associated with an increased num- BCP should follow the same standard procedures applied as
ber of obstetric and foetal complications (i.e. intrauterine in non-pregnant patients [11, 25]. A priori dose reduction as
growth restriction) [11, 25]. Prematurity is associated with well as increased doses and treatment intervals should be
impaired cognitive development [48, 49]; hence, prematurity avoided [11, 25].
should be avoided and, whenever possible, the goal is to tar- A 3-week interval between the last dose of chemotherapy
get full-term delivery [11, 25]. and the expected date of delivery should be allowed to avoid
Anthracycline-based or anthracycline/taxane-based che- delivery during the nadir period [11, 25]. Due to the possible
motherapy regimens are standard of care for the treatment of occurrence of spontaneous delivery after week 34 of gesta-
breast cancer [50, 51] and should be recommended also in tion, chemotherapy should be discontinued at week 34 of
patients with BCP during the second and third trimesters gestation [11, 25] (. Table 42.1). Weekly chemotherapy regi-
 

[11, 25] (. Table 42.1).

  mens (e.g. weekly epirubicin and weekly paclitaxel) have a

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 516 M. Lambertini et al.
lower risk of haematological toxicity and shorter nadir peri-
ods; hence, they might be considered as a valid treatment
option in pregnant patients, particularly as single drug treat-
ment in the metastatic setting [11, 25].
42.4.2 Anti-HER2 Agents
Trastuzumab, a humanized recombinant IgG1 monoclonal
antibody, is approved for the treatment of breast cancer
patients with HER2-positive disease in the neoadjuvant,
adjuvant and metastatic settings.
The HER2 pathway has a crucial role in organogenesis for
normal cardiac development and migration of neural crest
cells and seems to be also involved in the early conception
and implantation phases [62]. IgG antibodies can cross the
placenta starting from the second trimester of pregnancy
with a continued increase of passage from then on up to term
[63]. No embryolethal or fetotoxic effects with the use of
trastuzumab have been reported in animal studies so far [64].
In humans, around 34 breast cancer patients exposed to
trastuzumab during pregnancy have been described [65]. In
all of the five cases where trastuzumab was «intentionally»
started during the second or third trimester, the pregnancy
was complicated with oligohydramnios resulting in preterm
delivery [66]. The remaining 29 cases became accidentally
pregnant during trastuzumab treatment with consequent
exposure during the first trimester [66, 67]. First-­trimester
exposure was not associated with pregnancy complications
or foetal malformations, and no cases of oligohydramnios
were described [66, 67].
Hence, in contrast to chemotherapy, trastuzumab expo-
sure during the period of organogenesis (i.e. first trimester)
seems not to be associated with congenital malformations
while beyond the second trimester is likely to produce «on-­
target» effects with a high number of cases who developed
oligohydramnios (i.e. trastuzumab targets the HER2 onco-
gene which is also expressed in the foetal kidneys, the organs
responsible for producing the amniotic fluid) [65].
These findings should be used for counselling patients in
daily practice: first, women of childbearing potential treated
42 with trastuzumab should be advised to use effective contracep-
tion [65]. Second, for women who become accidentally preg-
nant while on trastuzumab, since a brief exposure during the
first trimester does not seem to increase pregnancy or foetal
risk, it is plausible to consider stopping the medication to allow
the continuation of the pregnancy [65]. Finally, according to
treatment guidelines, elective administration of trastuzumab
should be avoided during pregnancy but should be postponed
until after delivery [11, 25] (. Tables 42.1 and 42.2).
 
Other anti-HER2 monoclonal antibodies (i.e. pertu-
zumab and T-DM1) are currently approved for the treatment
of HER2-positive breast cancer, but no cases in women with
BCP have been reported so far [65]. Since pertuzumab is
approved in combination with trastuzumab, from a clinical
standpoint, a similar approach to that of trastuzumab would
apply for pertuzumab [65].
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T-DM1, an antibody drug conjugate composed of trastu-
zumab connected to the cytotoxic drug emtansine, is a large
molecule; hence, its transfer via the placenta as well as its
toxic effects are expected to mimic that of trastuzumab [65].
Until further data are available, pertuzumab and T-DM1
should not be used in pregnant patients [65] (. Tables 42.1
and 42.2).
Lapatinib, a dual tyrosine kinase inhibitor targeting the
epidermal growth factor receptor (EGFR) and HER2, is
approved for the treatment of metastatic HER2-positive
breast cancer. Being a small molecule, lapatinib is expected to
cross the placenta throughout the pregnancy [65]. In humans,
there is only one reported case of lapatinib exposure during
pregnancy in a patient with metastatic disease that became
accidentally pregnant during treatment [68]. Lapatinib was
stopped around week 14 of gestation: no pregnancy compli-
cations or foetal malformations were observed [68]. Due to
the very limited data on its safety during pregnancy, lapatinib
should be avoided in women with BCP [65] (. Tables 42.1
and 42.2).
42.4.3 Endocrine Therapy
According to the ASCO guidelines for adjuvant endocrine
therapy in young women with breast cancer, patients at low
risk of relapse (i.e. women with stage I disease not warranting
chemotherapy) should receive tamoxifen alone [69]. On the
contrary, patients at higher risk (i.e. women with stage II–III
disease candidates to adjuvant cytotoxic therapy or some
women with stage I–II breast cancers at higher risk of recur-
rence who might consider chemotherapy) should receive
ovarian suppression in addition to either tamoxifen or an
aromatase inhibitor [69]. Similar recommendations are sug-
gested by the BCY2 Panel [32].
In women with BCP, endocrine therapy is contraindi-
cated during pregnancy [11, 25] (. Tables 42.1 and 42.2). In
fact, foetal malformations (i.e. craniofacial malformations
and ambiguous genitalia) have been described in children
with in utero exposure to tamoxifen [70, 71]. Hence, the use
of endocrine agents should be postponed until after delivery
[11, 25].
42.4.4 Supportive Care
Although the majority of supportive regimens can be safely
administered during pregnancy [11], in patients with BCP,
these therapies should be used only if strictly indicated.
Anthracycline-based chemotherapy is associated with a
particularly high risk of developing nausea and vomiting.
According to the European Society for Medical Oncology
(ESMO), in non-pregnant patients receiving anthracycline-­
based regimens, a three-drug combination of a neurokinin
(NK) 1 receptor antagonist (days 1–3), a 5-­hydroxytryptamine-3
(5-HT3) receptor antagonist (day  1) and dexamethasone
(day  1) should be recommended to p ­revent nausea and
Breast Cancer in Special Groups: Breast Cancer in Pregnancy
v­ omiting [72]. Updated recommendations from ASCO sup-
port the same three-drug combination in all non-pregnant
patients who receive anthracycline plus cyclophosphamide:
palonosetron is the preferred 5-HT3 receptor antagonist in
this setting, and the oral combination of netupitant and palo-
nosetron (NEPA) plus dexamethasone represents an addi-
tional treatment option in this scenario [73].
In women with BCP, very limited data exist on the safety
of NK1 receptor antagonist and palonosetron; hence, these
compounds should not be used until more safety data
become available [11] (. Table 42.1). Among 5-HT3 recep-
 
tor antagonists, ondansetron was shown not to be associated
with an increased risk of developing adverse foetal out-
comes; hence, it can be safely administered during preg-
nancy [74] (. Table  42.1). Granisetron does not seem to
 
cross the placenta [75]. The use of steroids is contraindicated
during the first trimester because of the risk of cleft palate,
while they can be administered during the second and third
trimesters [11] (. Table  42.1). Methylprednisolone and
 
hydrocortisone are extensively metabolized in the placenta:
hence, they are the preferred options [11, 76] (. Table 42.1).
 
In contrast, ­dexamethasone and betamethasone cross the
placenta and can be associated with attention deficit disor-
der; hence, they should be avoided especially during the first
trimester [11, 76].
G-CSF support is used to counteract the negative conse-
quences of neutropenia and febrile neutropenia. Prophylactic
G-CSF is recommended in non-pregnant patients receiving
regimens associated with a high risk of developing febrile
neutropenia or in those with an intermediate risk in the pres-
ence of other risk factors [77–79]. However, the evidence for
the safety profile of G-CSF during pregnancy is scarce, lim-
ited to a small retrospective series [59]. Hence, prophylactic
G-CSF should be used only if strictly indicated [11, 26]
(. Table 42.1).
 
42.5  bstetric Care and Long-Term
O the outcomes of children after in utero exposure to chemo-
Outcomes of Children with in Utero
Exposure to Anticancer Therapies
Although systemic cytotoxic therapy can be safely adminis-
tered in the second and third trimesters, its administration
can be associated with an increased risk of obstetric and foe-
tal complications.
The most common complication associated with che-
motherapy exposure is intrauterine growth restriction,
with an incidence ranging from 7–9% up to 22% in the
largest case series [45, 80, 81]. However, the rates of «small
for gestational age» (i.e. body weight below 10th percentile
of the normal population according to gestational age at
birth and sex) have been shown to be higher in patients
treated for haematological cancer than in those with solid
tumours [81]. Among chemotherapy compounds admin-
istered in breast cancer patients, docetaxel seems to be
associated with the highest rates of small for gestational
age (19%) [44].
rares1geo@gmail.com
517 42
Other possible obstetric complications (e.g. premature
rupture of membranes) can occur in 17–27% of cases [45, 80,
81]. However, the use of chemotherapy during pregnancy
seems not to be associated with a higher rate of spontaneous
preterm birth (i.e. before 37 weeks of gestation) as compared
to the general population (8–9% vs. 12%, respectively) [44,
81].
Due to the possible risk of transient myelosuppression in
the newborn [44], to allow bone marrow recovery and pre-
vent haematologic toxicity to both mother and child, chemo-
therapy should not be administered 3  weeks prior to birth
[11, 25].
Pregnancy in cancer patients should be considered and
monitored as «high risk» [11, 25]. A multidisciplinary team
should be involved in the care of women with BCP from the
earliest phase possible. Women with BCP should be followed
according to standard prenatal care protocols, but specific
considerations should be taken into account in this setting.
An ultrasound confirming dates with detailed foetal ana-
tomic evaluation before treatment initiation is recommended
to exclude preexisting foetal anomalies [26]. During treat-
ment, ultrasound monitoring at least every 3 weeks is recom-
mended for foetal well-being and general development, to
assess amniotic fluid and the flow within the umbilical artery
[11]. In the case of pregnancy complications, additional visits
and at shorter intervals should be considered [11].
The mode of delivery should not differ from usual obstet-
ric indications, and delivery should occur in a tertiary centre
[82]. The placenta should be sent for histological evaluation
to assess possible breast cancer cell contamination [83].
For children with in utero exposure to chemotherapy,
correct monitoring for the possible occurrence of long-term
complications is mandatory.
Beyond congenital malformations, another concern with
the use of chemotherapy in women with BCP is the possible
induction of other adverse health effects that may not become
apparent until later in life. The majority of studies assessing
therapy showed normal growth and development, but with
limited data available beyond the second year of life [44].
Reassuring data at longer follow-up have been reported.
Amant and colleagues evaluated the long-term general
health, cardiac function and neurodevelopmental outcomes
of 70 children after prenatal exposure to chemotherapy [48].
The majority of the mothers included in the analysis had
BCP treated with anthracycline-based chemotherapy regi-
mens [48]. With an observation period ranging between
18 months and 20 years, the children’s general health, growth,
behavior and hearing did not differ to those of the general
population; moreover, cardiac dimensions and functions
were shown to be within normal ranges [48]. Cognitive
development scores were overall within normal ranges but
lower for children who were born preterm than for those
born at full term [48]. In a multicentre case-control study
from the same group, Amant and colleagues enlarged their
prospective cohort including 129 children in early childhood
(12–42 months) whose mothers received a diagnosis of can-
 518 M. Lambertini et al.
cer during pregnancy [49]. They compared the general health
status, growth, cognitive development and cardiac structure
and function in this cohort with those in matched children
born from women without a cancer diagnosis [49]. A neuro-
logic examination and the Bayley Scales of Infant
Development at months 18 and/or 36, as well as a cardiac
assessment at 36 months, were prospectively performed in all
children [49]. No significant difference between groups in
cognitive development was observed; however, it was found
that the gestational age at birth was correlated with the cog-
nitive outcome in both study groups confirming that prema-
turity is correlated with a worse cognitive outcome
independently of cancer treatment [49]. Cardiologic evalua-
tion showed normal findings [49].
Preterm delivery can lead to several complications, and
the risk for their occurrence increases with decreasing gesta-
tional age at birth [84]. Moreover, due to the fact that prema-
turity has an important impact on neuropsychological
outcome, full-term delivery (i.e. after 37 weeks of gestation)
is recommended whenever possible, and iatrogenic preterm
delivery should be avoided [11, 25]. In this regard, the
administration of chemotherapy up to the 34th week of preg-
nancy may help to achieve full-term pregnancies, with an
optimal maternal and foetal outcome.
Although these findings are encouraging, more data and
longer follow-up are needed to identify possible adverse
effects that may not be apparent until later in life, including
cardiac function impairment and infertility [85].
42.6 Conclusions
The diagnosis of BCP represents a unique challenge for the
patient, her caregivers and the treating physicians and often
raises several religious, moral or social issues that should be
taken into accounts [86]. The complex medical situation of
BCP requires the involvement of a multidisciplinary team
from the early phases of its management [11, 25]. Since abor-
tion does not improve patients’ prognosis, it is crucial to
manage correctly this critical clinical situation following
available guidelines for the diagnosis, staging and treatment
42 of BCP [11, 25].
Current guidelines on this topic rely on limited evidence.
Hence, further research efforts are needed to get more con-
clusive data. Particular attention should be given to the pos-
sible occurrence of long-term complications in children with
in utero exposure to chemotherapy: although no specific
guidelines exist for monitoring these individuals, a contin-
ued follow-up of the health of the exposed individuals into
adulthood and, perhaps, throughout their lives is recom-
mended.
Prospective studies for the management of BCP are ongo-
ing in both the US and Europe. Since running randomized
trials is impossible in this setting, the participation of patients
in international registries like the one organized in Europe by
the International Network on Cancer, Infertility and
Pregnancy (7 https://www.esgo.org/network/incip/) will help
rares1geo@gmail.com
to accrue adequate numbers to have more robust evidence on
the management of women with BCP.
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 521 43

Fertility Preservation in Women

with Breast Cancer
Anna Rachelle Mislang, Matteo Lambertini, and Laura Biganzoli

43.1 Introduction – 522

43.2 Impact of Breast Cancer on Fertility – 522

43.3 Fertility Preservation Techniques – 522

43.4 Pregnancy After Breast Cancer – 525

43.5 Conclusion – 526

References – 526

Anna Mislang acknowledges Fondazione Sandro Pitigliani for supporting her Fellowship in Geriatric
Oncology
Matteo Lambertini acknowledges the support from the European Society for Medical Oncology (ESMO)
for a Translational Research Fellowship at Institut Jules Bordet

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_43

rares1geo@gmail.com

522 A.R. Mislang et al.

43.1 Introduction therapy and their risk of causing permanent amenorrhea.

Up to 12% of all breast cancer cases occur in women of repro-
ductive potential [1]. Advances in early detection and man-
agement of early breast cancers have increased the survival of
young women. Adjuvant systemic therapy exposes these
women to long-term side effects, including premature ovar-
ian failure (POF) and early menopause causing infertility,
likely as a result of ovarian primordial follicle oocyte reserve
depletion [1].
This is a substantial concern, particularly in women who
are still at the prime of their reproductive life and may affect
their treatment decisions considerably [2]. Although many
younger women resume their menses after therapy, this does
not guarantee fertility preservation. Early referral to a fertil-
ity clinic is recommended as soon as the cancer diagnosis is
made to discuss the most appropriate means to preserve fer-
tility, if so desired [3–6].
43.2 Impact of Breast Cancer on Fertility
Chemotherapy (with or without endocrine or biologic ther-
apy) is the mainstay adjuvant treatment for women with
high-risk features for recurrence, i.e. advanced-stage,
endocrine-­negative, or HER2-positive breast cancer. Many
cytotoxic agents with proven efficacy in breast cancer are also
damaging to the ovaries, resulting in POF, early menopause,
and infertility, and the toxicity appears to be age-, dose-, and
regimen-dependent [3]. . Table  43.1 summarizes the com-
mon cytotoxic agents used in primary systemic or adjuvant
..      Table 43.1  Degree of risk of chemotherapy-induced
amenorrhoea based on age and treatment regimen (adapted
[7]) for breast cancer
Degree of risk of Age Cancer treatment regimen
permanent (years) for breast cancer
amenorrhoea
High risk (>80%) ≥40 CMF, CEF,CAF,TAC x 6 cycles
Moderate risk ≥40 AC x 4 cycles
(40–60%) 30–39 CMF, CEF,CAF,TAC x 6 cycles
43 any AC or EC x 4 → Taxanes
Low risk (<20%) ≤40 AC x 4 cycles
≤30 CMF, CEF,CAF,TAC x 6 cycles
Very low or no risk Any Methotrexate
Fluorouracil
CMF cyclophosphamide, methotrexate, fluorouracil, CEF
cyclophosphamide, epirubicin, fluorouracil, CAF cyclophospha-
mide, doxorubicin, fluorouracil, TAC docetaxel, doxorubicin,
cyclophosphamide, AC doxorubicin, cyclophosphamide, EC
epirubicin, cyclophosphamide, →: sequential
Reproduced from Reference [7] under the terms of the Creative
Commons Attribution 4.0 International License [7 http://
creativecommons.org/licenses/by/4.0/]
The age of the patient (≥40 years) and the type of treatment
(regimen, dose, duration, the need for endocrine therapy) are
the most important factors influencing the risk of infertility.
Other factors may include previous treatment for infertility
and comorbidities, which may reduce fertility still further
(e.g. morbid obesity) [8].
Although still controversial, several studies have reported
the favourable effects of chemotherapy-induced amenor-
rhoea on breast cancer outcomes [9–12]. However as more
women survive their cancers, more are confronted with the
long-term side effects of treatment, including infertility.
Though more than half of young women treated for breast
cancer may desire a future pregnancy [13], these patients
have the lowest pregnancy rate among cancer survivors, with
an overall 67% reduction in the chance of a future pregnancy
as compared to the general population of the same age [4].
This may be due to the gonadotoxic effect of chemotherapy,
prolonged treatment with tamoxifen, and/or fear of disease
recurrence causing reticence to become pregnant. Besides
infertility, POF can cause a significant impact on a patients’
quality of life, particularly from vasomotor symptoms, sleep
and mood disturbance, sexual dysfunction, and bone density
loss [14].
Even after completion of treatment, these women may
not be able to conceive immediately. Timing to ensure a safe
pregnancy is as important as concerns for future fertility after
cancer treatment. However, the optimal time interval from
treatment completion to pregnancy is still unknown. The risk
of mutagenesis is maximal during the maturation phase of
the oocyte, which is approximately 6 months [15]. As most
cytotoxic agents are mutagenic and teratogenic to oocytes, it
is common practice to delay conception by a minimum of
6  months after completing treatment. Thus, the timing
of pregnancy should take into consideration the duration of
treatment and time from completion, the patient’s age and
ovarian function, and the risk of relapse [4].
After completion of primary systemic or adjuvant treat-
ments, some women may not be able to conceive naturally
and assisted fertility techniques may be required. However,
there is only one small retrospective study available that
looked at the feasibility and safety of performing assisted
reproductive technology in patients who had already been
treated with chemotherapy [16]. The study suggested that
this approach could be considered in selected patients who
cannot conceive spontaneously after completion of adjuvant
therapy and who did not undergo fertility preservation tech-
niques at diagnosis [16]. Nevertheless, more data are needed
to confirm whether assisted reproductive technology after
anticancer treatments is safe in breast cancer survivors.
43.3 Fertility Preservation Techniques
The American Society of Clinical Oncology (ASCO), the
National Comprehensive Cancer Network (NCCN),
the European Society of Medical Oncology (ESMO), and the

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Fertility Preservation in Women with Breast Cancer
International Consensus Conference for Breast Cancer in
Young Women recommend reproductive counselling, ideally
before commencing any anticancer treatment [3–6].
Fertility preservation techniques may either use surgical
or medical strategies. These include embryo cryopreserva-
tion, oocyte cryopreservation, ovarian tissue cryopreserva-
tion, or ovarian suppression with gonadotropin-releasing
hormone (GnRH) agonists. The success of each method is
strongly dependent on the patient’s ovarian reserve. Notably,
the published success data on these techniques are widely
based on infertile women rather than on cancer survivors.
More importantly, resumption of menses does not necessar-
ily translate to successful fertility outcomes, i.e. pregnancy
and live birth. . Table 43.2 summarizes the different fertility
 
preservation strategies and outcomes.
1. Embryo cryopreservation and mature oocyte cryo-
preservation
Both embryo cryopreservation and oocyte cryo-
preservation are the standard recommended fertility
preservation strategies in female cancer patients, though
the acceptability and availability vary in certain coun-
tries. Vitrification (ultrarapid freezing) appears to be
superior to a slow freezing method [24], and the success
rate is age- (<38 years) and centre-dependent. Embryo
cryopreservation needs a sperm donor for embryo
creation, and therefore only those women with steady
partner will be able to undergo embryo cryopreservation.
Both strategies require at least 2 weeks of hormonal
manipulation (i.e. controlled ovarian stimulation) to
allow the collection of the oocytes to be then cryopre-
served or fertilized (i.e. embryos) before cryopreserva-
tion. Standard protocols for controlled ovarian
stimulation last about 9–15 days, starting at the onset of
menses. Hence, two main issues should be considered in
cancer patients: a possible 2–6 weeks delay in the
initiation of chemotherapy and the temporary increase in
oestradiol levels with a potentially negative impact on the
prognosis of patients, especially in those with hormone
receptor-positive breast cancer [7].
Two strategies have been developed to address these
issues in breast cancer patients, including the use of
«random-­start protocols» [25] to avoid delay in treatment
initiation or use of controlled ovarian stimulation with
tamoxifen or letrozole [26, 27] to reduce the exposure
risk to high oestradiol levels during ovarian stimulation.
«Random-start protocols» allow ovarian stimulation to
start at any time during the menstrual cycle, even in luteal
or late follicular phases, and experience has shown promis-
ing results in terms of successful oocyte collection [25].
In breast cancer patients, particularly in those with
hormone receptor-positive disease, ovarian stimulation
raises the added concern of inducing a sustained
hyper-oestrogenic state, with potential acceleration of
tumour growth and risk of cancer recurrence.
Gonadotropin stimulation combined with endocrine
agents (i.e. tamoxifen or letrozole) has led to successful
fertility preservation while maintaining oestrogen levels
rares1geo@gmail.com
523 43
within the physiologic range [26, 27]. Furthermore, no
observed negative consequences on the quality of oocytes
and embryos collected and cryopreserved were observed
with the use of these protocols [26, 27]. The only
prospective single-centre study investigating the long-
term safety of controlled ovarian stimulation with
letrozole supplementation (COSTLES) in breast cancer
patients showed reassuring results [28]. After 5 years of
median follow-up, no significant difference in the
relapse-free survival was observed between patients who
underwent embryo cryopreservation and those who did
not (hazard ratio [HR] = 0.77; p = 0.61) [28]. On
subgroup analysis, no significant difference in relapse-
free survival was observed in both patients with hor-
mone receptor-­positive and hormone receptor-negative
disease and in both patients with BRCA mutations and
those without mutations between those undergoing ovar-
ian stimulation and not [28]. However, longer follow-up
and more cases are needed to confirm these findings.
Recently, the same group reported for the first time
the success rate of the procedure in terms of fertility
preservation in breast cancer patients [19]. The authors
reported an overall live birth rate per embryo transfer
similar to that of the infertile population without cancer
of a similar age (45.0 vs. 38.2; p = 0.2) [19]. Out of 33
patients attempting pregnancy, 17 had at least one child
resulting in a fertility preservation rate of 51.5% per
attempting woman (. Table 43.2) [19].
2. Ovarian tissue cryopreservation
Ovarian tissue cryopreservation is an experimental
fertility preservation technique that requires two surgical
procedures – first, for removal of the cortical ovarian
tissue and, second, for future reimplantation into the
pelvic cavity (orthotopic site) or outside the peritoneal
cavity (heterotopic site), commonly in the forearm [29].
This technique offers several advantages including
rapid restoration of ovarian function (within
3–6 months) after successful transplantation and
minimal delay in the initiation of anticancer treatment
after surgery. However, malignant cell contamination is
one potential implication, though the risk is deemed low
in breast cancer, except for those with a known BRCA
gene mutation [30] where the development of ovarian
cancer poses a significant risk.
A successful recovery of ovarian function is expected
in the majority of patients, with possible sustained
longevity of function [31]. While successful pregnancy
has been reported with this strategy, live birth rates have
been variable and mostly reliant on less robust method-
ological studies, with an estimated pregnancy rate of
approximately 25% (. Table 43.2) [21].
3. Ovarian suppression with GnRH agonists during
chemotherapy
The ovaries may potentially be protected during
chemotherapy by putting them into a dormant state.
 43
524
A.R. Mislang et al.

..      Table 43.2  Fertility preservation strategies and outcomes

Techniques Procedure Strategy Ovarian Anticancer treatment Other concerns Pregnancy Live born
stimulation initiation delay rate (%) (%)

Embryo Surgery required for egg harvesting, Standard Required Yes Pregnancy rate is age-depen- 28–46a [17] 21–40a [17]
­cryopreservation in vitro fertilization, and freezing of practice dent 37 [18] 30 [18]
embryos Success dependent on the 65 [19] 45 [19]
number of embryo stored
Utilization of spare embryos
Need for a partner or accep-
tance of sperm donation

Oocyte Surgery required for harvesting and Standard Required Yes Pregnancy rate is age-depen- 26.3 per 15.8 [20]
cryopreservation freezing of unfertilized oocytes practice dent cycle and
Success dependent on the 29.4 per
number of oocyte stored transfer [20]

Ovarian tissue Surgery required for removal of Experimental Not required No Useful in adolescent girls 25 [21] 25 [21]

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cryopreservation cortical ovarian tissue and reimplan- strategy Minimal time required Possible risk of malignant
tation of frozen ovarian tissue after Can be performed at contamination
completion of cancer therapy any time of menstrual
cycle

Ovarian suppression Hormonal manipulation to protect Accepted Not required No Lack of chemotherapy-­induced 21 [22] 17 [22]
with GnRH agonists ovarian function during chemo- strategyb Cheaper option Easily accessible amenorrhoea 5.4 [23] 3.4 [23]
during chemotherapy therapy

aPercentage of cycles or transfers <35 to 40 years of age

bInpatients interested in preserving ovarian function and in those interested in preserving fertility after embryo/oocyte cryopreservation or when embryo/oocyte cryopreservation is not
available
GnRH gonadotropin-releasing hormone
Fertility Preservation in Women with Breast Cancer
This may be achieved by hormonal manipulation using
gonadotropins, although there are concerns. Concurrent
use of GnRH agonists with chemotherapy is a promising
strategy as it is easily accessible in terms of cost and
timing, well tolerated in terms of short-term side effects
(i.e. vasomotor symptoms), and therefore may be a good
alternative strategy when access to embryo cryopreser-
vation or oocyte cryopreservation is not feasible.
The concerns for concurrent GnRH agonist use are
mainly attributed to the lack of chemotherapy-induced
amenorrhoea having a possible negative prognostic
effect on survival, the potential negative interactions
with chemotherapy, and the initial flare-up effect causing
a transient hyper-­oestrogenic state, possibly increasing
the risk of breast cancer recurrence, particularly in
hormone receptor-positive tumours [32].
Previous trials evaluating the role of ovarian suppres-
sion during breast cancer chemotherapy have reported
conflicting results on the efficacy of the procedure in
terms of reducing the risk of developing POF after
chemotherapy at short follow-­up (6–36 months), while
limited data are available at longer follow-up; hence the
practice was considered unreliable [3, 33–35]. However,
ovarian suppression with GnRH agonists has recently
gained much interest, with two large randomized studies
showing favourable results.
The POEMS/S0230 trial randomized 257 premeno-
pausal women (median age of 38 years) with hormone
receptor-­negative breast cancer to standard chemother-
apy with or without goserelin, with a 2-year rate of
ovarian failure as the primary endpoint [22]. This was
defined as the absence of menses in the preceding
6 months and follicle-stimulating hormone levels in the
postmenopausal range. Despite the incomplete data
available, adding goserelin to chemotherapy resulted in a
significantly lower ovarian failure rate (8% vs. 22%, odds
ratio OR = 0.30, 95% confidence interval [CI] 0.09–0.97;
p = 0.04), lower 2-year ovarian dysfunction rate (14% vs.
33%, OR = 0.35, 95% CI 0.13–0.93, p = 0.03), higher
pregnancy rate (21% vs. 11%, p = 0.03), and superior
4-year disease-free survival (89% vs. 78%, p = 0.04) than
chemotherapy alone [22]. Following these positive
results, the panel of the St. Gallen Consensus 2015
supported the use of ovarian function suppression with
GnRH agonists during chemotherapy to preserve
ovarian function and fertility in women with hormone
receptor-negative disease [36]. Likewise, the NCCN
recommends ovarian suppression with GnRH agonists
during adjuvant chemotherapy in premenopausal
women with hormone receptor-negative tumours to
preserve ovarian function and diminish the risk of
chemotherapy-­induced amenorrhoea [5].
The PROMISE-GIM6 trial randomized 281 patients
with early breast cancer to chemotherapy with or
without triptorelin, with the incidence of early
­menopause as the primary outcome [37]. This was
defined as the absence of menstrual activity and
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525 43
follicle-stimulating hormone and oestradiol at post-
menopausal levels, 1 year after the last chemotherapy
cycle. The trial included patients with both hormone
receptor-­positive and hormone receptor-negative
tumours. Results showed a lesser rate of chemotherapy-
induced early menopause (8.9% vs. 25.9%, p < 0.001) in
the triptorelin arm [37]. Updated analysis revealed a
higher cumulative long-­term (5 years) probability of
ovarian function recovery with triptorelin than
chemotherapy alone (age-adjusted HR = 1.48,
p = 0.006) [23]. No statistical difference in the preg-
nancy rate was observed although more patients receiv-
ing ovarian suppression during chemotherapy had a
subsequent pregnancy (8 vs. 3; age-adjusted HR = 2.40,
p = 0.20) [23]. The strategy did not reveal a negative
disease-free survival impact in patients with hormone
receptor-positive disease.
The favourable safety and efficacy data from these two
consecutive trials have changed the mindset of several
experts on recommending ovarian suppression with
GnRH agonists during chemotherapy as a reliable strategy
for ovarian function and fertility preservation irrespective
of hormone receptor status of the tumour [6, 7].
Three meta-analyses of randomized controlled trials
on the effect of ovarian suppression during chemother-
apy as a strategy to preserve ovarian function and
fertility in breast cancer patients were published in 2015.
Lambertini and colleagues reported a reduced risk of
chemotherapy-induced POF and an increased preg-
nancy rate, without a negative impact on prognosis [38],
while Munhoz and colleagues showed a higher rate of
menstrual recovery at 6 and 12 months but not fertility
or pregnancy in premenopausal women with early breast
cancer when GnRH agonist was given concurrently with
chemotherapy [39]. Similarly, Shen and colleagues
reported a higher rate of menstrual return without any
protective effects on fertility [40]. These findings
highlight that resumption of menstruation is still a poor
surrogate for fertility and that GnRH agonist use,
although very promising, must not be the only method
relied on to preserve fertility, especially when access to
embryo cryopreservation or oocyte cryopreservation are
viable options.
43.4 Pregnancy After Breast Cancer
Pregnancy is considered safe after breast cancer therapy,
regardless of the hormone receptor status of the tumour [41].
A meta-analysis of 14 retrospective control-matched studies
evaluating the impact of pregnancy after a prior history of
breast cancer showed that women who got pregnant had a
41% reduced risk of death compared to women who did not
(pooled relative risk [PRR] = 0.59, 95% CI 0.50–0.70) [42].
Even after correcting for the so-called healthy mother effect,
there was no significant difference in survival between groups
(PRR = 0.85, 95% CI 0.53–1.35) [42].
 526 A.R. Mislang et al.
However, as previously discussed, the optimal time inter-
val from treatment completion to pregnancy is currently
unknown. Experts recommend avoiding pregnancy within
2 years from diagnosis in patients with a high risk of relapse
[43]. Timing could be «personalized» taking into account
several factors such as the patient’s age, previous treatments,
risk of relapse, and the need for adjuvant hormonal therapy.
The safety of becoming pregnant after breast cancer has
been evaluated both in the subgroups of patients with hor-
mone receptor-positive and hormone receptor-negative dis-
ease in a large multicentre retrospective cohort study [41].
The study showed no difference in disease-free survival
between pregnant and non-pregnant patients in the hormone
receptor-positive (HR = 0.91, 95% CI 0.67–1.24) or the hor-
mone receptor-negative (HR  =  0.75, 95% CI 0.51–1.08)
groups [41]. The pregnant group showed better overall sur-
vival (HR  =  0.72, 95% CI 0.54–0.97) with no interaction
according to hormone receptor status [41].
Overall, these data reassure the safety of pregnancy after
a prior history of breast cancer and highlight the importance
of personalized counselling of these patients regarding the
risk of POF and infertility from anticancer treatments.
Women with hormone receptor-positive breast cancer
may be at a higher risk of compromised fertility than those
with hormone receptor-negative tumours. This is primarily
from long-term use of adjuvant endocrine therapy causing
oocyte ageing in addition to the damaging effect of chemo-
therapy on ovarian reserve. With the recent data supporting
longer use of adjuvant endocrine therapy (aTTom and
ATLAS) [44, 45], more women will opt to delay initiating
their childbearing plans and will be a lot older at the time of
treatment completion.
The safety of interrupting adjuvant endocrine therapy to
allow conception is currently unknown and should not be in
principle recommended in clinical practice. To address this
relevant question, the BIG-NABCG network has recently
launched the IBCSG-coordinated trial POSITIVE [46]. This is
a prospective study dedicated to young patients with hormone
receptor-positive breast cancer aiming to investigate the safety
of interrupting endocrine therapy to allow pregnancy after
having received between 18 and 30 months of therapy [46].
43 43.5 Conclusion
Pregnancy after breast cancer is safe regardless of hormone
receptor status. Fertility preservation and the option to start
a family have an important impact on quality of life.
Advancing age, long treatment duration, and gonadal che-
motoxicity increase risks for diminished ovarian reserve. It is
important to note that resumption of menses is not a reliable
surrogate of fertility.
Effective and safe fertility preservation strategies are
required and must be discussed with the patients as soon as
possible after diagnosis. Both embryo cryopreservation and
oocyte cryopreservation are standard recommended strate-
gies. Ovarian tissue cryopreservation is promising yet still
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experimental, and GnRH agonists are steadily gaining favour
and may be proposed to patients to preserve ovarian func-
tion during chemotherapy, especially to those interested in
fertility preservation when access to either embryo or oocyte
cryopreservation is not feasible. Moreover, since these strate-
gies are not mutually exclusive, GnRH analogs might also be
proposed to patients who undergo embryo or oocyte cryo-
preservation to increase the chances of resuming ovarian
function after treatment and enhance future fertility.
Tamoxifen and letrozole are useful adjuncts in controlled
ovarian stimulation protocols and should be considered in
breast cancer patients undergoing subsequent embryo or
oocyte cryopreservation.
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 529 44

Breast Cancer in Older Patients

Anne Shrestha and Lynda Wyld

44.1 Introduction – 530

44.1.1 Patient Factors: Changes Associated with Ageing – 530

44.2 Assessment of the Fitness of an Older Patient – 531

44.3 Disease Stage – 531

44.4 Screening in Older Women – 532

44.5 Tumour Characteristics – 532

44.5.1 Tumour Biology – 532

44.6 Management of Breast Cancer in Older Women – 533

44.6.1 Surgery – 533

44.7 Systemic Therapy – 535

44.7.1 Adjuvant Hormonal Therapy – 535
44.7.2 Adjuvant Chemotherapy – 535
44.7.3 Primary Endocrine Therapy – 536
44.7.4 Adjuvant Radiotherapy – 537

44.8 Summary – 537

References – 537

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_44

rares1geo@gmail.com
 530 A. Shrestha and L. Wyld
44.1 Introduction
A third of all breast cancers occur in women aged over
70 years. The incidence of breast cancer is increasing due to
the rising population of older people and is a significant
cause of cancer-related deaths amongst older women [1].
Relative survival rates in older women are significantly worse
than those in younger women [2]. Data from the most recent
EUROCARE 5 audit confirms a significantly reduced relative
survival in women over age 75 but with significant variation
in outcomes across Europe [3]. Although breast cancer sur-
vival rates are improving in most age cohorts, they remain
static in the older age groups [4]. The reasons for inferior
outcomes are poorly understood and are multifactorial (lack
of screening, presentation at a later stage, reduced breast
awareness and generally reduced levels of treatment across
all therapeutic modalities relative to younger women) [5, 6].
Treatment omission may reflect reduced treatment tolerance
due to comorbidities, but the price of this may be an increased
breast cancer mortality which may offset any short-term
morbidity savings. The issue for this age group is individual-
ized care, tailored to their treatment tolerance and personal
preferences. A major issue for guiding care is the lack of
research evidence which has been stratified by fitness and
frailty levels as these are a highly heterogeneous group of
patients. In addition the values and preferences of older
women may differ from younger women with less focus on
prolonging life and more on quality of remaining life.
The gold standard for breast cancer treatment is complete
excision of the tumour, breast conservation surgery or mas-
tectomy, combined with therapeutic or staging axillary sur-
gery, followed by appropriate combinations of adjuvant
therapies. Older women may be treated at variance from
these recommendations for a number of valid reasons as
older women may differ from younger women in a number
of important ways: health and fitness levels, life expectancy,
social circumstances, psychological attitudes to a range of
issues, treatment preferences, disease characteristics and
treatment tolerance. There is an increasing body of research
evidence to guide practice in this age group, and this is
reviewed in the following sections.
44.1.1  atient Factors: Changes Associated
P 65) [14, 15]. Priorities vary compared to younger breast can-
with Ageing
44 Ageing is associated with a predictably increased incidence of
comorbidities and a decrease in life expectancy. There is a
natural decline in physiological reserve and organ function.
Fourteen percent of 70–79-year-olds and 22% of 80–85-year-
olds will have two or more comorbidities [7]. There is a
decrease in cardiovascular reserve driven by a reduction in
maximal heart rate, cardiac contractility and lung capacity.
Half of all cardiac failure diagnoses and 90% of cardiac failure-
related deaths occur in those over age 70 [8]. Cardiac failure
contraindicates the use of anthracycline chemotherapy and
trastuzumab and increases the risks of general anaesthesia.
rares1geo@gmail.com
Old age is associated with a decline in renal function,
with a decrease in the number of nephrons, increase in renal
hypertension and decrease in renal flow rates. The glomeru-
lar filtration rate declines by about 8  ml/min/1.73m2 per
decade, reducing tolerance to certain therapies, especially if
complications occur [9]. Nephrotoxicity and cardiac toxicity
are significant side effects of some anticancer agents and may
be a long-term issue for cancer survivors, especially if they
already have reduced reserve. The gain in life expectancy of
some of these treatments may therefore be opposed by treat-
ment-related morbidity and mortality [10].
Ageing may be associated with a decline in cognitive
function, mobility and general co-ordination which may
cause delayed recovery from surgery and anaesthesia. In
addition, rates of clinically diagnosable dementia are
increased with age, affecting one in six women aged
above 80 [11].
Frailty, defined as the combination of sarcopenia (or loss
of skeletal muscle mass), multiple chronic illnesses and loss
of functional independence [12], is more common in the
older patient resulting in functional decline. The rate of func-
tional decline may be exacerbated by acute illnesses or exac-
erbations of chronic illness and also by anaesthesia and
surgery. Patients who are already struggling to retain inde-
pendence may lose this as a result of treatment for their
breast cancer, and careful preoperative assessment of their
care needs, provision of both pre-habilitation and post-­
operative rehabilitation and social support are essential for
these women.
Alongside the physical impacts of ageing, consideration
must be given to the patients’ quality of life (QoL) and the
psychological impact of a cancer diagnosis. Older patients’
psychological response to a cancer diagnosis and the impact
this may have on their QoL may differ from that of a younger
woman. Older patients may struggle to balance their desire
to survive their cancer by undergoing complex and poten-
tially unpleasant treatments with awareness of their naturally
reduced life expectancy. There is often a high degree of prag-
matic acceptance of the inevitability of death [13] and the
impact of physical illness. A US study found that the desire to
maximize longevity in cancer treatment choices was stron-
gest in younger women (with 88% of women under 50 giving
this high priority compared to only 67% of women over age
cer patients and quality of life is often rated more highly than
survival prolongation [16, 17]. Many value their indepen-
dence and do not wish to be a burden either on society or
their friends and relatives [18]. Older patients are more likely
to decline treatment for reasons that may include fear of side
effects, uncertainty of treatment benefits, a perception that
they are «too old» for treatment and not willing to compro-
mise their current QoL [19]. Such trade-offs are complex and
may result in an increased rate of disease recurrence for
some, but not all, cases [20, 21]. It is important that the
wishes of older women are respected and they are supported
in the decision-making process with information about the
potential risks and benefits of their choices.
Breast Cancer in Older Patients
531 44
44.2  ssessment of the Fitness of an Older
A [27]. It is limited in that it makes no assessment of frailty and very
Patient limited assessment of some significant diseases such as dementia.
A full CGA assesses these domains in much more detail (e.g.
Whilst chronological age may give some indication of age-­ with a formal frailty assessment like the activity of daily living
related decline in organ function and an increased likelihood score (Barthel Index [28]) or one of a range of dementia scores,
of comorbidity and frailty, heterogeneity is great in this age e.g. the mini-mental state score [29]. Those who suffer from sig-
group, and no assumptions should be based on age alone. A nificant dementia have a generally reduced life expectancy so its
detailed assessment of comorbidity, medication, organ func- assessment is important. As these assessments are complex and
tion, cognition, functional status, current social support and time-consuming and require expertise to interpret their findings,
likely future support needs during and after treatment must very simple tools for assessing the fitness or frailty of older
be undertaken. Identification of reversible or suboptimally women are needed. Some are of value despite their simplicity
managed health problems may improve the ability of some such as the «Timed Up and Go» (TUG) test, Eastern Cooperative
patients to tolerate treatment. Such assessments are often Oncology Group (ECOG) performance status [30] and
complex and time-consuming and may require input from a American Society of Anesthesiologists (ASA) grade. Of these
multidisciplinary team including a geriatrician [22]. only the latter two are used routinely in clinical practice and have
There have been efforts to formalize and standardize such little value in case management other than excluding the most
assessments, and the most widely used is the comprehensive disabled categories from significant interventions.
geriatric assessment (CGA) which is a validated assessment In addition to helping to determine likely treatment toler-
protocol that has been widely evaluated in an oncology setting ance, such assessments can help to predict life expectancy which
[23–25]. The CGA includes a range of assessments of physical may assist in deciding whether lesser cancer treatment may be
illnesses and symptoms, medications, cognitive state, mental adequate. Patients with breast cancer who had three or more
health, functional ability and social support needs. The CGA comorbidities had a 20 times higher mortality from causes
reliably distinguishes between those who are frail and may be other than breast cancer and a four times higher overall mortal-
unable to tolerate standard therapy and the fitter older patient ity rate from all causes compared to those without comorbidi-
for whom standard treatment may be appropriate. Survival ties regardless of the tumour stage [31]. Numerous studies have
rates can be estimated with some degree of accuracy [26]. shown that patients with breast cancer and pre-­existing comor-
Patients who are currently unfit for standard therapy but may bidities have a higher all-cause mortality rate than those with-
benefit from pre-habilitation or chronic disease optimization out, especially in the first year of follow-up [32–34].
and subsequently tolerate standard therapy may also be identi-
fied. Patients predicted to have a very short life expectancy may
be identified and offered more limited therapy schedules such 44.3 Disease Stage
as primary endocrine therapy [22]. However, a CGA is very
time-consuming to administer and requires expertise that is The stage at which breast cancer presents in older women
not readily available in most breast clinics which has limited its tends to be later than in younger women. This reflects the fact
use in clinical practice. Briefer tools have been evaluated. that older women have lower rates of breast awareness and
The Modified Charlson Comorbidity Index (MCCI) is one self-examination [5]. In addition, most national screening
such tool which has been widely evaluated in the o ­ ncology set- programmes in European countries cease at age 70 or 75, so
ting and scores for each of 19 specific diseases. The MCCI is a detection of very small early-stage, low-grade cancers is
validated predictor of mortality of patients with breast cancer uncommon in older women (. Fig. 44.1) [35]. Comparative
 

..      Fig. 44.1  Data from the UK

National Cancer Registry on stage Prognostic factors by age cohort in UK breast cancer
and prognostic factors by age cases
subgroup (Modified from [35]) 80
70
60
50
40
30
20
10
0
% Grade 1 % less than 20mm % node negative
<40 40-49 50-59 60-69 70-79 80+

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 532 A. Shrestha and L. Wyld
..      Fig. 44.2  Incremental life
years, QALYs, and costs per
100,000 women invited to
Incremental Life years and QALYs per 100,000
screening (compared with the
invitatiom compared with the previous
previous screening strategy).
QALY, quality-adjusted life year
(Reproduced from Rafia et al. [39]
with permission from Elsevier)
screening strategy
–100.00
analysis of screened and symptomatic cases suggests that
screening has a major impact on this difference. Consequently
the median size of the primary cancer and rates of nodal dis-
ease are higher in older women, and there are higher rates of
locally advanced and metastatic disease [36].
There is some evidence that if this stage difference could
be eliminated, relative to younger cohorts, survival outcomes
for older women could be improved [37].
44.4 Screening in Older Women
Most of the trials of breast screening had upper age limits of
65–75  years with very few women in older age groups
included, and there is therefore little direct high-level evi-
dence of benefit in this age group and some good theoretical
reasons why it may be less effective (increasing risks of death
from other causes being the main concern). Detection of
breast cancer with mammography is more accurate in older
women as breast tissue is less dense and therefore more
radiolucent. The sensitivity of mammography in women over
the age of 60 is 95% [38]. However, the relative benefit of
screening is diluted by the relatively reduced life expectancy
and increased comorbidities of this age group. Many will die
of other causes before the cancer becomes symptomatic, and
44 therefore rates of overdiagnosis will be higher.
It has been suggested that a woman would need to survive
between 5 and 10 years to benefit from screening mammogra-
phy [40]. The problem is predicting women for whom this is
likely and even more problematic, administering such a sys-
tem at a population rather than an individual level. Whilst it is
not possible to use direct evidence from trials to support the
use of screening in older women, there are indirect methods
based either on the use of surrogate markers (such as reduced
stage at diagnosis) or statistical modelling studies [39]. Such
studies suggest that screening will have cost-­effective benefit
700.00 Per 100,000 women invited
600.00
500.00
400.00
300.00
200.00
100.00
72 75 78 81 84 87 90
Age at screening extension
Inc. life years Inc. QALYs
up to the age of ~78  years based on UK data (. Fig.  44.2).
Numerous other studies have suggested that screening is likely
to be beneficial beyond current age ranges [41], albeit with
reduced relative cost efficacy [42]. However, a note of caution
is needed: evidence from screening in the over 70s in the
Netherlands has shown a large increase in the diagnosis of
early-stage cancers but only a very small reduction in rates of
presentation with advanced disease [43]. This implies the ben-
efit will be small and rates of overdiagnosis large.
44.5 Tumour Characteristics
44.5.1 Tumour Biology
Breast cancer subtypes vary significantly between older and
younger cohorts. The biological characteristics are generally
more favourable in older age group, with a strong correlation
between expression of the oestrogen receptor (ER) and age
[44]. A large study of the US SEER database found that 83%
of women younger than 65 years old, 85% of women between
65 and 74 years of age and 91% of women older than 85 years
old had ER-positive tumours [36]. There are also higher rates
of expression of the progesterone receptor and lower expres-
sion of the human epidermal growth factor receptor type 2
(HER-2) which varies from 26% in women under 40 to 12%
in women over 80 [35]. There may also be a higher incidence
of diploid tumours, a lower proliferative (S-phase) fraction,
lower rates of mutation of the tp53 gene and lower rates of
lympho-vascular invasion [45]. Little work has been done
using the more recently described genomic classifications
(luminal A, B, Her-2 enriched and triple negative) [46, 47],
but early studies have confirmed that these differences are
present with lower rates of Ki67 expression, tp53 mutation
and cytokeratin expression rates. It is thought that subtle dif-
ferences within each subtype according to age (in favour of
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Breast Cancer in Older Patients
older women) may play a role in the lack of major variance in
relative survival rates between older and younger women,
subtype for subtype, despite the relative lack of adjuvant che-
motherapy in older women [48].
In modern breast practice, composite multigene arrays
are increasingly used to calculate prognosis or recurrence
risk (Oncotype DX©, Mammaprint© and many others, over-
view in 7 Chap. 9). In the case of Oncotype DX©, high recur-
 
rence scores are more commonly seen in women under age
40 versus women over age 40, but there is little variance
between older age subgroups [49]. Whether this carries the
same prognostic significance in this age group is yet to be
established in prospective studies. There is little data relevant
to this age group with the other multigene arrays at this time.
Invasive ductal carcinoma remains the most frequent
type of breast cancer regardless of age; however, studies have
suggested a higher incidence of mucinous and lobular
tumour subtypes in the older age group. Tumour grade may
vary by age. UK registry data has shown lower rates of grade
1 cancers in older women ([35] . Fig. 44.1), but this could be
 
a reflection of their later presentation [50] and the lack of
screening in this age group which tends to select for slow-­
growing good prognosis cancers [51].
44.6  anagement of Breast Cancer in 
M Breast-Conserving Surgery
Older Women
44.6.1 Surgery
Excision of the primary tumour and staging or therapeutic
axillary surgery, followed by appropriate combinations of
adjuvant therapies, should be the gold standard for patients
with breast cancer regardless of their age. Variable surgical
practices have been reported when managing an older patient.
Assumptions that older patients suffer from multiple comor-
bidities and are therefore unfit for general anaesthesia and
have a lower life expectancy have led to omission of surgery in
a significant proportion of older patients with ER-­positive
cancers. These women may be offered primary endocrine
therapy as an alternative to surgery in up to 40% of women
over the age of 70 [6, 52, 53]. There have been a number of
randomized [54] and non-randomized studies [55] which
have compared and evaluated primary endocrine therapy
compared to surgery in older women which are reviewed
below. Rates of surgery are highly variable in older women
[56] reflecting a lack of evidence-based guidelines on best
practice in this age group and differing surgeon opinions
about the use of surgery or primary endocrine therapy [57].
For those older women who do undergo surgery, most tend to
tolerate it well [58]. Mortality from breast surgery is generally
low. The UK National Mastectomy and Reconstruction Audit
reported an overall mortality from breast surgery of 0.26%
but did not break this down by age group [59]. There are sev-
eral surgical options which are discussed in more detail below
in the context of the older patient: breast conservation sur-
gery, mastectomy, axillary surgery and reconstructive surgery.
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533 44
Mastectomy
The morbidity and mortality rates from mastectomy are rela-
tively low in non-age-specific studies. Mortality rates for
patients above the age of 75 can vary from 0.95% to 4.5%
[60]. Although not statistically significant, the 90-day mor-
tality rate in patients over 70 is marginally lower for those
who undergo breast-conserving surgery compared to those
who undergo mastectomy, 0.3% versus 1.4% [61]. Patients
undergoing mastectomy are at greater risk of complications
than those who have breast-conserving surgery with the
common complications of wound infection, bleeding, hae-
matoma and seroma, being more likely to occur in older
patients, with the highest number of complications in those
over age 85 or those on multiple medications [62]. Rates of
mastectomy compared to conservation seem to vary with
age. The UK cancer registry shows that the highest rate of
conservation surgery is seen in the screened age range (1.8:1,
BCS versus Mx, age range 50–70), but in women aged 70 to
79, the ratio drops to 1:1 and to 1:0.7 in the over 80s [35]. It is
likely that this partly reflects the lack of screening and larger
tumour size in older women, partly a reluctance to undergo
radiotherapy and partly patient preference as older women
may be less concerned with the cosmetic aspects of such sur-
gery [63, 64].
Breast conservation surgery, usually followed by radiother-
apy, is an oncologically safe option for the majority of women
with breast cancer and is generally well tolerated and may be
performed under general or local anaesthesia. (The necessity
for radiotherapy after BCS in older women is discussed
below.) In the past decade, BCS techniques have expanded to
include oncoplastic procedures which may involve limited or
extensive mobilization of parenchymal flaps and much more
extensive surgery. There has been very little published data
on outcomes of oncoplastic surgery in older women [65, 66]
but that which there is suggests reasonable outcomes very
similar to those in younger women. Breast reduction surgery
for non-cancer cases in older women is also well tolerated
with generally higher satisfaction rates than in younger
women [67]. Most of the series have used 60 or 65 years of
age as the definition of elderly however and included few
women over age 70. Older women tend to present with larger
primary cancers and usually have significant levels of breast
ptosis which may make them more suitable for type 2 onco-
plastic procedures. However the fact that breasts are often
fatty, and arteriopathy more prevalent, may increase the risks
of fat necrosis if extensive parenchymal mobilization is done
injudiciously.
Axillary Surgery
In broad terms the gold standard for management of the
axilla is to perform a SLNB for the clinically uninvolved axilla
and a clearance for clinically node positive disease (see
7 Chaps. 22 and 23).
Sentinel node biopsy is a minor procedure with minimal
morbidity which can be performed under local anaesthesia if
 534 A. Shrestha and L. Wyld
needed [68]. In the clinically node-negative axilla, in a frail
or unfit, older patient, omission of axillary surgery or surgery
to the primary only plus adjuvant endocrine therapy is likely
to be a valid option.
It is generally accepted that axillary clearance surgery car-
ries only a minimal survival advantage [69–71] and is largely
performed to ensure locoregional control, establish progno-
sis and so guide adjuvant treatment decisions.
Before the introduction of sentinel node biopsy, older
patients were less likely to have axillary clearance compared
to their younger counterparts [72, 73]. A randomized control
trial by Martelli and colleagues (2005) of patients above the
age of 65 (median age 70, range 65–80), who underwent sur-
gery with or without axillary node clearance in patients with
T1 N0 breast cancer, concluded that axillary dissection was
not necessary and did not affect overall survival [74]. The
trial findings were updated with 15-year follow-up ­confirming
the lack of difference in overall survival and showing only a
small additional number of axillary recurrences (0% versus
6% in the no axillary clearance arm) [75]. Analysis of a cohort
of over 400 older women in whom axillary surgery was omit-
ted with 15-year follow-up showed a differential rate of axil-
lary recurrence by stage with 3.7 versus 8.9% in T1 versus T2
disease suggesting that a selective approach should be taken
[76]. As many older women have ER-positive cancers, addi-
tional local control is provided by endocrine therapy, and in
the post Z0011 era [77], it is now known that axillary disease
control may be enhanced with low axillary radiotherapy tan-
gents given during whole breast radiotherapy. There is good
evidence that even before the publication of the Z0011 trial
approximately half of all low-risk women (small ER positive,
older age) did not proceed to completion clearance after a
positive SLNB [78]. The need for completion clearance may
also be guided by the use of predictive axillary nomograms
[79]. The AMAROS (After Mapping of the Axilla:
Radiotherapy Or Surgery) study suggests that radiotherapy
may be a valid treatment option for women with a positive
SLN rather than surgical clearance. The trial data have not
been examined specifically with relation to older women, but
this strategy does provide a good alternative to women for
whom a second anaesthetic may carry risks.
As a result of the above, in an older woman with risk fac-
tors for anaesthesia, careful consideration should be given to
whether completion clearance is necessary, and if there are
significant risk factors for surgery, axillary radiotherapy or
no further axillary treatment may be appropriate alterna-
44 tives. Risk-stratified trials in older women regarding the
value of axillary clearance are lacking, but there is random-
ized trial data that this strategy is oncologically safe in women
of all age groups.
Reconstructive Surgery After Mastectomy
Whilst it is appropriate for older women to be considered for
reconstructive surgery after mastectomy if it is oncologically
appropriate, consideration must be given to the risks of more
major surgery with prolonged anaesthesia in older women
with significant comorbidities and frailty. For some women, it
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4000
3500
3000
2500
2000
1500
1000
500
0
<40 40–49 50–59 60–69 70–79 >80
Mastecomy only Reconstruction
..      Fig. 44.3  UK data modified from the National Mastectomy and
Breast Reconstruction Audit, 2010 [59]
may therefore pose an unjustifiable risk. The UK National
Mastectomy and Breast Reconstruction Audit showed that
older women are significantly less likely to undergo recon-
struction (. Fig.  44.3), a finding confirmed by many other
authors [80]. This probably reflects concerns about the
increased risks of surgery, assumptions about body image
being less important in this age group and reduced rates of
involvement in the decision-making process. The small num-
ber of older women who are offered reconstruction generally
reports good satisfaction rates and subsequent QoL. Indeed
there is some evidence that they may be more satisfied than
their younger counterparts [80]. The type of reconstruction
varies with age with older women more likely to be offered the
simpler and usually quicker implant-based techniques [80].
Rates of complications may vary with age, but the data is far
from conclusive. Most series that have compared morbidity
rates with younger versus older women have very small older
cohorts, and these are usually at the lower end of the age spec-
trum, usually defined as over 65, rather than over 70, often
with very few truly elderly subjects. It is therefore likely that
the elderly cohorts are very heavily selected to be at the
younger, fitter and more committed end of the spectrum and
hence not representative of the average elderly woman.
Matters are further complicated in that age is associated with
increased comorbidity rates, and whilst some studies have
corrected for this in multivariable analysis, it is not always
possible to do this fully and none have corrected for frailty.
One such study found that complications after implant-based
surgery were 2.5-fold higher in older women (over 65, only
5% of the series) [81]. Another study found that age was not
an independent risk factor for autologous flap failure when
correcting for comorbidities, but once again the series had
approximately 5% of patients over age 65. They found no dif-
ference in length of stay or rates of medical or surgical com-
plications, just an increased risk of blood transfusion [82].
The level of good-quality evidence of reconstruction
safety and outcomes is qualitatively weak but that which
Breast Cancer in Older Patients
535 44

LS HP
0.0%
–0.0% 0.0%
0.0%

–2.6% –2.0%
Percent Change

Percent Change
p=0.026
–5.0%
–3.9%
–4.0% –3.8%
–9.1%
–10.0%
–6.0%

0 6 12 0 6 12
Months in Treatment Months in Treatment
£65 >65 £65 >65

..      Fig. 44.4  Average bone mineral density change at the lumbar spine and hip by age group in 50 patients with normal BMD at baseline
receiving anastrozole (Reproduced from Markopoulos et al. [88] with permission from C Markopoulos)

there is suggests that in selected women, reconstruction is Adjuvant AIs also have adverse effects, predominantly
safe and associated with high levels of satisfaction. Good-­ joint pains, hot flashes and accelerated bone loss, and
quality prospective trials or cohort studies would be very although they are generally well tolerated, some toxicities are
valuable to give more details about QoL, frailty and comor- of increased relevance in older women. One of them is a
bidity in older reconstruction patients. reduction in bone mineral density (BMD) which may result
In terms of the older woman’s preferences for reconstruc- in an increased rate of bone fractures [84, 85]. This is of par-
tion surgery, there is a lower rate of interest. The underlyingticular concern in older women in whom osteopenia and
psychology of body image with ageing is complex. Physical osteoporosis are extremely common. There is evidence that
appearance becomes less important with age [64] although the rate of bone loss on AIs is less in women who are stably
body image is age-stable until quite an advanced age. What into menopause rather than in younger women (. Fig. 44.4)  

changes seems to be that age moderates the association [86, 87], but despite this, rates of fracture are still high in this
between body image and emotional distress [63]. age group (compounded by other age-associated risk factors
Consequently, older women may be less emotionally upset by such as low baseline BMD, fatigue, frailty and sarcopenia).
changes to their appearance and so less keen to undergo There is good evidence from numerous trials that IV or oral
reconstructive surgery, especially when faced with the bisphosphonates, when co-administered with an AI, signifi-
increased risks and complexity of surgery. cantly reduce bone loss [86, 88, 89]. The general consensus is
that women should be managed according to their risk
assessment and a baseline BMD result. Risk factors for frac-
44.7 Systemic Therapy tures include age over 65, smoking, a personal or family his-
tory of fragility fractures, a T-score of less than 1.5 and
44.7.1 Adjuvant Hormonal Therapy prolonged use of corticosteroids. Older women already have
one risk factor due to their age, so all should be advised to
There is good evidence to support the benefit for older take calcium and vitamin D, and many should be advised to
patients taking adjuvant hormonal therapy if they have ER-­ take a bisphosphonate and have BMD monitoring at inter-
positive disease. The EBCTCG review of 5 years of tamoxifen vals during treatment [90].
versus placebo found an approximate reduction in breast
cancer-specific mortality of one third. Although women over
70 were relatively poorly represented in these trials (~13%), 44.7.2 Adjuvant Chemotherapy
analysis of this cohort found the highest proportionate risk
reduction (RR 0.5) of any age group [83]. This is perhaps pre- Adjuvant chemotherapy is usually recommended for women
dictable given the biology of disease in this age group. with high recurrence risk breast cancer and is a major factor
Overview of the trials comparing AIs with tamoxifen had in the improvement in outcomes observed in the past few
excellent representation in the over 70 age group, where decades. It is thought to reduce breast cancer-specific mortal-
improved outcomes were seen with AIs, with a trend suggest- ity by approximately one third across all age groups (on
ing greater efficacy in older women (recurrence relative risk meta-analysis of trials), but few women over 70 have been
of 0.6  in favour of AI) Early Breast Cancer Trialists included in these studies [91], introducing statistical uncer-
Collaborative Group (EBCTCG 2015). tainty over the effect size. The benefit to overall survival is

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 536 A. Shrestha and L. Wyld
..      Fig. 44.5  Rates of adjuvant
chemotherapy use by age Percentage of UK women over 70 offered chemotherapy
subgroup and cancer recurrence 70
risk (Data modified from Ring
et al. [92]) 60
50
40
30
20
10
0
70–74
less in older women due to competing risks of death from
other causes and increased risks of death and severe morbid-
ity from chemotherapy itself. Mortality rates from chemo-
therapy in this age group are still low but higher than in
younger women.
Consequently, a smaller percentage of older women are
offered chemotherapy. A UK study of chemotherapy usage in
older women found rates were lower than in younger women
and highly age dependent (. Fig. 44.5) and also highly vari-
 
able between breast units. Rate of chemotherapy for all
women over age 70 varied between 0 and 29% and for high-­
risk women between 6 and 60% [92].
Recent studies suggest that older women with early-stage
breast cancer who are active and well with limited comor-
bidities should be offered the same chemotherapy as younger
women [25, 93]. Trials specifically looking at the safety and
efficacy of chemotherapy in this age group have been prob-
lematic due to small numbers and recruitment problems so
data are lacking relative to other age groups to support such a
policy. The CASA and ACTION trials, both randomized
comparing chemotherapy versus no chemotherapy, were pre-
maturely closed, due to difficulty recruiting patients [94].
The Cancer and Leukaemia Group B (CALGB) trial stud-
ied patients over the age of 65. They were randomized either
to standard chemotherapy arm treated with cyclophospha-
mide, methotrexate and fluorouracil (CMF) or capecitabine.
Patients who had capecitabine alone were more likely to have
44 relapse of the disease and a higher mortality rate. The patients
in the standard arm suffered more often from moderate to
severe toxicity from the chemotherapy treatment. Older
patients had higher chemotherapy-related deaths [95]. The
ELDA trial, a multicentre study, compared the standard che-
motherapy regimen (CMF) to weekly docetaxel. The stan-
dard chemotherapy regimen was found to be more effective
than docetaxel, as QoL and toxicity were noted to be worse in
the docetaxel arm [96]. Two agents (nab-paclitaxel and
capecitabine) have been reported to have a favourable toxic-
ity profile in older patients [97]. Results from the study by
rares1geo@gmail.com
75–79 80–84 85–89 >90
All over 70 High risk cancer over 70
Aapro and colleagues found that weekly nab-paclitaxel was
effective and well-tolerated first-line therapy for older
patients particularly at the dose of 150  mg/m2 weekly for
3 weeks followed by 1 week of rest [98]. A randomized phase
2 study comparing epirubicin and cyclophosphamide (EC)
or CMF versus nab-paclitaxel and capecitabine (NC) in
patients above the age of 65 with moderate- to high-risk early
breast cancer reported a higher grade of haematological
adverse events in the EC/CMF arm compared to the NC arm,
but non-haematological toxicities such as diarrhoea and sen-
sory neuropathy were more common in the NC arm [97].
Fitter older patients with HER-2-positive cancer may be
offered monoclonal antibody treatment, in the form of
trastuzumab, either as monotherapy [99] or in combination
with an endocrine therapy or with chemotherapy depending
on their level of fitness. Care must be taken to monitor car-
diac function however. Levels of efficacy of chemotherapy-­
free regimens are lower than with chemotherapy-associated
administration.
44.7.3 Primary Endocrine Therapy
Primary endocrine therapy is the treatment of oestrogen-­
sensitive breast cancer solely with endocrine therapy agents,
omitting surgery altogether. This was first suggested over
30 years ago [100] and since then has become quite widely
used in some countries. Randomized trials comparing sur-
gery and primary endocrine therapy, whilst methodologi-
cally flawed, showed that whilst rates of local control are
inferior, survival rates are little different except in younger
age groups where surgery is advisable [101, 102]. Very long-­
term follow-up studies have shown that for those patients
with a long predicted life expectancy, surgery is beneficial.
However, there is no guidance on the age and comorbidity
characteristics that predict that surgery is not necessary and
the only randomized trial that planned to collect detailed
comorbidity data, the ESTEEM trial, closed prematurely due
Breast Cancer in Older Patients
to poor patient participation and is unlikely to ever be repli-
cated [103].
For frail women with reduced life expectancy and for
whom surgery will confer little benefit and may impact nega-
tively on QoL, primary endocrine therapy may be appropri-
ate. Older women themselves tolerate this treatment very
well [104]. Although there have been no direct RCTs to com-
pare tamoxifen and aromatase inhibitors in the primary
endocrine therapy setting, cohort study analysis has demon-
strated that aromatase inhibitors are superior [55].
44.7.4 Adjuvant Radiotherapy
Treatment with whole breast radiotherapy is the standard of
care after breast-conserving surgery, and chest wall radio-
therapy is indicated in high-risk disease after mastectomy. In
the post-BCS setting, radiotherapy halves the local recur-
rence rate and, to a lesser extent and after longer follow-up,
reduces the mortality rate in studies of all age groups, includ-
ing in women over age 70 [105]. However, for an older
woman with a reduced predicted life expectancy, especially if
she has a low-risk, ER-positive cancer, the benefits of radio-
therapy may be small and not outweigh the risks and incon-
venience of radiotherapy. Fitter older patients, especially
those with higher-risk disease, are still likely to benefit from
radiotherapy. Systemic therapy plays a role in  local disease
control, and women with ER-positive cancers gain significant
protection from recurrence from adjuvant anti-oestrogen
therapy [105, 106]. The PRIME 2 trial evaluated either radio-
therapy or no radiotherapy after breast-conserving study in
older women with good prognosis cancer on adjuvant endo-
crine treatment in a randomized setting. The study demon-
strated that post-operative radiotherapy did reduce local
recurrence rates at the 5-year median follow-up from 4.1% to
1.3% [107]. The CALGB 9343 study similarly showed a sig-
nificant effect of radiotherapy on rates of loco-regional recur-
rence after 10  years of follow-up (10% versus 2%) [108].
However, neither trial showed any difference in overall or
breast cancer-specific survival which suggests that omission
of radiotherapy may be appropriate in some patients with a
reduced life expectancy or after discussion with the patient
about the relative risks. The PRIME 2 trial also found that
radiotherapy in this age group had no significant impact on
long-term overall QoL but did result in an increase in longer-­
term breast symptoms such as breast oedema [109].
Radiotherapy to the chest wall after mastectomy may be
associated with enhanced survival in older women with
high-risk disease [110]. The EBCTCG overview of post-­
mastectomy radiotherapy included 1340 patients over the
age of 70. The time to first recurrence halved in all age groups
and the local recurrence rate decreased significantly at
10 years and 15 years of follow-up [23]. A predictive nomo-
gram is now available to aid in the decision about the poten-
tial benefit of radiotherapy in older women: (7 http://www3.
mdanderson.org/app/medcalc/bc_nomogram5/index.
cfm?pagename=opcs) [111].
rares1geo@gmail.com
537 44
In an effort to reduce the travel and inconvenience associ-
ated with fractionated radiotherapy, some have suggested
intraoperative RT may be a good alternative for older women.
Several techniques and trials have been reported including
ELIOT and TARGIT.  For the TARGIT trial, early data on
5-year local recurrence rates showed IORT was inferior to
WBRT (3.3 versus 1.3%) [112]. A potential problem with this
technology is the need to extend anaesthetic times which
may be a disadvantage to the frail older patients who might
benefit most from not having multiple visits for EBRT.  At
present, its use in older women has not been fully evaluated,
and the technique is still the subject of expert debate [113].
Other less inconvenient options include various techniques
of accelerated partial breast irradiation with a reduced num-
ber of treatment sessions.
44.8 Summary
Management of breast cancer in older patients can be com-
plex, and careful assessment of fitness needs to take place
before treatment decisions are made. A multidisciplinary
team approach, ideally with input from a geriatrician in com-
plex cases, should be standard practice. Awareness of the
risks and benefits of treatments for an individual patient and
recognition that trading lower short-term treatment morbid-
ity may lead to increased cancer mortality later are essential
and should be discussed with the patient. Although there is
some research evidence to guide practice in this age group,
with evidence that omission of some treatments may be
appropriate with little loss of oncological safety in selected
patients, the data is usually not stratified by patient age and
fitness which means clinicians must use their clinical acumen
and experience to make these choices. In all cases, any revers-
ible comorbidity or frailty should be identified and optimized
to ensure treatment is as safe and oncologically comprehen-
sive as possible for each case. The high-value older women
may place on retaining their QoL, and independence should
be remembered, and in all cases they should be offered the
opportunity to engage with the decision-making process.
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domised trials. Lancet. 2012;379(9814):432–44.
92. Ring A, Harder H, Langridge C, Ballinger RS, Fallowfield LJ. Adjuvant
chemotherapy in elderly women with breast cancer (AChEW): an
observational study identifying MDT perceptions and barriers to
decision making. Ann Oncol. 2013;24(5):1211–9.
93. Bernardi D, Errante D, Gallligioni E, Crivellari D, Bianco A, Salvagno
L, et  al. Treatment of breast cancer in older women. Acta Oncol.
2008;47(2):187–98.
94. Crivellari D, Gray KP, Dellapasqua S, Puglisi F, Ribi K, Price KN, et al.
Adjuvant pegylated liposomal doxorubicin for older women with
endocrine nonresponsive breast cancer who are NOT suitable for a
“standard chemotherapy regimen”: the CASA randomized trial.
Breast. 2013;22(2):130–7.
95. Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM,
Kornblith AB, et al. Adjuvant chemotherapy in older women with
early-­stage breast cancer. N Engl J Med. 2009;360(20):2055–65.
96. Perrone F, Nuzzo F, Di Rella F, Gravina A, Iodice G, Labonia V, et al.
Weekly docetaxel versus CMF as adjuvant chemotherapy for older
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97. von Minckwitz G, Conrad B, Reimer T, Decker T, Eidtmann H,
Eiermann W, et al. A randomized phase 2 study comparing EC or
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 541 45

Breast Cancer in the 

Male Patient
M. Umit Ugurlu and Bahadir M. Gulluoglu

45.1 Epidemiology – 542

45.2 Aetiology and Risk Factors – 542

45.2.1 Genetics – 542
45.2.2 Age – 542
45.2.3 Race – 543
45.2.4 Family History – 543
45.2.5 Endocrine Risk Factors – 543
45.2.6 Other Risk Factors – 543

45.3 Clinical Presentation – 543

45.4 Imaging and Tissue Diagnosis – 544

45.5 Differential Diagnosis – 544

45.6 Genetic Counselling – 544

45.7 Staging – 544

45.8 Histopathology – 544

45.9 Treatment – 546

45.9.1 Breast Surgery – 546
45.9.2 Management of Axilla – 546
45.9.3 Radiation Treatment – 546
45.9.4 Systemic Treatment – 546
45.9.5 Treatment of Locally Advanced Disease – 547
45.9.6 Treatment of Distant Metastatic Disease – 547

45.10 Prognosis – 547

45.11 Psychological Impact and Support – 548

References – 548

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_45

rares1geo@gmail.com
 542 M. Umit Ugurlu and B.M. Gulluoglu
Male breast cancer (MBC) is a rare condition which accounts
for just under 1% of all breast cancers, and therefore few
clinical data exist [1]. Recommendations for MBC diagnosis
and management are mostly based on our understanding of
studies of female breast cancer (BC).
45.1 Epidemiology
The prevalence of MBC varies between continents. In Europe,
the annual rate of MBC is 1 in 100,000 men [2]. The incidence
has been stable at 0.4 per 100,000 until the 2010s but has
slightly increased thereafter in Europe. MBC is more com-
mon among elderly males and very rare in young males [3].
In the USA, SEER data showed a rise in incidence from 1 in
100,000 men in their late 70s to 1.2 in 100,000 men between
2000 and 2005 [4]. MBC incidence is higher among Jewish
men with an annual incidence of 2.3  in 100,000 men irre-
spective of geographic location, most likely as a result of the
higher incidence of the BRCA2 founder mutation [5]. Higher
incidence rates are also seen in Africa [6]. In contrast a lower
MBC incidence is seen in Japan (5 in 1,000,000 men) [7].
45.2 Aetiology and Risk Factors
Emerging evidence suggests that MBC has characteristic
which differs from those in female BC.
45.2.1 Genetics
There are a number of genetic factors which may increase
the risk of MBC. It is believed that around 15% of all MBC
cases are caused by germ-line mutations inherited through
previously described susceptibility genes [8]. Overall, it was
found that 0–4% of MBC patients have BRCA1 mutations
and 5–15% have BRCA2 mutations [8, 9] and are believed to
increase the risk of MBC development. In high-risk families,
mutations in BRCA 1 and BRCA 2 genes are found to be
responsible for 60–75% and 10–15% of MBC cases, respec-
tively [8]. Risk appears to be higher with BRCA2 rather than
BRCA1 mutations. Men who inherit BRCA1 and BRCA2
mutations have an estimated 1–5% and 5–10% lifetime abso-
lute risk of developing BC, respectively. Although they are
still lower risk than that of the average female, these figures
represent 10 to 100-fold higher risk than that of overall male
population [10]. The highest prevalence is reported in Iceland
45 where the BRCA2 999del5 founder mutation was implicated
in over 40% of Icelandic MBC patients [11]. Ashkenazi Jewish
men represent another special population with high rates of
the BRCA2 6174delT mutation [12]. However, BRCA1 gene
aberrations, either through methylation or loss of heterozy-
gosity (LOH), were found to be very rare in MBC [12]. The
median age at diagnosis was found to be 62 for men with both
BRCA1 and BRCA2 gene mutations [13], which is about two
decades higher than the equivalent age in female carriers.
rares1geo@gmail.com
Genes other than BRCA may also predispose to BC in
men although the evidence for any of these associations and
the impact of the genes are much less well developed than in
female carriers. Mutations in the PTEN tumour suppressor
gene, which are linked to Cowden’s syndrome, were reported
in two MBC patients [14].
The CHEK2 (also known as CHK2) mutation, which is
a cell cycle checkpoint kinase, was also considered as one
of the risk factors for MBC development. However, data
regarding this mutation is scarce and controversial. A study
revealed that the CHEK2 mutation was found in 13.5% of
individuals from families with MBC, and it is estimated that
the CHEK2*1100delC variant results in an approximate ten-
fold increase of BC risk in men compared to only a twofold
increase risk in women [15]. In contrast, another study from
Finland found that the rate of the CHEK2*1100delC muta-
tion is very low (1.8%) in MBC patients and similar (1.4%)
to rates in healthy men, implying that this variant does not
substantially increase the risk of MBC [16].
A link between androgen receptor expression and male
breast cancer has been explored but dismissed. It was sug-
gested that androgen receptor mutation along with the
Arg608 into Lys mutation causes a decrease in androgen
action in breast cells which may account for the development
of MBC by the loss of a protective effect of androgens on cells
[17]. However, no germ-line mutations were found in andro-
gen receptors, and the CAG and GGC repeat lengths in MBC
cases were similar to those in controls. It was therefore con-
cluded that androgen receptor mutations do not predispose
to MBC [18].
Two single nucleotide polymorphisms (SNP; rs3803662
and rs1314913) have been identified as potentially increas-
ing the risk of MBC. The rs1314913 SNP, located in intron 7
of the RAD51B gene (mapping to 14q23–24.2), belonging to
the RAD51 DNA repair family, was found to be associated
with an increased MBC risk but not with female BC [19].
Research into the impact of SNPs in breast cancer causa-
tion via huge multinational consortia are mainly exploring
their impact in females, and due to their small effect size and
potential interactive impact, coupled with the rarity of male
breast cancer, it may not be possible to define their roles eas-
ily in males.
Although they are established causes of increased female
BC risk, no association with MBC risk has been proven with
mutations in PALB2 and TP53 genes [20].
45.2.2 Age
Although incidence rates of MBC vary, age-specific patterns
are similar at most parts of the globe. Generally, incidence of
MBC increases with age and men tend to be 5–10 years older
than women at the time of cancer diagnosis [21]. Mean age
at diagnosis of MBC is 65–68 years, and only 10% of patients
are 50  years or younger [22]. However, in the Middle East
and Asia, in contrast to other regions in the world, male and
female BC patients have the same age distribution [12].
Breast Cancer in the Male Patient
45.2.3 Race
In the USA, MBC incidence was found to be higher in
blacks than whites and associated with presentation of more
advanced disease [21]. Moreover, non-Hispanic black men
have inferior survival rates and larger tumours with higher
grades, higher rates of triple-negative tumours and more
axillary lymph node involvement [23]. Studies revealed that
5-year survival rates were significantly different according to
race and ethnicity. Overall 5- and 10-year survival rates were
57% and 38% for black men, 66% and 59% for white men
and 75% and 75% for other ethnicities [24]. Obviously some
racial differences in incidence are linked to the presence of
autosomal dominant founder mutations and low penetrance
genes and multigenic factors as outlined above.
45.2.4 Family History
For a woman, having a family history of BC in a first-degree
male relative is associated with an increased risk of BC, but
it also confers and increased risk in males in that family. It
is estimated that 15–20% of the MBC patients have a family
history of the disease, but only 7% of the whole male popula-
tion have an affected family member [25]. A family history
of BC in female relatives is also a predisposing factor for
MBC. Men with a family history of BC in a female relative
are 2.5 times more likely to develop BC [25, 26].
45.2.5 Endocrine Risk Factors
There is a strong link between hormonal imbalances such as
relative oestrogen excess and a relative androgen deficiency
and the development of MBC [2]. Exogenous oestrogen
intake has been shown to increase the risk of MBC [27].
Men in the highest quartile of circulating oestrogen levels
are 2.5 times more likely to develop BC when compared to
those within the lowest quartile [28]. Endogenous produc-
tion of oestrogens occurs in men with hepatic dysfunction
and cirrhosis [29]. In prospective cohort studies, BC is more
common than expected in cirrhotic male patients [30]. Also,
the development of MBC was observed during follow-up
of patients with hepatocellular cancer [31]. MBC risk was
significantly associated with obesity, high body mass index
(BMI) and rapid weight gain which might be explained by
the finding that obesity and weight gain increase the circulat-
ing levels of oestrogen [28].
There is a hypothesis implicating high prolactin levels
and prolactinoma as risk factors for developing MBC. In one
study, plasma prolactin levels were found to be significantly
elevated in MBC patients [32].
Congenital or acquired testicular dysfunction increases
the risk for MBC development. Hormonal imbalance such as
androgen deficiency might play a causative role. Risk is rela-
tively increased in men with undescended testes, a history of
previous orchitis or orchiectomy, late puberty, infertility and
rares1geo@gmail.com
543 45
mumps occurring after puberty. Conversely having increas-
ing numbers of children, a surrogate marker for good testicu-
lar functions, was found to be associated with a low risk for
MBC [29]. Importantly, there is still a lack of evidence to link
gynaecomastia with MBC [20].
In this context, special mention should be made regard-
ing Klinefelter’s syndrome which is the strongest risk factor
for MBC. It is a rare condition resulting in alterations in the
oestrogen-to-androgen ratios. The risk of developing BC is
20–50 times higher in these patients than in normal men [20,
33]. This syndrome consists of atrophic testes, gynaecomas-
tia, high serum concentrations of luteinizing hormone and
follicle-stimulating hormone and low serum testosterone
levels in which the net effect is a high ratio of oestrogen-to-­
testosterone [33].
45.2.6 Other Risk Factors
MBC has been linked with occupational exposure to electro-
magnetic field radiation, high ambient temperature, exposure
to petroleum and other volatile organic compounds (e.g. tet-
rachloroethylene, perchloroethylene, trichloroethylene) and
polycyclic aromatic hydrocarbons (PAH, also found in exhaust
fumes and tobacco smoke). Also, PAH-DNA adducts were
found in benign and neoplastic breast tissue, with a higher fre-
quency in males with BC than controls (27% vs 13%) [20, 34].
As in women, exposure to chest wall radiation increases the
risk of MBC development [2]. Lack of physical activity seems
to be a risk factor for MBC as well. In a prospective study, MBC
risk was found to be significantly reduced in physically active
men even after adjustment for BMI [28]. In contrast poor diet,
alcohol use, tobacco, cigar smoking, marijuana use, amphet-
amine abuse, diabetes mellitus, gallstones, hyperthyroidism
and finasteride use have all been proposed as risk factors for
MBC, but findings to date have been inconclusive [26, 28].
45.3 Clinical Presentation
Only half of MBC cases are diagnosed at stage I or II and are
therefore diagnosed at a more advanced stage in men com-
pared to women [9]. This may relate to the lack of screening in
males as this is the major driver for the detection of early-­stage
BC in women. Rates of breast awareness are high in women
and very low in males which may also contribute to later
presentation. The mean duration from clinical presentation
to diagnosis ranges between 1 and 10 months [35]. The most
common symptom of MBC is a painless, firm, sub-­areolar
mass (75%) [20]. Due to the lack of breast and subcutane-
ous tissue in the male breast, nipple-areola complex (NAC)
involvement occurs early in the disease. Again nearly half of
patients present with enlarged lymph nodes in the ipsilateral
axilla [35], which is slightly higher than the rate in females.
Local pain, skin and/or NAC retraction, nipple discharge and
skin ulceration may accompany the lump to a lesser extent
[20]. Around 1% of cases present as bilateral cancer [9].
 544 M. Umit Ugurlu and B.M. Gulluoglu
..      Fig. 45.1  The role of breast MRI in this subset of patients is not
clear yet, although it may have a role in cases of diagnostic difficulty/
discordancy
45.4 Imaging and Tissue Diagnosis
Mammography and ultrasound are the main imaging tools
for investigation of clinical findings suggestive for malig-
nancy in men. The role of breast MRI in this subset of patients
is not clear yet, although it may have a role in cases of diag-
nostic difficulty/discordancy (. Fig. 45.1) [20]. The sensitiv-
 
ity and specificity of mammography for diagnosis of MBC
are 92% and 90%, respectively. Mammographic features of
MBC include the presence of a mass eccentric to the nipple
with spiculated margins and, less commonly, microcalcifica-
tions. The major challenge when interpreting male mammo-
grams is to distinguish MBC from gynaecomastia [36]. In
cases where sub-areolar MBC and gynaecomastia coexist, an
eccentric position of the sub-areolar density is suggestive of
malignancy [37]. MBC is typically a solitary hypoechoic solid
lesion on ultrasound examination. Axillary ultrasound is of
similar value in assessment of the male and female axillae.
For any suspicious breast mass or axillary lymph node, fine
needle aspiration cytology or preferably core biopsy is used
to confirm the diagnosis. Core biopsy is generally preferred
because it yields a definitive diagnosis of invasive cancer with
45 more certainty [20, 37].
45.5 Differential Diagnosis
The differential diagnosis of a breast mass in a male includes
gynaecomastia, pseudogynaecomastia/lipomastia, infec-
tion/breast abscess, lipoma, pseudoangiomatous stromal
hyperplasia (PASH), granular cell tumour, desmoid tumour,
rares1geo@gmail.com
schwannoma, myofibroblastoma, haemangioma, metastases
to the breast and other non-breast cancer primary tumours
such as sarcomas [9, 37]. Fibroadenomas of the male breast
are very rare due to the absence of breast lobules.
45.6 Genetic Counselling
All men diagnosed with BC should be referred for genetic
counselling and, if indicated, BRCA mutation testing.
Currently, the National Comprehensive Cancer Network
recommends consideration of BRCA1/2 testing in men with
a personal history of BC [38]. Also risk counselling should be
given to healthy men with Klinefelter’s syndrome. Although
routine mammographic screening is not advocated, breast
self-examination and regular physical breast examination are
recommended in men with Klinefelter’s syndrome [33].
45.7 Staging
After a diagnosis of MBC is established, the extent of disease
should be determined with a bone scan and CT scan of the
chest, abdomen and pelvis, as clinically appropriate accord-
ing to the same guidelines as in females. MBC is classified
according to the tumour, nodes, metastasis (TNM) staging
system [38] which does not differentiate between male and
female diseases.
45.8 Histopathology
Although most histologic subtypes of female BC also present
in men, there is still a need to better understand the pathol-
ogy of MBC.
The predominant histological type of MBC is invasive
ductal cancer which constitutes more than 90% of cases.
Lobular cancer is less common in males than females and
accounts for only 1.5% of cases (compared to 10% in females)
because the male breast is rudimentary and lacks acini and
lobules. Neither differentiation nor lobule formation occurs
unless the breast is exposed to increased concentrations of
endogenous or exogenous oestrogen. Other rare histological
types include papillary and mucinous cancers [39]. Regarding
ductal carcinoma in situ (DCIS), there are differences in men
when compared to women. DCIS constitutes a larger propor-
tion of female BCs than in MBCs overall (20% vs. 7–11%,
respectively). DCIS in men tend to occur in more elderly
males, often as an intraductal papillary form with a low grade
[40]. More than half of DCIS cases present as intermediate
grade. Only 17–33% of cases were found to be high grade
[9]. Registry data has shown that MBC patients have signifi-
cantly more nodal involvement than female BC patients and
therefore MBC cases present with more advanced disease
[41] (. Table 45.1).
As in postmenopausal women, the most common sub-
type of MBC is oestrogen receptor-positive (ER+) tumours.
Breast Cancer in the Male Patient
545 45

..      Table 45.1  Stage distribution of male and female breast ..      Table 45.2  Histologic and stage characteristics of male and
cancer cases female breast cancer patients with BRCA1 and BRCA2 mutations

Male breast cancer (%) Female breast cancer (%) Male breast cancer Female breast
cancer
Stage I 10–40 30–45
BRCA1 BRCA2 BRCA1 BRCA2
Stage II 15–45 40–50 (%) (%) (%) (%)
Stage III 20–50 5–15
Stage
Stage IV 5–15 3–5
  0–I 14 29 50 48

  II 43 47 43 41
SEER database findings revealed that more than 90% of MBC   III–IV 43 24 8 11
were oestrogen receptor (ER) positive which is more com-
Grade
mon than it is in female BC where 70% ER+ is the normal
proportion. The ER positivity rate increases with age in MBC   I 4 3 3 7
as it does in females. Also, 92–96% of MBCs are progesterone   II 27 40 18 42
receptor (PR) positive. [23, 41]. Men also have higher mean
  III 69 57 79 51
expressions of ER, PR and proliferation genes such as Ki-67,
MYBL2, Survivin, Cyclin B1 and STK15 [42]. IHC expression
Studies using standardized methodology by both immu-   ER positivity 90 97 24 77
nohistochemistry and fluorescence in situ hybridization
showed lower rates of Her2-neu overexpression in MBC   PR positivity 79 87 21 65
(2–15%) when compared to the rate observed in female BC   Her2 overex- 11 17 9 13
(18–20%) [9, 43]. pression
Findings from several studies showed that MBCs from
patients with BRCA1/BRCA2 mutations display different
pathologic characteristics when compared to female BC with number levels were identified among MBC: male-complex
BRCA1/BRCA2 mutations. MBC with BRCA1 mutations and male-simple cancers. The male-simple cancer subgroup
seemed to have a lower grade when compared to female BC consists of 20% of MBC cases and appeared to be comprised
with BRCA1 mutations, but grade distribution was more likely of less aggressive and small tumours. These cancers were
to be similar between female and male BC cases with BRCA2 remarkably different from those of previously described six
mutations. Also, MBC patients with either BRCA1 or BRCA2 BC subgroups and seemed to represent a new subgroup seen
mutations had more advanced disease at presentation when only in males [48, 49]. Male-complex cancers which were
compared to those with female BC carrying mutations. Also, found to be more aggressive were overall similar to those in
ER and PR expressions in MBC patients with BRCA1 and luminal-complex subgroup of female BC [49]. In another
BRCA2 mutations were higher than those observed in female study, MBC was grouped using global gene expression pro-
BC cases with same gene mutations (. Table 45.2) [13, 44].
  files, and here again two distinct subgroups were identified:
In female BC, DNA microarray studies have identi- Luminal M1 and Luminal M2. Across the study’s dataset,
fied five molecular subtypes which are normal breast-like, Luminal M1 cancers consisted of 70% of cases and the rest
Luminal A and B type, Her2 overexpressing and basal- were Luminal M2 cancers [50]. Luminal M1 cancers had low
like [45]. Although data on genomic subtyping of MBC is correlation to genes associated with ER signalling and were
scarce, the frequency of subtypes is different than that of found to carry more aggressive phenotype with worse prog-
those in female BC cases. In MBC cases, Luminal A subtype nosis, whereas Luminal M2 cancers had high expression of
(83–98%) is the most common type, followed by Luminal genes associated with ER signalling. When comparing these
B (0–17%). The Her2-overexpressing subtype and basal-like two new subtype groupings of MBC to standard intrinsic
tumours are infrequent in MBC (0–5%) [46]. Furthermore, groups defined for female BC, MBC cases in each subgroup
the basal-like MBC expresses ER in 75% of cases in contrast did not fit completely into previously described intrinsic sub-
to female BC in which only 30% of basal-like cases have ER types [50]. On the other hand, newly described above sub-
expression [47]. types overlap partly with each other in which nearly 90% of
Considering the possibility that MBC is a different dis- the Luminal M1 tumours were found to be male-complex,
ease than female BC by recognizing the dissimilarity of fre- whereas nearly half of the Luminal M2 cancers were male-­
quency of standard intrinsic subtypes in MBC and female simple [50, 51].
BC, studies with more comprehensive methods revealed dif- N-acetyltransferase-1NAT1, a xenobiotic metabolizing
ferent subtypings of MBC. One of these studies was based on enzyme, was identified as a promising prognostic biomarker
high-resolution genomic profiling. In this methodology, two for MBC.  NAT1 positivity was associated with better out-
genomic subgroups with significantly different aberrant copy come [50].

rares1geo@gmail.com
 546 M. Umit Ugurlu and B.M. Gulluoglu
Cell cycle regulatory proteins are also aberrantly expressed
in MBC. The tumour suppressor gene tp53 is mutated in 3.7–
54% of MBC cases. The oncogene c-myc is overexpressed in
12–100% of MBC. The proto-oncogene bcl-2 which inhibits
apoptosis and promotes cell growth was found to be signifi-
cantly higher in MBC than in female BC. Cyclin D1, related
to cell cycle regulation, is overexpressed in approximately
50% of MBC.  Upregulation of p21waf1 and cdk inhibitor
p27Kip1 is more frequent in MBC than that in women with
BC [2]. Intratumoural aromatase expression is shown in 27%
of MBC patients, and its expression was found to be associ-
ated with improved 5-year overall survival [52].
45.9 Treatment
As it is in female BC patients, the treatment strategy for MBC
involves surgery, radiation therapy (RT) and systemic treat-
ments.
45.9.1 Breast Surgery
Surgical treatment of MBC is similar to that of female BC and
depends on the extent of disease at presentation. Standard
treatment for early-stage disease (T1-T2, N0-N1) is surgical
resection with free margins. Although there is no reported
randomized trial comparing different types of surgical pro-
cedures in males, most patients (70%) undergo mastectomy.
This may necessitate chest wall muscle removal (8–30%) due
to the reduced volume of breast tissue, meaning muscle inva-
sion is more likely. Breast-conserving therapy (BCS; 1–13%)
is less commonly offered for the obvious reason that breast
mound preservation is less of an issue in males cosmetically
but also even in males with early-stage disease. BCS is less
likely to be considered due to lack of breast tissue. Only in
men who have sufficient breast tissue without overt nipple-­
areola involvement BCS is an appropriate option to allow
achievement of free surgical margins with acceptable local
recurrence rates [53]. No satisfactory data exist for the ade-
quacy of immediate or late reconstruction after skin sparing
(with or without nipple-areola sparing) mastectomy in MBC
patients.
45.9.2 Management of Axilla
A large database study reported that nearly 40% of male
45 patients present with nodal involvement; therefore, axillary
dissection is performed more frequently than in female BC
patients overall. In patients with clinically node-negative
MBC, sentinel lymph node biopsy (SLNB) was proven to be
feasible with low morbidity [2]. Although the accuracy of
SLNB in males has not yet been confirmed in a large series,
the American Society of Clinical Oncology (ASCO) expert
rares1geo@gmail.com
panel recommended its use in men with clinically node-­
negative BC.  According to this panel, men with a negative
SLN do not require further surgery. The necessity for com-
plete axillary clearance in men with a positive SLN is still a
controversial issue, as indeed it is in women. Therefore, the
approach to the male patient with a positive SLN should be
similar to that in women [54].
45.9.3 Radiation Treatment
The indications for RT for MBC patients are extrapolated from
those for women due to the scarcity of data. Radiotherapy is
indicated in MBC patients who undergo (i) mastectomy for
T3 or T4 cancer, (ii) following BCS, (iii) mastectomy with
deep surgical margin involvement and (iv) axillary clearance
in which at least one lymph node was found to be metastatic.
There are no established data which provide evidence that
postmastectomy RT is required for patients with multifocal-
ity, high-grade disease, high tumour proliferation markers
and peritumoural vascular extension. A cohort study found
that the majority of male patients are treated appropriately
with adjuvant RT showing that 36% of N1 and 15% of N2
patients did not receive RT [22].
As in women, the benefit from RT must be weighed
against the risks of treatment-related toxicities due to the
older age of the MBC patients. The standard RT dose is 50 Gy
in 2 Gy fractions: an extra boost dose may also be considered
in cases of suboptimal surgical margins where further sur-
gery is not possible [55]. However, although data is only valid
for female patients, hypofractionation (3 weeks instead of 5)
may have a role in these patients as well [56].
45.9.4 Systemic Treatment
Adjuvant Chemotherapy
In MBC patients, there are no well-designed, prospective
trials assessing the effects of adjuvant chemotherapy, either
in localized or metastatic disease series. Therefore, guidelines
written for women with BC apply for males regarding adju-
vant systemic therapy. In MBC, due to lack of a high-level
evidence, optimal chemotherapy (CT) regimens are not yet
defined.
Historically improved 5-year survival rates were shown
in the 1990s in MBC patients who received adjuvant cyclo-
phosphamide, methotrexate and 5-fluorouracil (CMF) or
5-­fluorouracil, adriamycin and cyclophosphamide (FAC)
regimens as compared to those who did not receive CT [57].
More recent data has revealed that CMF after mastectomy
provided a 5-year survival rate of over 80% in MBC patients
with nodal involvement. In another large cohort study, after
receiving adjuvant CT consisting of mainly anthracycline-­
based regimens, it was found that 5- and 10-year overall
survival rates were 86% and 75% and 70% and 43%, in MBC
Breast Cancer in the Male Patient
patients with lymph node-negative and lymph node-positive
disease, respectively [58]. A recent large registry study also
reported that there is an increasing trend for administering
anthracycline-based (43%) regimens alone or combination
with taxanes (32%) instead of CMF regimens (15%) [22].
Therefore, administering adjuvant CT to high-risk MBC
patients is thought to be effective with enhancing outcomes
and should ideally follow standard regime recommendations
as for female patients [59].
Adjuvant Hormonal Treatment
Increased expression of ER and PgR in MBC indicates the
likely efficacy of hormonal treatment in these patients.
Although there are no randomized trials focusing on hor-
monal treatment in MBC, tamoxifen administration for
5 years is accepted as the standard of choice in the adjuvant
treatment of HR-positive MBC. Use of tamoxifen decreases
recurrence rates and improves overall survival in MBC
patients when compared to those who do not receive tamoxi-
fen [58]. However, tamoxifen is not well tolerated in males.
The most common side effects include decreased libido,
weight gain, hot flashes, mood alteration, depression, insom-
nia and thrombosis. Side effects caused poor compliance, so
about 21% of cases discontinued their treatment [60].
Regarding other hormonal regimens such as luteinizing
hormone-releasing hormone (LHRH) agonists or aromatase
inhibitors (AI), there is no convincing data to support the use
of them in MBC patients at present [61].
As potential hormonal treatment agents for MBC, anti-­
androgen drugs such as bicalutamide, enzalutamide and abi-
raterone acetate are being studied currently in phase 2 trials
[62]. Since androgen receptor (AR) expression was reported
to be positive in 39–95% of MBC [63], favourable findings
of anti-androgen treatment in prostate cancer patients cre-
ate expectations for similar efficacy in MBC patients [64].
However, currently there is no evidence that anti-androgen
treatment is effective in MBC patients in any setting or
sequence. The results of these studies are awaited with interest.
Targeted Treatment
There is no data regarding the efficacy of adjuvant trastu-
zumab in MBC.  Her2 receptor expression in MBC is less
common than in women [46]. Given the proven therapeu-
tic benefit seen with adjuvant trastuzumab in women with
Her2-positive BC, it seems reasonable to offer trastuzumab
to men with Her2-positive tumours [22].
45.9.5  reatment of Locally Advanced
T not studied yet.
Disease
In men with T3/T4 or inflammatory breast cancer, the treat-
ment strategy should mirror that of females. Primary sys-
temic CT is recommended as the first-line treatment and
rares1geo@gmail.com
547 45
surgery to be reserved for those whose tumours later become
operable. Postmastectomy RT is generally recommended in
such cases and adjuvant tamoxifen is used for ER-positive
disease [9]. There is lack of data about using primary sys-
temic hormonal treatment in men with HR-positive locally
advanced BC.
45.9.6  reatment of Distant Metastatic
T
Disease
A large registry study reported that 3.8% of MBC patients
are found to be metastatic at initial diagnosis [22]. Distant
metastases subsequently develop in between 18 and 54%
of male BC patients [65]. Due to the high incidence of
ER-­positive tumours, hormonal treatment is often the first
approach in the metastatic setting. As in the adjuvant set-
ting, tamoxifen is the first choice with a response rate of
80% in this subgroup [58, 59]. On the other hand, further
data are warranted to understand the efficacy of AI and
LHRH analogues in MBC patients. If AIs are considered,
they should be administered together with LHRH agonists.
CT for metastatic MBC is used as second- or third-line
treatment after failure to tamoxifen or in HR-negative dis-
ease. Here, limited evidence suggests that FAC as the CT
regimen is more effective than single or other combination
drug treatments [66].
45.10 Prognosis
In reports comparing MBC and female BC, matched for age
at diagnosis, grade and stage did not show a worse survival
in men when compared to that in women [9]. Blacks with
MBC have a worse prognosis than whites in the USA based
on historic SEER database data (however socioeconomic fac-
tors relating to health funding may impact on US data) [67].
Significant prognostic factors of MBC are identical to those
in the female, namely, tumour size, nodal status and immu-
nophenotype (ER+). The prognostic value of AR expression
is still controversial [22, 63]. Also, whether Her2 overex-
pression is a marker for poor prognosis in MBC remains
uncertain. Until now there is limited data regarding the
role of multigene prognostic and predictive profiling tests
in MBC.  Only study which analysed a small cohort from
Israel found that distribution of 21-gene recurrence score
in ER-­positive MBC patients is similar to that of female BC
patients [68]. But profiling tests’ accuracy in MBC cases was
SEER database revealed that survival rates in MBC
patients were found to be worse as the stage of cancer
advanced (. Table 45.3) [69]. Another large registry showed
that median survivals are 10.4, 8.4 and 2.6 years in N0 M0,
N+ M0 and M1 patients, respectively [22].

548 M. Umit Ugurlu and B.M. Gulluoglu

studies and discussion of selected aetiological factors. Int J Cancer.

..      Table 45.3  Survival rates in male breast cancer patients 1993;53:538–49.
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  10 year 93 74 44 21
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  3 year 89 79 66 29 8. Rizzolo P, Silvestri V, Tommasi S, et al. Male breast cancer: genetics,
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  5 year 78 66 39 14
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  10 year 55 39 21 5 9. Gomez-Raposo C, Zambrana Tevar F, Sereno Moyano M, Lopez
Gomez M, Casado E.  Male breast cancer. Cancer Treat Rev.
2010;36:451–7.
10. Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among
male BRCA1 and 2 mutation carriers. J Natl Cancer Inst.
2007;99:1811–4.
45.11 Psychological Impact and Support 11. Thorlacius S, Sigurdsson S, Bjarnadottir H, Olafsdottir G, Jonasson
JG, Tryggvadottir L, et  al. Study of a single BRCA2 mutation with
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patients are very limited, and psychosocial support for these 1997;60:1079–84.
12. Ferzoco RM, Ruddy KJ.  The epidemiology of male breast cancer.
patients has never been adequately considered. It was found Curr Oncol Rep. 2016;18:1.
that the consequences of diagnosis and treatment of BC in 13. Silvestri V, Barrowdale D, Mulligan AM, et al. Male breast cancer in
males were associated with the perception of the disease as BRCA1 and BRCA2 mutation carriers: pathology data from the con-
a female disorder. Patients felt themselves as more feminine. sortium of investigators of modifier of BRCA1/2. Breast Cancer Res.
Therefore the psychological effects of BC include stigma, 2016;18:15.
14. Fackenthal JD, Marsh DJ, Richardson AL, Cummings SA, Eng C, Rob-
embarrassment, a sense of isolation and depression in males inson BG, et  al. Male breast cancer in Cowden syndrome patients
[70]. Furthermore, it was found that changes due to treat- with germline PTEN mutations. J Med Genet. 2001;38:159–64.
ment such as alopecia, reduced mobility of the arm and 15. Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de
shoulder, altered body image, perceived decrease in personal Snoo A, Oldenburg R, et al. Low-penetrance susceptibility to breast
attractiveness and, in general, anxiety, fear of disease recur- cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2
mutations. Nat Genet. 2002;31:55–9.
rence and death as well as loss of self-confidence were expe- 16. Syrjakoski K, Kuukasjarvi T, Auvinen A, Kallioniemi OP.  CHEK2

rienced by patients [70, 71]. 1100delC is not a risk factor for male breast cancer population. Int J
Yet, there is no study regarding management of psycho- Cancer. 2004;108:475–6.
logical distress seen in MBC.  Evidence for the efficacy of 17. Lobaccaro JM, Lumbroso S, Belon C, Galtier-Dereure F, Bringer J,
interventions to ameliorate or decrease the psychological Lesimple T, et al. Androgen receptor gene mutation in male breast
cancer. Hum Mol Genet. 1993;2:1799–802.
events and enhance quality of life in MBC is lacking [72]. 18. Syrjakoski K, Hyytinen ER, Kuukasjarvi T, Auvinen A, Kallioniemi OP,
Very few organized support groups for MBC patients were Kainu T, et al. Androgen receptor gene alterations in Finnish male
found to be available, adding to their isolation. The only breast cancer. Breast Cancer Res Treat. 2003;77:167–70.
published report of a psychosocial management of MBC 19. Orr N, Cooke R, Jones M, Fletcher O, Dudbridge F, Chilcott-Burns S,
assessed the efficacy of a telephone-based support group for et  al. Genetic variants at chromosomes 2q35, 5p12, 6q25.1,
10q26.13, and 16q12.1 influence the risk of breast cancer in men.
geographically distant patients. Participants found the group PLoS Genet. 2011;7(9):e1002290.
helpful for information sharing, obtaining peer support and 20. Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lan-
reducing isolation. There was a very high compliance with cet. 2006;367:595–604.
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45 support in this particular male BC patient group [73]. cer similar or different than female breast cancer? Breast Cancer Res
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22. Cardoso F BJ, Slaets L , van Deurzen C, van Leewen-Stok E, Porter P
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 551 46

Sarcoma of the Breast
Erkki Tukiainen and Andrew Lindford

46.1 Introduction – 552

46.2 Clinical Presentation and Diagnosis – 552

46.3 Treatment – 552

46.4 Clinical Outcomes – 552

46.5 Different Breast Sarcoma Subtypes – 552

46.6 Phyllodes Tumors – 552

46.7 Primary Breast Sarcomas – 554

46.8 Radiation-Induced Sarcoma – 555

46.9 Conclusions – 556

References – 557

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_46

rares1geo@gmail.com
 552 E. Tukiainen and A. Lindford
46.1 Introduction
Sarcomas of the breast are a rare group of malignant hetero-
geneous tumors arising from the mesenchymal tissues of the
breast and account for less than 1% of all breast malignancies
and less than 5% of all sarcomas [1–3]. They are biologically
different in their origin and behaviour from other primary
breast tumors (mostly adenocarcinomas and epithelial in ori-
gin) and therefore necessitate a different diagnostic and
treatment strategy. The rarity of this condition has resulted in
a lack of consensus on optimal management which generally
follows guidelines derived from randomized controlled trials
of soft tissue sarcomas of the extremities and chest wall [4].
46.2 Clinical Presentation and Diagnosis
The median age at diagnosis is about 50 years. The majority of
breast sarcomas present with a palpable, firm, well-defined
unilateral breast mass [4]. However, angiosarcomas often
cause blue or purple discoloration of the overlying skin [5].
Fine needle aspiration may have low diagnostic accuracy in
breast sarcomas, and therefore core biopsy is the procedure of
choice for diagnosis in many centres. Immunohistochemistry
is routinely performed and may be very helpful in establish-
ing the diagnosis and enables further classification according
to histological subtype [6, 7].
Radiological imaging often reveals non-specific findings
such as an opaque mass on mammography. Similarly, ultra-
sound findings are usually inconclusive with a typical appear-
ance of an irregular mass with indistinct edges and no
shadowing. Therefore, if a sarcoma is suspected or confirmed,
further diagnostic imaging is indicated, including magnetic
resonance imaging (MRI) and/or computed tomography
(CT) of the chest. MRI may be useful in diagnosing malig-
nancy with rapid enhancement of malignant tumors with
«washout» characteristics and lobulation [7–9].
46.3 Treatment
A multidisciplinary team approach is essential, with complete
surgical resection with negative margins the mainstay of treat-
ment [4, 8]. Controversy exists regarding surgery with mastec-
tomy versus wide local excision. However, no significant
advantage to more radical surgery has been demonstrated
[10]. Indeed, negative surgical margins are more important for
local recurrence and overall survival than the extent of surgical
resection [3, 9, 11]. Of course, large tumors may still warrant
mastectomy in order to obtain clear margins. A tumor size of
less than 5 cm is associated with better overall survival [12, 13].
46 Metastases tend to spread haematogenously rather than
via lymphatics (in contrast to breast epithelial neoplasms)
and typically occur in the lungs, bones and liver. Lymph node
metastasis is very rare, and most studies quote less than 5%
lymphatic involvement (although perhaps 10% in malignant
phyllodes tumors). Routine lymphadenectomy exposes the
patient to additional morbidity with no proven benefit in
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terms of disease-free or overall survival [13–16]. Lymph
nodes should only be removed in the presence of histologi-
cally proven lymph node involvement.
The precise role of adjuvant therapies such as radiother-
apy and chemotherapy remains unclear, although a small
survival benefit has been demonstrated for post-operative
­radiotherapy [3, 13]. In view of the lack of specific data on
breast sarcoma, indications for adjuvant therapy should fol-
low the criteria for soft tissue sarcomas in general, and adju-
vant therapy is recommended for high-risk cases (high
histological grade, >5  cm diameter, inadequate margins if
re-excision is not possible) [17, 18].
46.4 Clinical Outcomes
Breast sarcomas have a high risk of recurrence and a poorer
prognosis than breast adenocarcinoma. Five-year disease-­
free survival ranges from 40% to 66% and 5-year overall sur-
vival 49–70% [2, 3, 10–13, 15, 18]. The variability of reported
outcome figures may reflect the varying composition of his-
tological subtypes and small numbers of cases. Therefore
many advocate that treatment should be centralized to high-­
volume reference centres for sarcoma to enable standardiza-
tion of the multidisciplinary management of breast sarcoma
and improve outcomes [4, 8].
46.5 Different Breast Sarcoma Subtypes
There are a large number of different histopathological breast
sarcoma subtypes with the most common being malignant
phyllodes tumor and angiosarcoma. In many clinicopathologi-
cal studies, breast sarcomas are divided into three subgroups:
1. Malignant phyllodes tumors
2. Primary breast sarcomas
3. Secondary sarcomas arising in the post-­irradiation breast
46.6 Phyllodes Tumors
Phyllodes tumors (PTs) represent a specific subset of breast
soft tissue tumors. They are composed of a connective tissue
stroma and epithelial elements. Their epithelial components
have led some authors to exclude them from their studies.
They often clinically resemble fibroadenomas. Preoperative
diagnosis with fine needle biopsy (FNA) can be difficult as
microscopically they appear as epithelial lined cysts with a
hypercellular stroma. Therefore core biopsy in combination
with imaging is recommended. Mammography is non-­
specific. PTs look like well-defined, smooth lesions some-
times with a peri-lesional halo, which is the result of
compression of the surrounding normal breast tissue.
Ultrasonography may be more sensitive for demonstrating
an abnormality than mammography. MRI should be used to
define the extent of the lesion and its anatomical location (see
. Figs.  46.1 and 46.2). However, not even MRI can reliably
distinguish benign from malignant lesions [6, 7].
Sarcoma of the Breast
553 46

a b

..      Fig. 46.1  a–d A 40-year-old patient presented with a lump in a left
lateral breast. Ultrasound a mammography b and core biopsy all sug-
gested only a benign fibroadenoma. Excision biopsy was performed
in a regional hospital and a 3.5 × 3 × 3 cm tumour was removed. Phyl-
lodes tumour was suspected on histological analysis, and the patient
referred to the tertiary hospital Breast Cancer and Sarcoma teams. The
final histological consensus confirmed a malignant phyllodes tumour.
CT scan performed at 5 weeks from the original excision biopsy c
showed a recurrent tumour measuring 3.7 cm, and MRI scan d showed
an even larger, intensive tumour measuring 5 × 3.8 × 4 cm. Radical
mastectomy including pectoralis fascia was performed, and the axillary
lymph nodes were not removed. The patient is symptom-free at 2-year
follow-up

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 554 E. Tukiainen and A. Lindford

..      Fig. 46.3  An 84-year-old lady with primary extraskeletal osteo-

sarcoma involving lateral breast and axillary fold. No history of radio-
therapy. The skin erythema and oedema proved to be atypical vascular
proliferation. Excision with 2 cm margins

..      Fig. 46.2  An unusual case of malignant phyllodes tumor deep to

breast implant and invading through the chest wall into the chest cav-
addition, exposure to radiation therapy and the presence of
ity (CT image provided). Extensive resection including the full thickness
chronic lymphoedema are also known to be associated with
of chest wall was necessary. Reconstruction with mesh and methyl
the development of sarcoma.
methacrylate cement sandwich and pedicled latissimus dorsi flap was
performed Sarcomas display varying degrees of mesenchymal differ-
entiation. The variety of mature connective tissue cells, such
as fat cells, muscle cells or endothelial cells, found in the
Three subtypes of PTs are recognized: benign, borderline breast, explains the heterogeneity of the histological breast
and malignant. The differentiation is based on the histologi- sarcoma types, which may occur. The most common sub-
cal characteristics of the stromal elements. Benign PTs types are pleomorphic undifferentiated sarcoma, (myxo)
behave clinically like fibroadenomas and very rarely recur or fibrosarcoma, angiosarcoma and spindle cell sarcoma.
metastasize. In contrast, malignant PTs have a tendency to Several other subtypes (desmoid tumors, liposarcoma, leio-
local recurrence and/or systemic metastasis, sometimes myosarcoma, stromal sarcoma, rhabdomyosarcoma, hae-
within several years after primary treatment [6, 7]. Hence, in mangiopericytoma, synovial sarcoma, ­dermatofibrosarcoma
most cases, mastectomy is performed, especially if the protuberans, osteosarcoma, chondrosarcoma and neurosar-
tumour is large and the breast small to moderate in size. coma) have been described in very small numbers (see
Malignant PTs also warrant long-term follow-up. . Fig. 46.3).  

Two studies have shown how tp53 staining can under- Angiosarcomas (AS) are considered to be the most malig-
score malignancy in PTs and that positive stromal immuno- nant of all breast tumors and are thought to arise from the
reactivity for CD 117 (also known as c-kit positivity) endothelial cell lining of vascular or lymphatic channels.
correlates with tumor grade and recurrence [19, 20]. Primary breast AS (not associated with radiotherapy) typi-
Several studies have shown that malignant PTs share a cally presents as an ill-defined mass in the breast parenchyma
similar prognosis with primary breast sarcomas. Hence both in younger females and constitutes only 1 in every 1700–2000
subtypes of breast sarcoma should be approached with the breast cancers [21, 22]. A secondary (radiation-induced)
same management strategies [11, 18]. breast angiosarcoma is much more likely to be encountered.
AS differs from other breast sarcomas in that they may
metastasize to the axilla [16]. Therefore positron emission
46.7 Primary Breast Sarcomas tomography/computed tomography (PET/CT) scanning
may help in assessing axillary lymph node status prior to
Primary breast sarcomas arise de novo from the mesenchy- ­surgery.
mal tissues of the breast. Predisposing factors are mostly Immunohistochemical analysis often reveals positivity in
unknown, but some genetic conditions that are associated AS for factor VIII-related antigen, Ulex europaeus I lectin,
46 with soft tissue sarcomas, in general, may be implicated (Li-­ CD34 and CD31 [23–26].
Fraumeni syndrome, familial adenomatous polyposis and Dermatofibrosarcoma protuberans (DFSP), in spite of
neurofibromatosis type 1). Certain environmental factors their fibrosarcomatous component, are essentially derived
such as exposure to alkylating agents, vinyl chloride and from the skin and have more benign features than other soft
arsenic compounds may also be potentially related [8]. In tissue sarcomas. DFSP is a rare low-grade sarcoma of the skin

rares1geo@gmail.com
Sarcoma of the Breast
a
b
..      Fig. 46.4  a–b Dermatofibrosarcoma protuberans of lateral breast.
A 44-year-old lady was earlier treated with sclerotherapy for a lateral
breast lymphatic malformation. Dermatofibrosarcoma was later diag-
nosed with MRI and biopsy in the same region. Resection with 2 cm
margins was performed
with a tendency to locally recur after inadequate excision.
Metastatic spread is very rare and therefore should be clearly
distinguished from conventional sarcomas. Due to the histo-
logical tumor-free margins differing greatly from clinical
gross margins, wide excision of a few centimetres is recom-
mended [27] (see . Fig. 46.4).
 
Fibromatosis or desmoid tumors are histologically
benign, slow-growing fibroblastic neoplasms originating
from musculoaponeurotic stromal elements. They possess an
infiltrative and locally aggressive growth pattern with a ten-
dency for local recurrence, but have no metastatic potential.
rares1geo@gmail.com
555 46
The aetiology is unknown but there is an association with
trauma and genetic disorders, e.g. Gardner syndrome. In the
breast, desmoid tumours are extremely rare and often misdi-
agnosed (see 7 Chap. 47, for further details). They comprise
only 0.2% breast tumors and they may clinically resemble
other breast tumors. Until recently, surgical resection with
clear margins has been the favoured treatment option.
However, the histological extent of the tumor is larger than
the apparent macroscopic clinical margins. Although wider
surgical resection often results in significant breast deformity
[28], and a more conservative approach has been advocated
[29], the authors’ own preference is for adequate surgical
resection in order to achieve clear margins.
46.8 Radiation-Induced Sarcoma
Ionizing radiation is known to be a potent carcinogen.
Radiation can result from natural sources, accidental radia-
tion exposure or cancer radiotherapy. The classical definition
of radiation-induced sarcoma is based on criteria proposed
in 1948 by Cahan and colleagues [30]:
1. History of radiotherapy
2. Asymptomatic latency period of several years
3. Occurrence of sarcoma within a previously irradiated field
4. Histological confirmation of sarcoma that is histologi-
cally unique from the primary cancer
In general, taking into account all anatomical locations, the
most common histological types of radiation-induced sar-
coma are pleomorphic undifferentiated sarcoma, osteosar-
coma and fibrosarcoma [31] (see . Fig.  46.5). However, in
the irradiated breast, angiosarcoma (AS) is the most com-
mon type (see . Fig. 46.6).
Although secondary AS of the breast is still a rare tumor,
it has been increasingly reported as a severe long-term com-
plication of modern breast cancer treatment, in which breast-­
conserving surgery is combined with radiotherapy. Hence,
secondary breast AS usually occurs in older women with a
history of breast cancer and treatment with radiotherapy. AS
develops after a latent period of 3–25 years (median 7) fol-
lowing radiotherapy [32–36]. Chronic lymphoedema of the
breast and arm is another potential risk factor for AS arising
from lymphatic vessels. Stewart and Treves in 1948 first
described postmastectomy lymphangiosarcoma arising in
the upper extremity, breast and axilla after long-standing
severe lymphoedema [37].
The secondary form of AS (usually) related to radiother-
apy clinically presents as an erythematous patch, plaque or
nodule, often with local oedema. It may also initially resem-
ble a bruise. Other early findings include ulceration, eczema
and non-pigmented macules. Pain is uncommon. Differential
diagnoses include trauma, infection, haemangioma-like
lesions or inflammatory carcinoma. Involvement of the
breast and surrounding skin can become extensive, and the
lesions are commonly multiple [32, 36].
 556 E. Tukiainen and A. Lindford
a b
..      Fig. 46.5  a–b Radiation-induced osteosarcoma 23 years after mastectomy and radiotherapy. Presentation with a lump below the mastectomy
scar. The tumour was excised along with the pectoralis major muscle and reconstructed with a pedicled latissimus dorsi flap
Early diagnosis of AS is important due to the aggressive
local nature of the tumor. Unfortunately, there is often a
delay in the diagnosis due to patient- and physician-related
reasons; typically the small primary reddish purple skin
lesion is ignored or not examined histologically at the out-
set. ­Furthermore, there may be a difficulty in histologically
distinguishing AS from a benign atypical vascular lesion.
Due to variable presentation, there should be a low thresh-
old for performing multiple punch biopsies or excision
biopsy, to confirm diagnosis. It should be noted that AS may
also develop in a breast reconstructed with a pedicled or
free flap. In this scenario the tumor develops in any remain-
ing breast or chest wall skin and then spreads into the flap
tissue [36].
AS behaves in a different way to most other sarcomas
with a propensity for local relapse and systemic dissemina-
tion. Local skin recurrences can be extensive and require
major plastic surgical reconstruction after resection, such as
with skin grafts or pedicled or free flaps [37]. This high local
recurrence risk may in part be explained by AS possessing
diffuse infiltrative behaviour and a tendency for widespread
local intravascular spread. This is in contrast to many other
soft tissue sarcomas that often have a capsule (or «pushing
border»). In many advanced cases AS seems to have a multi-
focal pattern. Therefore wide peripheral surgical macroscopic
margins of at least 3 cm are recommended. In addition, close
and thorough follow-up is essential involving clinical pho-
tography and MRI.  The axilla is not usually treated in sec-
ondary AS, especially when an earlier axillary dissection has
been performed for the primary breast carcinoma [32–36]
and/or there is no evidence of axillary involvement.
Hyperthermia has been proposed as a complementary
treatment and strong sensitizer of radiotherapy and chemo-
46 therapy that involves selective heating of the tumor area by
the use of an electromagnetic heating device. Improved local
control when combined with adjuvant radiotherapy has been
demonstrated in radiation-induced breast and chest wall AS
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[38]. In general however, further post-operative radiotherapy
is not usually administered.
As with breast sarcomas in general, most reports of AS
treatment are limited to retrospective case series, and there
are no evidence-based guidelines [32–36]. Five-year overall
survival rates for radiation-induced sarcoma range from 27%
to 48%, and a 5-year disease-free survival rate of 35% has
been reported [32, 33]. A recent study confirmed this signifi-
cantly worse disease-free survival for post-radiation breast
sarcoma as compared to primary sarcoma [39].
With regard to future treatments, c-kit proto-oncogene
product (KIT, CD 117) expression in secondary AS has been
reported and may provide a potential treatment target [40].
The potential of antiangiogenic molecules such as the
VEGF-­A monoclonal antibody, bevacizumab, has recently
been reported in a phase II study [41].
There has recently been some concern that AS may be
more common in BRCA mutation carriers who have had ear-
lier breast radiotherapy. However, a study by Kadouri and
colleagues demonstrated that the risk is not significant and
should not influence the decision regarding radiotherapy in
these patients [42].
46.9 Conclusions
Breast sarcoma is rare and characterized by its wide histo-
logical heterogeneity. Radiation-induced angiosarcoma is the
commonest type and occurs as a long-term sequela to radia-
tion therapy for breast carcinoma. Surgical resection with
clear margins is the mainstay of treatment, and axillary dis-
section is usually unnecessary as nodal involvement is
uncommon. A multidisciplinary approach is important for
management, and adjuvant therapies should be offered in
cases of high-grade and large (>5 cm) tumors. Novel treat-
ments are currently being developed based on better under-
standing of tumor biology.
Sarcoma of the Breast
557 46

a
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 559 47

Desmoid (Aggressive)
Fibromatosis of the Breast
Nicholas C. Eastley, Jaroslaw Krupa, and Robert U. Ashford

47.1 Introduction – 560

47.2 Presentation – 560

47.3 Assessment – 560

47.3.1 Radiological – 560
47.3.2 Histopathological (Biopsy) – 561

47.4 Management – 561

47.4.1 Natural History/Active Observation – 561
47.4.2 Surgery – 561
47.4.3 Nonoperative Treatment – 562

References – 562

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_47

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 560 N. Eastley et al.

47.1 Introduction

Desmoid fibromatosis (DF) (also known as aggressive fibro-

matosis and desmoid tumour) is a rare, benign soft tissue
tumour with an incidence of 0.2–0.4/100,000 [1]. Desmoid
tumours can arise in almost any anatomical location and
make up 3% of all soft tissue tumours. Breast DF accounts for
just 0.3% of all solid breast tumours [2] and may arise from
the gland itself or the underlying musculo-aponeurotic tissue.
Desmoid tumours are classified broadly speaking into
one of two groups. The first group contains sporadic tumours
which are characterised by somatic β-catenin-activating
mutations in the gene CTNNB1 [3]. This group is the largest
and accounts for more than 85% of DF cases. The second,
smaller group includes those desmoid tumours associated
with familial adenomatous polyposis (Gardner’s syndrome)
in which mutations in the APC gene are thought to drive
tumour development [4].
DF is categorised as an intermediate tumour by the World
Health Organisation, based on its locally aggressive behav-
iour and inability to metastasise. Macroscopically desmoid
tumours may easily be mistaken for invasive malignant
tumours due to their infiltrative appearance and the absence
of a clear tumour margin. Microscopically DF is character-
ised by fibroblastic proliferation, abundant collagen and
positive beta-catenin staining on immunofluorescence.
47.2 Presentation
Breast DF usually presents between the ages of 37 and 49
(range 13–80). The vast majority of patients are female
(although male cases are reported in the literature) and pres-
ent complaining of a solitary lump which may be associated
with pain. A history of previous breast surgery is not uncom-
mon (seen in up to 44% of patients in some series [5]), and
whilst there have been a few case reports linking hydrophilic
polyacrylamide gel injections and silicone implant breast
augmentation with desmoid tumours (see . Fig. 47.1) [6, 7],
 
the level of evidence for this association remains low. On
examination most desmoid tumours commonly present with
an isolated, hard lesion which may be associated with skin or
nipple retraction (although nipple discharge is rare) [7].
47.3 Assessment
All potential cases of DF should undergo full radiological
and histopathological assessment prior to any management
decision. All patients presenting with symptomatic breast
lumps should undergo triple assessment, including physical
examination, breast imaging and tissue sampling.
..      Fig. 47.1  Axial T2-weighted magnetic resonance imaging (MRI)
image showing desmoid fibromatosis (DF) of the left breast of a
28-year-old female with bilateral breast implants in situ (2 years post
implant surgery)
47.3.1 Radiological
Every suspected case of DF should ideally undergo ultraso-
nography (US) and magnetic resonance imaging (MRI) that
includes the chest wall prior to intervention. Mammography
is not particularly helpful in the diagnosis of DF and may
miss a significant proportion of lesions (up to 62% [5])
although it is still routinely used to exclude breast cancer and
other breast lesions. It should be noted that DF can also
mimic carcinoma on mammography and can rarely present
with dense calcifications.
US allows many characteristics of DF to be deduced
including tumour size, location, echogenicity, homogeneity
and vascularity [8]. The widespread availability of US means
it is often the first-line investigation used in cases of
DF. Despite this MRI remains the gold standard modality to
assess and monitor DF [9]. Over time desmoid tumours
undergo a temporal change in their histological makeup
which correspond to an evolution in their appearance on
MRI [10, 11]. Early in their evolution desmoid tumours are
highly cellular with a low collagen component. This corre-
sponds to a low signal intensity on T1-weighted images and
high signal intensity on T2-weighted images. As they evolve
the relative cellular component of DF decreases, whilst the
relative collagen component increases. This corresponds
with an increasingly heterogeneous picture on T2-weighted
MRI sequences. Finally, in their later stages of evolution, des-
moid tumours become fibrous in nature. This results in low
signal intensity on both T1- and T2-weighted sequences.

47

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Desmoid (Aggressive) Fibromatosis of the Breast
If MRI is contraindicated, computed tomography with
intravenous contrast should be performed to provide cross-­
sectional anatomical information. Some form of cross-­
sectional imaging is advisable due to the possibility of chest
wall invasion.
47.3.2 Histopathological (Biopsy)
All potential cases of DF should undergo a planned biopsy
prior to treatment, with the resulting histopathology being
reviewed by a specialist sarcoma pathologist. Soft tissue
tumours should be biopsied using a core needle biopsy
(CNB) as this is more sensitive than other minimally invasive
biopsy techniques, i.e. fine needle aspiration (FNA) [5], and
provides tissue samples suitable for architectural, immuno-
histochemical and molecular analyses.
47.4 Management
DF’s unique biological behaviour and rarity mean that every
biopsy-proven case should be referred to and managed by a
soft tissue tumour (sarcoma) multidisciplinary team (MDT).
This MDT will by definition include soft tissue sarcoma sur-
geons, musculoskeletal radiologists, histopathologists and
medical and clinical oncologists with expertise covering the
radiological and histological appearances and management
of DF. There are a number of different scenarios as to how DF
may present to a breast surgeon (see . Table  47.1). In the
561 47
47.4.1 Natural History/Active Observation
When observed over time, a significant proportion of des-
moid tumours stop growing or stabilise, with up to 50% of
cases undergoing spontaneous regression [12]. Historically
DF treatment has revolved around surgical resection aimed
at achieving wide histological margins. In recent years how-
ever, after recognising this complex and unique natural his-
tory, the majority of soft tissue tumour clinicians have shifted
to a more conservative approach and now adopt a front-line
policy of active observation wherever possible [13, 14].
This approach has been shown to result in long-term
progression-­free survival rates comparable to other more
invasive treatments [12] and avoids the high recurrence rates
and significant morbidity that often complicate DF resec-
tions [15]. Recognising these advantages, all cases of histo-
logically proven breast DF should be managed with active
observation in the first instance. During observation all
patients should be closely followed up clinically and radio-
logically (with serial MRI scans) to pick up disease progres-
sion and those with painful tumours provided adequate
analgesia.
All patients should be counselled extensively about the
benign nature of DF and warned that regression may take
many months and that progression may occur requiring
medical (or rarely surgical) treatment.
47.4.2 Surgery

majority of cases however, the diagnosis is made following a Following the recent changes in approach to DF manage-
core biopsy of a suspicious breast lesion performed to rule ment, surgical resections should now only be routinely uti-
out carcinoma. lised for those cases that have undergone an inconclusive
biopsy which may represent DF, those patients unwilling to
opt for a nonoperative approach despite appropriate counsel-
ling or those cases of DF associated with breast implants
..      Table 47.1  Typical scenarios for breast desmoid fibromato- (which may necessitate removal of the implant) [16, 17].
sis (DF) and management strategies The association between DF recurrence and histological
margins is unclear. Although intra-lesional (R2) DF resec-
Scenario Management
tions are associated with disease progression [18], no signifi-
Core biopsy diagnostic Request MRI (including chest wall) cant relationship has been identified between microscopically
of DF Refer to sarcoma service incomplete (R1) resections and recurrence. It is clear that
Core biopsy suggestive Review by specialist sarcoma
recurrence may follow a complete (R0) resection, but will not
but not diagnostic of DF histopathologist – if still not necessarily follow a microscopically incomplete (R1) resec-
diagnostic excision biopsy tion. Considering this, in the few cases where surgery is still
Breast lump excised – Refer to sarcoma service
indicated, surgeons should not seek wide (R0) histological
histology confirms DF Do not re-excise chasing margins margins at the expense of function or cosmesis. Glandular
(incompletely excised) excision should be used sparingly, and therapeutic mammo-
plasties or other oncoplastic techniques may be required in
Breast lump excised – Refer to sarcoma service for ongoing
histology confirms DF surveillance order to avoid significant deformities. In such cases close
(completely excised) cooperation between sarcoma specialists and oncoplastic
breast surgeons is needed to ensure an optimal cosmetic out-
Implant-related DF Refer to sarcoma service (surgery
normally required because of come. Furthermore incomplete (R1/2) resections need not be
deformity to implant). Combined re-resected but instead a baseline MRI performed and close
surgery breast and sarcoma surgeon clinical and radiological follow-up adopted to identify any
potential disease progression or recurrence.

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 562 N. Eastley et al.
Breast implant-associated anaplastic large cell lymphoma
(ALCL) [19, 20] should be excluded in all patients with DF
and silicone implants, particularly in the presence of peri-­
implant seroma or severe capsular contraction. If mastec-
tomy is required, then the decision about immediate breast
reconstruction should be considered cautiously in view of
significant risk of local recurrence, especially within first
3 years of follow-up.
47.4.3 Nonoperative Treatment
A detailed review of the nonoperative management of DF is
outside the scope of this chapter. Many guidelines are avail-
able for clinicians considering nonoperative treatment of DF
[21–23]. Treatment options include non-steroidal anti-­
inflammatory drugs (NSAIDs), hormonal therapy with anti-
oestrogens, radiotherapy, chemotherapy and tyrosine kinase
inhibitors [24–27]. These should be instigated in a stepwise
fashion in accordance with the strength of the evidence sup-
porting their use and their associated side effects. The deci-
sion to implement nonoperative DF treatment should only
be made in conjunction with a soft tissue tumour MDT and
administered under the supervision of an oncologist with an
interest in sarcoma.
NSAIDs are often the first-line therapy utilised following
a failed trial of active observation. NSAID sensitivity was first
noted in desmoid tumours in 1980 [28]. Since this time sev-
eral agents including sulindac, colchicines and indometacin
have been used with encouraging results [24].
NSAIDs are often combined with hormonal therapy [29].
Desmoid tumours found outside the breast are twice as com-
mon in female patients and often progress during pregnancy
or following administration of oestradiol or oral contracep-
tives. This suggests hormonal sensitivity and explains the
high response rates seen to agents including tamoxifen, tore-
mifene and goserelin [24].
There is a growing recognition that desmoid tumours are
radiosensitive and that radiotherapy can consistently lead to
local control in 78–82% of patients [22, 23, 25, 30]. Despite
this the significant long-term side effects of radiotherapy
(including most worryingly the development of radiation-­
induced malignancies including angiosarcoma) mean that
radiotherapy is generally not employed for DF until a trial of
observation and hormonal therapy have both been attempted.
Adjuvant radiotherapy’s effects on recurrence rates fol-
lowing surgery are not clear, with conflicting evidence pub-
lished in the literature, and no clear guidance on its use in DF.
A number of chemotherapeutic regimes have been uti-
lised in DF with encouraging results [24]. However the
absence of malignant cells combined with the potential for
significant side effects means that cytotoxic agents are usually
only employed after failed trials of observation, hormone
47 therapy and NSAIDs and radiotherapy.
Tyrosine kinase inhibitors including imatinib and
sorafenib have also been investigated in DF, although more
evidence is required on long-term outcomes [31].
rares1geo@gmail.com
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dence, sex-, age- and anatomical distribution in the Finnish popula-
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2. Greenberg D, McIntyre H, Ramsaroop R, Arthur J, Harman J. Aggres-
sive fibromatosis of the breast: a case report and literature review.
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3. Mullen JT, DeLaney TF, Rosenberg AE, Le L, Iafrate AJ, Kobayashi W,
et al. β-catenin mutation status and outcomes in sporadic desmoid
tumors. Oncologist. 2013;18:1043–9.
4. Giarola M, Wells D, Mondini P, Pilotti S, Sala P, Azzarelli A, et al. Muta-
tions of adenomatous polyposis coli (APC) gene are uncommon in
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5. Neuman HB, Brogi E, Ebrahim A, Brennan MF, Van Zee KJ. Desmoid
tumors (fibromatoses) of the breast: a 25-year experience. Ann Surg
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ncbi.nlm.nih.gov/pubmed/17896146.
6. Aaron AD, O’Mara JW, Legendre KE, Evans SR, Attinger CE, Mont-
gomery EA. Chest wall fibromatosis associated with silicone breast
implants. Surg Oncol. 1996;5(2):93–9.
7. Long X, Qiao Q.  Breast fibromatosis after hydrophilic polyacryl-
amide gel injection for breast augmentation: a case report and
review of the literature. Chin Med Sci J. 2011;26:126–8.
8. Lou L, Teng J, Qi H, Ban Y.  Sonographic appearances of desmoid
tumors. J Ultrasound Med. 2014;33(8):1519–25.
9. O’Keefe F, Kim EE, Wallace S. Magnetic resonance imaging in aggres-
sive fibromatosis. Clin Radiol. 1990;42:170–3.
10. Sundaram M, McGuire MH, Schajowicz F.  Soft-tissue masses:
­histologic basis for decreased signal (short T2) on T2-weighted MR
images. Am J Roentgenol. 1987;148:1247–50.
11. Vandevenne JE, De Schepper AM, De Beuckeleer L, Van Marck E,
Aparisi F, Bloem JL, et  al. New concepts in understanding evolu-
tion of desmoid tumors: MR imaging of 30 lesions. Eur Radiol.
1997;7:1013–9.
12. Fiore M, Rimareix F, Mariani L, Domont J, Collini P, Le Péchoux
C, et  al. Desmoid-type fibromatosis: a front-line conservative
approach to select patients for surgical treatment. Ann Surg Oncol.
2009;16:2587–93.
13. Bonvalot S, Ternès N, Fiore M, Bitsakou G, Colombo C, Honoré C,
et al. Spontaneous regression of primary abdominal wall desmoid
tumors: more common than previously thought. Ann Surg Oncol.
2013;20:4096–102.
14. Eastley N, Hennig I, Esler C, Ashford R. Nationwide trends in the cur-
rent management of desmoid (aggressive) fibromatosis. Clin Oncol
(R Coll Radiol). 2015;27(6):362–8.
15. Rock MG, Pritchard DJ, Reiman HM, Soule EH, Brewster RC.  Extra-­
abdominal desmoid tumors. J Bone Joint Surg Am. 1984;66:
1369–74.
16. Mazzocchi M, Onesti MG, Di Ronza S, Scuderi N.  Breast desmoid
tumor after augmentation mammoplasty: two case reports. Acta
Chir Plast. 2009;51:73–8.
17. Schuh ME, Radford DM. Desmoid tumor of the breast following aug-
mentation mammaplasty. Plast Reconstr Surg. 1994;93(3):603–5.
18. Salas S, Dufresne A, Bui B, Blay JY, Terrier P, Ranchere-Vince D, et al.
Prognostic factors influencing progression-free survival deter-
mined from a series of sporadic desmoid tumors: a wait-and-see
policy according to tumor presentation. J Clin Oncol. 2011;29:
3553–8.
19. Miranda RN, Aladily TN, Prince HM, Kanagal-Shamanna R, De Jong
D, Fayad LE, et  al. Breast implant-associated anaplastic large-
cell lymphoma: long-term follow-up of 60 patients. J Clin Oncol.
2014;32(2):114–20.
20. Kim B, Roth C, Young VL, Chung KC, van Busum K, Schnyer C, et al.
Anaplastic large cell lymphoma and breast implants: results from a
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21. Kasper B, Baumgarten C, Bonvalot S, Haas R, Haller F, Hohenberger
P, et  al. Management of sporadic desmoid-type fibromatosis: a
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A, et al. Sporadic desmoid-type fibromatosis: a stepwise approach
to a non-metastasising neoplasm – a position paper from the Ital-
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578–83.
24. Janinis J, Patriki M, Vini L, Aravantinos G, Whelan JS. The pharmaco-
logical treatment of aggressive fibromatosis: a systematic review.
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25. Nuyttens JJ, Rust PF, Thomas CR, Turrisi AT.  Surgery versus radia-
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26. Yao X, Corbett T, Gupta AA, Kandel RA, Verma S, Werier J, et  al. A
systematic review of active treatment options in patients with des-
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27. Penel N, Le Cesne A, Bui BN, Perol D, Brain EG, Ray-Coquard I, et al.
Imatinib for progressive and recurrent aggressive fibromatosis
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with a long-term follow-up. Ann Oncol. 2011;22:452–7.
28. Waddell WR, Gerner RE.  Indomethacin and ascorbate inhibit des-
moid tumors. J Surg Oncol. 1980;15(1):85–90.
29. Hansmann A, Adolph C, Vogel T, Unger A, Moeslein G.  High-dose
tamoxifen and sulindac as first-line treatment for desmoid tumors.
Cancer. 2004;100:612–20.
30. Keus RB, Nout RA, Blay JY, de Jong JM, Hennig I, Saran F, et al. Results
of a phase ii pilot study of moderate dose radiotherapy for inoper-
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 565 VII

Advanced Breast Cancer

Contents

Chapter 48 Locally Advanced Breast Cancer – 567

Elżbieta Senkus and Aleksandra Łacko

Chapter 49 Metastatic Breast Cancer: Prognosis, Diagnosis

and Oncological Management – 579
Elżbieta Senkus and Aleksandra Łacko

Chapter 50 The Role of Surgery in Metastatic

Disease to the Bone – 595
Amit Kumar and Robert U. Ashford

Chapter 51 Roles of Surgery and Modern Radiation Techniques in

Metastatic Disease Affecting the Brain – 603
Garth Cruickshank

Chapter 52 Local Therapies for Liver Metastases from

Breast Cancer – 613
Robert P. Jones, Hassan Z. Malik, and Carlo Palmieri

Chapter 53 Role of Surgery in Lung Metastases from

Breast Cancer – 619
Michael Shackcloth and Susannah Love

Chapter 54 Surgery for Locally Advanced Breast Cancer – 625

Jaroslaw Skokowski and Pawel Kabata

Chapter 55 The Role of Surgery to the Primary Cancer

in Stage IV Disease – 633
Seema A. Khan and Patience Odele

Chapter 56 Palliative Care – 641

Tiina Saarto

Chapter 57 Supportive Care – 649

Renata Zaucha

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 567 48

Locally Advanced Breast Cancer

Elżbieta Senkus and Aleksandra Łacko

48.1 Introduction – 568

48.2 Epidemiology, Prognosis and Risk Factors – 569

48.3 Initial (Pretreatment) Patient Evaluation – 569

48.4 Pathobiology and Prognostic Factors – 570

48.5 Inflammatory Breast Cancer (IBC) – 570

48.6 Treatment Options for Patients with LABC – 571

48.6.1 Surgery in LABC and IBC – 571
48.6.2 Radiation Therapy in LABC and IBC – 572
48.6.3 Systemic Preoperative Treatment – 572

48.7 Response Assessment – 574

48.8 Adjuvant Therapy – 574

References – 575

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_48

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 568 E. Senkus and A. Łacko
48
48.1 Introduction
The definition of locally advanced breast cancer (LABC) usu-
ally includes stage III disease defined as any primary tumours
with clinically detectable axillary (fixed or matted), ipsilateral
infraclavicular, supraclavicular or internal mammary lymph
nodes (N2 or N3 disease) or tumour extension to the chest
wall or skin (T4). Some LABC definitions also include
patients with primary tumour ≥5 cm and no or movable axil-
lary nodal involvement (T3  N0–1). However, most sources
categorise those as «large operable» breast cancers, in con-
..      Fig. 48.1  Clinical presentation of locally advanced breast cancer
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trast to truly inoperable cases with inflammatory features
and/or skin or chest wall involvement, fixed or bulky axillary
nodal metastases and/or supraclavicular or internal mam-
mary nodal disease [1] (. Fig. 48.1).
Inflammatory breast carcinoma (IBC) is a rare and aggres-
sive entity characterised by erythema and skin oedema (peau
d’orange) occurring over a third or more of the breast
(. Fig. 48.2). On pathology tumour emboli in dermal lym-
phatics are usually present, although this is neither necessary
nor sufficient (in the absence of clinical symptoms) to diag-
nose IBC.
Locally Advanced Breast Cancer
569 48
s­ tandard of care and should be performed in all patients, if
feasible (. Fig.  48.3). Breast magnetic resonance imaging
 

(MRI) is helpful to evaluate disease extent in the breast, in

particular the presence of multicentric disease and invasion
of the chest wall (. Fig. 48.4). As MRI demonstrates the best
 

concordance with pathologic tumour size, it is increasingly

used in patients with LABC, in particular those who are
deemed to be potential candidates for conservation surgery.
As in any other case, the diagnosis of BC should be confirmed
by histopathology. Biomarker status (oestrogen receptor
[ER], progesterone receptor [PgR], human epidermal growth
factor receptor 2 [HER2] and proliferation markers such as
Ki-67) of the tumour must be assessed. Core needle biopsy
under image guidance is the preferred technique. In patients
with suspected IBC or skin involvement, a full thickness skin
biopsy is indicated. If BCT is planned, a radiopaque marker
..      Fig. 48.2  Clinical presentation of inflammatory breast cancer should be placed in the tumour before primary systemic ther-
apy (PST) to facilitate surgery (not applicable to IBC) and
48.2  pidemiology, Prognosis and Risk
E pathologic assessment in case of complete response. In patients
Factors with palpable or suspicious axillary lymph nodes, an ultrasound-­
guided fine needle aspiration biopsy should be performed.
LABC is relatively rare in developed/high-income countries. A complete history, physical examinations and laboratory
In the US National Cancer Database and European tests, including full blood count, liver and renal function tests
CONCORD study, approximately 9.6% and 4% of BC and serum alkaline phosphatase and calcium, are essential
patients, respectively, presented with LABC [2, 3]. parts of the staging workup. Computed tomography (CT) of
This percentage is higher among very young and very old the chest, abdomen and pelvis and a bone scan should be
patients and in underserved populations, is lower in popula- performed to rule out metastases. An 18F-­fluorodeoxyglucose
tions undergoing regular screening programmes and can be positron emission tomography scan (FDG-PET) may be
as high as 60% in low-resource countries [4, 5]. Importantly, used as an alternative and in case of inconclusive results of
in the areas and populations of high LABC incidence, such as other imaging studies. Brain imaging is not necessary in
Africa, Central America and deprived population subgroups in asymptomatic patients.
more developed nations, a higher incidence of the most aggres-
sive phenotypes, such as triple-­negative BC, is observed [6–12].
In contrast, in areas undergoing rapid development, such as
China, the incidence of LABC has reduced substantially (from
>20% to ~7%) over the years between 1990 and 2007 [13].
In 2007–2008, 5-year survival rates of US patients present-
ing with stages IIIA and IIIB were 52% and 48% respectively,
with the median survival for stage III disease of 4.9 years [14].
Primary IBC is a relatively rare disorder and accounts for
approximately 1–5% of invasive BC [15, 16] and 8.5% of LABC
[17, 18]. In the MD Anderson series of 752 stage III BC patients,
24 (3%) had IBC [19]. IBC develops at a younger age compared
to other forms of LABC and early BC (mean of 58.8, 66.2 and
61.7 years, respectively) [20]. Several risk factors, often in con-
trast to «traditional» BC risk factors, have been associated with
the development of IBC: race (higher incidence and younger
age at diagnosis among Black and Hispanic populations),
obesity, young age at first delivery, rural residence and longer
cumulative duration of breast-feeding [20, 21].

48.3 I nitial (Pretreatment) Patient

Evaluation

An accurate determination of the diagnosis, the biologic fea-

tures of the tumour and the stage of disease is necessary to ..      Fig. 48.3  Mammography of inflammatory breast cancer with stro-
plan treatment. Mammography and ultrasound are the mal oedema and skin thickening

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 570 E. Senkus and A. Łacko
48
..      Fig. 48.4  CT and MR images of locally advanced breast cancer
48.4 Pathobiology and Prognostic Factors
The histopathology of LABC, most commonly with infiltrat-
ing ductal (NST) and lobular carcinomas, is relatively similar
to that of early disease. «Favourable» histologies, such as
tubular or medullary carcinomas, rarely present at an
advanced stage (apart from neglected cases) and are more
often encountered with advanced age [22, 23].
The prognosis in LABC depends on clinical stage and
tumour characteristics, in particular histology, grade, expression
of hormone receptors (ER, PgR) and HER2 status. Most prog-
nostic and predictive factors are analogous to those of early BC.
The most important prognostic factor for survival is path-
ological complete response (pCR) after PST. In a recent pooled
analysis of 12 large trials of 11,955 patients treated with PST
for LABC or «large operable» BC, those who obtained pCR
(ypT0/is ypN0) had significant improvements in both event-
free survival (EFS) (HR 0.48; 95% CI, 0.43–0.54) and overall
survival (OS) (HR 0.36; 95% CI, 0.31–0.42) [24]. The associa-
tion between pCR and long-term outcomes largely depends
on tumour biology and is strongest in triple-­negative breast
cancer (TNBC) and HER2-positive/HR-­negative BC treated
with HER2-directed therapy. In hormone receptor-positive or
histologically low-grade tumours, pCR is less likely to occur
and may not predict long-term outcomes [25].
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48.5 Inflammatory Breast Cancer (IBC)
With the absence of definitive molecular or pathological
diagnostic criteria for IBC, the diagnosis is usually based on
typical clinical features: rapid onset of skin erythema and
oedema (peau d’orange) occupying at least one-third of the
breast and/or an increased temperature of the breast.
Symptom duration is usually short, often measured in weeks.
Because clinical diagnosis of IBC represents a broad spec-
trum of disease presentations, sometimes IBC is misdiag-
nosed as an infection, mastitis, abscess, ductal ectasia or
other malignancies such as breast lymphoma, and biopsy,
including full thickness skin biopsy as one of the options, is
mandatory in case of any doubt. The hallmark of IBC is der-
mal lymphatic invasion by tumour cells. This phenomenon
is, however, observed in less than 75% of IBC, and it is not
required for a diagnosis of IBC which is purely clinical [26].
IBC compared to non-IBC has higher tumour grade, and
the frequency of hormone receptor positivity is lower. It is
characterised by a high proliferation rate, frequent p53 alter-
ation, E-cadherin overexpression, RhoC overexpression and
loss of WISP3 (also known as «lost in IBC», LIBC) [27, 28].
Another feature is the high expression of angiogenic factors
reflecting angiogenetic properties, aggressiveness and meta-
static potential [29].
Locally Advanced Breast Cancer
571 48
..      Fig. 48.5  Algorithm of locally
advanced breast cancer manage-
ment. ALND axillary lymph node LABC
dissection, BCT breast-conserving
therapy, ER oestrogen receptor,
HER2 human epidermal growth
factor receptor 2, LABC locally ER+/HER2- TNBC HER2+ (any ER)
advanced breast cancer, RT radio-
therapy, TNBC triple-negative
breast cancer

endocrine chemotherapy
therapy chemotherapy + anti-HER2 therapy

surgery non-feasible

„curative” RT

surgery feasible palliative

treatment

BCT* + ALND MASTECTOMY + ALND

±immediate reconstruction*

postoperative RT
if not given before

adjuvant * not feasible in IBC

systemic therapy

The long-term prognosis of IBC remains poor. In the SEER
data, a 2-year BC-specific survival (BCSS) in IBC was signifi-
cantly worse than in noninflammatory LABC (84 versus 91%,
HR 1.43), and the 5-year survival rate is approximately 30%
[20, 30]. However, due to advances in multidisciplinary man-
agement, the 20-year BCSS for IBC patients treated in 1975
and 1995 has increased from 9% to 20% [31]. In a SEER-based
study of 7679 IBC patients diagnosed between 1990 and 2010,
a significant and stepwise survival improvement in more
close cooperation between all specialties involved is
­mandatory. Initial systemic treatment is generally employed
as it can increase resectability and breast conservation rates
without compromising survival outcomes [33–37]. In IBC,
underutilisation of trimodal therapy (systemic, surgery and
radiation therapies) negatively impacts survival, and postop-
erative RT is indicated in all patients, regardless of pathologic
findings [38].
. Figure 48.5 presents a proposal for LABC management.

recent cohorts was seen among women with stage III IBC,
regardless of race, age or hormone receptor status [32].
48.6.1  Surgery in LABC and IBC

48.6  reatment Options for Patients

T Surgery usually follows initial systemic therapy and precedes
with LABC radiation treatment. Historically, mastectomy was the rou-
tine surgical approach for LABC.  However, the efficacy of
LABC patients should be managed with multidisciplinary PST has significantly increased the feasibility of breast-­
therapy involving systemic and locoregional modalities, and conserving treatment (BCT) [39], making it amenable for up

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 572 E. Senkus and A. Łacko
48
to 50% of LABC patients (however, this is not recommended
for IBC even after a complete pathological response) [40].
Indications for breast surgery after PST are similar to
those in newly diagnosed BC and are discussed in more
detail in 7 Chap. 21). The choice of surgical procedure is
 
dependent both on pretreatment disease stage and on its
response to neoadjuvant treatment. Whenever breast-­
conserving surgery is considered, it is essential to mark the
primary tumour at the time of pretreatment biopsy to
ensure excision of the correct portion of the breast and
facilitate pathological assessment for residual tumour [41,
42]. The approach to the axilla following PST is currently
evolving; however, routine avoidance of ALND in patients
presenting with inoperable LABC is not recommended,
regardless of axillary stage before systemic treatment (see
7 Chap. 25).
 
For patients with IBC, mastectomy with delayed breast
reconstruction is recommended, as BCT and skin-sparing
mastectomy may be associated with increased local failures
[43, 44]. Axillary dissection is the standard of care for
IBC [45].
48.6.2  Radiation Therapy in LABC and IBC
There are no available data from phase III radiotherapy trials
in exclusively inoperable LABC.  In high-risk operable BC,
the addition of radiotherapy after surgery results in better
locoregional control and an OS benefit [46–48].
Risk factors for locoregional recurrence (LRR) following
mastectomy include large primary tumour size, invasion of
the pectoralis fascia, higher number of nodal metastases,
fewer nodes removed and ER negativity [49–51]. For patients
with T4 tumours or multiple positive nodes, treated with PST
followed by mastectomy, adjuvant radiation improves locore-
gional control, relapse-free survival (RFS) and OS [52, 53].
LABC patients who achieve pCR with PST still have a high
LRR risk, which can be significantly reduced with radiation
therapy (33% versus 3% at 10 years, p-0.006) [54].
Recommendations regarding technical issues in postop-
erative radiotherapy in LABC patients do not differ from
those in early breast cancer patients and are discussed in
more detail in 7 Chap. 39). LABC patients that cannot be
 
rendered operable by systemic therapy are usually treated
with definitive radiotherapy; external beam irradiation is
associated with a locoregional failure (LRF) rate of approxi-
mately 30%; lower LRF rates of 10–20% can be achieved
using external beam radiotherapy in combination with high-
dose interstitial implantation [55].
48.6.3  Systemic Preoperative Treatment
The main goal of primary systemic (neoadjuvant) therapy in
LABC is tumour downstaging to permit local treatment and
to improve surgical outcomes in patients for whom primary
rares1geo@gmail.com
surgery is technically not feasible. In selected women, preop-
erative systemic therapy enables BCT. In addition, preopera-
tive therapy allows for evaluation of its effectiveness and
provides additional prognostic information related to patho-
logical response at surgery. Standard systemic therapy options
include chemotherapy (ChT), endocrine therapy (ET) and
molecularly targeted therapy with HER2-directed agents.
The choice of systemic treatment should depend not only
on tumour biology (histology, grade, proliferation markers,
ER/PgR and HER2 expression) but also patient-related fac-
tors (menopausal status, performance status, comorbidities,
preferences) and availability of therapies.
Because reduction in tumour size is the primary goal, in
the majority of LABC patients regardless of BC subtype, ChT
(with anti-HER2 therapy in HER2-positive patients) is used.
However, there are substantial differences regarding options
of systemic therapies and their efficacy across BC subtypes.
Of note, most data regarding the use of systemic therapies in
LABC come from studies with PST, performed in a broader
patient population (large operable BC and LABC combined).
The treatment approach in non-metastatic IBC is similar
to other LABC classes, with primary systemic ChT (with
anti-HER2 therapy in HER2-positive patients) followed by
surgery and RT. Optimal treatment regimens in the preop-
erative setting are not defined, but in general, systemic treat-
ment is the same as for high-risk noninflammatory
LABC. Systemic neoadjuvant treatment is discussed in more
details in 7 Chap. 38).
Triple-Negative LABC
TNBC is highly chemosensitive. In a meta-analysis, achieve-
ment of pCR in TNBC patients was associated with risk
reductions of approximately 76% for EFS and up to 84% for
OS [24]. However, in patients without pCR at surgery, prog-
nosis remains poor [56].
With no currently approved targeted agents for TNBC,
ChT remains standard. There is no specific ChT for TNBC,
but due to the aggressive nature of TNBC and lack of effective
targeted therapies, the most active anthracycline- and taxane-­
containing regimens are recommended. Multiple studies
have demonstrated that primary systemic ChT incorporating
both anthracyclines and taxanes is associated with higher
pCR and breast conservation rate and improved OS com-
pared with the use of non-taxane-containing regimen [57,
58]. Taxanes can be administered either concurrently or in
sequence with anthracycline-based regimens. Based on the
results of adjuvant trials, a sequential approach is preferred
due to a more favourable toxicity profile and improved effi-
cacy [59]. The optimal sequence of anthracyclines and tax-
anes is not known. Data from a single neoadjuvant study
suggest that the use of taxanes prior to anthracyclines may
improve efficacy and is better tolerated [60].
Primary systemic ChT can be administered using stan-
dard or dose-dense (ddChT) schedules. In a recent meta-­
analysis, ddChT increased the probability of achieving pCR
by almost 50% [61]. Nonetheless, this has not so far translated
Locally Advanced Breast Cancer
into DFS or OS improvements. Given the benefits from
ddChT observed in adjuvant trials, it may be appropriate to
offer ddChT for high-risk tumour subtypes, such as TNBC
[62]. The optimal duration of primary systemic ChT has not
been studied, but usually six to eight cycles of ChT are rec-
ommended. The whole course of primary systemic ChT
should be administered before surgery.
Anthracycline-free ChT such as docetaxel and cyclophos-
phamide, may be an option in patients with contraindica-
tions to anthracyclines [63]. However, recently presented
joint analysis of the ABC (Anthracyclines in Early Breast
Cancer) trials demonstrated that treatment with taxanes and
anthracyclines versus anthracycline-free ChT resulted in
superior invasive DFS. The largest benefit from anthracycline-­
containing regimens was seen in patients with ER-negative
disease and/or ≥4 lymph nodes involved. In ER-positive/
node-negative patients, the benefit of anthracyclines was
questionable. Thus, anthracycline-free ChT should be
avoided in high-risk, ER-negative cancer cases [64].
Another combination evaluated in a small single-arm
study is carboplatin partnered with a taxane [65]. Preclinical
evidence suggests that platinum compounds may be useful,
in particular in TNBC- and BRCA-associated BC.  Several
studies evaluated platinum salts in LABC. Carboplatin incor-
porated to primary systemic ChT in TNBC improves pCR
rates, in particular in BRCA mutation carriers [66, 67].
However, it is associated with increased haematologic toxic-
ity, and data on whether a higher pCR translates into a sur-
vival benefit are conflicting. In the GeparSixto study, the
effect of carboplatin on DFS was mostly seen in BRCA wild-
type patients in spite of higher pCR rates in BRCA mutation
carriers, and favourable prognosis in women with pCR was
independent of germline BRCA status [68, 69].
Several trials evaluated the role of bevacizumab (mono-
clonal antibody targeting vascular endothelial growth factor)
added to primary systemic ChT. Significantly increased pCR
rates were observed across most of the studies, but a group of
patients most likely to benefit from bevacizumab was not
identified [67, 70]. Given the lack of benefit from bevaci-
zumab in the adjuvant setting, the uncertain benefits from
adding bevacizumab to primary systemic ChT with regard to
OS and the substantial risk of serious toxicities including
early and late postsurgical complications, bevacizumab
should not be routinely used. A possible exception may be a
situation when better tumour response (due to addition of
bevacizumab) could allow for less extensive surgery. Indeed
in the CALGB 40603 study, addition of bevacizumab or car-
boplatin + bevacizumab to standard primary systemic ChT
in patients with TNBC increased the rate of conversion from
BCT ineligible to BCT eligible by 14% [71].
Currently no data support improved efficacy of routine
addition of another non-cross-resistant cytotoxic agent (e.g.
capecitabine, gemcitabine) to an anthracycline-taxane-­
containing regimen [72]. As NAChT offers an opportunity to
observe response «in vivo», it has been hypothesised that
patients with a poor response after two cycles of ChT might
rares1geo@gmail.com
573 48
benefit from subsequent administration of a non-cross-­
resistant ChT regimen, rather than continuation of the same
ChT.  This concept, representing a treatment tailoring
approach, is tempting, but results of clinical trials evaluating
response-adjusted sequential therapy are inconclusive [73].
Nonetheless, non-cross-resistant ChT is indicated in patients
who have not responded to standard NAChT.  Cytotoxic
agents typically used after failure of taxanes and anthracy-
clines include carboplatin, capecitabine and vinorelbine. If
response is not observed after subsequent lines of primary
systemic ChT, preoperative RT may downstage the primary
tumour and allow for resection. As the lack of response after
two or three lines of ChT indicates chemoresistance, continu-
ing NAChT beyond this is not recommended, and patients
should proceed to local treatment.
Luminal, HER2-Negative LABC
Luminal/HER2-negative tumours, in particular those of
lobular histology, have low chemosensitivity and pCR after
NAST is rarely achieved (less than 10%). There is a paucity of
data regarding the use of ET in LABC, in particular of com-
parative studies of ET versus ChT. With the scarce data avail-
able, the superiority of ChT over ET has not been clearly
demonstrated [74, 75]. Importantly, ET use in large operable
BC was associated with a higher breast conservation rate
compared to ChT [74, 75]. Therefore, in postmenopausal
women with luminal/HER2-negative disease, ET may be
considered as an alternative to ChT.  Aromatase inhibitors
(AIs) are the agents of choice, as their use (compared to
tamoxifen) results in a higher response rate and higher rate
of BCT [76, 77]. The efficacy of particular AIs (anastrozole,
letrozole and exemestane) in the primary systemic therapy
setting is comparable [78]. Very few data exist on primary
systemic ET in premenopausal patients, and this approach is
not recommended outside clinical trials.
Time to response in ET is longer than in patients under-
going primary systemic ChT. Therefore, ET should be contin-
ued for 6–8  months before local treatment, provided that
response is observed and patients are carefully monitored.
The duration of ET prior to surgery may be individualised
based on clinical response and the patients’ clinical status.
Longer ET may increase the rate of BCT.
HER2-Positive LABC
Rate of pCR to PST in HER2-positive BC is high, in particu-
lar in hormone receptor-negative patients. Combining pri-
mary systemic ChT with HER2-directed therapy not only
increases pCR but also impacts long-term outcomes.
Randomised trials have demonstrated that the addition of
trastuzumab (monoclonal antibody targeting HER2) to pri-
mary systemic ChT resulted in pCR and EFS improvement
[24, 79, 80]. A trend towards OS benefit was also observed in
a pooled meta-analysis of two studies [81].
Trastuzumab is usually combined with standard
anthracycline-­taxane-based primary systemic ChT. In patients
with contraindications to anthracyclines, trastuzumab can be
 574 E. Senkus and A. Łacko
48
partnered with taxanes and either carboplatin or cyclophos-
phamide for six cycles [82]. Concurrent administration of
trastuzumab and anthracyclines is not recommended due to
the risk of cardiotoxicity and no clear benefit compared to
sequential use [83].
Combination of ChT and lapatinib (tyrosine kinase inhibi-
tor of HER2 and epidermal growth factor receptor) is inferior
to ChT-trastuzumab and is not recommended [84–86].
Double anti-HER2 blockade with trastuzumab and lapatinib
in the majority of trials significantly increased pCR [84–86].
However, this had no effect on DFS or OS, and lapatinib was
associated with more adverse events, primarily gastrointesti-
nal toxicity. Thus, lapatinib-containing regimens remain
investigational and should not be used in routine clinical prac-
tice. Another option is the dual anti-HER2 antibody inhibi-
tion with trastuzumab and pertuzumab (monoclonal antibody
that blocks the formation of HER2-HER3 heterodimers). In
the phase II Neoadjuvant Study of Pertuzumab and Herceptin
in an Early Regimen Evaluation (NeoSPHERE), addition of
pertuzumab to trastuzumab and docetaxel resulted in increas-
ing the pCR rate to 46% compared to 29% in docetaxel-trastu-
zumab arm. Interestingly, combination of pertuzumab and
trastuzumab alone without a ChT backbone resulted in a pCR
rate of 16.8% in the breast [87, 88]. In the Trastuzumab plus
Pertuzumab in Neoadjuvant HER2-Positive Breast Cancer
(TRYPHAENA) trial, even higher pCR rates of 65–84% in the
ER-negative group and 46–50% in the ER-positive group,
depending on treatment sequence, were achieved [89]. Based
on these results, pertuzumab was approved in the USA and
EU in the primary systemic therapy setting in combination
with trastuzumab and docetaxel or docetaxel and carboplatin.
Despite the promising pCR rates, mature long-term outcome
data and confirmatory results from phase III studies in either
the primary systemic or adjuvant setting are needed before
primary systemic pertuzumab-containing regimens can be
considered standard. In recently published APHINITY trial
the absolute benefit from adding pertuzumab to adjuvant
ChT with trastuzumab was modest and clinically not mean-
ingful, with 3-year invasive DFS difference of only 1% [90].
48.7 Response Assessment
Clinical response should be assessed regularly during preop-
erative therapy by physical examination of the breast and
axilla to avoid missing disease progression and after comple-
tion of the whole course of neoadjuvant therapy to choose
the optimal locoregional treatment. For patients receiving
primary systemic ChT, clinical evaluation should be per-
formed at every 2–4 ChT cycles, in women undergoing ET,
every 2–4 months, using standard RECIST 1.1 criteria [91]. If
progression is suspected and before the decision on locore-
gional therapy, imaging is mandatory. Breast MRI if per-
formed prior to neoadjuvant treatment and after completion
of therapy allows for best evaluation of response and assess-
ment of the extent of residual disease when breast-­conserving
surgery is planned.
rares1geo@gmail.com
There is modest concordance between imaging with
ultrasound, mammography or MRI and pathologic assess-
ment of response [92, 93]. The highest specificity among
imaging techniques is attributed to contrast-enhanced MRI
and FDG-PET.  In a meta-analysis of 25 studies in 1212
patients receiving PST, contrast-enhanced MRI had a speci-
ficity of 91%, but a relatively low sensitivity of only 63% to
predict pCR. The value of FDG-PET in response prediction
with a sensitivity and specificity of about 80%, though very
promising, is not sufficient to justify its routine use [94–96].
Additionally, due to the heterogeneity in breast cancer biol-
ogy, FDG-PET seems to predict pCR with higher accuracy in
certain tumour subtypes such as in HER2-positive and
TNBC, whereas in luminal HER2-negative tumours, in
which pCR is less likely and has little prognostic value, the
ability of FDG-PET to assess response and detect pCR is not
sufficient. Serial biopsies of the tumour with the assessment
of tumour markers such as Ki67, though may provide infor-
mation on the biological effect of therapy, are not recom-
mended outside clinical trials.
Post-treatment pathologic staging in patients treated with
PST should be assessed using The American Joint Committee
on Cancer and the International Union for Cancer Control
(AJCC-UICC) tumour, node, metastasis (TNM) staging cri-
teria. This system uses «y» to designate the pathologic stage
after preoperative therapy (ypTNM). There are multiple defi-
nitions of pathological complete response (pCR), varying
from the absence of residual invasive disease only in the
breast regardless of pathologic findings in the axillary nodes
(ypT0/is ypN0/+) to full eradication of invasive tumour or
invasive and in situ cancer in the breast and axillary lymph
nodes (ypT0 ypN0), but only the latter or ypTis ypN0 should
be considered as pCR in clinical practice, as it is most closely
associated with improved outcomes [24].
In the majority of patients undergoing PST for LABC,
pCR is not achieved. When invasive cancer is present, the
pathology report should include a description of the effect of
PST in the tissue of the breast and lymph nodes. There are
several tools to quantitate pathological response which seems
to correlate with BC outcome: the residual cancer burden
(RCB) score, the Breast Cancer Index (BCI) and the preop-
erative endocrine prognostic index (PEPI) score (for patients
treated with primary systemic ET) [97–100]. However, none
of the methods predicting patients’ prognosis based on
pathologic findings have been sufficiently standardised; thus,
their use in clinical practice is limited.
48.8 Adjuvant Therapy
With the lack of data supporting the use of additional ChT,
even in patients with gross residual disease, adjuvant ChT after
primary systemic ChT is not routinely recommended [101,
102]. However, in a study (CREATE X) performed in Japan
and Korea in patients with residual disease after primary sys-
temic ChT postoperative treatment with capecitabine resulted
in increased DFS and OS [103]. As accumulating ­evidence
Locally Advanced Breast Cancer
575 48
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cross-resistant adjuvant chemotherapy on the basis of pathologic
 578 E. Senkus and A. Łacko

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response to a neoadjuvant doxorubicin-based regimen in women
with operable breast cancer: long-term results from a prospective
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02. Alvarez RH, Booser DJ, Cristofanilli M, et al. Phase 2 trial of primary
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 579 49

Metastatic Breast Cancer:

Prognosis, Diagnosis
and Oncological Management
Elżbieta Senkus and Aleksandra Łacko

49.1 Introduction – 580

49.2 Luminal, HER2-Negative BC – 582

49.3 HER2-Positive Breast Cancer – 585

49.3.1 HER2-Positive, Non-luminal Breast Cancer – 585
49.3.2 Luminal B HER2-Positive Breast Cancer – 587

49.4 Triple-Negative Breast Cancer – 588

49.5 Local Treatment of MBC – 589

49.6 Bone Metastases – 590

49.6.1 Bone-Directed Therapy – 590
49.6.2 Radioisotopes – 590

References – 590

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_49

rares1geo@gmail.com
 580 E. Senkus and A. Łacko

49.1 Introduction peritoneum and retroperitoneum, hollow viscera, internal

49
Metastatic breast cancer (MBC) affects between 19% (in the
USA) and 50% (in parts of Africa) of women with breast
cancer (BC) (depending on the cure rate of their country of
residence as shown in . Fig. 49.1).
MBC is diagnosed during the course of the disease in
approximately 20–50% of women with early BC and in
the majority of women originally diagnosed with locally
advanced BC. Additionally 5–10% of women with newly
diagnosed BC may present with metastatic disease (de novo
MBC), again varying by geographic region/local screening
practices/sociocultural and economic factors. BC metas-
tasizes preferentially to the lungs, bones, liver, brain and
distant lymph nodes. Different patterns of dissemination
are observed in lobular BC, with frequent spread to the
genital organs and leptomeninges [1]. Patients frequently
develop metastases at multiple sites.
MBC is incurable, which means that all patients will
succumb to their disease eventually. Progress seen over
the last few decades has led to significant improvements in
the duration of survival, with recent series demonstrating
median survival rates of between 2 and more than 5 years,
depending on tumour phenotype and metastatic burden
and site [2].
Most patients are diagnosed on examinations performed
because of symptoms suggestive of metastatic disease; how-
ever, advances in the sensitivity and availability of imaging
often lead to the diagnosis of metastatic disease earlier than
in the past. This may be one of the factors contributing to
the increased duration of post-MBC diagnosis survival;

..      Fig. 49.1  Breast cancer inci-

dence and mortality in the world Male Female
(GLOBOCAN 2012) (Reprinted
Northern America
from Breast Cancer. Estimated
Incidence, Mortality Worldwide in Western Europe
2012. Estimated age-standardised
Northern Europe
rates (World) per 100,000. From
Ferlay et al. [138] Reprinted with Australia/New Zealand
permission from International
Agency for Research on Cancer,
Southern Europe
World Health Organization) More developed regions
Polynesia
South America
Micronesia
Central and Eastern Europe
Caribbean
Northern Africa
World
Western Asia
Melanesia
Southern Africa
Western Africa
South-Eastern Asia
Central America
Less developed regions
Eastern Africa
South-Centrla Asia
Eastern Asia
Middle Africa
100 80 60 40 20 0 20 40 60 80 100

Incidence
GLOBOCAN 2012 (IARC) Mortality

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Metastatic Breast Cancer: Prognosis, Diagnosis and Oncological Management
however, the scale of this phenomenon is unknown. The
most commonly used imaging modalities include computed
tomography (CT) for the chest (plain X-ray is acceptable
for lesions surrounded by aerated lung), CT, magnetic reso-
nance imaging (MRI) or ultrasonography for the abdomen,
CT or MRI for the brain and radioisotope bone scan for
the skeleton (often supplemented by CT or MRI in cases
of diagnostic uncertainty). Positron emission tomography
(PET) (usually merged with CT) is the most sensitive imag-
ing modality; its drawbacks, however, include a relatively
high false-positive rate and high cost. At diagnosis of MBC,
patients should undergo imaging of the chest, abdomen and
bone. In asymptomatic patients, brain imaging is unneces-
sary, irrespective of the phenotype of the tumour. Further
tests should be performed in cases with symptoms sug-
gesting involvement of sites not included in routine imag-
ing. Additionally, routine haematology and biochemistry,
in particular liver and renal function and serum calcium,
should be performed to assess organ function and the feasi-
bility of planned systemic therapy.
In most cases, imaging is conclusive for the diagnosis
of MBC; however, in cases of doubt regarding the charac-
ter of the lesion identified on imaging, a biopsy confirming
its malignant character is obligatory before establishing the
final diagnosis. Biopsy of the metastatic lesion is also increas-
ingly recommended to confirm the biomarker status of the
metastatic tumour as tumour phenotype may change. Some
sources recommend metastatic biopsy at least once in all
patients (if feasible); others believe that biopsy is not man-
dated if its results are not going to influence treatment choice
[3, 4]  – examples being a patient relapsing with bone-/soft
tissue-only disease many years after diagnosis of a luminal
breast cancer (who should be given a trial of endocrine ther-
apy (ET)) or a HER2-­positive patient relapsing with massive
visceral disease (who should be given chemotherapy (ChT)
with anti-HER2 treatment).
Treatment of MBC requires regular monitoring for tox-
icity and efficacy. Response assessment with clinical exami-
nation, lab evaluation and radiographic imaging should be
performed on a regular basis (imaging every 2–3 cycles for
ChT and every 2–4 months for ET) to enable timely termina-
tion of ineffective therapies and avoid exposing patients to
unnecessary treatment and its toxicity. Lower imaging fre-
quency is acceptable in patients with symptomatic improve-
ment, long-standing remissions or disease stabilization. The
same imaging modality should be used for all assessments,
and a validated response assessment system, such as RECIST
(Response Evaluation Criteria in Solid Tumours), should be
used [5]. Because of good reproducibility, preferred imaging
modalities are CT and MRI; ultrasound and radioisotope
studies are not recommended due to lack of reproducibility
or standardization. Circulating (serum) tumour markers,
such as CA15-3 and CEA, are not recommended for routine
rares1geo@gmail.com
581 49
use but may be useful as a supplementary tool in cases with
difficult to assess disease, such as bone involvement only.
Treatment decisions, however, should not be based solely
on the degree of change of circulating tumour markers.
Circulating tumour cells (CTCs), cell-free DNA and che-
motherapy sensitivity and resistance assays (CSRAs) are
experimental and should not be routinely used for treatment
decision-­making.
The prognosis in MBC depends predominantly on the
tumour phenotype, with triple-negative BC carrying the
worst prognosis, with a median survival of approximately
2  years and luminal tumours (including luminal HER2
positive) having the best outcomes, with median survivals
in modern series extending to over 5 years. Other important
prognostic factors include the patient’s performance status,
the site and volume of metastatic disease, the duration of the
disease-free interval and the history of previous anticancer
treatments, including their efficacy.
MBC should be managed by a multidisciplinary team of
all appropriate specialties (medical, radiation, surgical and
imaging oncologists, palliative care, psychosocial and phys-
iotherapy, among others) – preferably within the setting of a
specialized Breast Unit. Treatment decision-making should
include open discussion with the patients and their next
of kin and setting realistic treatment goals. From the first
diagnosis of MBC, patients should be offered personalized
appropriate psychosocial, supportive and symptom-related
interventions as a routine part of their care [6]. Treatment
choice should take into account endocrine responsiveness,
HER2 status, menopausal status, disease-­free interval, pre-
vious therapies and response obtained, tumour burden
(defined as number and site of metastases), biological age
and comorbidities (including organ dysfunctions), per-
formance status, need for rapid disease/symptom control,
socio-economic and psychological factors, patient’s prefer-
ences and available therapies in the patient’s country [6]. As
the aim of treatment is palliation and the realistic treatment
goals include prolongation of life and improvement or pres-
ervation of its quality, but not cure, the least aggressive treat-
ment modalities sufficient to achieve disease control should
be used. This would usually mean ET for luminal breast
cancer and single-agent ChT in hormone-­ nonresponsive
disease. In HER2-positive disease, the «backbone» therapy
should be combined with anti-HER2 agent(s).
Treatment for metastatic disease is complex and mul-
timodal and may require combinations of systemic and/or
regionally ablative/palliative therapies for optimal care. The
latter are discussed generally in this chapter and covered in
more details in 7 Chaps. 56 (lung), 53(bone), 55(hepatic) and
54 (brain).
Systemic treatment will be discussed separately for each
BC phenotype – . Fig. 49.2. For definition of the phenotypes,
please refer to 7 Chap. 15.
 582 E. Senkus and A. Łacko
49
without extensive/symptomatic
visceral involvement
+
with extensive/symptomatic
visceral involvement
ER
without extensive/symptomatic
visceral involvement
–
with extensive/symptomatic
visceral involvement
..      Fig. 49.2  Strategy of systemic treatment of MBC. a/HER2 anti-HER2
therapy, ChT chemotherapy, ER oestrogen receptor, ET endocrine ther-
apy, HER2 human epidermal growth factor receptor 2, T trastuzumab
49.2 Luminal, HER2-Negative BC
Luminal HER2-negative (ER/PgR+/HER2-) BC in 2010  in
the USA accounted for 61.2% of primary stage IV BC and,
as it constitutes almost three quarters of all newly diagnosed
BC, remains also the most prevalent subtype among patients
who relapse following treatment for early disease [7].
The systemic treatment of choice in luminal BC is ET;
it should be considered in all patients, unless contraindica-
tions exist, as its use is associated with better health-related
quality of life (QoL), greater satisfaction with treatment, less
treatment-­related side effects and less activity impairment
[8]. Contraindications to ET include massive visceral involve-
ment/directly life-threatening disease (visceral crisis) and
proven resistance to ET.  Unfortunately data supporting the
informed choice between ET and ChT is rather limited and
comes mainly from non-randomized comparisons. All avail-
able randomized studies were conducted in the 1970s and
1980s and compared often obsolete ChT schedules and sub-
optimal endocrine agents. A meta-analysis of these studies
demonstrated, however, no effect of the treatment strategy on
overall survival (OS) in spite of a higher response rate (RR) in
the ChT group [9]. No randomized comparisons are available
between aromatase inhibitors (AI) or fulvestrant and mod-
ern chemotherapeutic agents, such as taxanes, capecitabine,
vinorelbine or eribulin. Lack of high level of evidence support-
ing treatment choices in metastatic luminal BC forces oncolo-
gists to rely on indirect evidence from retrospective studies
or prospective non-comparative data. Although fair compari-
rares1geo@gmail.com
HER2 (-) ET
ET + a/HER2
HER2 (+)
or ChT + a/HER2
HER2 (-) ChT
HER2 (+) ChT + a/HER2
HER2 (-) ChT (monotherapy)
HER2 (+) ChT + a/HER2
HER2 (-) ChT
HER2 (+) ChT + a/HER2
(Reprinted from F. Cardoso et al. [139], . Fig. 49.2. With permission
from Oxford University Press on behalf of the European Society for
Medical Oncology ©)
sons of results in patients treated with ChT and ET outside
studies randomizing subjects between these two options are
impossible, in general, those treated with first-line ET achieve
longer progression-free survival (PFS) and OS.  Obviously,
populations selected for ChT and ET are different, but these
differences are smaller than could be expected: in general, the
percentage of ER/PgR-positive patients in ChT studies ranges
between 70% and 80%, whereas visceral involvement is pres-
ent in about 50–80% of patients undergoing ChT and in about
50% of those treated with ET [10].
The main ET options include selective oestrogen receptor
modulators (SERM, tamoxifen), selective oestrogen receptor
downregulators (SERD, fulvestrant) and AIs. Premenopausal
patients should additionally undergo oophorectomy or
medical castration by use of luteinizing hormone-releasing
hormone (LHRH) agonists. In selected cases with a good
response to previous lines of ET, more toxic compounds such
as progestins, oestrogens or androgens can also be considered.
Available clinical data don’t point to obvious superiority of
any of the available ET compounds. Some of first-line studies
comparing tamoxifen with AI have reported improvements in
response rates (RR) and time to progression (TTP) for AIs.
In the second-line setting, AIs have consistently demonstrated
improved efficacy and decreased toxicity in comparison to the
first-generation AI aminoglutethimide and megestrol acetate
[11]. Additionally, a minor OS benefit (HR 0.9) of AI vs.
non-AI treatment was seen in the Cochrane review of avail-
able studies [11]. Early studies with low-dose (250 mg every
4 weeks) fulvestrant showed no additional benefit from this
Metastatic Breast Cancer: Prognosis, Diagnosis and Oncological Management
..      Fig. 49.3  Strategy of systemic
treatment of luminal BC. ChT, che-
motherapy; ET, endocrine therapy ET1
benefit
trastuzumab
no
be
ne
fit
/v
isc
er
al
cr
isi
agent [12]; more promising are the data for high-dose ful-
vestrant (500 mg 4 weekly + an additional dose after the first
2 weeks). A greater degree of efficacy, both in terms of TTP
and OS, of high-dose fulvestrant was first demonstrated in the
CONFIRM study comparing it with the originally approved
dose of 250 mg [13]. Particularly, promising are the data from
the phase II FIRST study comparing high-dose fulvestrant to
anastrozole in first-line treatment, which demonstrated sig-
nificant and clinically relevant OS prolongation (HR 0.7) [14],
and results of the confirmatory phase III FALCON study have
recently been released demonstrating significant PFS prolon-
gation [15]. In a single study (SWOG S0226), the combined
use of fulvestrant (low dose) and an AI vs. an AI alone resulted
in significant PFS and OS prolongation, with the largest ben-
efit in patients not exposed to prior tamoxifen and in those
with the longest DFI [16]; this was not, however, confirmed
in the subsequent study (FACT) and in the meta-analysis of
both [17, 18].
In premenopausal patients, the only compound with
demonstrated activity as monotherapy is tamoxifen; how-
ever, available randomized trials demonstrated RR, PFS and
OS improvement from the addition of a LHRH agonist to
tamoxifen, so combination treatment is recommended [19].
AI are inactive as single agents in premenopausal patients
and should always be combined with ovarian ablation or
suppression. Caution is needed to assure «postmenopausal»
oestrogen levels in AI-treated patients, as in approximately
40% of those who developed amenorrhoea as a result of ChT
and in 17–25% of patients on an AI plus LHRH agonist ther-
apeutically effective levels of oestrogen suppression may not
be present [20, 21]. Ovarian suppression or ablation should
be continued throughout the course of ET [22]. No data are
available on the efficacy of fulvestrant as a single agent in pre-
menopausal MBC women, although its mechanism of action
and a single preoperative study suggests it may actually be
effective [23].
Particular ET compounds differ in their toxicity profiles:
AI use is related to an increased risk of arthralgia, myalgia,
tendonitis and carpal tunnel syndrome, vaginal dryness and
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583 49
ET2 ET3 ET…
benefit benefit
no be
sis
l cri
is
ris
nefit
c
ra
al
er
isce
isc
/ visc
v
v
t/
fit /
efi
en
eral c
e
b
ben
no
risis
no
s
ChT
decreased libido, hot flashes, bone mineral loss and fractures,
and tamoxifen use increases the risk of menopausal symp-
toms including hot flashes and gynaecologic complications
as well as endometrial hyperplasia and cancer, and thrombo-
embolic events [24, 25]. Fulvestrant in comparison to «other
endocrine therapy» (mostly AI) demonstrated a similar tox-
icity profile, except for a lower incidence of arthralgia [12].
The general philosophy of systemic therapy for metastatic
luminal breast cancer is to continue treatment with endo-
crine agents for as long as the patient is deriving benefit [3,
4, 26] which means that patients progressing following effec-
tive first-line ET should be offered next ET lines, and switch-
ing to ChT should be undertaken only in those with proven
resistance to endocrine manoeuvres or with rapidly progres-
sive visceral disease (. Fig. 49.3). The optimal ET sequence
is unknown, and treatment choice depends on menopausal
status, prior ET, response duration, drug toxicity profile and
availability and the patient’s preferences.
Importantly, among ET-treated luminal MBC, the tumour
response is not a surrogate for long-term benefit, and similar
OS is observed in those achieving objective tumour regres-
sion or long-term disease stabilization [27]. It thus needs to
be kept in mind that, as most patients undergoing early lines
of treatment for MBC are asymptomatic or mildly symptom-
atic and do not require rapid symptomatic improvement,
the aim of the treatment in the majority of cases is delaying
disease progression (prolonging PFS) and not necessarily
obtaining tumour shrinkage.
Additionally, not all BCs are equally sensitive to ChT, and
in some patients, ET may actually be more effective. As dem-
onstrated in neoadjuvant studies, the frequency of complete
pathological remissions following ChT varies significantly
between BC phenotypes, being the lowest for ER/PgR+/
HER2- patients, in particular for lobular cancers [28–30].
Additionally, some of the effect of ChT in oestrogen recep-
tor (ER)-positive premenopausal patients may not necessary
come from its cytotoxic-antineoplastic activity. As demon-
strated in the adjuvant NSABP B-30 and IBCSG 13–93 stud-
ies, long-term outcomes are superior in patients who become
 584 E. Senkus and A. Łacko
amenorrhoeic as a result of ChT [31, 32], so it can be hypothe-
49 sized that at least some of the therapeutic effect in this popula-
tion is actually effected by the endocrine mechanism of action
and could be more simply obtained directly with ET.
ET is also feasible in patients with visceral involvement,
as long as there is no directly life-threatening disease (vis-
ceral crisis) [3, 4, 26]. Indeed, as demonstrated in data from
1396 patients from four phase III studies of first-­line ET, the
response rate is higher in non-visceral metastases, but if dis-
ease control is achieved, its duration is equal in patient with
and without visceral involvement [33].
Unfortunately, no biomarkers predictive of ET benefit
beyond ER and PgR have been identified for luminal HER2-­
negative BC. Some help may be provided by analysis of clini-
cal factors, although results are often inconsistent. Various
studies suggest the largest benefit from ET is seen in patients
with lower tumour grade; longer disease-­free interval; lack
of liver, CNS or multiple-site involvement; no history of
adjuvant ET; strong expression of ER and PgR; a history of
clinical benefit from first-line ET; and a lower tumour pro-
liferation rate (identified by Ki67 expression) [34–39]. A
number of novel molecular factors potentially predictive of
endocrine responsiveness have been described, but none has
been properly validated. Recently, the prognostic role of the
21-gene recurrence score (Oncotype DX) for both TTP and
2-year OS in ER/PgR+/HER2- patients was demonstrated in
a prospective series of de novo stage IV BC [40].
ET (and indeed any other therapy) in MBC has limited
activity, and all patients inevitably develop progressive dis-
ease. This endocrine resistance in MBC, for the purpose of
patient stratification for clinical research, has been somewhat
artificially divided into primary resistance, defined as pro-
gressive disease (PD) within the first 6  months of first-line
ET for MBC, while on ET and secondary resistance, i.e. PD
developing 6 or more months after initiating ET for MBC,
while on ET [3, 4]. There are various mechanisms suggested
as responsible for endocrine resistance development, includ-
ing ER loss, ER mutation or activation of alternative signal-
ing pathways.
Loss of the oestrogen receptor may be caused by epigen-
etic changes to the ESR1 gene coding for the ER (methyla-
tion, histone modifications), and studies are ongoing testing
histone deacetylase inhibitors (HDACi, which inhibit a key
means of epigenetic regulation of gene expression) in com-
bination with ET. A phase II ENCORE 201 study evaluating
the combination of exemestane and HDACi entinostat dem-
onstrated OS prolongation in patients progressing on a non-­
steroidal AI, and the compound was granted «breakthrough
therapy designation» by the FDA; confirmatory phase III
study results are awaited [41].
Genomic alterations in the ER, very rare in early breast
cancer, are observed with increasing frequency in advanced
disease, reaching >30% in late MBC [42, 43]. They usually
include gain of function point mutations in the ligand-­
binding domain of the ER protein leading to its constitutive
(ligand-independent) activity [44].
Development of a malignant phenotype is associated with
dysregulation of numerous cell signaling pathways. Those
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implicated in the development of endocrine resistance and
potentially pharmacologically «targetable» include activation
of tyrosine kinase growth factor receptors, PI3K-Akt-mTOR
pathway and dysregulation of the cell cycle [45].
Targeting growth factor receptors has provided the most
valuable clinical data for HER2-positive disease; this is fur-
ther discussed in the «Luminal B HER2-Positive Breast
Cancer» section. Studies evaluating the role of blocking other
growth factor receptors (EGFR, HER3, IGF, FGFR, MET) in
combination with ET have so far not been successful [45].
Alterations of the PI3K/AKT/mTOR pathway are among
the most frequent genomic abnormalities present in luminal
BC [46]. In ER-positive breast cancer cell lines and tumour
models, PI3K pathway activation confers endocrine resis-
tance via crosstalk between ER and the receptor tyrosine
kinases activating the pathway, as well as through ligand-­
independent ER activation through mTORC1 [47].
The first approved treatment targeting the PI3K/AKT/
mTOR pathway in combination with ET was the mTOR inhibi-
tor everolimus combined with exemestane. In the randomized
phase III BOLERO-2 study, clinically significant PFS prolonga-
tion has been demonstrated for this combination in patients
progressing on or after treatment with a non-­steroidal AI;
unfortunately this has not translated into an OS benefit, and
the treatment was associated with significant toxicities, often
leading to treatment interruptions and dose reductions, occa-
sionally requiring permanent drug discontinuation [48, 49].
Phase II experience with PI3K inhibitors both in combination
with ET and ChT has so far been disappointing, at least par-
tially due to toxicity limiting optimal dosing [50, 51]. In the
phase III BELLE-2 study, PFS prolongation was seen in patients
treated with a combination of a pan-PI3K inhibitor buparlisib
and fulvestrant, with the largest benefit observed in patients
with PIK3CA mutations present in circulating tumour DNA,
possibly providing a predictive factor for this therapy [52].
Unfortunately, significant toxicity (transaminase rise, rash,
hyperglycaemia and mood disorders) led to frequent treatment
discontinuations, potentially limiting treatment applicability.
Other attractive targets are cyclin-dependent kinases
(CDK) which control the cell cycle. Combination of the
CDK4/CDK6 inhibitor palbociclib and ET in patients with
advanced ER/PgR+/HER2- BC resulted in a significant PFS
prolongation in three randomized trials either in combina-
tion with an aromatase inhibitor in the first-line setting
(PALOMA-1, PALOMA-2) or with fulvestrant in patients
who had relapsed or progressed during prior endocrine
therapy (PALOMA-3) [53, 54]. This has led to accelerated
FDA approval of this compound in patients with ER-positive
advanced BC as initial endocrine-based therapy for meta-
static disease and recently also for second-line therapy.
Unfortunately, no OS benefit has been so far observed [53].
Recently, positive results of a phase III MONALEESA-2 study
of letrozole ± ribociclib and MONARCH 2 study (of fulves-
trant +/– abemaciclib) (another CDK4/CDK6 inhibitor) were
also announced, and drug approval [55, 56]. The advantage of
agents in this class is their favourable toxicity profile.
As an interaction exists between endocrine regulation
and angiogenesis mediated by VEGF, and higher levels of
Metastatic Breast Cancer: Prognosis, Diagnosis and Oncological Management
VEGF are associated with a decreased response to ET [57,
58], and the combination of anti-VEGF treatment with ET
could potentially increase the efficacy of ET.  To test this
hypothesis, bevacizumab (a monoclonal antibody against
VEGF) was evaluated in combination with endocrine treat-
ment in the LEA and CALGB 40503 trials. Although the
CALGB 40503 trial demonstrated a PFS improvement for
the combination of letrozole and bevacizumab, neither of the
studies demonstrated an OS benefit, and the combined treat-
ment was associated with increased toxicity [59, 60].
In spite of the endocrine responsiveness and the prefer-
ence for ET, all patients at some stage require cytotoxic ChT.
Its principles, however, do not differ from those in other BC
subtypes and will be discussed in the «triple-­negative BC»
section.
585 49
HER2-positive BC represents two molecular subtypes:
HER2-positive non-luminal and HER2-positive luminal BC
(co-expressing HER2 and ER/PgR). In both groups, anti-­
HER2 agents are important components of therapy; however,
there are substantial differences regarding tumour biology
and treatment choices.
Despite the breadth of trials with HER2-directed agents,
a number of questions remain regarding the optimal use
of anti-HER2-targeted therapy in MBC such as treatment
sequence, regimens, duration of the ChT component and the
combination with ET in luminal HER2-positive tumours.
49.3.1  ER2-Positive, Non-luminal Breast
H
Cancer

Trastuzumab was the first targeted agent studied and sub-

49.3 HER2-Positive Breast Cancer sequently approved for the treatment of advanced HER2-­
positive BC.  In the pivotal trial, trastuzumab added to
Human epidermal growth factor receptor type 2 (HER2) standard ChT improved time to progression (median TTP,
is overexpressed in approximately 15 to 20% of invasive 7.4 vs. 4.6 months; p < .001) and increased median OS from
breast cancers and was historically associated with a poor 20.3 to 25.1 months (p = .046) [62]. There are a number of
prognosis [61]. The development of HER2-directed thera- cytotoxic agents which can be partnered with trastuzumab,
pies in the past 15  years has changed the natural course of but the preferred first-line agents for use in combination
the disease and offers patients with HER2-positive BC sur- are paclitaxel, docetaxel, vinorelbine and capecitabine. The
vival at least equivalent to patients without HER2 altera- optimal duration of ChT in combination with trastuzumab
tion. Currently, median OS in metastatic HER2-positive BC is not known. Based on the design of clinical trials, current
exceeds 50 months, which compares favourably with survival guidelines recommend continuance of ChT for 4–6 months
of approximately 20 months observed before the anti-HER2 or longer in the absence of disease progression and relevant
treatment era [2]. Approved HER2-directed agents include toxicities. Duration of ChT should depend on toxicity and
trastuzumab (human monoclonal IgG antibody that selec- response. If ChT is stopped due to adverse effects or maxi-
tively targets HER2), pertuzumab (monoclonal antibody that mal response, anti-HER2 therapy alone should be continued.
blocks the formation of HER2:HER3 heterodimers), trastu- Currently, there is no evidence to support treatment breaks
zumab emtansine (conjugate of trastuzumab and cytotoxic in patients who have a durable response.
emtansine – T-DM1) and lapatinib (an oral tyrosine kinase Pertuzumab was incorporated into standard combina-
inhibitor that functions downstream of HER2, inhibiting tions of trastuzumab and ChT, because it had been hypoth-
both EGFR and HER2 receptors). esized that blocking the ability of HER2 to heterodimerize
There are several rules guiding the treatment of HER2-­ with other members of the HER family, inhibits HER2 sig-
positive metastatic disease: naling by preventing ligand-activated HER2/HER3 or
55 HER2-directed therapy should be initiated early in the HER2/HER1 heterodimerization and may partially over-
course of the disease. come resistance to trastuzumab. In the CLEOPATRA trial,
55 Anti-HER2 agents can be partnered with ChT or ET and the combination of trastuzumab, docetaxel and pertuzumab
can also be used in combination (dual HER2 inhibition). outperformed trastuzumab with docetaxel, with an increase
55 In women progressing on an anti-HER2 therapy, con- in median PFS of 6 months (18.6 vs. 12.4 months; p < .001)
tinuation of HER2-directed therapy with alternative or and an increased median OS of more than 15 months (56.5
the same (only for trastuzumab) agent is recommended vs. 40.8  months; p  =  .002) [63]. Currently double HER2
since continued suppression of the HER2 pathway blockade with trastuzumab and pertuzumab combined with
improves outcomes. docetaxel is the preferred first-line regimen. With the lack of
55 With the exception of trastuzumab, no data support con- predictive biomarkers other that HER2, it is not known, how-
tinuing treatment with the same agent beyond progression. ever, whether all patients with HER2-positive BC derive more
benefit from dual HER2 blockade, compared to trastuzumab
Due to the risk of cardiac toxicity associated predominantly plus ChT [64]. There is no further evidence of superiority of
with trastuzumab, cardiac assessment is recommended pertuzumab-containing regimens in first-line treatment. In
before initiation of treatment and regularly during therapy. the MARIANNE study, addition of pertuzumab to T-DM1
Serious cardiac comorbidities and/or a left ventricular ejec- provided no efficacy benefit compared to trastuzumab and
tion fraction of less than 50% are contraindication to the taxane or T-DM1 alone in this setting [65].
treatment. In addition, trastuzumab should not be adminis- If pertuzumab is not available, trastuzumab with ChT remains
tered concurrently with anthracyclines. a valid first-line treatment option. Trastuzumab-­ containing

rares1geo@gmail.com
 586
E. Senkus and A. Łacko

regimens are superior to those with lapatinib. Two trials (MA31
49 and CEREBEL) comparing trastuzumab and ChT vs. lapatinib
and ChT in the first and further lines setting demonstrated lower
PFS and more adverse events in the lapatinib arms [66, 67].
In the second-line setting, several regimens are effective.
In the EMILIA trial comparing T-DM1 versus lapatinib plus
capecitabine in patients who had previously received trastu-
zumab and a taxane, a significant increase in median PFS of
3.2 months (9.6 vs. 6.4 months, HR 0.65; p < .001) and median
OS of 5.8 months (30.9 vs. 25.1 months; HR 0.68; p < .001)
in favour of T-DM1 was shown [68]. In addition, T-DM1
was better tolerated than the lapatinib plus capecitabine
and is recommended as the standard second-­line treatment.
Another option is continuation of trastuzumab with a differ-
ent cytotoxic agent. In the German GBG-26 trial of trastu-
zumab and capecitabine vs. capecitabine alone, combined
treatment resulted in a superior TTP and a non-significant
OS benefit; the study was, however, underpowered due to
poor recruitment [69]. Similarly, continuing trastuzumab
with lapatinib beyond progression on a trastuzumab-based
regimen outperformed lapatinib alone in both PFS and OS
[70]. Lapatinib added to capecitabine in patients previously
treated with an anthracycline, a taxane and trastuzumab
resulted in an improvement in median TTP (8.4 vs. 4.4; HR
0.49; p < .001), without significant OS benefit, compared to
capecitabine alone [71, 72]. The use of pertuzumab beyond
the first line is not recommended. In the PHEREXA study,
addition of pertuzumab to trastuzumab and capecitabine in
the second-line setting did not significantly improve PFS but
increased median OS by 8  months; this was not, however,
statistically significant [73].
Patients who have not received T-DM1  in the second-
line setting may still benefit from T-DM1 beyond the second
line. The TH3RESA trial performed in patients who have had
prior therapy with a taxane, trastuzumab and lapatinib, com-
paring T-DM1 with treatment of physician’s choice, demon-
strated doubling of PFS and an OS benefit of about 7 months
in favour of T-DM1 [74] (. Fig. 49.4).  

..      Fig. 49.4  TH3RESA study:

Kaplan-Meier curves of Physician’s choice Trastuzumab
progression-­free survival and (n=198) emtansine
overall survival (From Krop et al. 100 (n=404)
[74]. Reprinted with permission Median PFS 3.3 (2.89–4.14) 6.2 (5.59–6.87)
progression-free survival (%)

from Elsevier) 80 (95% CI), months

Events 129 219

Stratified HR 0.528 (95% CI 0.422–0.661); p=0.0001

60
Unstratified HR* 0.521 (95% CI 0.418–0.648); p<0.0001

40

20
Physician’s choice
Trastuzumab emtasine
0

Number at risk
Physician’s 198 120 62 28 13 6 1 0
choice
Trastuzumab 404 334 241 114 66 27 12 0
emtansine
100 Physician’s choice
Trastuzumab emtasine
80
Overall survival (%)

Physician’s choice Trastuzumab

60 (n=198) emtansine
(n=404)
Medians PFS 14.9 (11.27–NE) NE
40 (95% CI), months
Events 44 61
20 Stratified HR 0.552 (95% CI 0.369–0.826); p=0.0034
Efficancy stopping boundary: HR 0.370; p<0.0000016
Unstratified HR* 0.570 (95% CI 0.386-0.840); p=0.0040
0
0 2 4 6 8 10 12 14 16
Months since randomisation
Number at risk
Physician’s 198 169 125 80 51 30 9 3 0
choice
Trastuzumab 404 381 316 207 127 65 30 7 0
emtansine

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Metastatic Breast Cancer: Prognosis, Diagnosis and Oncological Management
Because most first-line anti-HER2-therapy trials were
performed in treatment-naive or predominantly anti-HER2
treatment-naive populations, management of patients who
have relapsed after adjuvant trastuzumab is not well deter-
mined. Women with a disease-free interval (DFS) of more
than 12 months since prior neoadjuvant/adjuvant treatment
with trastuzumab may be offered pertuzumab with trastu-
zumab and docetaxel, as such a group was enrolled in the
CLEOPATRA trial. Of note, 90% of women in this trial had
not received prior trastuzumab therapy. Due to the small
numbers and large confidence intervals, it’s not clear whether
women who were previously exposed to trastuzumab derive
comparable benefit from pertuzumab as those who are
trastuzumab naive. Despite improvement demonstrated in
the subgroup analysis in patients who relapsed after adjuvant
trastuzumab, the outcome in this population was inferior
compared to the trastuzumab-naive group (OS 46.6 months
vs. 53.8  months, respectively; HR 0.8; 95% CI, 0.44–1.47)
[63]. If pertuzumab is not available, trastuzumab with ChT
is the recommended regimen. Data from two studies in the
first-line setting, including patients diagnosed with de novo
HER2-positive MBC and those who have relapsed after adju-
vant therapy, suggest superiority of retreatment with trastu-
zumab and ChT over lapatinib and ChT [66, 67]. Women
with early relapses (DFS of less than 6  months) indicating
resistance to trastuzumab are candidates for second-line
therapy, preferably T-DM1. There is a paucity of data regard-
ing treatment in women with a DFS of more than 6 months
and less than 12  months and both first- and second-line
options can be considered.
The use of dual anti-HER2 blockade without a ChT back-
bone in metastatic HER2-positive BC is not supported by
high level of evidence. Combination of lapatinib plus trastu-
zumab compared with lapatinib alone in patients with trastu-
zumab refractory disease improved PFS and OS; however,
lapatinib alone seems to be a suboptimal comparator [70].
In the MARIANNE study, dual blockade with pertuzumab
and T-DM1 was not superior to trastuzumab combined
with a taxane, although the combined targeted therapy was
associated with a much more favourable toxicity profile [65].
Despite the activity of ChT-free anti-HER2 therapies, due to
lack of biomarkers which identify the subgroup of patients
for whom the combination of anti-HER2 agents alone may
be sufficient, such an approach cannot be recommended as
standard.
49.3.2  uminal B HER2-Positive Breast
L with anti-HER2 therapy, a subset of luminal HER2-positive
Cancer
Luminal HER2-positive tumours represent approximately
half of all HER2-positive BC.  ER/PgR and HER2 status
are the key factors determining a patients’ prognosis and
response to therapy. Tumours co-expressing HER2 and ER/
PgR are less responsive to ET than luminal HER2-negative
tumours. On the other hand, multiple studies have demon-
strated that benefits from HER2-directed agents depend on
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587 49
ER/PgR status and HER2 inhibition is less effective in ER-­
positive BC compared to ER-negative tumours [75, 76].
The importance of concurrent ER and HER2 blockade in
the treatment of this subset of patients is well recognized, and
the concept of combined endocrine and anti-HER2 therapies
is supported by preclinical and clinical data, but the optimal
use of ET and anti-HER2 agents has not been determined.
The majority of patients with luminal HER2-positive
tumours are offered HER2-directed therapy combined with
ChT, because the benefits from ChT-containing regimens
were demonstrated in both luminal and non-luminal HER2-­
positive subtypes across all studies, with improvements in
response rates, PFS, TTP and OS. Data regarding ET use in
luminal HER2-positive patients is limited to three relatively
small trials, which showed that HER2-targeted therapy
added to ET improved the response rate and PFS, but the
impact on OS was not formally assessed. In the TAnDEM
(Trastuzumab and Anastrozole Directed Against ER-Positive
HER2-Positive Mammary Carcinoma) trial comparing anas-
trozole plus trastuzumab with anastrozole alone, median PFS
was doubled in the combination group (4.8 vs. 2.4 months;
HR 0.63 95% CI, 0.47 to 0.84; p = .0016) [77]. Despite sub-
stantial crossover (70% of patients) at disease progression, a
numerical difference in median OS of 4.6 months favouring
trastuzumab and anastrozole (28.5 vs. 23.9 months; log-rank
p = .325) was observed. Similar results were achieved in the
EGF100151 study of lapatinib plus letrozole versus letro-
zole, performed both in HER2-positive and HER2-negative
BC patients [78]. Significant improvement in PFS (median
PFS of 8.2 vs. 3.0  months; HR 0.71; 95% CI, 0.53 to 0.96;
p = .019) in the HER2-positive group and increased overall
RR (28% v 15%; p = .021) translated into a non-significant OS
difference (median OS of 33.3 vs. 32.3 months; HR = 0.74;
95% CI, 0.5 to 1.1; p  =  .113). The third study  – eLEcTRA
(Study of the Efficacy and Safety of LEtrozole Combined
with TRAstuzumab) – was closed prematurely due to poor
accrual, and analysis restricted to 92 patients showed non-
significant improvement in TTP [79]. Importantly, combi-
nation of ET plus anti-HER2 therapy was associated with
minimal adverse effects.
Overall, the improvement in PFS across trials with ET
and HER2-directed therapy was modest, and although direct
comparison of ET plus HER2-targeted therapy with ChT plus
HER2-targeted therapy has never been performed, indirect
data suggest better outcome in patients who received ChT
with an anti-HER2 agent. However, given the significant
PFS benefit and favourable toxicity profile of ET combined
patients with asymptomatic/mildly symptomatic, indolent,
low-volume disease, a long disease-free interval or contrain-
dications to ChT may be candidates to such treatment.
ET may also be used in combination with HER2-targeted
agent as a maintenance regimen in patients who initially
received ChT combined with anti-HER2 therapy, and the
cytotoxic component was stopped at the point of maximal
response and/or toxicity. Such an approach, not supported by
high level of evidence, is widely used in practice, as it offers
 588 E. Senkus and A. Łacko
effective and minimally toxic treatment. Data from observa-
49 tional studies such as RegistHER favours sequential use of
ChT and ET over concurrent use with regard to both PFS and
OS (adjusted PFS HR (0.81), 95% CI (0.54–1.21); adjusted
OS HR (0.48), 95% CI (0.26–0.89)) [80].
49.4 Triple-Negative Breast Cancer
Metastatic triple-negative breast cancer (TNBC) compared to
other BC subtypes is characterized by aggressive biology, sig-
nificantly shorter disease-free and overall survival times and
a tendency toward visceral (vs. bone) metastases. Patients
with early-stage TNBC have a high risk for early relapse. The
pattern of relapse in TNBC is distinct, with a rapidly rising
rate in the first 2 years following diagnosis, reaching a peak
at 2 to 3 years and a decline in recurrence risk over the next
5 years [81]. Unlike other subtypes, no targeted therapy has
proven efficacy in the treatment of TNBC; thus, chemother-
apy (ChT) remains a mainstay of systemic treatment. ChT
may be used also in the treatment of other BC subtypes, i.e.
in endocrine-resistant luminal BC or in patients with rapid
progression, symptomatic or high-volume visceral disease, in
whom ET is unlikely to result in prompt response and clini-
cal improvement. Most of the general principles regarding
ChT discussed in this chapter apply also to advanced breast
cancers of other phenotypes requiring ChT.
There is no uniform standard ChT for patients with MBC,
and the choice of regimen should be tailored to individual
needs, based on multiple factors. These include the burden of
disease, in particular the presence of directly life-threatening
disease (visceral crisis), the presence and intensity of symptoms,
prior therapy and response, anticipated side effects of treat-
ment and patient-related factors such as performance status,
comorbidities and preferences. Because MBC remains incur-
able, the goals of therapy are to ameliorate symptoms, delay
progression, improve or maintain quality of life (QoL) and
prolong survival. In this context, the general rule is to choose
the least toxic therapy. More intensive ChT (combination ChT)
is indicated for patients with a visceral crisis or severe symp-
toms, when rapid disease control is urgently needed. Visceral
crisis was defined by the ESO-ESMO guidelines as severe
organ dysfunction, as assessed by signs, symptoms and labo-
ratory studies and demonstrating rapid disease progression,
leading to a clinical indication for a more rapidly efficacious
therapy, particularly since another treatment option at pro-
gression will probably not be possible [3, 4]. In the remaining
patients, sequential monotherapy is preferred [82]. Individual
trials as well as meta-analysis of published studies investigating
multidrug combination regimens vs. single-agent therapy have
demonstrated the superiority of combination ChT in terms of
RR, TTP and PFS but without significant impact on OS and at
the cost of increased toxicities [83–86].
There are a number of cytotoxic drugs with single-agent
activity. Taxanes and anthracyclines are considered the most
active; therefore, anthracycline- or taxane-based regimens
are the preferred first-line ChT agents. However, as standard
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adjuvant regimens employ anthracyclines and taxanes, most
patients have already been exposed to one or both agents.
Due to the risk of dose-dependent, cumulative cardiac tox-
icity caution is necessary when considering retreatment
with anthracyclines, in particular doxorubicin. Liposomal
doxorubicin and epirubicin are less toxic and equally active
alternatives to doxorubicin [87, 88]. Taxanes may be used in
patients with anthracycline-pretreated BC but also in women
who have received both an anthracycline and a taxane in the
adjuvant setting but recurred after at least 12  months fol-
lowing adjuvant therapy [89]. Toxicity and efficacy of tax-
anes depend on the agent and schedule of administration.
Docetaxel compared to paclitaxel induces more haemato-
logic and non-haematologic side effects [90]. Three-weekly
dosing of docetaxel and weekly paclitaxel are commonly
used as these schedules demonstrated superiority to alterna-
tive schedules of particular compounds in the adjuvant set-
ting [91], and in MBC weekly administration of paclitaxel
resulted in an OS improvement compared with every three-­
week treatment [92]. Other cytotoxic agents active in the
metastatic setting include capecitabine, gemcitabine, vinorel-
bine and eribulin, although very little data exist on the opti-
mal sequence or combination beyond the first line [93–100].
The choice of single agent or agents in combination depends
also on patient’s preferences (e.g. oral vs. intravenous ChT, a
wish to avoid certain side effects and anticipated toxicities).
Progression or disease recurrence within 12  months from
prior therapy with any cytotoxic agent is an indicator of resis-
tance to this class of agents.
The duration of ChT in the metastatic setting cannot be
predetermined and depends on disease course, the presence
of symptoms, side effects of treatment, QoL and patient’s
preferences. Most trials, as well as meta-analyses examin-
ing the duration of ChT, have consistently showed that pro-
longing treatment is associated with extended TTP but has
little effect on OS [101, 102]. Patients with chemosensitive
tumours and adverse prognostic features derive more benefit
from a more intensive approach [103]. Although guidelines
recommend continuation of ChT until disease progression or
significant side effects, in practice, the duration of the ChT is
adjusted to particular clinical scenarios. Usually, in patients
treated with prolonged ChT, toxicity accumulates requir-
ing dose reduction, and clinical benefit decreases over time.
That is why a substantial number of patients prefer intermit-
tent treatment with «chemotherapy holidays». Maintenance
single-­agent ChT delivered with low-dose intensity is a com-
mon practice; however, there is no evidence supporting such
a strategy [104].
Approximately 6% of all BC cases can be attributed to
BRCA1/BRCA2 germline mutations, and a substantial per-
centage of BRCA-mutated BCs are TNBC [105, 106]. BRCA1
and BRCA2 genes play key roles in DNA repair, and BRCA-­
mutated or BRCA-deficient tumours lack homologous repair
capabilities (HR); therefore, they are more sensitive to DNA
damage and to DNA-damaging agents. Accumulating evi-
dence suggest that platinum compounds (which cause DNA
cross-linking and double strand breaks) may be effective
Metastatic Breast Cancer: Prognosis, Diagnosis and Oncological Management
in TNBC, in particular in BRCA-mutated tumours. In the
phase III TNT trial comparing carboplatin with docetaxel
in first-line treatment of either BRCA-mutated or TN MBC,
overall no difference in outcome was found. Notably, for
patients with a BRCA mutation, the response rate and PFS
with carboplatin was significantly improved when compared
to docetaxel [107]. Another class of promising agents are
poly(ADP-ribose) polymerase inhibitors (PARPi), which
exert their antitumour activity via so-called synthetic
lethality, by blocking the alternative DNA repair pathway
in HR-deficient cells. PARPi activity seems to be limited to
BRCA-mutated BC; in an unselected TNBC population, the
efficacy of PARPi was not meaningful [108]. In a phase III
trial of olaparib vs treatment of physician’s choice olaparib
led to improvement in response rates and PFS with favour-
able toxicity profile and impact on quality of life [109].
TNBC is not a single entity but encompasses a number
of molecular subtypes. Analysis of tumour gene expression
profiles identified at least six TNBC subtypes, including two
basal-like (BL1 and BL2), an immunomodulatory (IM), a
mesenchymal (M), a mesenchymal stem-like (MSL) and a
luminal androgen receptor (LAR) subtype [110]. The LAR
subtype represents at least 10% of TNBC and is androgen
driven; thus, the AR is a potential target. Early antiandrogen
therapy studies are promising, with a median PFS of 14 and
16 weeks in phase II studies in TNBC patients expressing the
AR [111, 112].
Different classes of antiangiogenic agents have been
investigated for the treatment of TNBC, but none of them
has demonstrated an impact on OS.  Multiple randomized
phase III trials of bevacizumab with ChT consistently showed
improvements in PFS across all BC subtypes without OS ben-
efit and at the cost of severe adverse effects [113, 114]. With
the lack of an effective selection strategy for identification of
patients which could benefit the most from bevacizumab and
any other antiangiogenics, it should not be considered as a
standard treatment approach.
Recently several trials with immunotherapy reported
activity of various anti-PD1 and anti-PDL1 agents in TNBC
with an overall response rate ranging from 5% to 34% [115–
117]. Research continues to better identify targets and effec-
tive treatment options in TNBC.
49.5 Local Treatment of MBC
Most of the local treatments for MBC are given with purely
palliative intent. In this setting, surgery is mostly utilized
for fixation or prevention of pathological fractures, result-
ing from bone metastases, decompression of spinal cord
compression and  – occasionally  – for removal of fungat-
ing masses which cannot be managed by other modalities
[118]. In recent years, following developments in surgical
technique and improvements in systemic therapy, attempts
at «curative» local treatments are more often undertaken;
their impact on long-term outcomes, including OS, is, how-
ever, still unknown. Surgical management of the primary
rares1geo@gmail.com
589 49
tumour and metastatic disease will be discussed in more
detail in respective chapters (7 Chaps. 56 (lung), 53 (bone),
55 (hepatic) and 54 (brain) and 58 (surgery to the primary in
stage IV disease)).
Palliative radiotherapy is used widely for bone metasta-
ses, brain metastases and/or leptomeningeal involvement,
malignant spinal cord compression or symptomatic soft tis-
sue masses [119]. The goals of palliative radiotherapy include
alleviation of symptoms, pain relief, local tumour control,
prevention or improvement of neurological deficits and stabi-
lization of the spine or other bones [119]. In bone metastases,
palliative irradiation results in pain improvement in 50–85%
of patients, with 15–60% having complete disappearance of
pain. In terms of symptomatic response, as demonstrated by
multiple randomized studies, single-fraction radiotherapy
is as effective as a more prolonged regimen, although more
patients treated with a single fraction may need repeated
irradiation [120].
Technological advances in recent years have enabled the
safe delivery of very high, ablative doses of radiotherapy to
limited, well-defined areas with little toxicity to surround-
ing normal tissues. Delivery of these high radiation doses
not only directly kills tumour cells but also destroys the
tumour vascular bed, thereby damaging the intratumoural
microenvironment leading to indirect tumour cell death.
Furthermore, some data suggest that the massive release
of tumour antigens from tumour cells may stimulate anti-
tumour immunity, thereby suppressing metastatic tumour
growth (abscopal effect) [121].
This technology, primarily exploited for brain tumours,
was named stereotactic radiosurgery, due to its local efficacy
which is comparable to surgery. Originally, the technique was
developed by means of specialized gamma units («Gamma
Knife») utilizing 201 stationary cobalt beams and – later –
with linear accelerators, either specialized for stereotactic
treatments («CyberKnife») or isocentric (as for other radio-
therapy indications) [122, 123]. Later, similar technology
was also introduced for the treatment of extracranial oligo-
metastatic disease (stereotactic body radiotherapy – SBRT).
The most common indications include lung, liver, adrenal
and bone metastases. Numerous studies have confirmed the
local efficacy and good tolerability of SBRT. In a prospective
series, 39 BC patients with oligometastatic disease irradiated
for various sites (lung and bone lesions in 11 patients (28
lesions) both) had a 2-, 4- and 6-year lesion local control
(LC) rate of 87%; 2-, 4- and 6-year OS rate of 74%, 54% and
47%; and a 2-, 4- and 6-year freedom from further distant
metastases of 52%, 43% and 36%, respectively. The 2-year
OS rate was 55% for 11 breast cancer patients who before
SBRT experienced progression of lesions after systemic
therapy vs. 81% for the 16 patients who experienced stable
or regressing disease. These results were significantly better
than those in patients with a non-breast primary [124]. In
another series of 33 patients with lung or liver lesions, actu-
arial local control rates were 98% at 1 year and 90% at 2 and
3 years; the median PFS was 11 months and the median OS
was 48 months [125].
 590 E. Senkus and A. Łacko
In a series of 174 patients with spinal metastases from
49 mixed primaries (28 «breast or prostate», i.e. «favourable his-
tologies» patients), median OS was the longest (14 months)
in the «favourable histologies» group, and treatment was
well tolerated; no local control data were, however, provided
[126]. In another series of 24 oligometastatic breast or recur-
rent gynaecological cancer patients (5 with lung lesions and
13 with bone metastases), the objective response rate was
77.7% including 16 lesions achieving complete response
(44.4%), and infield disease control expressed on a per lesion
basis was 69% [127].
Stereotactic radiotherapy for brain metastases will be dis-
cussed in detail in 7 Chap. 51.
 
Importantly, no reliable data exist on the impact of SBRT
or any other local treatment for MBC on overall survival, and
promising results seen in available non-randomized studies
may be heavily biased by patient selection.
49.6 Bone Metastases
49.6.1 Bone-Directed Therapy
In patients with bone metastases, treatment with bone-­
modifying agents such as bisphosphonates and denosumab
(monoclonal antibody against the RANK-ligand) delays the
progression of pain and decreases the risk of first and subse-
quent skeletal-related events (SRE) [128, 129] and should be
used in all patients with confirmed bone metastases, unless
contraindicated [3, 4]. Denosumab is more active than
zoledronic acid in preventing SRE and is associated with
fewer renal complications and acute-phase reactions, but
a higher risk of hypocalcemia and osteonecrosis of the jaw
[128]. Data regarding the analgesic efficacy of denosumab
is limited, and its superiority over bisphosphonates has not
been documented. Once initiated, bone-modifying agents
should be continued until evidence of substantial decline in
a patient’s general performance status [130]. Studies however
suggest that the standard 3–4-weekly regimen of zoledronic
acid may be safely replaced with 12-weekly administration,
at least in patients who have already received 9 to 12 monthly
doses [131]. Starting bone-modifying agents in women
without evidence of bone metastases, even in the presence
of other extraskeletal metastases, or with an abnormal bone
scan without evidence of bone destruction on imaging is not
recommended [130], although a delay in the development
of bone metastases has been reported for bone-modifying
agents when given in the adjuvant setting [132].
49.6.2 Radioisotopes
There is limited clinical evidence supporting the use of
bone-­seeking β-emitting radionuclides (strontium (Sr)-89,
samarium (Sm)-153 and rhenium (Re)-186) in relieving
pain from bone metastasis in BC: there are no well-designed
trials showing superiority of radioisotopes versus placebo
rares1geo@gmail.com
and no trials showing non-inferiority or superiority against
documented pain palliative therapies, such as external
beam palliative radiotherapy or dose-intensified opioid
treatment [133]. In a systematic review, the «efficacy» of
radioisotopes in BC patients was 79% [134]. In symptom-
atic castration-resistant prostate cancer (CRPC), however,
pain treatment with local field radiotherapy was associated
with a better OS compared to Sr-89. The lower costs of local
field radiotherapy also favour the use of this treatment in
patients with CRPC [135]. Haematological toxicity is not
well described for BC patients. In a systematic review of
trials in CRPC, among 26 studies, grade 3 or 4 leukopenia
or neutropenia was reported 0% in 15 trials, whereas in the
other 11 studies, it ranged from 1% to 25%. Grade 3 or 4
thrombocytopenia did not occur in 14 trials and varied
from 1% to 21% in the other 12 trials [136]. Alpha par-
ticle-emitting radium (Ra)-223 is approved in CRPC after
having demonstrated SRE delay and OS prolongation and
is extensively studied in BC [137]. Its advantages include
the very short range, leading to low myelotoxicity and high
cell-kill efficacy.
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 595 50

The Role of Surgery

in Metastatic Disease
to the Bone
Amit Kumar and Robert U. Ashford

50.1 Introduction – 596

50.2 Clinical Presentation/Diagnosis and Investigations – 596

50.2.1 Biopsy – 597

50.3 Surgical/Orthopaedic Management – 597

50.3.1 Treatment of Pathological Fracture – 597

50.4 Anaesthetic Assessment – 600

50.5 Conclusion – 601

References – 601

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_50

rares1geo@gmail.com
 596
A. Kumar and R.U. Ashford

50.1 Introduction Skeletal metastases in breast cancer patients can involve

Skeletal metastases are common in many advanced malig-
50 nancies. Breast cancer is the commonest cancer in Europe
and is one of the commonest cancers that spread to the bone
with more than 1  in 20 patients having skeletal metastases
at diagnosis [1]. Only multiple myeloma involves the bone
more commonly. The incidence of skeletal metastases is
shown in . Table 50.1. Early diagnosis of skeletal metastases
any bone, with the femur and spine the commonest.
Impending bone fracture is a risk, and therefore an orthopae-
dic surgeon should be involved early in their management.
50.2 Clinical Presentation/Diagnosis
and Investigations

and appropriate multidisciplinary team (MDT) management
with orthopaedic surgeons are imperative to improve the
outcome for the patient in terms of improved QoL, reduced
fracture risk and duration of hospitalisation and less pain.
It is important to remember that the orthopaedic surgeons
should be seen as part of the multidisciplinary team. Indeed
in large cancer centres, there is often a specialized bone MDT
to discuss complex cases between oncologists, pathologists,
radiologist and orthopaedic surgeons with a special interest
in bone malignancy.
Breast screening has helped to decrease breast cancer
mortality with earlier detection and management of the
disease. In 2012, there were more than 464,000 new cases
of breast cancer in Europe, with a mortality rate of approxi-
mately 25%. It is the second most common cause of death
from cancer, after lung, in females in the UK [1].
With a 10-year survival of 72%, the cumulative incidence
of bone metastases at any time is 8.2% at 2 years and 27.3% at
10 years [3]. Therefore, at 10 years bone metastases in breast
cancer potentially pose a substantial problem with over
Patients with bone metastases can present clinically in a
number of ways:
55 Acute presentation with a pathological fracture or neu-
rological involvement
55 Symptoms of metastatic spinal cord compression or
cauda equina syndrome
55 Bone pain
55 Staging imaging tests revealing evidence of bone
involvement or destruction
55 Acutely with biochemical disturbance, e.g. hypercalcaemia
The orthopaedic surgeon has a number of roles to play
in the management of metastatic bone disease, including
diagnosis, fixation and prevention of pathological fractures,
and occasionally for potentially curative (en bloc) excision
of solitary metastatic tumours, although this is still contro-
versial.
The simplest diagnostic tool to assess whether patients
are at risk of impending fracture is the Mirels’ scoring system
(. Table 50.2) [4]. Patients scoring in excess of 8 should be

10,400 cases in the UK per annum. referred urgently for an orthopaedic surgical opinion to con-
sider prophylactic intramedullary nail fixation.
Guidelines have been developed over the last decade or
..      Table 50.1  Incidence of skeletal metastases so, initially by the British Association of Surgical Oncology
(BASO) and subsequently the British Orthopaedic
Cancer Incidence (%) Post-mortem incidence of
bone metastases in % [2]
Association (BOA) and the British Orthopaedic Oncology
Society (BOOS) [5]. These BOA/BOOS guidelines have
Multiple 100 100 been recently updated (7 www.boos.org.uk). Further inter-
 

myeloma national guidelines have been published by the Japanese

Breast 47–85 73 Associations of Medical Oncology, Radiation Oncology and
Orthopaedics [6].
Prostate 54–85 68

Thyroid 28–60 42

Bladder 42
..      Table 50.2  Mirels’ scoring system
Renal 33–40 35

Lung 32–40 36 Variable 1 2 3

Liver 16 Site Upper limb Lower limb Peri-trochanter

Ovarian 9 Pain Mild Moderate Severe
G.I. 3–11 5 Lesion Blastic Mixed Lytic
Oesophageal 5–7 Size/bone <1/3 1/3–2/3 >2/3
diameter
Rectal 8–13

Uterine Very rare From Mirels Ref. [4] with permission from Wolters-Kluwer

rares1geo@gmail.com
The Role of Surgery in Metastatic Disease to the Bone
The new British guidelines have declared four minimum
standards of care for the orthopaedic management of patients
with metastatic bone disease:
55 Access to an orthopaedic surgeon as part of multidisci-
plinary care
55 Access to an up-to-date oncologist’s opinion with
dialogue between the oncologist and the orthopaedic
surgeon
55 Appropriate orthopaedic follow-up whilst the patient
remains symptomatic
55 Data collection on the outcome of skeletal metastases
In the case of many breast cancers, cases are discussed in a
multidisciplinary setting; however orthopaedic surgeons are
not typically part of these. Options available are to discuss
cases outside of the multidisciplinary team as soon as pos-
sible or to have a dedicated separate MDT or section of the
advanced breast cancer MDT where an orthopaedic surgeon
can attend.
50.2.1 Biopsy
Biopsy plays a very important role in the diagnosis of bone
metastases. The following points should be noted:
55 Not every bone metastases needs a biopsy; however, if
there is doubt, then biopsy should be the default option.
55 A new (first) bone lesion requires a biopsy to confirm
bone metastases except in the presence of visceral meta-
static disease.
55 A biopsy should be considered if the patient has a
known malignancy with pathological fracture, solitary
or multiple bone lesions and is mandatory in any patho-
logical fracture in an otherwise healthy patient.
55 In metastatic breast cancer, it is not uncommon for the
cancer phenotype to change, e.g. ER + ve to ER –ve.
Biopsy for a change of phenotype has important impli-
cations for non-surgical oncological treatment. This is a
relatively a new indication for bone biopsy and is likely
to increase. Biopsy for phenotypic changes can also
be performed on visceral metastases, if present, which
may be technically easier than bone biopsy in some
cases.
55 A biopsy can be performed by the orthopaedic surgeon
paying special attention to ensuring accurate tissue sam-
pling, haemostasis and preferably via a surgical approach
that can be utilised should future surgery need to take
place.
Appropriate staging should be performed for the patient
along with sufficient radiological investigation (radiographs,
CT and/or MRI) of the affected bone following discus-
sion between the orthopaedic surgeon and oncologist. This
should ideally be performed prior to bone biopsy and may be
necessary to exclude a primary bone tumour.
rares1geo@gmail.com
597 50
50.3 Surgical/Orthopaedic Management
The principal role of the orthopaedic surgeon in surgery for
skeletal metastases is to provide pain relief to the patient.
Further goals, in advanced disease surgery, may be to main-
tain or restore neurological function and enable functional
rehabilitation particularly if the upper limb is involved. This
will depend on both the current status of the bone involved
in the metastases and the general health of the patient.
Pathological fracture following destruction of the bone by
metastatic disease may ensue following microfractures caus-
ing bone pain. This can lead to an inability to use the limb,
affecting stability and weight-bearing status.
If the disease is sufficiently symptomatic and the patient
referred prior to fracture, then prophylactic fixation can be
offered. If the bone has already fractured, then stabilization
can be achieved by a number of techniques. The recon-
structive surgical goals of palliative fixation are to enable
immediate weight bearing and that the fixation should last
the lifetime of the patient. The authors recommend that all
patients undergoing palliative fixation should undergo radio-
therapy, and the whole bone should be included in the radio-
therapy field.
50.3.1 Treatment of Pathological Fracture
The major goal of palliative orthopaedic surgery is the alle-
viation of pain, and this can all be achieved by one or more
methods including ablation (amputation), cement augmen-
tation and insertion of metalwork (plates, nails and pros-
thetic replacement).
Amputation is not commonly utilised for metastatic bone
disease but can be useful if patients are experiencing intractable
pain secondary to metastatic tumours. It may also be utilised
in fungating tumours and in those tumours which have pro-
gressed aggressively particularly involving neurovascular struc-
tures, although this is rare in breast cancer-­related bone disease
(more usual in bone sarcomas, for example). In the event of
infected metalwork following fixation of pathological fractures,
amputation may be required to eradicate the infection.
Whilst amputation may be seen as an aggressive solution,
it has advantages of subjecting the patient to one operation,
alleviating pain in the short term with rapid local tumour
control. There is however minimal chance of rehabilitation
(with the exception of a below-knee amputation) and exposes
the patient to the known complication of phantom limb pain.
Bone cement (polymethyl methacrylate) is a common
material used in orthopaedics particularly in arthroplasty. It
can also be used in metastatic disease particularly in focal
osteolytic disease (e.g. vertebroplasty) or as an adjunct to
metalwork fixation. It can be used in open surgery but also
percutaneously for sites such as the acetabulum, particularly
in patients with poor performance status, with limited life
expectancy.
 598 A. Kumar and R.U. Ashford

The use of metalwork is common in metastatic surgery Long Bone Disease

and can play a role in prophylactic or definitive internal fixa- Long bones affected by metastatic bone disease can be treated
tion or the use of implants for joint replacement which may by the use of long intramedullary nails (IM) with their aim
50 be with the use of conventional types of implants or larger being to internally splint the whole long bone ideally with
endoprosthetic replacement implants. stabilization of the nail with proximal and distal locking
Different sites of metastatic bone disease require differ- screws conferring rotational stability.
ent surgical strategies and solutions. The broad principles are
that metastases near a joint are likely to need replacement
and those in the middle of a bone will require some form of
support (either external to the bone (plate) or internal (nail)).

Pelvis and Acetabulum
Metastatic bone disease of the pelvis is usually treated with
radiotherapy; however acetabular reconstruction can take
place to support the hip or in impeding fracture. If there are
significant contained defects within the acetabulum, then
cement can be used as a good filler. Trabecular metal aug-
ments and cages can be used to support the acetabulum. For
extensive bone loss, an inverted ice cream cone (. Fig. 50.1)
 

endoprosthesis which creates a new socket for the hip joint

supported by the ilium can be used.

Proximal Femur
If metastatic disease is confined to the femoral head or neck
(. Fig. 50.2a), then a cemented arthroplasty can be used to
 

reconstruct this area. Longer stem implants may be required

to support more of the femur if affected. Cephalomedullary
type intramedullary nails may also be used to support this
area as long as there is sufficient bone stock in the femoral
head (. Fig. 50.2b).
 

Sliding hip screws should not be used due to the high

failure rates in such cases due to nonunion of pathological
fractures, progressive disease and implant failure. ..      Fig. 50.1  CE Marked, Coned Hemi-Pelvis manufactured by Stan-
Endoprostheses (proximal femoral replacements) are more Implants Worldwide Ltd. (Image courtesy of 3CE Marked, Coned
increasingly being utilised (see below). Hemi-Pelvis manufactured by Stanmore Implants Worldwide Ltd)

..      Fig. 50.2  a Large lytic

a b
femoral neck metastasis; b long
cephalomedullary nail

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The Role of Surgery in Metastatic Disease to the Bone
Preoperative embolisation may be required in highly
vascular tumours. This reduces intraoperative bleeding and
should be performed by an interventional radiologist just
prior to the procedure (within 48 h).
The treatment-specific complications of long bone fixa-
tion with an IM nail are fat embolism and contamination
of the whole bone with cancerous cells. Both of these are in
addition to the risks of any major operation. With associ-
ated comorbidities, the risks of surgery need to be balanced
against the benefits and discussed with the patient.
It can be beneficial to try to predict patients at risk of
impending pathological fracture with the help of Mirels’
scoring system. Prophylactic fixation of impending fractures
leads to reduced hospital stays, increased survival and hence
reduces the costs involved in treating the patient than if the
pathological bone had fractured [7].
It is usual for postoperative radiotherapy to commence
once the long bone has been stabilized and the wound
healed. It has to be assumed that these fractures typically do
not unite, and therefore a large diameter solid nail should
be used to enable the patient to bear weight. Cement can be
used to pack defects and confer increased stability.
Upper Limb/Shoulder Girdle
Scapula and clavicular metastases are usually managed with
radiotherapy; if the humeral head is involved, then again a
cemented arthroplasty/hemi-arthroplasty can be utilised.
Extensive rotator cuff resection may require a reverse shoul-
der replacement.
Endoprosthetic or Modular Surgery
Custom-made or modular endoprostheses can be useful in
reconstructing the long bones if there is extensive disease
and bone destruction (. Fig. 50.3a, b). It can be the surgical
 
..      Fig. 50.3  a Mixed sclerotic
a b
and lytic metastatic breast cancer
deposit in the proximal femur; b
proximal femoral replacement
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599 50
treatment of choice (in conjunction with appropriate chemo-
therapy and hormone treatment) for skeletal metastases from
primary tumours with a relatively good prognosis such as in
breast cancer with low-volume bone disease particularly in
the femur but also in the tibia, humerus or pelvis [8]. This
potentially curative procedure should be considered for iso-
lated metastases (especially those with a long latent period
from onset of breast cancer to development of a solitary bone
metastasis) and those with no visceral disease. Whilst costly,
they provide good functional outcomes including the ability
for early mobilization [5, 9, 10].
Spinal Metastases
In the event of cord compression or cauda equina syndrome
due to metastatic breast disease, an urgent referral (within 24 h)
should be made to the local orthopaedic or spinal surgeon.
Clinical presentations of spinal metastases to be aware of
include:
55 Pain in the cervical or thoracic spine
55 Progressive lumbar spinal pain
55 Severe unremitting lower spinal pain
55 Spinal pain increased by straining
55 Localized spinal tenderness
55 Nocturnal spinal pain preventing sleep
In the UK National Institute of Health and Clinical Excellence
(NICE), guidelines have been developed to optimize man-
agement of patients with impending spinal cord compression
[11]. The spinal surgeon can then consider the role of spinal
cord decompression and/or stabilization. Not all cases will be
suitable for surgery, and radiotherapy remains a viable treat-
ment option in some cases.
Guidance includes laying the patient completely flat
in the bed with permitted log rolling only. Daily full
 600 A. Kumar and R.U. Ashford

50

a b

..      Fig. 50.4  Sagittal MRI showing altered signal in T9 on both a T1 and b STIR sequences. c CT scan through T9 shows large lytic metastasis from
breast cancer

neurological assessment should be performed and docu- and in any case of neurological deterioration during radio-
mented with particular note to bladder and bowel function. therapy and cases of spinal instability due to disease.
An urgent whole MRI spine should be performed at the first
instance (. Fig. 50.4a, b) with further imaging as appropriate
 

(. Fig. 50.4c).
  50.4 Anaesthetic Assessment
Advances in spinal surgery have rapidly developed, and
stability can be conferred with a variety of devices. The use of Many patients with metastatic bone disease have other signif-
bone cement again is useful in stabilizing vertebral bodies, as icant comorbidities for surgery. Prior to anaesthetic assess-
are the use of cages, rods and pedicle screws to confer spinal ment for surgery, there are prognostic factors that can help
stability. determine survival [2, 12].
Interventional radiologists and spinal surgeons may offer Positive predictors of long survival include:
vertebroplasty and kyphoplasty. 55 Less than three metastatic sites
Spinal surgeons should be involved in any case of spinal 55 Absence of visceral metastases
cord compression, with or without a history of malignancy, 55 No history of hypercalcaemia

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The Role of Surgery in Metastatic Disease to the Bone
55 Primary breast tumour excision
55 Disease-free interval of more than 2 years
In addition, the Oswestry Quadruple A Score (age, albumin,
alkaline phosphatase and adjusted calcium) has been dem-
onstrated to predict survival at 1 year, although the score has
yet to be validated [13].
These factors can help the orthopaedic surgeon to formu-
late an operative plan tailored to the patient’s physical condi-
tion and oncologic prognosis.
References
Preoperative assessment should routinely assess physi-
ological reserve, anticipated blood loss and the need for
high dependency unit care post-operatively. If any health
parameters can be optimized, then it should be done as soon
as feasibly possible. Surgery should routinely take place dur-
ing daytime hours on weekday operating lists as pathological
fractures are rarely an emergency.
50.5 Conclusion
Metastatic bone disease from breast cancer can have potential
devastating consequences. Any patient with bone pain and
a history of breast cancer should be investigated for skeletal
metastases until proven otherwise. If the pain is back pain,
then spinal cord compression must be ruled out. Appropriate
imaging should be organized, and the minimum imaging
required is a plain radiograph of the entire bone. Early refer-
ral to and multidisciplinary involvement of an orthopaedic
surgeon are desirable to improve outcomes for the metastatic
bone disease patient and for improving their chance of recov-
ery by avoidance of the development of orthopaedic sequelae
(e.g. pathological fracture and spinal cord compression). The
availability of a bone metastases clinic and MDT may play a
role in the future of management of such patients.
Key Points
55 Over 8000 patients die with bone metastases from
breast cancer in the UK each year.
55 Bone metastases can present in many ways includ-
ing bone pain, impending or pathological fracture,
biochemical disturbance (particularly hypercalcae-
mia) or in routine staging imaging.
55 Early input from the orthopaedic surgeon is
imperative to the MDT management of the patient,
allowing surgical intervention where appropriate.
rares1geo@gmail.com
601 50
55 Appropriate radiological investigations and biopsy
are paramount in the management of the patient.
55 Orthopaedic surgical intervention can be varied and
includes prophylactic fixation, cement augmenta-
tion, endoprosthetic replacement and occasionally
amputation.
1. Cancer Research UK.  Breast screening statistics. Available from:
www.cancerresearchuk.org. [Accessed 26 Mar 2016].
2. Insa A, Lluch A, Prosper F, Marugan I, Martinez-Agullo A, Garcia-­
Conde J. Prognostic factors predicting survival from first recurrence
in patients with metastatic breast cancer: analysis of 439 patients.
Breast Cancer Res Treat. 1999;56(1):67–78.
3. Colleoni M, O’Neill A, Goldhirsch A, Gelber RD, Bonetti M, Thurli-
mann B, et  al. Identifying breast cancer patients at high risk for
bone metastases. J Clin Oncol. 2000;18:3925–35.
4. Mirels H. Metastatic disease in long bones: a proposed scoring sys-
tem for diagnosing impending pathologic fractures. Clin Orthop
Relat Res. 1989;249:256–64.
5. British Orthopaedic Oncology Society & British Orthopaedic Asso-
ciation. Metastatic Bone Disease: A guide to good Practice 2015
revision. Available from: http://www.boos.org.uk/wp-content/
uploads/2016/03/BOOS-MBD-2016-BOA.pdf [Accessed 18 Apr
2016].
6. Shibata H, et al. Diagnosis and treatment of bone metastasis: com-
prehensive guideline of the Japanese Society of Medical Oncology,
Japanese Orthopedic Association, Japanese Urological Association,
and Japanese Society for Radiation Oncology. ESMO Open.
2016;1(2):e000037. Accessed 31 Dec 2016. doi:10.1136/esmoo-
pen-2016-000037.
7. Ward WG, Holsenbeck S, Dorey FJ, Spang J, Howe D. Metastatic dis-
ease of the femur: surgical treatment. Clin Orthop Relat Res.
2003;415:s230–44.
8. Ashford RU, Hanna SA, Park DH, Pollock RC, Skinner JA, Briggs TWR,
Cannon SR. Proximal femoral replacements for metastatic bone dis-
ease: financial implications for sarcoma units. Int Orthop.
2010;34:709–13.
9. Abudu A, Carter SR, Grimer RJ. The outcome and functional results
of diaphyseal endoprosthesis after tumour excision. J Bone Joint
Surg Br. 1996;78-B:652–7.
10. Bernthal NM, Greenberg M, Heberer K, Eckardt J, Fowler EG. What
are the functional outcomes of endoprosthetic reconstructions
after tumour resection. Clin Orthop Relat Res. 2015;473(3):812–9.
11. NICE Clinical guideline [CG75]. Metastatic spinal cord compression
in adults: risk assessment, diagnosis and management. November
2008. https://www.nice.org.uk/guidance/cg75.
12. Stevenson JD, McNair M, Cribb GL, Cool WP. Prognostic factors for
patients with skeletal metastases from carcinoma of the breast.
Bone Joint J. 2016;98-B(2):266–70.
13. Galasko CSB.  Development of skeletal metastases. In: Skeletal
metastases. London: Butterworth; 1986. p. 21–51.
 603 51

Roles of Surgery and Modern

Radiation Techniques
in Metastatic Disease Affecting
the Brain
Garth Cruickshank

51.1 Introduction – 604

51.2 Numbers – 604

51.3 Pathology – 604

51.4 Clinical and Imaging Features – 606

51.5 Approaches to Treatment – 607

51.5.1 Medical – 607
51.5.2 Definitive Therapy – 607

51.6 Whole Brain Radiotherapy (WBRT) – 607

51.7 Surgical Resection – 608

51.8 Evidence – 609

51.9 Stereotactic Radiosurgery (SRS) – 609

51.10 Final Comments – 610

References – 611

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_51

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 604 G. Cruickshank
51.1 Introduction
Around 53,000 patients in the UK develop breast cancer
yearly. Some 15,000 develop metastatic disease, and it is esti-
mated that 5000 develop brain metastases accounting for
nearly 40% of secondary brain tumours second only to lung
51 cancer [1, 2]. The reported incidence is increasing largely due
to improved detection from diagnostic imaging and better
systemic treatments, enhancing survival until cerebral metas-
tases manifest [3]. The median length of time between breast
cancer diagnosis and diagnosis of brain metastases is
34  months [4]. Median survival with brain metastases
remains poor at 7–12 months. There is evidence that patients
with triple-negative and human epidermal growth factor
receptor 2 (HER2)-positive breast cancer have an increased
risk for the development of brain metastases [5].
There is mounting evidence from combined genetic data
from primary and secondary tumours to indicate biomarkers
for relative and/or conditional risk of cerebral metastatic
spread [6]. Treatment of cerebral metastatic disease has been
traditionally centred on whole brain irradiation (WBRT)
and/or supportive care as chemotherapy access to the brain
has been abrogated by poor blood brain barrier penetration.
Advances in surgery and in particular conformal stereotactic
radiosurgery (SRS) now offer a range of choices for a greater
proportion of these patients. With new data on surgical and
SRS safety and the potential for new drug treatments, there is
considerable debate on who, how and when to apply new
treatment strategies: the subject of this chapter.
51.2 Numbers
Although more than half of patients with metastatic breast
cancer will develop brain metastases at some time, less than
10% of patients present with cerebral metastases as their first
symptom. Of those who develop cerebral metastases, most
..      Fig. 51.1  MRI multiple cerebral breast cancer metastases. T1 plus
gadolinium contrast scan shows several variable sized lesions in the
cerebral hemispheres, cerebellum and brain stem. The midbrain lesion
(sagittal plane) shows a pineal region metastasis threatening CSF path-
rares1geo@gmail.com
will present approximately 2 years after initial primary diag-
nosis [1]. This is often at a time when systemic and/or pri-
mary disease is either controlled or absent suggesting that
pre-diagnostic micrometastatic disease with a latent period
for growth reflects the microenvironmental biology of the
cerebral compartment. Breast comes second to lung as a
source for brain metastases, but patients with melanoma
tend to have the highest incidence of cerebral metastases
overall (40–60%). Approximately 60–70% of brain metasta-
ses occur in those between the ages of 50 and 70 [7, 8].
It is difficult to accurately define the true incidence of
metastases in contrast to those presenting clinically. Post-
mortem studies have suggested that small or insignificant
multiple metastases are found in a very high number of
cases [9].
51.3 Pathology
Macroscopically breast-derived brain metastases are mostly,
when less than 2 cm in diameter, spheroidal and apparently
well demarcated from the surrounding brain tissue (see
. Fig. 51.1). However they may appear as cystic lesions at this
size, and more commonly appear cystic when larger, due to
central haemorrhage and necrosis. The apparent tumour
margin is probably indefinite as invasion into the surround-
ing brain frequently occurs along neovascular and residual
vessel structures originally responsible for metastatic aggre-
gate lodgement. On visual as well as magnetic resonance
imaging (MRI) assessment, metastases appear as discrete
circumscribed lesions at the junction between grey and white
matter. Many of these tumours appear to have a dural origin
similarly related to vasculature and frequently pose a differ-
ential diagnosis with more benign meningiomas (see
. Fig. 51.2b). The significance of noting local dural invasion
relates to surgical treatment where removal of the dural base
offers better clearance and lower risk of recurrence. There is
way drainage and incipient hydrocephalus as a further complication
of these lesions and a cause of headache and balance deterioration.
A ventriculoperitoneal shunt may be indicated. These cases are best
managed with WBRT
Roles of Surgery and Modern Radiation Techniques in Metastatic Disease Affecting the Brain
605 51
..      Fig. 51.2a–c  a T1 axial MRI
a
with contrast. Large left frontal
metastasis – unsuitable for any
RT and best managed by cra-
niotomy and surgical removal,
as demonstrated b T1 axial MRI
with contrast. 3+ cm midline left
occipital lesion with dural base
with immediate postoperative
view showing good excision of
mass lesion c T1 axial MRI with
contrast. 2.7 cm lesion involving
motor strip on the right side.
Surgical excision involved pre-
operative magnetic stimulation
to mark out active motor strip
components and preoperative
electrocortigraphy (mapping) to
define approach to removal of
this lesion. Immediate postopera-
tive scans confirm removal with
minimal haematoma in resection
b
bed and no deficit

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 606 G. Cruickshank
little evidence to suggest that routine internal seeding of
metastases occurs by cerebral spinal fluid (CSF) pathways,
but there is some evidence that local seeding around prior
operations can certainly occur as opposed to failure to
remove the local lesion.
Histologically breast metastases resemble the primary
51 lesion. Occasionally frozen section will be indicated where
diagnosis is in question. However it is the presence of known
primary disease that makes the likelihood of a new cerebral
lesion being secondary disease greater than 90% [10].
Immunohistochemistry can identify the primary origin:
Breast tumours are positive for cytokeratin 7 as are lung, gas-
trointestinal tract (GIT) and ovary. Most lung tumours how-
ever are positive for TTK unlike breast, and cytokeratin 20 is
positive in breast and lower GIT. The presence of oestrogen
and progesterone receptors might support a diagnosis but
can be present in secondaries from other sites. Gross cystic
disease fluid protein (GCDFP15) expression is a useful posi-
tive marker for breast origin where present and lack of E cad-
herin expression is useful particularly in lobular carcinomas.
51.4 Clinical and Imaging Features
Two thirds of brain metastases are symptomatic during the
patient’s lifetime. The signs and symptoms are the same as for
any other slowly expanding intracranial lesion ultimately
resulting in raised intracranial pressure. There are three main
symptoms: seizures, focal symptoms and signs and head-
aches.
Seizures  Up to 20% of patients with metastases will present
with seizures. However around 50% will have seizures at some
time in their illness. New onset seizures are better treated with
early introduction of effective antiepileptic drugs (AEDs) such
a Levetiracetam 250–500 mg bd rather than steroids, although
the latter may be required where there is obvious evidence of
cerebral oedema on T2-weighted MRI or CT scanning or addi-
tional indications of globally raised intracranial pressure.
Seizures most commonly are focal in nature but may present
acutely with a major convulsion. Prolonged seizures in patients
with intracranial metastases is an emergency even with focal
seizures, as ensuing brain swelling added to existing oedema
can result in dramatic brain swelling and death.
Focal Symptoms and Signs  As well as focal seizures suggesting
a locus for an intracranial lesion, progressive loss of function,
hemiparesis and hemianopia can be useful indicators of the
presence of an expanding lesion. Where the pattern reflects
more than one metastasis, the clinical signs can help decide
which is the most potentially harmful in terms of clinical
impact. Hence the assessment of focal symptoms and signs
may be confounded by suggesting more than one location
where multiple lesions are present. Sudden focal deterioration
can occur often suggestive of a «stroke», but CT/MRI scan-
ning may indicate haemorrhage associated with a metastatic
deposit.
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Headache  This occurs in less than 50% of patients with intra-
cranial metastases and classically reflects a later stage in the
disease where the cumulative mass effect of the tumour or
tumours and their associated oedema results in raised intracra-
nial pressure. In these situations assessment for papilloedema
as part of the examination is mandatory to assess the risk of
acute deterioration. Headache due to raised intracranial pres-
sure from tumour-related mass effect is a neurosurgical emer-
gency, and advice should be sought immediately. The rapid
introduction of intravenous or oral dexamethasone (with gas-
tric protection) is advocated.
Headache may also occur where the lesions are attached
to the dural surface towards the midline or in the middle
fossa or to the falx itself. Probably local inflammation and
associated direct trigeminal innervation are responsible (see
. Fig. 51.1).
Most importantly in patients with known primary or
metastatic breast cancer, any patient with unexpected new
neurological symptoms should be carefully screened and
imaged for spread of disease to the CNS. For patients without
a history or evidence of previous or coexisting cancer, the
likelihood of a single brain lesion being a metastasis is less
than 15%.
Immediate screening of patients with suspicious symp-
toms and signs is frequently performed with CT head scans.
To enhance and expedite MDT decision-making where
intracranial lesions are seen, MRI head scanning is essential,
and in some tumour types, or where symptoms are sugges-
tive of CNS involvement outside the cranium, e.g. thoracic
pain, imaging should include the whole cranio-spinal axis.
Commonly patients with isolated cranial lesions will need
staging or screening with CT of the chest, abdomen and
pelvis for the multidisciplinary team/tumour board (MDT)
to be in a position to decide on action. Contrast-enhanced
MRI is more specific and much more sensitive at showing
up small or multiple lesions. It is also critical for determining
lesions in the cerebellar or posterior fossa area where bone
shadows make CT interpretation unreliable. MRI slice thick-
ness tends to be finer, and hence the chance of visualising
small lesions for both radiotherapy planning and monitoring
is improved. Increasingly units offering access to both stereo-
tactic radiosurgery (SRS) and surgery for these patients will
request specific thin cut planning scans that can be used for
image-directed surgery and/or fused with CT scans or alone
for RT planning. With enhanced T1-weighted MRI scans,
metastatic deposits show as discrete areas of increased signal
intensity (white spots) with a tendency to a ringlike appear-
ance as the size of the lesions increases. Not infrequently con-
trast penetration and retention is time- and dose-dependent,
and where there is doubt about a lesion’s nature or presence,
then the use of double-dose contrast can be useful. This lat-
ter approach is especially useful for SRS planning. Tumour-­
related oedema is often considerably greater than one might
expect for the size of the lesion and is usually well seen on
T1-weighted (decreased intensity) imaging but often more
measurable and visible on T2 scans where the parenchymal
«white signal» is seen. Cystic metastatic tumours may have a
Roles of Surgery and Modern Radiation Techniques in Metastatic Disease Affecting the Brain
thicker wall than that seen in high-grade gliomas, but there
is little to separate these from the appearances of an abscess
cyst except the obvious clinical presentation. Tumours
adherent to the dura or falx need careful anatomical review
to clarify the local extent on this surface for both surgical
and SRS planning. It is not possible to resolve the degree of
local invasion of the tumour deposits from either very clear
or fuzzy margins on MRI imaging. There is some suggestion
paradoxically that sharp imaging margins may need more
careful examination of adjacent vessels at surgery for tumour
involvement.
Diffusion-weighted imaging may offer some help with
deciding on the extent of additional resection required, but
the data so far is anecdotal. MRI/ADC mapping may offer
information on very early responses to treatment in residual
lesions and hence may be a method for evaluating new (med-
ical) therapies. Magnetic resonance spectroscopy (MRS) can
be helpful in particular situations where the differentiation
between glioma, abscess, lymphoma and metastasis is in
question.
51.5 Approaches to Treatment
51.5.1 Medical
Patients with symptoms related to their brain metastases
usually obtain both focal and global benefit from the early
introduction of oral steroids. Dexamethasone is normally
available in 0.5 and 2  mg tablets. Up to 16  mg per day in
divided doses can be very effective and should be accompa-
nied by a single morning dose of a gastric protectant such as
lansoprazole 30  mg or omeprazole 10  mg. The neuro-­
beneficial effects come on within hours, but care is needed
with diabetic patients that glucose levels do not rise unac-
ceptably. Prolonged use of steroids will often cause a
Cushingoid appearance and hence an additional burden on
already debilitated patients. A few, mostly older, patients can
develop steroid-related psychological changes, even psycho-
ses that can be misconstrued as tumour-related deterioration
and exacerbated by dosing in the evenings which can lead to
disturbed sleep patterns. With early control of symptoms
with higher steroid doses, the dose should be reduced and
titrated against symptoms to reduce or limit the risks of con-
founding steroid-induced proximal myopathy. The longer-
term problems with steroid use are well known including
hypothalamic-­ pituitary-­
adrenal axis suppression where
patients have been taking steroids for more than 6 weeks and
profound osteoporosis which can lead to vertebral bone pain
from microfracturing as well as fractures from avascular
necrosis in the hip and long bones. Careful management of
steroid dosing is an important and essential part of these
patients’ care. Every effort should be made to reduce steroids
to the lowest dose required, and indeed one of the benefits of
cranial surgery may be to help achieve this.
Concomitant medications may need review especially
diabetic treatment for patients on steroids. It is useful if sur-
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607 51
gery is being considered to review the use of antiplatelet
therapies including routine aspirin as this may delay access to
surgery.
51.5.2 Definitive Therapy
The treatment of brain metastases is based on the selected
use of surgical resection and/or radiation therapy.
Determining how best to use these techniques depends firstly
on the number, size and location of the lesions. Secondly the
general health of the patient and the staging of their systemic
disease and their neurological performance provide a crucial
basis for decision-making and are strong indicators of the
outcome from intervention. Thirdly it is necessary to con-
sider the likely radiosensitivity of the lesions and their likely
response to systemic therapies based on their molecular sub-
type (Her2 receptor expression, ER receptor expression, for
example) and the bioavailability of suitably targeted agents in
the brain. Consideration of these three main areas informs
the MDT discussion and allows the team to direct approaches
to patients with controlled primary disease with the objective
of long-term cure/control of disease in the brain or more pal-
liative control towards improvement in quality of life for
patients with both extracranial and brain lesions. Graded
prognostic assessments (GPA) may provide a basis for strati-
fying molecular-defined patient groups for further interven-
tional studies, with Her2-positive patients harbouring
cerebral metastases showing improved survival over Her2
negative [11].
51.6 Whole Brain Radiotherapy (WBRT)
The use of whole brain radiation therapy for the treatment of
brain metastases offers a seemingly simple and non-invasive
way of treating the entire brain and hence would appear ide-
ally suited to treating multiple metastases, and there is good
evidence that breast and lung cancers demonstrate relative
radiosensitivity by comparison with melanoma or renal cell
tumours.
For many patients the presence of multiple deposits with
very small or apparently microscopic collections makes this
the only really viable treatment that can be offered. However
it is increasingly recognised that large volumes of normal
brain are exposed to ionising radiation, and in situations
where the expectation of good control or cure means that life
expectancy is increased, then it might be questioned whether
preservation of normal function may be threatened despite
fractionated treatments. Brain tissue sensitivity to RT is vari-
able and depends on the total dose, fraction size, volume and
dosing interval. Acute side effects from a multiple fraction
course to the brain include hair loss, headaches, nausea, oti-
tis media and very commonly lethargy with all-pervading
tiredness and on occasion acute skin irritation and desqua-
mation. The symptoms of fatigue can take several weeks to
abate after the RT course, and patients may be left with this
 608 G. Cruickshank
as their major chronic symptom. A further acute issue can
be dramatic brain swelling that can require large (even very
large) dose of steroids, and on occasion acute decompressive
surgery may be considered appropriate. A number of
patients see their lethargy develop into a «somnolence syn-
drome» characterised by a chronic debilitating fatigue [12].
51 Late effects are also well recognised including atrophic
change in the brain with associated memory or cognitive
deficits, radiation necrosis that can masquerade as a new or
recurrent tumour mass, progressive white matter disease
(leucoencephalopathy) and with mainly frontal RT, a
dementing disease which may or may not be associated with
apparent small vessel inflammatory or vasculopathic
changes. The risk of secondary induced tumours runs at
approximately 1 in 2000 cases. Numerous attempts to under-
stand the critical factors have pointed clearly to dose and
particularly fraction sizes as related to neurocognitive prob-
lems, with induced leucoencephalopathy, and damage to
small blood vessels markedly increasing above fraction
doses of >2 Gy [13, 14]. There thus becomes the issue of the
burden of radiation therapy duration in palliative-intent
patients versus the increased risk of side effects from short-
ening treatment regimens by using higher dose fractions.
Usual current fractionation schedules thus compromise to
deliver 30 Gy in 10 fractions where the aim is rapid stabilisa-
tion for palliative control and 40 Gy in 20 fractions where
the aim is longer-term disease control.
WBRT as primary therapy should be considered for all
patients with multiple brain metastases particularly for
patients with breast metastases where radiosensitivity is
good. In patients with single metastases or with multiple
metastases but with individually large space-occupying
lesions, surgery has a role to play. WBRT may also be the
treatment of choice in patients with extensive comorbidity or
who are at high risk for surgery or SRS. It also may have ben-
efit as an adjuvant treatment if given after surgery to reduce
the risk of local recurrence, as discussed below.
51.7 Surgical Resection
The surgical excision of cerebral metastases has become an
important treatment option. It is the only process which
allows the establishment of a histological diagnosis, as 11% of
patients with known primary breast cancer have lesions that
are not metastatic. Surgery rapidly relieves symptoms by
reducing local and intracranial pressure and removing the
source of oedema allowing the rapid reduction in steroid use,
a significant problem complicating SRS and WBRT treat-
ments. Surgery is possible and very effective against larger
tumours >3 cm (see . Fig. 51.2). It also offers focal control of
 
disease in the brain where systemic treatment, e.g. trastu-
zumab, cannot penetrate, thus often offering a low morbidity
alternative to RT.  Overall surgical resection rates for single
metastases are associated with median survivals of
8–16 months and local recurrence rates of 7–15% [15, 16].
Patients who go at least 1 year from surgery without signs of
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recurrence on imaging have a high likelihood of remaining
free of local recurrence at the resected site (<5%). Access to
tumours using image-directed neurosurgery allows safe tra-
jectories and minimal disturbance to brain tissue
(. Fig.  51.2b). Such approaches where surgery will extend
close to eloquent areas can now undergo preoperative func-
tional assessment with either functional MRI or, perhaps bet-
ter, magnetic mapping to determine the potential safety of
planned resection. At operation cortical stimulation can pro-
tect motor strip-related brain in close proximity to the surgi-
cal site (neuromonitoring) (see . Fig.  51.2c). Awake
craniotomy can also enhance safety in «at risk» areas with
increasingly reliable speech mapping and use of «silent area»
corticotomy to access subcortical lesions. Coupled with real-­
time information from intraoperative ultrasonography or
intraoperative MRI (where available), even deep-seated
lesions may be considered for surgery. Overall there is an
increasing amount of data to suggest that neurosurgeons can
expect to keep morbidity below 10% and mortality, given the
often debilitated state of patients, below 5% [15]. Clearly in
patients with a limited survival expectation, a short postop-
erative recovery period from low morbidity surgery is highly
desirable (see . Fig. 51.3).
Tumour removal during surgery still offers a challenge to
reduce local recurrence rates as low as possible [16]. These
tumours will often apparently be removable en bloc, and
neurosurgeons feel less fragmentation is associated with
lower recurrence rates [17, 18]. There is some evidence to
support this, and increasingly the focus is on the immediate
brain tumour interface and adjacent or attached feeding ves-
sels as the key to improved local control from surgery. Co-­
removal of a clear rim of brain tissue albeit swollen from
oedema may be expected to increase local control by removal
of local invasion, but the evidence is inconclusive and the
elastic nature of these feeding vessels retracting into normal
brain during resection is a potential problem. Where meta-
static disease is attached to the dura, there is evidence that
removal of the dural component along with the tumour does
improve local control. Where this is not possible, then metic-
ulous local diathermy to the whole thickness of the dura
should be performed. Large tumours may have to be removed
piecemeal and hence seem to carry a greater risk of local
recurrence.
Neurosurgical Treatment of Cerebral Metastases
1. Allows confirmation of Histology
2. Allows Rapid relief of Symptoms
3. Abolishes need for prolonged use of Steroids
4. Enables effective treatment of larger otherwise untreatable
lesions
5. Allows Secondary treatment post WBRT in selected patients
6. Provides an alternative management pathway to avoid
WBRT induced congnitive decline
..      Fig. 51.3  Table of benefits from neurosurgical treatment of cere-
bral metastases
Roles of Surgery and Modern Radiation Techniques in Metastatic Disease Affecting the Brain
Surgery is most appropriately directed at patients with
single lesions, limited systemic disease and a good perfor-
mance level. An important practical issue is that lesions
larger than 3 cm are unsuitable for SRS and poorly controlled
with WBRT and best treated with surgical excision.
51.8 Evidence
Data from surgical studies in metastases is complicated by
the inclusion of tumours of different origins and using differ-
ent endpoints, i.e. local control versus survival. Hence Mintz
and colleagues showed no advantage of surgery plus WBRT
over WBRT in terms of survival in patients with a single
metastasis [19]. But in most of these patients (73% with
advanced disease), survival was dictated by the systemic dis-
ease. Other studies have shown surgery plus WBRT superior
to surgery alone, but on closer examination of the patients in
these two studies, those with a good performance status and
limited systemic disease lived significantly longer, had fewer
recurrences and had a better quality of life than patients
treated with WBRT [20].
What about the value of surgery where more than one
metastasis is present? Studies evaluating the true value of sur-
gery where up to three lesions were removed versus removal of
just some of the lesions showed significant improvements in
survival (14 months versus 6 months) for total removal over
partial removal [21]. Furthermore survival in the totally
resected group was the same as for a control group of patients
with a single metastasis undergoing resection. Thus evidence
would favour surgery where systemic disease load is limited
and life expectancy better than 3 months for one to three lesions
especially if they are large and perhaps less radiosensitive.
Surgery in the spectrum of patients with multiple metas-
tases is indicated where one or more of the lesions are caus-
ing symptomatic problems or is life threatening, where
removal can reverse deterioration and provide a window of
opportunity to treat residual lesions with either SRS or
WBRT.
More recent studies have compared surgery with surgery
plus WBRT and have demonstrated a reduction in the rate of
local recurrences but without much impact on overall sur-
vival. In the WBRT-treated patients, the side effects of RT
were significant and troublesome such that the authors rec-
ommended a hypofractionated course for patients with little
sign of disease after resection [22].
A phase III study compared the impact of WBRT after
surgery versus surgery alone and stratified patients by the
extent of disease and tumour type. Tumour recurrence was
markedly lower in patients receiving additional radiation
with a clear reduction in recurrence at the surgical site. The
EORTC study has shown that SRS or WBRT after surgery
reduced local recurrence rates but had no effect on overall
survival. Also the rate of decline and toxicity in these patients
was similar suggesting that there was no major gain from
WBRT and providing little additional benefit for patients.
These data have thus provided some support for withholding
rares1geo@gmail.com
609 51
additional RT. In the WBRT arm, not only was there no sur-
vival advantage but QOL studies showed worse values than
in the WBRT arm [23]. This has certainly posed questions for
the treatment of radioresistant metastases such as melanoma
and renal cancer but also in more radiosensitive tumours
where improved overall chances of survival question the
price paid in QOL for WBRT, as withholding WBRT did not
result in a higher rate of distant recurrence. This of course
might reflect the fact that with primary disease control,
metastases seen are those actually treated and hence con-
trolled, and this fits with our understanding that seeding in
the brain probably occurs early and ceases when the primary
disease is controlled.
51.9 Stereotactic Radiosurgery (SRS)
SRS enables precise volumetric conformal dosing of small
0.5–2.0 cm lesions in a single treatment using multi-­trajectory
beams collimated to the profile of the lesion. Such an
approach dramatically limits, but does not completely abol-
ish, the overspill of radiation to surrounding tissues and
hence can rightly be described as radiosurgery (see
. Fig.  51.4). It is an outpatient procedure, nowadays, not
requiring the use of stereotactic frames to be attached to the
patient. It is thus minimally invasive, well accepted by
patients, low risk and with modern planning and delivery
systems able to treat several lesions in one session. Advantages
include the ability to access single lesions in surgically inac-
cessible regions and lack of delay from waiting for s­ urgery or
recovery (see . Fig.  51.5). Unfortunately, response time is
considerably slower than the immediate impact of surgery
and may well require prolonged steroid usage. Other disad-
vantages include no histology and increasing difficulty with
overlap of fields with multiple lesions. Although acute prob-
lems are few, they can be troublesome with intratumoural
haemorrhage (5–8%) and worsening of brain swelling and
seizures. A further issue is the fall-off in efficacy and local
control with increase in lesion size: 86% local control for a
1  cm or less tumour versus 56% local control for tumours
greater than 1 cm [24]. Several studies have compared SRS
alone to SRS plus WBRT for one to four lesions. WBRT
added does seem to improve overall control but is associated
with a fall-off in QOL [25].
Clinical monitoring post-SRS can also be complicated by
apparent tumour increase and symptom worsening in the
first 6  weeks or so, before control and/or decrease in vol-
ume. Patients undergoing SRS or surgery are best then fol-
lowed up for at least 1 year with 2-monthly MRI scans in a
multidisciplinary clinic before returning to usual oncology
follow-up.
On balance SRS offers significant benefits for single- and
low-volume multiple metastases (? < 5), and we can integrate
this modality of treatment for cerebral metastatic disease to
identify three categories of patients: those with tumours
greater than 3 cm for whom surgery is the best option, those
with surgically inaccessible lesions <1.5 cm for whom WBRT
 610 G. Cruickshank
..      Fig. 51.4  Pre-SRS and 6 weeks
post-SRS to single small temporal
metastasis
51
..      Fig. 51.5  SRS planning desk showing isodose line for two metastases in proximity on the tentorial edge. The post-treatment scan is taken at
6 weeks
would have been the only alternative and for whom SRS
offers the best choice and those with small 1.5–3 cm lesions
in accessible sites for whom we can select the treatment likely
to afford the best local control.
51.10 Final Comments
Patients with tumours greater than 3 cm, especially where the
lesion is symptomatic, will do better with surgery, obtain
faster relief and will usually require less in the way of steroid
use. Small lesions <1.5  cm, particularly in difficult regions,
are best treated with SRS. Patients with lesions between these
limits would have their treatment selected by virtue of their
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symptoms and with those who are symptomatic treated with
surgery as long as their comorbidity profile or access risk
does not preclude this (see . Fig. 51.6).
WBRT will still be needed for the many patients who do
not fit into this pattern; however with these choices and with
the possibility of systemic control of disease, a decision now
facing clinicians and patients is whether the well-known cog-
nitive risks of WBRT can be avoided, even temporarily, by
the judicious use of SRS or surgery combined with regular
MRI follow-up. The increasing technical advances in surgery
coupled with our increasing understanding of what is
required from the surgical process offer increasing chances of
extended local disease control with reduced morbidity and
long-term preservation of function.
Roles of Surgery and Modern Radiation Techniques in Metastatic Disease Affecting the Brain
611 51
..      Fig. 51.6  A decision model
for managing patients with cere- Current Decision Model for Management of Cerebral Metastases
bral metastases based on size,
Lesions 1.5 - 3cm
symptoms and clinical status Lesions < 1.5 cm Lesions > 3 cm

Stereotactic RadioSurgery MDT Decision Surgery

Inaccessible Accessible
Radiosensitive Radioresistant
Asymptomatic Symptomatic
CoMorbidity Low CoMorbidity
Advanced Disease Controlled or minimal systemic
WBRT disease
Multiple > ? 5 lesions

References 13. Klein M, et al. Neurobehavioral status and health-related quality of

life in newly diagnosed high-grade glioma patients. J Clin Oncol.
2001;19(20):4037–47.
1. Gavrilovic IT, Posner JB. Brain metastases: epidemiology and patho-
14. Laack NN, Brown PD. Cognitive sequelae of brain radiation in adults.
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Semin Oncol. 2004;31(5):702–13.
2. Soffietti R, Ruda R, Mutani R.  Management of brain metastases. J
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3. Soffietti R, et  al. A European Organisation for Research and Treat-
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ment of Cancer phase III trial of adjuvant whole-brain radiotherapy
resection of a single brain metastasis. J Neurosurg. 2010;113(2):181–9.
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17. Suki D, et  al. Comparative risk of leptomeningeal disease after
from solid tumors after surgical resection or radiosurgery: quality-
resection or stereotactic radiosurgery for solid tumor metastasis to
of-life results. J Clin Oncol. 2013;31(1):65–72.
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4. Rostami R, et al. Brain metastasis in breast cancer: a comprehensive
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5. Aversa C, et al. Metastatic breast cancer subtypes and central ner-
tentorial solid tumor metastasis. Neurosurgery. 2009;64(4):664–74.
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6. Pangeni RP, et  al. The GALNT9, BNC1 and CCDC8 genes are fre-
19. Mintz AH, et al. A randomized trial to assess the efficacy of surgery
quently epigenetically dysregulated in breast tumours that metas-
in addition to radiotherapy in patients with a single cerebral metas-
tasise to the brain. Clin Epigenetics. 2015;7:57.
tasis. Cancer. 1996;78(7):1470–6.
7. Barnholtz-Sloan JS, Sloan AE, Schwartz AG. Racial differences in sur-
20. Slotman B, et al. Prophylactic cranial irradiation in extensive small-
vival after diagnosis with primary malignant brain tumor. Cancer.
cell lung cancer. N Engl J Med. 2007;357(7):664–72.
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21. Bindal RK, et al. Surgical treatment of multiple brain metastases. J
8. Hojo S, Hirano A. Pathology of metastases affecting the central ner-
Neurosurg. 1993;79(2):210–6.
vous system. In: Metastatic tumours of the central nervous system.
22. Patchell RA, et  al. Postoperative radiotherapy in the treatment
Tokyo: Igaku-Shoin; 1982.
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9. Amer MH, et al. Malignant melanoma and central nervous system
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23. Kocher M, et al. Adjuvant whole-brain radiotherapy versus observa-
1978;42(2):660–8.
tion after radiosurgery or surgical resection of one to three cerebral
10. Patchell RA, et  al. A randomized trial of surgery in the treatment
metastases: results of the EORTC 22952-26001 study. J Clin Oncol.
of single metastases to the brain. N Engl J Med. 1990;322(8):
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494–500.
24. Shinoura N, et al. Local recurrence of metastatic brain tumor after
11. Sperduto PW, et al. The effect of tumor subtype on survival and the
stereotactic radiosurgery or surgery plus radiation. J Neuro-­Oncol.
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2111–7.
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12. Sawaya RBR, Lang FF, Suki D.  Metastatic brain tumours. In: Brain
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vier; 2012. p. 866–94.

rares1geo@gmail.com
 613 52

Local Therapies for Liver

Metastases from Breast Cancer
Robert P. Jones, Hassan Z. Malik, and Carlo Palmieri

52.1 Introduction – 614

52.2 Hepatic Resection – 614

52.3 Radioembolisation – 616

52.4 Stereotactic Beam Radiotherapy – 617

52.5 Conclusions – 617

References – 617

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_52

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 614 R.P. Jones et al.
52.1 Introduction
Breast cancer is a leading cause of morbidity and mortality
with 53,696 new cases diagnosed in 2013  in the UK alone
[1]. Despite the improvements in outcomes seen over the
past 30 years due to early diagnosis and improved local and
systemic therapies, around 30% of women will subsequently
develop metastatic disease [4].
52 Around 10% of all metastatic lesions are found in the liver
[5], with the liver being the sole site for metastases in between
5% and 25% of cases (see . Fig. 52.1) [6]. Specific cancer sub-
types [2, 3] are associated with differing patterns of metastatic
a control may be achieved by their removal or obliteration. The
b resection of 40 months (range 23–77). Although the number
..      Fig. 52.1  a Contrast CT demonstrating solitary liver lesion in the
right hemi-liver detected on routine CT scan 4 years after lumpectomy
for breast cancer. b Positron emission topography scan of the same
patient showing a PET-avid lesion in the liver, with no extrahepatic
disease
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distribution [7, 8], with HER2-­positive tumours showing a
particular propensity to spread to the liver [7]. The current
standard of care for such patients is palliative systemic ther-
apy dependent on biological subtype [2, 3], prior treatment
and patient performance status. Whilst the development of
sequential lines of systemic therapy including targeted agents
in metastatic breast cancer has led to significant improvements
in disease control and long-term outcomes, all these treat-
ments are limited by de novo and acquired resistance which
inevitably lead to disease progression. There is now growing
interest in whether organ-directed therapy or local treatment
for liver-limited disease may improve outcomes. The rationale
for liver-directed therapies in these patients appears attrac-
tive. The presence of oligometastatic disease may represent a
state of limited metastatic spread, where potential long-term
clonal selective pressures of prior treatment may select for
resistance to systemic treatment, and these lesions may there-
fore be less likely to respond to systemic treatment. Evolution
in systemic therapy (chemotherapy, biologicals) has led to sig-
nificant improvements in patient survival, but these improved
outcomes have come at an exceptional financial cost [9, 10],
and local therapy may also therefore offer a more cost-effective
treatment strategy than systemic treatments.
52.2 Hepatic Resection
Numerous small series have reported on outcomes after liver
resection for breast cancer metastases. A 2011 systematic
review [11] identified 19 studies over an 11-year period report-
ing on hepatic resection of at least ten patients. Hepatectomy
was performed infrequently, with an average of 1.8 (range 0.7–
7.7) cases per year in reported series. Although metastatic dis-
ease is now almost universally considered synchronous (with
occult micrometastases already present at diagnosis and treat-
ment of the primary), patients selected for resection had slowly
progressive disease with a median time between diagnosis and
of resections for breast cancer metastases was low, all were per-
formed in high volume liver resection centres, and so mortal-
ity and morbidity after surgery were low at 0% (range 0–6%)
and 21% (range 0–44%), respectively, in keeping with reported
rates after resection for other liver lesions. Median overall sur-
vival from hepatectomy was 40 months (range 15–74) with a
median 5-year survival rate of 40% (range 21–80). Although
these results appear impressive, all the included studies were
retrospective ­single-­centre series without a comparator group.
In addition, all used different patient selection criteria and
medical treatment protocols, and so prognostic markers were
difficult to identify. The authors suggested that a histologically
positive margin after liver resection and hormone refractory
disease were associated with inferior long-term outcomes,
although the impact of case selection itself on outcome cannot
be assessed and may have had a profound effect on observed
survival rates as has previously been suggested in mathemati-
cal modelling studies [12]. In addition, the impact of improved
Local Therapies for Liver Metastases from Breast Cancer
615 52
radiotherapy after breast surgery, treatment with hormonal
therapy, number of metastases, time from breast cancer diag-
1.0
nosis to metastases and type of breast surgery. The selection
for surgical intervention was performed on a case-by-case
0.8 basis at a multidisciplinary meeting where a consensus con-
cerning resectability and appropriateness of liver resection
were determined. Most presented as metachronous disease,
0.6
Probability

had one or two liver metastases, unilobar in distribution

and a longer interval between breast cancer detection and
0.4 diagnosis of metastases as compared to the medical cohort.
Interestingly, the percentage of patients who underwent
ST
hepatectomy and/or ablation declined from 54% in the first
0.2
half of the study period (1991–2002) to 36% in the latter half
NST (2003–2014). Surgery was safe, with a 0% 90-day mortality
0.0 and 23% 90-day morbidity. Patients in the surgical cohort
0 24 48 72 96 120 144 168 more frequently had oestrogen receptor-positive tumours
Time (months) and received adjuvant chemotherapy and radiotherapy for
their primary breast tumour. The hepatic tumour burden
was less, and the interval from breast cancer diagnosis to
..      Fig. 52.2  Mariani and colleagues performed a case control series detection of metastases was significantly longer (53 months
which suggested improved overall survival after liver resection for vs. 30  months) in the surgical cohort. Patients undergoing
breast metastases [13]. A statistically significant difference was dem-
onstrated using the log-rank test (p < 0.0001) (Reprinted from Mariani
surgical treatment had a median recurrence-free interval of
et al. [13] with permission from Elsevier) 28.5  months (95% confidence interval CI: 19–38) with ten
patients (15%) recurrence-free after 5 years. Despite the high
case selectivity (which appeared to increase through the study
systemic therapy for metastatic disease over the 11-year study period), there was no significant difference in overall survival
period could not be assessed. (OS) between the surgical and medical cohorts (median OS
Since this review, two case-control series have been 50 vs. 45  months; 5-year OS: 38% vs. 39%). However, over
published that offer the advantage of a comparator group. half the patients were free of recurrent disease and off chemo-
Mariani and colleagues [13] reported a case-matched control therapy for 2 years after resection, which the authors high-
study of 51 highly selected patients with stable breast can- lighted as having significant implications in terms of quality
cer liver metastases and compared medical treatment alone of life and cost of therapy. It is important to also note in this
versus surgery plus medical treatment. Patients were selected context that surgery and ablation are now safe therapies asso-
for surgery if they had technically resectable liver metasta- ciated with short-lived and manageable morbidity.
ses (≤4) and demonstrated at least disease control with sys- Spolverato and colleagues [15] attempted to character-
temic therapy. No extra hepatic disease was allowed apart ise this putative benefit further by performing a cost-utility
from controlled bone metastases. Patients were matched for analysis of liver resection combined with systemic therapy
known prognostic factors (such as stage, hormone receptor versus systemic therapy alone and suggested that liver
status and histopathological subtype) as well as the year of resection in patients with breast cancer liver metastasis was
diagnosis to account for evolution in palliative treatment cost-­effective, particularly when used for oestrogen receptor-
outcomes over time. The authors suggested that patients positive tumours or when newer biological agents (letrozole
undergoing surgery plus systemic therapy had better survival and palbociclib for ER + patients; docetaxel, trastuzumab or
compared with chemotherapy alone with a 3-year disease-­ pertuzumab for HER2  +  patients) were used. For example,
specific survival of 81% versus 51%, respectively (P < 0.001) Markov modeling suggested that for patients with ER+
(see . Fig.  52.2). Multivariate analysis suggested a relative disease, surgery combined with letrozole gave a net health
 

risk of 3.04 (CI: 1.87–4.92) (p < 0.0001) in favour of surgical benefit (a combination measure of survival benefit and incre-
treatment, although median follow-up was not reported. The mental cost) of 10.9 quality-adjusted life months compared
authors identified the nodal status of the primary disease, the with chemotherapy alone. By contrast, resection plus che-
number of regimens of systemic therapy to achieve disease motherapy was not as cost-effective for patients with HER2+
control, the presence of bone metastases and surgical resec- tumours with a net health benefit of 0.3 quality-­adjusted life
tion of liver metastases as independent prognostic markers of months compared with treatment with trastuzumab-­based
long-term survival. systemic therapy.
The Memorial Sloan Kettering Cancer Center (MSKCC) As well as formal surgical resection, there is limited evi-
group published a 167-patient case-control series compar- dence surrounding thermal ablation of breast cancer liver
ing medically treated patients and those treated with surgi- metastases. Meloni and colleagues [16] reported 52 patients
cal resection +/−ablation [14]. Patients were matched for ER undergoing ultrasound-guided radiofrequency ablation.
status, adjuvant chemotherapy after breast surgery, adjuvant Worryingly, local tumour progression occurred in 25%  –

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616 R.P. Jones et al.

significantly higher than the reported lesional recurrence CT scan, survival was dismal (median 3.6 months). However
rate after the ablation of colorectal liver metastases (≈4% responders experienced a longer survival, which, with a fol-
[17]). Whether this is due to technical issues or differences low-­up of 14 months, had not yet reached median.
in underlying disease biology remains unclear. The authors Haug and colleagues assessed functional response to SIRT
reported a median and 5-year survival rate of 30 months and as measured by 18-FDG PET/CT as a potential predictive bio-
27%, respectively. Mack and colleagues [18] described a tech- marker [20]. Fifty-five consecutive patients with irresectable
nique using magnetic resonance image-guided laser ablation chemo-refractory breast cancer liver metastases were treated
using laser-induced interstitial thermotherapy applied in 232 with SIR-Spheres with a mean of 1.8  GBq SIRT.  Overall
52 patients where median survival was 52  months and 5-year median survival was 47  weeks. Response (defined as >30%
survival was 41%, with a more reasonable lesional failure rate reduction in SUV(max)) correlated significantly with survival
of 5%. However, comparisons with surgical resected or medi- (responders median 16.2  months vs. 10.8  months for non-
cally managed patients are impossible. responders, p  <  0.05). On multivariate analysis, change in
SUV(max) was identified as the only independent predictor of
survival (hazard ratio, 0.23; P < 0.005). Furthermore, a high
52.3 Radioembolisation pre-therapeutic SUV(ibid) (>20) was associated with a signifi-
cantly shorter median survival.
The unique blood supply of the liver, with portal flow supply- Cianni and colleagues [21] then reported on a further 52
ing healthy hepatic parenchyma and arterial flow supplying patients treated in the same fashion. Inclusion criteria were
metastatic disease, has led to the concept of delivering liver-­ liver-dominant inoperable chemo-refractory metastases.
only therapy in an effort to increase metastatic exposure to the Hepatic involvement was reported as less than 50% for the
agent whilst reducing the systemic dose and off-target side- majority of patients, with bilobar distribution in approxi-
effects. Radioembolisation involves the delivery of yttrium- mately two thirds. As such, the underlying biology of these
90-loaded resin microspheres, which are pure β-emitters with patients was likely markedly different to those selected for
a half life of around 65 h, to the liver in an effort to provide surgery. Disease control at 3  months after a median treat-
local radiotherapy (SIRT, selective internal radiotherapy). The ment dose of 1.92  GBq was seen in 90% of subjects, with
total dose delivered depends on the number of microspheres a median survival of 11.5  months. Two patients developed
delivered but is typically between 2 and 3 GBq. severe hepatic failure after treatment, although both had
Three retrospective studies have assessed the efficacy >50% liver replacement with metastases.
of SIRT in liver-limited breast cancer (see . Table  52.1).   Two prospective studies have also been performed.
Coldwell and colleagues [19] treated 44 women with symp- Bangash and colleagues [22] performed an open-label phase
tomatic liver metastases (primarily RUQ pain) who had II study in 27 patients with progressive liver metastases despite
failed third-line systemic therapy and were not candidates for systemic therapy. Patients received sequential lobar treatments
ablation or resection. Extrahepatic disease was also present in with TheraSphere (BTG International, London, UK) and
66% of cases. A median of 2.1 GBq was delivered in a single reported disease control in 91% and a RECIST response rate of
session using SIR-Spheres microspheres (Sirtex Medical Ltd., 39.9% at 3 months. Jakobs and colleagues [23] reported simi-
Sydney, Australia). Eight patients (18%) required overnight lar results, with 33 patients with progressive liver metastases
hospitalisation for post-embolisation syndrome (consisting treated during a single session (i.e. whole liver treatment) with
of pain and nausea), with no mortality. Imaging 6 weeks after a mean of 1.9 GBq. They reported a response rate of 61%, with
SIRT demonstrated a 95% disease control rate. In the six disease control in 96%. Radiological responders had a median
patients who did not experience a measurable response on survival of 23.6 months versus 5.7 months for those that did

..      Table 52.1  Survival after treatment with radioembolisation for breast cancer liver metastases

Investigator n Treatment type ORR SD PFS Survival

Prospective series

Bangash et al. [22] 27 TheraSphere 39.9% 51.1% nr 9.4 months (hepatic tumour burden <25%)
2.0 months (hepatic tumour burden >25%)

Jakobs et al. [23] 30 SIR-Spheres 61% 35% nr 11.7 months (3–45.1)

Retrospective series

Coldwell et al. [19] 44 SIR-Spheres 47% 47% nr 86% at 14 months

Haug et al. [20] 58 SIR-Spheres 26% 63% nr 11.0 months

Cianni et al. [21] 52 SIR-Spheres 56% 35% 6.6 months 11.5 months

(8.4 months liver PFS)

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Local Therapies for Liver Metastases from Breast Cancer
617 52
not (p  =  0.005). Perhaps unsurprisingly, those with liver-­ However, the cost-effectiveness and disease-control aspects of
limited disease enjoyed better long-term survival than those resection are increasingly attractive, and it may be that these
with disseminated metastases (16 months vs. 9.6 months). offer an alternative rationale for future investigation.
For patients with diffuse liver-limited disease, there
is growing interest in radioembolisation. Although simi-
52.4 Stereotactic Beam Radiotherapy lar cautions should be applied, patient selection appeared
less extreme and was associated with impressive long-term
Stereotactic body radiation therapy (SBRT) or stereotactic outcomes and manageable toxicity. Further prospective tri-
ablative radiotherapy (SABR) for oligometastatic disease als assessing the addition of radioembolisation to first-line
has been investigated in recent years and has demonstrated systemic therapy are crucial to better define the role of this
promising results. Scorsetiti and colleagues [24] investigated approach in patients with liver-limited stage IV breast cancer.
SBRT for patients with limited liver or lung metastases in a As such, current selection of patients for liver-directed
prospective observational study. All patients had fewer than therapy should be based on assessment by specialist breast
five lung and liver lesions (with maximum diameter < 5 cm), oncologists and surgeons in combination with specialist hep-
with systemic chemotherapy completed at least 3  weeks atobiliary surgeons, with clear preoperative patient counsel-
before treatment. Treatment dose varied between 48 and ing around the risks and benefits of such a strategy.
75 Gy in 3 or 4 consecutive fractions. Thirty-three patients
with a total of 43 lesions were irradiated. Median follow-
up was 24  months (range 3–59). Local control was 98% at References
1 year and 90% at 2 and 3 years. Complete response, partial
response and progressive disease were detected in 25 (53.2%), 1. Cancer Research UK. Cancer stats key facts – breast cancer. Cancer
16 (34%) and 6 (12.8%) lesions, respectively. Median OS was Research UK; 2016.
48  months, with actuarial survival at 1 and 2  years of 93% 2. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pol-
and 66%, respectively. At univariate analysis a disease-free lack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A,
Williams C, Zhu SX, Lønning PE, Børresen-Dale AL, Brown PO, Bot-
interval of >12 months and hormone receptor positivity were stein D.  Molecular portraits of human breast tumours. Nature.
all predictive of overall survival. Treatment was well toler- 2000;406(6797):747–52.
ated, with no significant toxicities. Such promising results 3. Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K,
have led to the development of prospective studies to better Karaca G, Troester MA, Tse CK, Edmiston S, Deming SL, Geradts J,
define the precise role of SBRT. NRG BR001 is a phase I dose Cheang MC, Nielsen TO, Moorman PG, Earp HS, Millikan RC.  Race,
breast cancer subtypes, and survival in the Carolina Breast Cancer
de-escalation study in which breast, lung and prostate can- Study. JAMA. 2006;295(21):2492–502.
cer patients with limited metastases will receive radiation to 4. Trialists'Group EBCC.  Comparisons between different polychemo-
all known sites of disease, with dose selected on the basis of therapy regimens for early breast cancer: meta-analyses of long-­
tumour location. An alternative approach, comparing fixed term outcome among 100 000 women in 123 randomised trials.
dose SBRT plus standard systemic therapy versus standard Lancet. 2012;379(9814):432–44.
5. Disibio G, French SW. Metastatic patterns of cancers: results from a
systemic therapy, is being investigated in the COMET trial, large autopsy study. Arch Pathol Lab Med. 2008;132(6):931–9.
which includes different cancer subtypes (SABR COMET, 6. Caralt M, Bilbao I, Cortés J, Escartín A, Lázaro JL, Dopazo C, Olsina JJ,
NCT01446744). The results of these trials will be critical to Balsells J, Charco R. Hepatic resection for liver metastases as part of
better define the role of stereotactic radiotherapy for oligo- the “oncosurgical” treatment of metastatic breast cancer. Ann Surg
metastatic breast cancer patients. Oncol. 2008;15(10):2804–10.
7. Kennecke H, Yerushalmi R, Woods R, Cheang MCU, Voduc D, Speers
CH, Nielsen TO, Gelmon K. Metastatic behavior of breast cancer sub-
types. J Clin Oncol. 2010;28(20):3271–7.
52.5 Conclusions 8. Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans
WF, Gonzalez-Angulo AM, Hennessy B, Green M. Response to neo-
It remains unclear whether liver-limited metastatic breast adjuvant therapy and long-term survival in patients with triple-
negative breast cancer. J Clin Oncol. 2008;26(8):1275–81.
cancer is a biologically distinct entity requiring a different 9. Durkee BY, Qian Y, Pollom EL, King MT, Dudley SA, Shaffer JL, Chang
management approach to other stage IV disease. Although DT, Gibbs IC, Goldhaber-Fiebert JD, Horst KC. Cost-­effectiveness of
there is considerable interest in liver-directed treatment for pertuzumab in human epidermal growth factor receptor 2-positive
these patients, the evidence supporting such an approach metastatic breast cancer. J Clin Oncol. 2016;34(9):902–9.
is unclear. This is further clouded by lack of direct com- 10. Lopes G, Glück S, Avancha K, Montero AJ. A cost effectiveness study
of eribulin versus standard single-agent cytotoxic chemotherapy
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disease. 11. Chua TC, Saxena A, Liauw W, Chu F, Morris DL. Hepatic resection for
Only two series have attempted to provide a direct com- metastatic breast cancer: a systematic review. Eur J Cancer.
parison of surgical resection with well-matched medically 2011;47(15):2282–90.
12. Utley M, Treasure T. Interpreting data from surgical follow-up stud-
managed patients and gave conflicting results. Although ies: the role of modeling. J Thorac Oncol. 2010;5(6 Suppl 2):S200–2.
long-term survivors have been identified in numerous retro- 13. Mariani P, Servois V, De Rycke Y, Bennett SP, Feron JG, Almubarak MM,
spective single-centre series, these are highly selected patients. Reyal F, Baranger B, Pierga JY, Salmon RJ. Liver metastases from breast

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treated patients. Ann Surg. 2015;264(1):147–54.
15. Spolverato G, Vitale A, Bagante F, Connolly R, Pawlik TM. Liver resec-
tion for breast cancer liver metastases: a cost-utility analysis. Ann
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FT. Breast cancer liver metastases: US-guided percutaneous radio-
frequency ablation--intermediate and long-term survival rates.
Radiology. 2009;253(3):861–9.
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800–4.
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L, Cortesi E.  Radioembolisation with (90)Y-labelled resin micro-
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 619 53

Role of Surgery in Lung

Metastases from Breast Cancer
Michael Shackcloth and Susannah Love

53.1 Introduction – 620

53.2 Rationale for Pulmonary Metastasectomy – 620

53.3 ESO-ESMO Consensus Guidelines for Advanced

Breast Cancer – 620

53.4 Indications – 621

53.5 Preoperative Assessment – 621

53.6 Preoperative Imaging – 621

53.7 Diagnosis – 621

53.8 Surgical Approach – 621

53.9 Surgical Techniques – 622

53.10 Non-surgical Techniques of Treatment of Pulmonary

Metastasis – 622

53.11 Conclusions – 622

References – 622

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_53

rares1geo@gmail.com
 620 M. Shackcloth and S. Love
53.1 Introduction
Breast cancer is the most frequent malignant disease of
women in Europe. Despite advanced multi-modality treat-
ment, 30% of patients will develop recurrent disease, of
which 64% will have distant metastases [1] and 12% will have
isolated lung metastasis [2]. Also, 3% of women with breast
cancer will develop a solitary pulmonary nodule of which
one third will be a breast cancer metastasis, but the other two
thirds will be other types of tumours, mainly early-­stage lung
53 cancer [3] (. Fig. 53.1).
Pulmonary metastasectomy has previously been con-
sidered a palliative procedure [4], but more recently, there
has been a paradigm shift in the management of metastatic
cancer. No longer is it one of palliation, metastatic cancer
can now be viewed as a chronic disease with resection of
metastasis from multiple sites and even repeated surgery
[5]. This has been fuelled by the reduction of mortality and
morbidity from lung resection over the last few decades
and the advances in minimally invasive lung and liver
resections.
53.2 Rationale for Pulmonary
Metastasectomy
Pulmonary metastasectomy has been used for over 60 years
to treat lung metastases from solid tumours. It was first
described in 1927 when Tudor Edwards excised pulmonary
metastases from a sarcoma of the leg which had been
removed 6 years beforehand [6]. Since then it has become a
widespread procedure performed by thoracic surgeons to try
and improve the survival of patients with systemic spread of
tumours from various primary sites.
The resection of pulmonary metastases in breast cancer
does not just offer a therapeutic benefit; it also offers diag-
nostic and histological benefits. Resection allows a defini-
..      Fig. 53.1  CT scan of a lady with multiple bony metastases from her
previously treated breast cancer. These had been stable on hormonal
treatment for a number of years. She has an enlarging mass in the right
upper lobe of the lung. CT-guided biopsy revealed a primary adeno-
carcinoma of the lung. This was excised by performing a right upper
lobectomy
rares1geo@gmail.com
tive diagnosis of the lesion to be made. Up to two thirds of
solitary nodules in patients with previous breast cancer may
be other tumours [7], mainly lung cancer, and if so the
patient could require more extensive lung resection to ade-
quately treat their cancer. It also provides a new histological
specimen, which would allow the pathologist to assess the
phenotype of the metastasis, which may be different to the
original tumour and would help guide further systemic
treatment.
There is a lack of high-level evidence, such as randomised
controlled trials, to support, or refute, the use of surgical
excision of pulmonary metastases [8]. The majority of evi-
dence for pulmonary metastasectomy is from case series,
which often amalgamate the results from different primary
cancer sites and do not test their results versus control groups.
The largest data series involving breast cancer patients comes
from the International Registry of Lung Metastases. It reports
data from 467 breast cancer patients who have undergone
pulmonary metastasectomy [9]. Complete resection was
achieved in 84% of cases and reported a median survival of
37 months.
The European Society of Thoracic Surgeons via a Lung
Metastasectomy Working Group attempted to develop
guidelines to assist clinicians, but they concluded that there
was insufficient evidence upon which to base the proposed
guidelines. They conducted a survey of current clinical prac-
tice for pulmonary metastasectomy and found that 99.3%
and 84.3% of European thoracic surgeons would perform
the procedure for colorectal cancer and breast cancer,
respectively [10]. The survey also identified that the majority
of surgeons would not offer the procedure if the primary
tumour was uncontrolled or if complete resection could not
be achieved.
Fan and colleagues [11] published a systematic review
and meta-analysis of the best evidence available for the resec-
tion of isolated pulmonary metastases in breast cancer
patients. They reported the data from 16 cohort studies
which included 1937 patients. The pooled 5-year survival
was 46%. They identified several prognostic factors which
conferred poorer outcomes: a disease-free interval of less
than 3 years, incomplete resection of metastases, number of
metastases and negative hormone receptor status.
53.3  SO-ESMO Consensus Guidelines
E
for Advanced Breast Cancer [12]
The European School of Oncology in conjunction with the
European Society for Medical Oncology recommends in
their joint international consensus guidelines for advanced
breast cancer that «a small but very important subset of met-
astatic breast cancer patients, for example, those with a soli-
tary metastatic lesion, can achieve complete remission and a
long survival. A more aggressive and multidisciplinary
approach should be considered for these selected patients».
They also acknowledge that a clinical trial addressing this
specific situation is required.
Role of Surgery in Lung Metastases from Breast Cancer
53.4 Indications
The indications for pulmonary metastasectomy are con-
stantly evolving. Over the last decade, the development of
new effective chemotherapy and targeted therapies has
altered the indications for pulmonary metastasectomy [13].
A patient with a solitary metastasis with a long disease-free
interval is probably still best treated surgically [13].
However, the role of surgery in a patient with multiple
metastases with a relatively short disease-free interval is
uncertain.
Analysis of case series has established well-accepted sur-
gical selection criteria:
1. Primary disease is under control.
2. Metastases are limited to the lung.
3. Metastases can be completely excised.
4. Patient has the physiological reserve to tolerate the
planned procedure.
53.5 Preoperative Assessment
Patients planned for lung metastasectomy should undergo
preoperative assessment in a similar manner to patients
undergoing a resection for a primary lung cancer to ensure
their resectability and operability [14]. Patients require a
thorough history and examination, assessment of WHO
performance status, full spirometry and radiological
staging.
53.6 Preoperative Imaging
Apart from specific imaging of the breast, no routine imaging
such as chest radiographs or computerised tomography (CT)
scans is routinely performed during the follow-up of breast
cancer patients. However, as these are patients presenting
with pulmonary nodules which have the potential to be pri-
mary lung cancer, they should be assessed as per lung cancer
guidelines [14].
CT scanning of the chest, abdomen and pelvis should
be performed to assess the location and extent of pulmo-
nary nodules to allow surgical planning and detect if fur-
ther extra-thoracic disease is present. Ideally the CT scan
should be within 4 weeks of surgery to minimise the risk
of new nodules developing between the CT scan and
surgery.
An 18F-2 fluorodeoxyglucose (FDG) positron emission
tomography (PET) scan can assess activity of the lung nod-
ules and assess for mediastinal involvement or the presence
of extra-thoracic disease (see . Fig. 53.2). It is advised that
 
this is carried out in patients with a solitary pulmonary
nodule.
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621 53
..      Fig. 53.2  PET scan of a lung lesion in a patient with previous breast
cancer. The lesion is avid (thick arrow), but the subcarinal (mediastinal)
node shows no uptake (thin arrow) suggesting they do not contain
metastatic cancer. This patient would therefore be suitable for surgical
resection
53.7 Diagnosis
Where possible a tissue diagnosis should be obtained before-
hand to determine the exact nature of any pulmonary nod-
ule. This usually can be achieved by CT biopsy, bronchoscopy
or endobronchial ultrasound.
53.8 Surgical Approach
The surgical approach when performing a pulmonary metas-
tasectomy will be influenced by a surgeon’s preference and
the extent of the intended surgical resection. The majority
will be performed via thoracotomy or minimally invasive
video-assisted thoracic surgery (VATS).
Thoracotomy is the more traditional approach to lung
resections especially metastasectomy as it allows bimanual
palpation of the lung which can be useful to identify nodules
not detected on preoperative CT imaging. Thoracotomies
can be associated with significant postoperative morbidity,
pain and slower return to normal activity.
A VATS approach has become increasingly popular for
the management of pulmonary metastases as surgeons have
become more familiar with using it in their everyday practice
for many intrathoracic conditions and with improvements in
digital technology. The smaller incisions for VATS surgery
confer many benefits including a shorter hospital stay and
fewer complications [15].
The overriding concern regarding the use of VATS instead
of a thoracotomy has been the lack of palpation of the lung
allowed via VATS incisions. A study published by Eckardt
and Licht [16] compared the detection of pulmonary nod-
ules in a patient first undergoing a VATS procedure and then
converting directing to thoracotomy to reassess for nodules.
They found that of the 55 nodules detected preoperatively
 622 M. Shackcloth and S. Love
on CT, 51 were found by VATS, and additional 29 nodules
were found during thoracotomy. However, this may now be a
historical concern following the advances in CT technology
and the availability of 256-slice CT which allows contiguous
volumetric (<0.5 mm) sections and detection of nodules only
2 mm in size. Kang and colleagues [17], using a 1 mm slice
thickness multi-detector row CT, did not find any additional
nodules at the time of surgery [18].
Other advantages of VATS include excellent visualisation
of the pleura enabling identification of small pleural metasta-
53 sis and that fewer adhesions form between the lung and chest
wall, making repeat resections easier.
53.9 Surgical Techniques
Preferentially the metastases will be excised via lung
parenchyma-­sparing technique such as a wedge resection or
segmentectomy. However, if the lesion is large and occupying
most of a lobe or is centrally placed, too proximal to the
hilum to allow a lung-sparing resection, then a lobectomy
would be performed assuming the patient’s lung function
and performance status permitted it.
An alternative to traditional surgical resection via cautery
and staplers is laser-assisted resection utilising the Nd:YAG
laser to resect pulmonary metastases. Approached via a stan-
dard or mini thoracotomy, the lung is bimanually palpated to
identify metastases, and the Nd:YAG laser is used to excise
the tumour whilst simultaneously coagulating and sealing
the surrounding lung parenchyma. The benefit of laser resec-
tion is that multiple metastases can be excised, including
those in close proximity to the hilum, whilst minimising the
amount of healthy lung resected. Early cohort studies report
complete resection (R0) achieved in 93%, 5-year survival of
55% for R0 solitary nodules and over 25% for those with 10
to over 20 metastases resected [18].
53.10 Non-surgical Techniques of Treatment
of Pulmonary Metastasis
Even less invasive than a VATS approach is the percutaneous
ablation of pulmonary metastasis or stereotactic radiother-
apy. Percutaneous ablation does not require general anaes-
thesia, but it has the disadvantage that margins cannot be
examined histologically to confirm completion resection.
However, their use does not preclude the future use of surgi-
cal excision if the lesion continues to grow on follow-up
imaging. There are three types currently available: radiofre-
quency ablation (RFA), microwave ablation and cryoabla-
tion. Evidence of symptomatic or survival benefits is very
limited.
Radiofrequency ablation is performed by inserting an
electrode into the lesion under CT guidance. The non-insu-
lated distal end of the electrode generates medium-frequency
electromagnetic waves of 400–500 kHz. This frequency agi-
tates the ions in the tissues, creating frictional heat, which
rares1geo@gmail.com
denatures and destroys the surrounding tissue. The proce-
dure is well tolerated with a low complication rate, which
includes pneumothorax, haemorrhage, haemoptysis, infec-
tion and abscess formation.
Microwave ablation follows a similar technique to RFA
ablation but uses microwave energy to destroy the tumour by
thermocoagulation.
Stereotactic radiotherapy has been used to treat lung
metastasis and will be described elsewhere within this
book.
53.11 Conclusions
In carefully selected patients with pulmonary metastasis
from breast cancer, metastasectomy offers a 46% 5-year sur-
vival [11]. However there is no randomised data to compare
surgery with alternatives so its role is presently unclear.
Operations can often be performed using a minimally inva-
sive approach and have a low mortality and morbidity. Clear
criteria are available to guide patient selection for consider-
ation of surgery.
The majority of solitary pulmonary nodules in patients
with previous breast cancer are not metastasis, with primary
lung cancer the most common diagnosis. It is important that
these patients are referred for surgical management, as early-­
stage lung cancer is curable with surgery.
Key Points
1. Pulmonary metastasectomy is widely accepted in
many malignancies.
2. It can often be performed minimally invasively with
low mortality and morbidity.
3. 5-year survival is around 46%.
4. A solitary pulmonary nodule in a patient with previ-
ous breast cancer is more likely to be a primary lung
cancer than a metastasis.
References
1. Coleman RE, Rubens RD.  The clinical course of bone metastases
from breast cancer. Br J Cancer. 1987;55(1):61–6.
2. Kreisman H, Wolkove N, Finkelstein HS, Cohen C, Margolese R, Frank
H.  Breast cancer and thoracic metastases: review of 119 patients.
Thorax. 1983;38(3):175–9.
3. Garcia-Yuste M, Cassivi S, Paleru C.  Pulmonary metastasectomy in
breast cancer. J Thorac Oncol. 2010;5(6:Suppl 2):Suppl-1.
4. Cardoso F, Harbeck N, Fallowfield L, Kyriakides S, Senkus E, ESMO
Guidelines Working Group. Locally recurrent or metastatic breast
cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow-up. Ann Oncol. 2012;23:Suppl-9.
5. Morise Z, Sugioka A, Fujita J, Hoshimoto S, Kato T, Hasumi A, et al.
Does repeated surgery improve the prognosis of colorectal liver
metastases? J Gastrointest Surg. 2006;10(1):6–11.
6. Edwards A.  Malignant disease of the lung. J Thorac Surg. 1934;4:
107–24.
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7. Singletary SE, Walsh G, Vauthey JN, Curley S, Sawaya R, Weber KL,
et al. A role for curative surgery in the treatment of selected patients
with metastatic breast cancer. Oncologist. 2003;8(3):241–51.
8. Treasure T.  Pulmonary metastasectomy for colorectal cancer:
weak evidence and no randomised trials. Eur J Cardiothorac Surg.
2008;33(2):300–2.
9. Friedel G, Pastorino U, Ginsberg RJ, Goldstraw P, Johnston M, Pass H,
et al. Results of lung metastasectomy from breast cancer: prognos-
tic criteria on the basis of 467 cases of the International Registry of
Lung Metastases. Eur J Cardiothorac Surg. 2002;22(3):335–44.
10. Internullo E, Cassivi SD, Van RD, Friedel G, Treasure T, ESTS Pulmo-
nary Metastasectomy Working Group. Pulmonary metastasectomy:
a survey of current practice amongst members of the European
Society of Thoracic Surgeons. J Thorac Oncol. 2008;3(11):1257–66.
11. Fan J, Chen D, Du H, Shen C, Che G. Prognostic factors for resection
of isolated pulmonary metastases in breast cancer patients: a sys-
tematic review and meta-analysis. J Thorac Dis. 2015;7(8):1441–51.
12. Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, et al. ESO-
ESMO 2nd international consensus guidelines for advanced breast
cancer (ABC2). Breast. 2014;23(5):489–502.
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13. Rusch VW.  Pulmonary metastasectomy: a moving target. J Thorac
Oncol. 2010;5(6):S130–1.
14. Lim E, Baldwin D, Beckles M, Duffy J, Entwisle J, Faivre-Finn C, et al.
Guidelines on the radical management of patients with lung can-
cer. Thorax. 2010;65:Suppl-27.
15. Mutsaerts EL, Zoetmulder FA, Meijer S, Baas P, Hart AA, Rutgers
EJ. Long term survival of thoracoscopic metastasectomy vs metas-
tasectomy by thoracotomy in patients with a solitary pulmonary
lesion. Eur J Surg Oncol. 2002;28(8):864–8.
16. Eckardt J, Licht PB. Thoracoscopic versus open pulmonary metas-
tasectomy: a prospective, sequentially controlled study. Chest.
2012;142(6):1598–602.
17. Kang MC, Kang CH, Lee HJ, Goo JM, Kim YT, Kim JH.  Accuracy of
16-channel multi-detector row chest computed tomography with
thin sections in the detection of metastatic pulmonary nodules. Eur
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18. Rolle A, Pereszlenyi A, Koch R, Richard M, Baier B.  Is surgery for
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 625 54

Surgery for Locally Advanced

Breast Cancer
Jaroslaw Skokowski and Pawel Kabata

54.1 Introduction – 626

54.2 Definition of Locally Advanced Breast Cancer – 626

54.3 Management of Locally Advanced Breast Cancer

and Inflammatory Breast Cancer – 626

54.4 Mastectomy after NAC – 627

54.5 Mastectomy Versus Conservation Surgery

in LABC after NAC – 628

54.6 Axillary Surgery in the LABC Setting – 629

54.7 Treatment Results – 629

References – 630

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_54

rares1geo@gmail.com

626 J. Skokowski and P. Kabata

54.1 Introduction ..      Table 54.1  TNM stage of LABC

In populations where regular screening mammography pro- IIB T3N0M0 A reasonable initial surgical Primary
grammes exist, the percentage of patients with locally approach is likely to operable
IIIA T3N1M0
advanced breast cancer (LABC) is less than 5%, while inflam- achieve pathologically
matory breast cancer (IBC) accounts for 2.0–2.5% of cases. negative margins and
provide long-term local
The occurrence of IBC also varies geographically, with lower control
proportions in the USA (1–2%) than in other parts of the
world [1]. IIIA T0N2M0 An initial surgical approach Primary
T1N2M0 is unlikely to successfully inoperable
Surgical treatment of LABC patients remains a therapeu-
T2N2M0 remove all disease or to
tic challenge. These patients represent a heterogeneous group provide long-term local
including both indolent and rapidly progressing lesions; IIIB T4N0M0 control
T4N2M0
therefore therapeutic decisions must be made by a multidis-
54 ciplinary team based on a combination of clinical and patho- IIIC Any
logical features. Moreover, the optimal management of LABC TN3M0
requires a well-coordinated treatment plan and close coop-
eration between the breast surgeon, medical oncologist and
radiation oncologist. When planning treatment, a number of
factors must be taken into consideration. These include the «Inflammatory breast cancer (IBC)» (. Fig.  54.1a) is a
 

size and location of the tumour; the need to remove the clinicopathologic entity different from «noninflammatory
entire, initial or residual tumour volume; the size of the LABC» (. Fig. 54.1b). The very specific nature of the disease
 

breast; the radiologic appearance after neoadjuvant therapy;
the tumour subtype; and patient’s preferences. Whether pri-
mary closure of the skin is likely to be possible or will require
a skin flap or graft is also critical to deciding on surgical tech-
niques.
54.2  efinition of Locally Advanced Breast
D breast and «secondary IBC» used for development of inflam-
Cancer
The majority of studies on LABC patients covered the whole,
heterogeneous population from stage IIB to IIIC and some-
times also IBC. Little research has been conducted on stage
III tumours only, or on specific subgroups, like T3N0 cancer.
Therefore, the treatment recommendations are not sup-
ported by evidence based on narrower definition of LABC or
stage-specific groups [2].
Haagensen introduced the term «grave signs of LABC»
which defined inoperable cancer, not qualifying for radical
mastectomy [3]. More recently, the definition of LABC has
evolved and is used for tumours exceeding 5 cm (T3N0–1) or
with the presence of bulky metastatic lymph nodes on physi-
cal examination. Most experts consider stages IIB–IIIA
(T3N0–1) cancers as «large operable», in contrast to inoper-
able ones with inflammatory and/or extensive skin involve-
ment, advanced axillary nodal disease with fixed or bulky
lymph nodes and/or spreading into supraclavicular or inter-
nal mammary regions [4]. Although the clinical presentation
of LABC often varies depending on its biological subtype,
staging and operability criteria are still based on the anatomic
features of tumour size and lymph node involvement [5].
Even though nonanatomic prognostic factors have become
widely used, the tumour-node-metastasis (TNM) classifica-
tion remains the most important factor for prognostic clas-
sification (. Table 54.1) [6].
 
renders classification attempts difficult. However, some
investigators have classified IBC into three separate groups:
[1] IBC with clinical features only, [2] IBC with clinical and
pathologic features and [3] IBC with pathologic features
only. Other clinical varieties which have been identified, and
are commonly cited, include «primary IBC» used to describe
the de novo development of IBC in a previously healthy
matory skin changes mimicking primary IBC in a breast ear-
lier treated for cancer or on the chest wall after mastectomy
for non-IBC [7].
54.3  anagement of Locally Advanced
M
Breast Cancer and Inflammatory Breast
Cancer
Management involves careful coordination of all multidis-
ciplinary modalities, including imaging, systemic chemo-
therapy, surgery and radiation therapy. The use of
neoadjuvant chemotherapy (NAC) has contributed signifi-
cantly to improvements in overall survival (OS) since the
first descriptions of this treatment and has made the role of
locoregional therapy, including surgery and radiation,
critical to continued improvements in outcome for this dis-
ease [8].
Locoregional treatment is based on a combination of sys-
temic therapy, surgery and radiotherapy. In the multidisci-
plinary team, the role of the surgical oncologist is to localise
the tumour, clarify the goals of NAC and ensure appropriate
imaging before and after the treatment. An image-guided
metallic clip should be placed in the tumour pre-neoadjuvant
chemotherapy in patients potentially eligible for breast-­
conserving surgery (BCS) to permit surgical localisation, as
well as in those for whom mastectomy may be required, to

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Surgery for Locally Advanced Breast Cancer
a b
..      Fig. 54.1  a Inflammatory breast cancer; b Noninflammatory locally advanced breast cancer
assist in location of the primary site by the pathologist which
is especially important in cases which undergo a good partial
or complete response. It can also be placed during systematic
treatment, when significant regression in tumour size is
observed [9]. This practice is advised especially in small and
rapidly regressing tumours, while it may be omitted in
patients with large and nonresponsive cancers which are
more likely to have residual disease after NAC.
In patients not responding to neoadjuvant treatment,
second-line chemotherapy, preoperative radiotherapy or sal-
vage mastectomy should be discussed by the team. Sentinel
lymph node biopsy (SLNB) could be considered for patients
with clinically negative axillary lymph nodes before chemo-
therapy. For patients with node-positive disease, axillary
lymph node dissection should be performed although this is
a subject of current research interest and is discussed in more
detail in 7 Chap. 25 [10]. Patients with inflammatory breast
cancer should always undergo ANC as SLNB is contraindi-
cated.
In patients with IBC, general recommendations are simi-
lar to noninflammatory LABC and include NAC as the treat-
ment of choice. First-line chemotherapy must be followed by
mastectomy with axillary clearance in most cases, even for
patients who have responded well to chemotherapy.
Immediate breast reconstruction (IBR) is not recommended.
Surgery must be followed by radiotherapy to the chest wall
and axilla, even when complete response was achieved with
chemotherapy. Local relapse in patients with IBC is almost
always followed by distant metastases and death [11].
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627 54
54.4 Mastectomy after NAC
Before consideration is given to the type of surgery to be
offered after NAC, it is worth considering whether surgery of
any sort has oncological benefit in the LABC setting. There
have been a number of studies which have failed to show any
survival or local control benefits from combining surgery
and chemotherapy when patients with a poor response to
systemic treatment are included in the analysis. In contrast
patients with a good response to NAC demonstrate both
enhanced long-term survival and improved disease-free sur-
vival (DFS) after undergoing mastectomy [25].
The role of mastectomy in the treatment of LABC is tra-
ditional and obligatory in some cases such as IBC where the
dermal lymphatics are permeated with tumour. In such cases
skin-sparing mastectomy is contraindicated as well. In cases
of IBC, there is a need to resect the currently or previously
involved skin at the time of mastectomy. Increased wound
and skin flaps tension after mastectomy must be avoided as it
may delay the start of radiotherapy significantly. If necessary,
repair with an autologous tissue flap is preferable to achieve
tension-free closure, for example, with a latissimus dorsi
myocutaneous flap or a thoracodorsal artery perforator flap
(TDAP) unless extremely broad coverage is needed [8]. In
cases where an extremely wide defect is likely, a muscle-only
LD flap with skin grafting may be used (or a DIEP flap may
be used). Caution is needed if applying a split-thickness skin
graft to achieve skin closure as subsequent radiotherapy may
damage the skin graft (. Fig. 54.2a, b).
 628 J. Skokowski and P. Kabata
a b
54
..      Fig. 54.2  a Resection of the thoracic wall with mesh and LD flap reconstruction – intraoperative; b Resection of the thoracic wall with mesh
and LD flap reconstruction – postoperative
In cases with chest wall invasion, if this is confined to
the musculature (pectoralis, serratus anterior), it is easy to
excise the muscle en bloc with the mastectomy specimen.
However, deeper invasion of the thoracic wall is a much
more significant issue. Primary or secondary tumours infil-
trating the ribs and sometimes the sternum require broad
resection of ribs, partial sternectomy and occasionally
resection of endothoracic organs. Chest wall reconstruction
after such resections is performed using different types of
prosthesis (surgical mesh, combined prosthesis with methyl
metacrylate) covered with vascularised pedicle muscle
flaps, most commonly LD and TRAM.  Ulceration of the
chest wall due to radiation necrosis can also be resected by
these techniques, contributing to patient comfort and well-
being [12].
Recently Italian surgeons published a study of 40 patients
treated surgically with chest wall resection for recurrent
breast cancer reaching a 5-year overall survival of 68.5% [13].
The best survival rates were achieved in younger patients
without synchronic metastatic disease, not requiring addi-
tional post-resection treatment.
54.5 Mastectomy Versus Conservation
Surgery in LABC after NAC
The study of the oncologic safety of breast-conserving sur-
gery compared to mastectomy in patients receiving NAC for
LABC demonstrated that it is a safe option for cases which
responded well to NAC.  Shrinking the tumour with NAC
allows for breast-conserving surgery without compromising
optimal oncologic outcomes [14, 15]. In a large NSABP B-18
study, no significant differences between mastectomy and
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BCT with regard to the primary end points of OS, DFS and
relapse-free survival were found [16].
In operable cancers NAC improves the rate of breast-­
conserving surgeries, particularly among tumours >5  cm;
however the risk of local recurrence in the conserved breast
increases with this approach [17]. Given the good efficacy of
antihuman epidermal growth factor receptor 2 (HER2)-
based neoadjuvant systemic treatment, breast-conserving
surgery should be standard practice for most patients. It can
be offered after NAC if the following selection criteria are
met: complete resolution of skin oedema, residual tumour
size <5  cm, no evidence of multicentricity and absence of
extensive intramammary lymphatic invasion/extensive
microcalcification [18]. The rate of conservative surgery will
be higher in patients with a complete or partial clinical
response, treated at specialised centres with experience in
administering such treatments [19].
When feasible, oncoplastic techniques may be offered in
LABC patients. Its usage does not affect oncological safety or
local control after surgery. On long-term follow-up, no sur-
vival or local control issues were observed. Cosmetic out-
comes were also acceptable at 5-year follow-up [20]. Therefore
selected stage III breast cancer patients can be safely offered
oncoplastic surgery. If a good response to neoadjuvant treat-
ment is achieved, breast-conserving surgery can be performed
with acceptable complication rates, local recurrence rates,
good aesthetic and quality of life result [21]. In these patients
oncoplastic surgical techniques decrease the rates of radical
surgery despite the presence of initially large tumours [22].
It has been proven that even though NAC does not
improve survival rates compared to adjuvant treatment, it
helps to down-stage the disease and enables breast-­conserving
surgery in 63% of patients [23].
Surgery for Locally Advanced Breast Cancer
a b
..      Fig. 54.3  a The left arm oedema caused by inoperable axillary recurrence; b Stenosis of the axillary artery and complete axillary vein
occlusion; c The site of the recurrence is marked by surgical clips
54.6 Axillary Surgery in the LABC Setting
This issue is also addressed in some detail in other chap-
ters (7 Chaps. 25, 23, and 24) in both the pre- and post-­
 
neoadjuvant setting. For many cases of LABC, NAC will
render axillary disease operable or convert a positive to a
negative axilla permitting standard surgical techniques.
This chapter will address the issue of salvage surgery for the
heavily involved axilla where NAC has not caused disease
response. Surgery to clear bulky residual axillary disease may
be challenging or even impossible. In such cases preoperative
imaging, in particular with MRI, may give excellent defini-
tion of the extent of disease and how it relates to the axil-
lary neurovascular bundle, pectoral muscle and latissimus
dorsi muscle and pedicle. Breast cancer rarely invades these
structures but may become adherent to them. Clinically omi-
nous features are lymphoedema (. Fig. 54.3a), dilatation of
 
the arm veins suggesting occlusion of the main axillary vein
and opening up of collateral channels and nerve entrapment
symptoms. Such signs should signal likely inoperability. In
these cases palliative treatments such as further systemic
therapy and axillary RT may be most appropriate. CT, MRI
or even angiography (. Fig. 54.3b, c) may also clarify local
 
invasion into these structures.
Surgery for cases where these structures may be involved
should be avoided, but occasionally a surgeon may find unex-
pected extranodal invasion during axillary surgery. It may
then be necessary to sacrifice the thoracodorsal pedicle or even
use vascular clamps or «side-biting clamps» to permit limited
excision of the axillary vein. In such cases, vascular surgical
input before proceeding is strongly advised. Adequate surgical
access may be facilitated by division of the pectoralis minor or
major if access is difficult, and in many cases it may be better to
abandon the procedure and treat with systemic therapies or
radiotherapy post-operatively. Not surprisingly there is no
data on the oncologic outcomes of surgery in this setting.
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629 54
c
54.7 Treatment Results
Treatment results for patients with locally advanced breast
cancer grossly depend on the tumour subtype and response
to neoadjuvant treatment. A meta-analysis of over 3900
patients treated with neoadjuvant chemotherapy for LABC
showed no difference in OS and disease progression between
neoadjuvant and adjuvant treatment [16, 24]. Patients who
achieve pCR defined as ypT0 ypN0 or ypT0/is ypN0 have
improved survival. Its prognostic value is greatest in aggres-
sive tumour subtypes [25]. The prognosis and overall out-
come of patients treated for inflammatory breast cancer are
much worse compared to noninflammatory LABC.  In this
group of patients, those who undergo trimodality therapy
for IBC are at higher risk of local recurrence and residual
disease in the axilla. According to SEER data, women with
stage III breast cancer reach 3-year survival rates of up to
70% and 5-year survival up to 55%, with median survivals of
4.9 years [26].
Constant improvement in treatment options for nonin-
flammatory breast cancer in recent years has also led to sig-
nificant improvements in treatment efficacy in IBC patients
[27]. Before systemic chemotherapy was introduced for
treatment of IBC, attempts were taken to treat it with surgery
alone or in combination with radiotherapy. Results of such
treatment were poor, with median survival of 15 months and
local recurrence rate up to 50%. Despite improvement in sur-
vival time with multimodal therapy, the overall results,
reaching 35–40%, are still much lower than with other types
of breast cancer [7].
As shown in this chapter, even in patients for whom NAC
is less effective, salvage surgery is often possible and achieves
good local control and palliation of symptoms, although its
benefit in terms of survival is less certain. Use of such tech-
niques therefore requires careful multidisciplinary consider-
ation and full and frank discussion with the patient.
 630 J. Skokowski and P. Kabata
Key Points
55 Locally advanced breast cancers (LABC, TNM stage
3) are a group of breast carcinomas characterised by
a size exceeding 5 cm and/or the presence of bulky
metastatic lymph nodes and/or skin or chest wall
involvement.
55 In patients with inflammatory breast cancer (IBC),
general recommendations are similar to noninflam-
matory LABC and include neoadjuvant chemother-
apy as the initial treatment of choice.
55 The rates of breast surgery and even breast conser-
10. Arnaout A, Boileau J-F, Brackstone M.  Surgical considerations
vation surgery (BCS) in LABC can be improved by
54 administration of neoadjuvant chemotherapy and
oncoplastic surgical techniques.
55 Application of neoadjuvant chemotherapy may con-
vert 70% of node-positive disease to node-negative
disease and may render inoperable disease operable
or even breast conservable with some cancer sub-
types. The extent of axillary lymph node dissection
can be narrowed in patients who achieve pCR after
­neoadjuvant treatment (discussed in more detail
in 7 Chap. 25). Neoadjuvant chemotherapy for the
primary breast cancer is discussed in more detail in
7 Chap. 21.
55 After chemotherapy, for cases where disease is still
bulky in the breast, use of various flaps and grafts
may be required to achieve tension-free closure in
some cases, and collaboration between oncologists,
breast oncology surgeons and plastic and even vas-
cular surgeons is often required in more advanced
cases. The techniques and oncological indications
for, and outcomes of, such «heroic» surgery are
discussed.
References
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org/10.3322/CA.2008.0001.
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S, et  al. Inflammatory breast cancer: the disease, the biology, the
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60(6):351–375. Available from: http://dx.doi.org/10.3322/caac.20082.
8. Woodward WA, Cristofanilli M.  Inflammatory breast cancer. Semin
Radiat Oncol [Internet]. 2009 [cited 2016 May 14];19(4):256–265.
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9. Oh JL, Dryden MJ, Woodward WA, Yu T-K, Tereffe W, Strom EA, et al.
Locoregional control of clinically diagnosed multifocal or multi-
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11. Cardoso F, Costa A, Norton L, Senkus E, Aapro M, André F, et  al.
ESO-ESMO 2nd international consensus guidelines for advanced
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science/article/pii/S0960977614001581.
12. Hanagiri T, Nozoe T, Yoshimatsu T, Mizukami M, Ichiki Y, Sugaya M,
et al. Surgical treatment for chest wall invasion due to the local recur-
rence of breast cancer. Breast Cancer Japan. 2008;15(4):298–302.
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Chest wall resection and reconstruction for locally recurrent breast
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15. Semiglazov V, Eiermann W, Zambetti M, Manikhas A, Bozhok A,
Lluch A, et  al. Surgery following neoadjuvant therapy in patients
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doux A, et al. Preoperative chemotherapy: updates of national sur-
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Sukarayothin T, Supsamutchai C, et  al. Oncoplastic technique in
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19. Kaufmann M, Hortobagyi GN, Goldhirsch A, Scholl S, Makris A,
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20. Emiroglu M, Sert I, Karaali C, Aksoy SO, Ugurlu L, Aydın C. The effec-
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21. Bogusevicius A, Cepuliene D, Sepetauskiene E.  The integrated
evaluation of the results of oncoplastic surgery for locally
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22. Zucca Matthes AG, Uemura G, Kerr L, Matthes ACS, Michelli RAD,
Folgueira MAAK, et al. Feasibility of oncoplastic techniques in the
surgical management of locally advanced breast cancer. Int J Surg
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23. Debled M, MacGrogan G, Breton-Callu C, Ferron S, Hurtevent G,
Fournier M, et al. Surgery following neoadjuvant chemotherapy for
HER2-positive locally advanced breast cancer. Time to reconsider
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performance of sentinel lymph node biopsy post-neoadjuvant che-
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ar.iiarjournals.org/content/36/4/1461.abstract
25. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N,
et  al. Pathological complete response and long-term clinical ben-
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 633 55

The Role of Surgery

to the Primary Cancer in Stage
IV Disease
Seema A. Khan and Patience Odele

55.1 Introduction – 634

55.2 Reasons to Consider Locoregional Therapy

for the Primary – 634

55.3 Retrospective Studies Evaluating the Role

of Primary Site Local Therapy (PSLT) – 634
55.3.1 Advantages of LRT – 634
55.3.2 Potential Biases – 635

55.4 Randomized Clinical Trials – 635

55.4.1 Completed Trials – 636
55.4.2 Ongoing Trials – 637

55.5 Prospective Registry Trial – 637

55.6 Conclusion – 638

References – 638

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_55

rares1geo@gmail.com
 634 S.A. Khan and P. Odele

55.1 Introduction ing between primary tumour and metastatic sites [16, 17].
Hence, it has been proposed that if the intact primary is a
With improvements in medical therapy such as more sensi- basin for CTCs or CSCs that can seed distant metastatic sites,
tive diagnostic modalities and the introduction of targeted the number of CTCs should decrease after surgery and sub-
therapy, stage IV breast cancer is emerging as a chronic ail- sequently improve survival.
ment. Approximately 5% of women with primary breast can- From an immunological standpoint, removal of an intact
cer in the USA and Western Europe present with de novo primary may be beneficial due to tumour-induced immuno-
stage IV breast cancer [1], and several trials have shown that suppression [18, 19]. Using a mouse model, Danna and asso-
between 3% and 30% of these patients treated with multimo- ciates were able to demonstrate that removal of an intact
dality therapy can achieve long-term survival of many years primary mammary tumour in the setting of metastatic dis-
[2, 3]. Andre and colleagues evaluated 724 patients with de ease could restore the immunocompetence of the host [19],
novo stage IV breast cancer and showed that 3-year survival although there has been some concern for progression of
of women diagnosed between 1987 and 1993 was 27%, disease after primary tumour resection in laboratory mod-
whereas it was 44% among women diagnosed between 1994 els. These include a study where two foci were induced by
and 2000 [3, 4]. Although this difference may be attributable inoculation of tumour cells, and the growth of the second
55 in part to improvements in diagnostic imaging (i.e. a lead-­ focus was observed after resection of one focus [20] and the
time bias) in the later period, it nevertheless suggests an observation that cell proliferation increased at metastatic
improvement in survival related to better therapy. Standard sites when a primary xenografted tumour was resected [21].
treatment for metastatic disease involves systemic therapy Other postulated pathways for the intact tumour restraining
with endocrine therapy, cytotoxic agents, or targeted therapy, growth at metastatic sites have come from work demonstrat-
selected according to patient and tumour characteristics [5]. ing the release of angiogenesis inhibitors by the primary in
However, with improved survival, there is potentially oppor- animal models [22]. However there are no human data so far
tunity for troublesome local progression of the primary to support the idea that the presence of an intact primary
tumour, and therefore management of the primary site has tumour will prolong survival of patients with metastatic
become a topic of significant interest. disease.

55.2  easons to Consider Locoregional

R 55.3  etrospective Studies Evaluating
Therapy for the Primary
Resection of the primary tumour in patients with metastatic
breast cancer carries intuitive appeal for patients, since it is a
site of disease they are aware of, and it can be removed with
relatively low morbidity. For both patients and physicians,
there is concern about the quality of life impairment that
could occur with progression and the appearance of uncon-
trolled local disease.
The potential value of resection of the primary tumour in
the setting of metastases has been examined in other visceral
cancers; in renal cell carcinoma, this examination has been
achieved with randomized trials, whereas in gastric and
colon cancer patients, the data are generally from retrospec-
tive analyses. An improved survival with resection of pri-
mary disease with or without resection of distant disease has
been observed in metastatic renal, ovarian, colorectal, and
gastric cancers [6–13]. These cancers, particularly ovarian
R
the Role of Primary Site Local Therapy
(PSLT)
55.3.1 Advantages of LRT
Nineteen retrospective studies have evaluated the benefit of
primary site locoregional therapy in metastatic breast cancer.
These include six multi-institutional studies including popu-
lation databases, with a total of 27,000 patients, 14,443 of
whom underwent surgery for the primary [23–28], and 13
single institution studies, from academic institutions in the
USA, Europe, and Asia, with analysis of 4000 patients, 1670
of who had surgery [29–41]. A meta-analysis by Petrelli and
Barni included 15 of these retrospective studies and evalu-
ated the relationship between survival and local therapy for
the primary tumour. They found a protective association
with the use of local therapy, with a hazard ratio of 0.69
(p < 0.00001) (. Fig 55.1). Survival benefit was independent

cancer, are sometimes managed with tumour debulking
before chemotherapy, based on the idea that chemotherapy is
more efficient in a small tumour burden environment [9, 12].
There are also biologic reasons proposed to explain can-
cer progression and metastasis that support locoregional
therapy in the setting of metastatic disease. Cancer stem cells
(CSCs) have been identified in multiple tumours and have
the potential to support tumorigenesis [14, 15]. Circulating
tumour cells can represent a particular subset of CSCs that
have the ability to establish a metastatic colony [14, 15].
These stem cells can also provide an avenue for communicat-
of multiple factors such as age, tumour burden, type of sur-
gery, margin status, site of metastases, hormone receptor
status, and HER2 status [42]. The role of axillary surgery
independently or with surgery for the primary is not well
documented; however a meta-analysis by Hartmann et  al.
[43] included six retrospective studies [24, 27, 29, 30, 34, 35]
that gave information on whether an axillary surgical proce-
dure was performed. Of the patients reviewed, 42% had sur-
gery and 527 patients of those (69%) had axillary procedures.
Only three studies investigated the impact of axillary surgery
on survival and did not find a benefit [24, 27].

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The Role of Surgery to the Primary Cancer in Stage IV Disease
..      Fig. 55.1  Forest plot of meta-
analysis by Petrelli and Barni, 100
including 15 retrospective studies
that examined the association
between primary site local
therapy and survival in de novo
Overall survival (%)
stage IV breast cancer patients
(Reprinted from Petrelli and Barni
[42], Fig. 2, page 3288 [42] with
permission from Springer)
Number at risk
No locoregional treatment 177
Locoregional treatment 173
It is difficult to assess the benefit of postoperative versus
primary radiotherapy (RT) as not all studies distinguish
delivery and rate consistently. One of the larger studies by Le
Scodan and colleagues identified patients with de novo stage
IV breast cancer treated over a 20-year period. Of this cohort,
320 received locoregional RT, 30 received only surgery, and
41 women received both surgery and RT, which was deliv-
ered to both breast/chest wall and nodal fields with a boost to
the tumour site for most patients. The overall survival rate
was improved by a third in the group receiving PSLT versus
those who did not, with an adjusted hazard ratio of 0.7 (95%
CI 0.58–0.85) [31]. In another cohort of 733 patients evalu-
ated in the British Columbia study from 1996 to 2005, 378
patients had PSLT which consisted of surgery alone in 67% of
patients, radiotherapy alone in 22%, and both in 11%. The
5-year overall survival rates were 21% versus 14% (p < 0.001),
and the rates of locoregional progression-free survival were
72% versus 46% (p < 0.001) [36]. These studies suggest that
patients that had surgery had higher rates of RT delivery as
well as some benefit in OS and progression-free survival.
Very limited information is available regarding chest wall
outcomes. However, the largest study by Hazard and col-
leagues [34] evaluated 111 patients presenting with stage IV
breast cancer. Early compared to delayed or no surgical
resection of the primary tumour reduced symptomatic chest
wall disease by 86%, but there was no statistically significant
difference in terms of overall survival. It was also noted that
patients who maintained a controlled primary (whether
through local or systemic therapy) had better survival out-
comes (HR = 0.42, P < 0.002) compared to those with uncon-
trolled primary sites.
55.3.2 Potential Biases
The results of the retrospective studies have to be reviewed
closely as they carry some significant bias that lead to the
concern that the demonstrated survival from local therapy
rares1geo@gmail.com
635 55
80
60
40
20
No locoregional treatment
Locoregional treatment
0
0 6 12 18 24 30 36
Time (months)
148 101 75 50 36 24
152 105 73 49 32 21
may be due to patient selection. The use of surgery was higher
in women who have more favourable profile such as young
age, smaller tumours, non-visceral disease, fewer comorbidi-
ties [27, 39, 40], and better access to care [25, 33]. Additionally,
it is likely that the timing of surgery may introduce bias [27,
28, 32, 44]. For example, if women with T1–2 tumours, for
whom a preoperative metastatic survey is not standard of
care, were staged post-operatively because of a high nodal
burden and were then discovered to have asymptomatic or
low-volume metastatic disease, their prognosis may be better
than women with symptomatic and high burden metastases
diagnosed preoperatively. This consideration particularly
affects tumour registry data, where the final stage is usually
recorded several months after completion of primary ther-
apy, by which time asymptomatic metastases may have been
discovered. In addition, in any cohort study subtle differ-
ences in disease burden and patient fitness for intervention
and disease biology may bias selection for surgery and hence
outcomes.
55.4 Randomized Clinical Trials
Several randomized trials have been initiated in an effort to
validate the results of the retrospective studies, particularly
due to the concern that the apparent benefit of PSLT is driven
by patient selection. A total of seven trials were initiated; two
have completed accrual. Final results have been published by
Badwe and colleagues from India, and preliminary results
have been reported by Soran and colleagues from Turkey.
Trials are ongoing in the USA/Canada (ECOG-ACRIN
2108) and Japan, whereas the Austrian trial (POSYTIVE,
ABCSG 28) closed after accrual of 93 patients. Two addi-
tional trials were launched; the trial in the Netherlands
closed with minimal accrual, and one in Thailand was with-
drawn prior to accrual. Three of these trials (India, Japan, the
USA/Canada) required induction systemic therapy prior to
surgery.
 636 S.A. Khan and P. Odele

55.4.1 Completed Trials pre-planned subset analyses also showed no significant dif-
ferences in overall survival. Locoregional PFS was signifi-
The first trial to be published was from India. It opened in cantly better in the surgical group (HR 0.16, p  <  0.001),
2005 at the Tata Memorial Cancer Institute in Mumbai whereas distant PFS was decreased in the PSLT arm com-
(NCT00193778) [45]. Participants were enrolled from a pool pared to the continued systemic therapy arm, with a HR of
of 716 patients, of whom only 25 had resectable primary 1.42. Overall, the trial showed no survival gain with surgical
tumours; of these, 440 responded to initial systemic therapy therapy for de novo stage IV breast cancer [45].
which consisted almost exclusively of chemotherapy (six Of note, the median survival of the Tata Memorial trial
cycles of anthracycline-based treatment in 96% with taxanes population was 19 months, which is significantly lower than
added in under 5% of patients). After exclusion of 90 subjects that observed in reports from developed countries, where
for a variety of reasons, 350 patients were randomized to recent stage IV trials show median overall survival to be in
PSLT versus continuation of systemic therapy. PSLT con- the range of 40 months (for hormone receptor-positive breast
sisted of surgery with or without radiotherapy (when indi- cancer) [46], and 49 months (in a prospective observational
cated). Primary outcomes were overall survival and study of de novo stage IV breast cancer patients) [47]. Fewer
disease-free survival. Secondary outcomes were locoregional than 30% of patients in the Tata Memorial trial had bone-­
55 progression-free survival (PFS), distant PFS, and health-­ only disease, and about one-quarter had three or fewer meta-
related quality of life. static lesions. Following completion of protocol-directed
Of the 350 randomly assigned patients, 173 patients were locoregional therapy, the patterns of continued systemic
assigned to PSLT, and 177 were assigned to continuation of therapy did not include HER2-directed agents for the most
systemic therapy without PSLT.  The groups were well part (trastuzumab was used in 8/90 women with HER2-­
matched in terms of disease characteristics and demograph- positive tumours). A shorter distant PFS was observed in the
ics. Median duration of follow-up was 23 months with a total PSLT group, but this did not translate into a survival disad-
of 235 deaths at the data cut-off date. Patients who had vantage.
locoregional or distant progression as the first event were In contrast to the Tata Memorial trial, the Turkish
censored at that time for locoregional PFS or distant PFS Federation of Breast Diseases study (NCT00557986) [48]
analysis, resulting in a shorter distant PFS in the PSLT arm. was designed without an induction systemic therapy phase.
The final trial results show no difference in median overall A total of 274 patients were accrued and were randomized to
survival (HR 1.04, 95% CI 0.80–1.34, . Fig. 55.2); a series of
 
surgery (mastectomy or lumpectomy followed by radiation

Hazard Ratio Hazard Ratio

Study or Subgroup Log [Hazard Ratio] SE Weight IV, Random, 95% CI Year IV, Random, 95% CI
Khan 2002 R1 –0.286 0.028 10.1% 0.75 [0.71, 0.79] 2002
Khan 2002 R0 –0.491 0.027 10.1% 0.61 [0.58, 0.65] 2002
Rapiti 2006 R0 –0.511 0.261 2.8% 0.60 [0.36, 1.00] 2006
Rapiti 2006 R1 –0.262 0.246 3.1% 0.30 [0.80, 2.10] 2006
Babiera 2006 –0.693 0.443 1.2% 0.50 [0.21, 1.19] 2006
Fields 2007 –0.635 0.119 6.7% 0.53 [0.42, 0.67] 2007
Gnerlich 2007 –0.478 0.032 10.0% 0.62 [0.58, 0.66] 2007
Blanchard 2008 –0.342 0.125 6.4% 0.71 [0.56, 0.91] 2008
Hazard 2008 –0.226 0.354 1.8% 0.80 [0.40, 1.60] 2008
Ruiterkamp 2009 –0.478 0.102 7.4% 0.62 [0.51, 0.76] 2009
Bafford 2009 –0.75 0.25 3.0% 0.47 [0.29, 0.77] 2009
Shien 2009 –0.117 0.06 9.1% 0.89 [0.79, 1.00] 2009
Neuman 2010 –0.342 0.216 3.7% 0.71 [0.46, 1.09] 2010
Perez-Fidalgo 2011 –0.654 0.202 4.0% 0.52 [0.35, 0.77] 2011
Dominici 2011 –0.062 0.057 9.2% 0.94 [0.84, 1.05] 2011
Booh Pathy 2011 –0.545 0.093 7.8% 0.58 [0.48, 0.70] 2011
Rashaan 2012 –0.105 0.216 3.7% 0.90 [0.59, 1.37] 2012

Total (95% CI) 100.0% 0.69 [0.63, 0.77]

Heterogeneity: Tau2 = 0.03; Chi2 = 110.08, df = 16 (P < 0.00001); I2 = 85%
0.2 0.5 1 2 5
Test for overall effect: Z = 7.15 (P < 0.00001)
Favours surgery Favours no surgery

..      Fig. 55.2  Overall survival outcomes of stage IV breast cancer patients treated with or without locoregional therapy of the primary breast
tumour at Tata Memorial Centre, Mumbai, India (Reprinted from Badwe et al. [45], Fig. 2, page 1385 [45] with permission from Elsevier)

rares1geo@gmail.com
The Role of Surgery to the Primary Cancer in Stage IV Disease
therapy, with or without axillary dissection in patients with
positive nodes) prior to systemic therapy or systemic therapy
alone. The trial was powered to detect an improvement in
3-year survival of 18%. The primary outcome was overall
survival, with secondary outcomes related to progression-­
free survival, quality of life measures, and morbidity related
to locoregional therapy. According to results reported at the
2016 American Society of Clinical Oncology (ASCO) meet-
ing, there was no difference in survival at 36 months (p = 0.5).
However local therapy did improve survival at 40 months of
median follow-up with a 9-month difference (46 vs
37 months). The overall 5-year survival rate was 42% among
women who received locoregional therapy, compared to 25%
in women who did not (HR 0.66; 95% CI 0.49–0.88; P = .005)
The systemic therapy group had worse locoregional progres-
sion rate compared to the locoregional therapy group (11%
vs 1%, p = 0.001). A number of unplanned subset analyses
were conducted, which also showed a significant survival
benefit in hormone receptor-positive disease, HER2-negative
tumours, younger patients, and those with solitary bony
lesions. Particularly for bone-only metastasis, the median
survival was 56  months in the locoregional group versus
42  months in the systemic therapy-only group (HR 0.67;
95%CI 0.43–1.07; P  =  0.09) with the important caveat that
there was no tissue diagnosis of solitary bone lesions. Worse
outcomes were noted for patients with TNBC (median over-
all survival of 16 vs 24 months in patient who did not have
surgery) and those with multiple visceral metastases if sur-
gery was performed, presumable due to the need to discon-
tinue or delay systemic therapy to permit safe surgery [48].
55.4.2 Ongoing Trials
The US and Canada trial, run by the Eastern Cooperative
Oncology Group (EA2108, NCT01242800) [49], closed in
July 2015 with 383 patients accrued. Patients received induc-
tion systemic therapy consisting of endocrine, cytotoxic, or
biologic regimens appropriate to the patient’s age and tumour
type. Those who responded, or whose disease remained sta-
ble following 16–32  weeks of therapy with the induction
regimen, were randomized to surgery and radiotherapy (as
dictated by standards of care for non-metastatic patients) or
to continuation of systemic therapy. The trial was powered to
detect an overall survival difference of 19% at 3  years. The
primary outcome is overall survival; secondary outcomes are
local progression-free survival and quality of life. Biological
samples are being banked for correlative studies. Importantly,
this trial addresses the role of axillary clearance and radiation
therapy.
A similar trial designed by the Japanese Clinical Oncology
Group (JCOG 1017) [50] opened in June 2011; this too
requires induction chemotherapy prior to locoregional ther-
apy. After 3 months of systemic therapy, women who show
no disease progression are randomized to undergo surgery
or to continue systemic therapy; radiotherapy is not required.
The primary outcome is overall survival. Secondary out-
rares1geo@gmail.com
637 55
comes are local recurrence rate and local control rate. The
trial has accrued 350 patients thus far with a target of 440.
The POSYTIVE trial in Austria (NCT01015625) [51] ini-
tially allowed randomization prior to initial locoregional
therapy; however the protocol was subsequently revised to
allow for systemic therapy prior to randomization. The
accrual goal was 254 patients, but the study has closed with
accrual of 93 patients due to slow accrual (personal commu-
nication, Prof. Florian Fitzal). Patients with synchronous
metastatic breast cancer were randomly assigned to receive
lumpectomy or mastectomy + axillary surgery /± radiother-
apy versus not. Patients in the no-surgery group could have
delayed surgery if necessary. Primary outcome is median
overall survival. Secondary outcomes are time to distant pro-
gression and time to local progression.
55.5 Prospective Registry Trial
The Translational Breast Cancer Research Group has com-
pleted a prospective multi-institutional data registry gather-
ing data on the modern management of stage IV breast cancer
(TBCRC 0313) [52]. The goal of the registry is to record
information on the incidence of uncontrolled local disease,
metastatic disease, rate of surgical intervention for palliation
for the intact primary (in patients not undergoing PSLT),
the frequency and effect of uncontrolled chest wall disease,
and quality of life. Biologic and molecular data has been col-
lected and will be used to determine interactions between the
primary and metastatic sites. A total of 127 eligible patients
have been enrolled thus far and are categorized into cohorts
of those with an intact primary (A) or those with a resected
primary and metastases discovered within 3 months of sur-
gery (B). All patients received first-line systemic treatment
according to standard institutional guidelines. Preliminary
results presented at ASCO in 2016 showed that for patients
in cohort A, after a 54-month median follow-­up, 3-year
OS is 70% and is better for patients who are responders to
chemotherapy compared to nonresponders (78% vs 24%,
p  =  0.001). However, amongst responders no benefit was
noted with surgery in 3-year overall survival (p = 0.85) irre-
spective of tumour subtype, although HER2-­positive status
and response seem to provide longer survival (93%). In
addition, surgery did not improve progression-free survival
with the median time to progression at 13 versus 12 months
[52]. The data also demonstrated that surgical palliation of
the primary tumour is uncommon in the modern eras as the
majority of patients are responders to first-line therapy. The
results of this registry cohort study show trends in survival
in metastatic breast cancer; however the role of surgery in
de novo stage IV breast cancer is still an issue for debate.
In a preliminary analysis of survival relative to the 21-gene
Recurrence Score (RS), King and colleagues observed that a
high RS was independently prognostic for 2-year OS (hazard
ratio, 1.83; 95% CI, 1.14–2.95; P = 0.013), and this group of
women had a shorter 2-year survival if treated with initial
endocrine therapy rather than initial chemotherapy [47].
 638 S.A. Khan and P. Odele
55.6 Conclusion
The mainstay of treatment for the patient with metastatic
breast cancer is systemic therapy. The optimal role for pri-
mary site local therapy in individuals with an intact primary
tumour remains to be determined. After a flurry of enthusi-
asm following multiple retrospective analyses showing an
apparent benefit of PSLT, the first mature randomized trial
addressing this question yielded null results in terms of over-
all survival although there appears to be a benefit in terms of
local control [45]; while the second complete trial remains
unpublished at this time, results presented at ASCO 2016
appear to show a survival benefit for the use of locoregional
therapy for the primary tumour [48]. The results from other
randomized trials are pending, and until these are available,
55 practitioners should be circumspect in offering PSLT to
patients with metastatic disease. The role of radiotherapy in
conjunction with surgery or as primary therapy also remains
to be determined. Locoregional management of the primary
tumour in stage IV breast cancer patients remains appropri-
ate in the presence of symptoms; it may also be appropriate in
highly selected patients if the distant disease is well controlled
and the primary site shows unequivocal evidence of progres-
sion. If the primary site is also responding to systemic ther-
apy however, prospective data from the TBCRC and the Tata
Memorial trial showed that very few patients require pallia-
tive surgery. If both local and distant sites are well controlled,
the rationale for LRT is also weak, since the primary site is
likely to remain well controlled for the patient’s life span. The
only possible exception may be the patient who has had a
complete response to systemic therapy at distant sites and
would be rendered stage IV with no evaluable disease by
resection of the primary tumour. In this setting, highly
selected series show that a third or more patients may achieve
long-term survival [50]. If PSLT is decided upon following
the above considerations, breast conservation (if feasible) is
clearly the least morbid approach, and the lack of expectation
of a survival benefit should be clear to the patient. Finally, in
making recommendations for primary site locoregional ther-
apy, it is of utmost importance to consider the potential mor-
bidity and the costs of therapy. Notably, guidelines from the
European Society for Medical Oncology published in 2014
state that «that surgery of the primary (tumour) should not
be offered as a routine practice but can be discussed on a
case-by-case basis and offered to selected patients ». The
basis for selection is not specified [53].
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46. Tan PS, Haaland B, Montero AJ, Lopes G. A meta-analysis of anastro-
zole in combination with fulvestrant in the first line treatment of
hormone receptor positive advanced breast cancer. Breast Cancer
Res Treat. 2013;138(3):961–5.
47. King TA, Lyman JP, Gonen M, Voci A, De Brot M, Boafo C, et al. Prog-
nostic impact of 21-Gene recurrence score in patients with stage IV
breast cancer: TBCRC 013. J Clin Oncol. 2016;34(20):2359–65.
48. Soran A, Ozmen V, Ozbas S, et  al. A randomized controlled trial
evaluating resection of the primary breast tumor in women pre-
senting with de novo stage IV breast cancer. J Clin Oncol. [ASCO
annual conference abstract]. 2016;34(Suppl):1005.
49. Khan SA.  A randomized phase III trial of the value of early local
therapy for the intact primary tumor in patients with metastatic
breast cancer. 2015. EA2108, NCT01242800.
50. Shien T, Nakamura K, Shibata T, Kinoshita T, Aogi K, Fujisawa T, et al.
A randomized controlled trial comparing primary tumour resection
plus systemic therapy with systemic therapy alone in metastatic
breast cancer (PRIM-BC): Japan Clinical Oncology Group Study
JCOG 1017. Jpn J Clin Oncol. 2012;42(10):970–3.
51. Fitzal FGM, Steger G.  Primary Operation in Synchronous metasta-
sized invasive breast cancer (POSYTIVE), NCT01015625.
52. King TA LJ, Gonen M, et  al. A prospective analysis of surgery and
survival in stage IV breast cancer. J Clin Oncol. [ASCO annual confer-
ence abstract]. 2016;34(Suppl):1005.
53. Cardoso F, Costa A, Norton L, Senkus E, Aapro M, Andre F, et al. ESO-
ESMO 2nd international consensus guidelines for advanced breast
cancer (ABC2). Breast. 2014;23(5):489–502.
 641 56

Palliative Care
Tiina Saarto

56.1 What Is Palliative Care – 642

56.2 Advance Care Planning – 642

56.3 Quality of Life – 643

56.4 Relief of Symptom Burden – 643

56.4.1 Pain – 643
56.4.2 Dyspnoea – 644
56.4.3 Loco-Regional and Skin Problems – 644
56.4.4 Symptoms Related to Brain Metastases – 644
56.4.5 Gastrointestinal Symptoms – 645

56.5 Psychosocial Support – 645

56.5.1 Symptoms Impairing Emotional Well-Being – 645
56.5.2 Psychosocial Support – 645

56.6 Rehabilitation – 646

56.7 End-of-Life Care – 646

References – 647

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_56

rares1geo@gmail.com
 642 T. Saarto

Metastatic breast cancer is an incurable disease with a
median overall survival varying from 2 to 3 years but with a
very variable range from a few months to a decade [1].
Survival with metastatic disease is dependent on the disease
burden and localisation (e.g. bone and soft tissue disease
only tends to have a more indolent course, whereas brain
and liver metastases tend to be associated with a reduced
survival time). Disease biology and response to treatment
are also important predictors. Half a million women world-
wide and 130,000 in Europe annually die of breast cancer [2,
3]. There is a large unmet need for palliative care worldwide.
The active therapy of metastatic disease has been addressed
in several other chapters (7 Chaps. 49, 50, 51, 52, and 53 ),
 
and this chapter will focus on palliative care.
56.1 What Is Palliative Care
56 According to the World Health Organization (WHO) defini-
liative care should be introduced at the time of diagnosis
of advanced disease in conjunction with other therapies
that are intended to prolong life, such as chemotherapy
or radiation therapy, to improve QoL and lower symptom
burden [5].
56.2 Advance Care Planning
Longer survival due to multiple often sequential treatment
options leads to complex decision making. Therapy has many
goals in the metastatic setting: prolonging survival, balancing
treatment toxicity against enhanced survival, quality of life and
the abrogation of treatment side effects. There is a need for
advanced care planning to share patient preferences and
expectations but at the same time to discuss realistic goals of
treatment and possible advantages and disadvantages of differ-
ent treatment options (. Table 56.1, . Fig. 56.1). The majority

of patients prefer treatments with longer durations of disease

tion, palliative care is an approach that improves the quality
of life of patients and their families facing the problems asso-
ciated with life-threatening illness, through the prevention
and relief of suffering by means of early identification and
impeccable assessment and treatment of pain and other
physical, psychosocial and spiritual problems.
Palliative care should be part of the treatment of can-
cer patients throughout their disease trajectory including
treatment of cancer treatment-related distress and physi-
cal symptoms, psychosocial support, rehabilitation, nutri-
tional therapy, bereavement counselling and end-­of-­life
care. Palliative care will enhance quality of life, helping
patients live as actively as possible until death and help
the family cope during the patient’s illness and in their
own bereavement. It may also positively influence the
course of illness; as demonstrated among patients with
metastatic non-small cell lung cancer, early palliative care
led to significant improvements in quality of life and lon-
ger survival compared with standard care [4]. Thus, pal-
control, but at the same time, good quality of life and better
..      Table 56.1  Primary treatment goals during the disease
trajectory of breast cancer patient
Curative treatment
  Intent to cure
Disease-modifying or disease-stabilizing treatment
  Curative treatment no longer possible
  Intent to prolong life and improve quality of life
Palliative care
  Life prolonging or disease-modifying treatment no longer
possible or is not in the best interests of the patient
  Intent to improve quality of life and prevent and treat suffering
End-of-life care
  Death is imminent in the near future
  Intent to improve quality of life and prevent and treat suffering
of dying patient and their families

..      Fig. 56.1  The role of

palliative care in cancer disease
trajectory and treatment goals
Palliative care Palliative End-
care of-
Curative life
treatment care
Disease modifying or
stabilising treatment

Intent to cure Intent to prolong life and improve QoL Intent to Intent to
improve improve
QoL QoLof
dying
patient
and the
family

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Palliative Care
643 56
physical and emotional functioning are expected [6]. The dis- may include chest pain related to pleural or lung metastases,
cussion of the terminal phase of the disease and end-of-life abdominal pain due to peritoneal carcinomatosis, pain due
care should be part of care planning especially in cases of far to liver capsule stretching, bowel dysfunction, headache
advanced disease with diminished treatment options. Early caused by brain metastases or pain related to loco-regionally
discussion of end-of-life care is not associated with higher advanced breast cancer or skin metastases.
rates of anxiety or worry, but leads to less aggressive treatments
near to the time of death and better end-of-life care [7]. Analgesics
Analgesics are the corner stone of treatment of cancer pain.
The WHO’s analgesic ladders have three levels (. Fig. 56.2).
 

56.3 Quality of Life The first step is non-opioids (NSAIDs or paracetamol) for
mild cancer related pain, but very soon opioids should be
The primary goal of palliative care is to improve quality of life combined with non-opioids from ladder two (weak opioids
(QoL). However, health-related QoL is a complex issue. The like codeine or tramadol) or three (morphine-like strong
WHO has defined health «as not merely the absence of dis- opioids). Recently it has been recommended to start with low
ease or infirmity, but a state of complete physical, mental and doses of strong opioids rather than with weak opioids as
social well-being». Quality of life, in a general sense, reflects there is no advantage of weak opioids over a small dose of
the ways in which a person’s mental, social and physical well-­ strong opioids. Opioids should be started with oral doses of
being is evidenced in his or her everyday life. Patients with long-acting sustained-release opioids (e.g. morphine
advanced breast cancer experience impaired quality of life 10–30 mg twice a day) using lower initial doses for elderly
[8–12]. Their Qol is especially poor in the field of physical, patients and in case of mild or moderate pain intensity.
social and role functioning with impaired activities of daily However, the dose should increase by 20–30% of the total
living [8, 11, 12]. In the terminal phase of the disease, all daily dose every 1–3 days until the pain is adequately con-
dimensions of QoL are significantly impaired. Heavy symp- trolled. In addition to regular sustained-release opioid,
tom burden, especially activity-limited symptoms like pain patients need short-acting, normal-release formulation of
and fatigue, and emotional distress have the greatest effects opioids as rescue medication for breakthrough pain (i.e.
on quality of life of breast cancer patients with metastatic dis- transient increase in pain intensity over background pain).
ease [8, 11, 12]. Constipation is a common adverse effect of opioids; thus pre-
ventive laxative use is recommended. In case of neuropathic
pain, antidepressants (tricyclic antidepressants or serotonin/
56.4 Relief of Symptom Burden norepinephrine reuptake inhibitors) or anticonvulsants (gab-
apentin, pregabalin) are used as an adjuvant treatment in
In advanced breast cancer, the symptom burden is a signifi- combination with opioids [18].
cant problem, with over one third of women reporting high
levels of symptoms with pain, fatigue, insomnia and emo- Radiotherapy
tional distress being the leading problems [8, 9, 11, 12]. Radiotherapy is an effective treatment for cancer pain [19].
Healthcare professionals underestimate the symptom The onset of pain relief takes, however, from a few days to
burden. In patients with advanced cancer, symptoms should 4  weeks, so it rarely relieves pain quickly enough to avoid
be systematically assessed. The prevalence is highest if analgesic use. Approximately 70% of patients with painful
assessed by a questionnaire [13]: for example, the Edmonton bone metastases get significant pain relief, and a complete
Symptom Assessment Scale (ESAS) and EORTC-QLQ-C15- response is seen in one third, with the duration of pain relief
PAL questionnaires are widely used in this setting. from 3 to 6 months [19]. Single-fraction radiotherapy is as
effective as a multifraction schedule. The time to treatment
failure is shorter and retreatment twice as common (25%)
56.4.1  Pain after a single fraction compared with multiple fractions
(10%) [19]. However, re-irradiation is effective [20].
Pain is one of the most common symptoms reported by ­Radionuclides like samarium-153 can be used in treatment
patients with advanced breast cancer. Bone metastases are of multiple painful sclerotic or mixed bone secondaries [21].
the most common cause of pain in this patient group as 70% Radiotherapy is also effective for alleviation of pain arising
of breast cancer patients with advanced disease have bone from soft tissue tumours even though it is not as well docu-
metastases [14]. Approximately 65–75% of patients with mented as with bone pain.
bone secondaries suffer from bone pain, and more than half
of the patients experience pain during movement, which Bisphosphonates
impair activities in daily living [11, 15]. As metastatic bone Bisphosphonates and the RANK-ligand inhibitor denosumab
destruction progresses, the increasing incidence of patho- are potent inhibitors of osteolysis and bone resorption. They
logical fractures, spinal cord compression and malignant reduce the risk of developing skeletal events, i.e. new skeletal
hypercalcaemia further increases suffering [14–17]. Pain lesions, hypercalcaemia, pain and pathological fractures, and
arising from non-osseous metastases is also common and need for palliative radiotherapy or surgery. Bisphosphonates

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 644 T. Saarto
..      Fig. 56.2  WHO analgesic
ladders
56
are the drugs of choice in the treatment of malignant hyper-
calcaemia. However, the pain-relieving effect of bisphospho-
nates and denosumab is relatively low, and they take several
weeks to alleviate pain [22–24].
56.4.2  Dyspnoea
Lung metastases and pleural effusion cause dyspnoea, which
is a very distressing symptom. In addition to dyspnoea, cough
and chest discomfort are common concerns for these patients.
In cases of bronchial obstruction or haemoptysis, palliative
radiotherapy is effective [25]. Like in the treatment of bone
metastases, a single fraction alleviates symptoms as effectively
as multiple fraction radiotherapy. Treatment of symptomatic
pleural effusion by thoracocentesis either with needle aspira-
tion (approximately 1000 ml each time) or catheter drainage
(using an indwelling catheter system) gives rapid relief of dys-
pnoea and discomfort. Pleurodesis, thoracoscopy and inject-
ing talc into the pleural cavity (talc poudrage) appeared to be
effective in preventing fluid build-up [26].
Opioids are effective in alleviation of dyspnoea [27, 28].
For opioid-naive patients, starting with 2.5–5  mg of oral
short-acting morphine for rescue medication is recom-
mended. If more than 2–3 daily doses are needed, a low dose
of long-acting opioids for regular use can be considered espe-
cially in patients with persistent dyspnoea. Opioids are also
effective in the treatment of a dry cough resulting from air-
way irritation.
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56.4.3  Loco-Regional and Skin Problems
Loco-regionally advanced breast cancer with skin metastases
may cause severe and distressing symptoms significantly
impairing body image and social life. Lymphoedema of the
upper extremity and chest wall, skin ulceration, bleeding, pru-
ritus, exudate, infection, odour and pain may be extremely
distressing. With limited disease surgery, radiotherapy or
electrochemotherapy is effective especially with stable sys-
temic disease, but with extensive progressive disease, they are
seldom possible [29]. Palliative care with careful wound care is
needed [30]. For bleeding either systemic or local tranexamic
acid or an adrenalin dressing can be used. Single-­fraction
radiotherapy is also used to control bleeding. Systemic or
topical antibiotics (e.g. metronidazole) in addition to odour-
reducing (charcoal) dressings may be used to reduce unpleas-
ant smells. Modified supportive bandaging, support and
positioning a paralysed swollen arm, passive movements and
gentle massage can comfort lymphoedema [31].
56.4.4   ymptoms Related to Brain
S
Metastases
One third of women with metastatic breast cancer develop
brain metastases during the course of their illness, less com-
monly leptomeningeal metastases [32]. The prognosis of
brain metastases varies depending on the histopathology of
the disease, the extent of and stability of extracranial disease
Palliative Care
and whether there are solitary or multiple brain metasta-
ses. In the palliative stage of the disease, the prognoses are
usually poor. Palliative radiotherapy is recommended for
patients with two or more months of life expectancy. In the
end-of-­life situation, the symptoms caused by brain metas-
tases are alleviated by corticosteroids and convulsions by
antiepileptics and benzodiazepines. Treatment options for
cerebral metastases are dealt with more fully in 7 Chap. 54.
 
56.4.5  Gastrointestinal Symptoms
Liver metastases, without symptoms of liver failure, are
mainly asymptomatic. Pain may be caused by an enlarged
liver causing stretching of the liver capsule. This may be alle-
viated by corticosteroids. Lobular carcinoma in particular
may spread to the peritoneum and even invade the viscera
(stomach, bowel, bladder) and cause bowel dysfunction and
ascites formation. In addition, ascites may be related to liver
metastases and liver failure. Abdominal paracentesis (3–6 l /
day) affords rapid symptom relief. For patients with high vol-
ume and rapid formation of ascites, a tunnelled catheter can
be used. However, tiredness, hyponatraemia and a progres-
sive fall in plasma albumin have been reported after repeated
paracentesis. The role of diuretics in the treatment of malig-
nant ascites is controversial, and they are not routinely used.
Bowel obstruction and paralysis (ileus) caused by peritoneal
carcinomatosis are a severe and very distressing symptom. If
not operable, the prognosis is poor, at only a few months. As
the obstruction is rarely total, the symptoms can be alleviated
with antisecretory agents (somatostatin analogues such as
octreotide, anticholinergic agents like glycopyrrolate and
butylbromide), opioids and antiemetics via subcutaneous
infusions to reduce bowel secretion, pain and nausea/vomit-
ing [33]. After vomiting has been reduced, the nasogastric
tube can be removed, and patient can take some food and
liquids orally with small portions, which significantly
improves the quality of life of dying patients and makes care
at home possible. In a case of severe vomiting, percutaneous
gastrostomy might be needed to alleviate vomiting.
56.5 Psychosocial Support
56.5.1   ymptoms Impairing Emotional
S as they cannot manage with professional or domestic works
Well-Being
Fatigue, insomnia, depression and anxiety impact negatively
on patients’ daily lives and emotional well-being. Fatigue is
the most common symptom of advanced cancer, reported by
three quarters of patients and subjectively is the most dis-
turbing [8, 11–13, 34]. It is an activity-limiting symptom that
significantly affects functional capacity and interferes with
role functioning and ability to conduct daily activities [34,
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645 56
35]. It may begin with a simple decrease in physical activity,
but can cause feelings of loss of control, loneliness and isola-
tion [36]. Significant fatigue is associated with higher level of
depression, pain and sleep disturbance forming a symptom
cluster negatively affecting to QoL [35, 37]. The prevalence of
depression and anxiety among breast cancer patients with
metastatic disease is higher (up to 40%) than the prevalence
within patients with early-stage disease (26%) [11, 34, 38,
39]. Insomnia is also a common problem among cancer
patients. 40–60% of patients with advanced breast cancer
report sleep disturbances, in one third of them moderate or
severe [8, 11, 12].
56.5.2  Psychosocial Support
There is an increased need for psychosocial support of breast
cancer patients throughout the disease trajectory. The diag-
nosis of metastatic disease with limited life expectancy rep-
resents a time of shock, crisis and anxiety for patients and
their families. There is an ongoing need for repeated, truth-
ful but sensitive discussion and information provision about
their disease. Emotional distress should be systematically
assessed. Visual analogue tools such as the distress ther-
mometer can be used to screen patients and identify those
with the utmost need for psychosocial counselling and sup-
port. A scale of four or more out of ten compares well with
other multiple item scales. Accompanying problem lists help
to identify distress from emotional, spiritual or religious
concerns, social or family issues or physical problems.
Especially vulnerable are young women and women with
small children or adolescents. Psychosocial support deliv-
ered by professionals and peer support from patient groups
may help women discuss their experiences and improve
their emotional well-being particularly in those women who
are more distressed [40]. Also families are profoundly influ-
enced by incurable malignant disease of a family member.
Terminal illness alters daily life, roles and relationships
within the family. Additional worries arise regarding how
the family will cope after the death of the patient [41]. Thus,
psychosocial support may also be helpful for family mem-
bers and caregivers.
Advanced breast cancer and ongoing treatments disrupt
patients’ social lives. Many women feel impaired self-identity
and therefore are not able to maintain their previous roles
(mother, partner, professional role) they used to have before
the diagnosis. Deterioration in sexual function causes fur-
ther distress and diminishes self-identity. Maintaining nor-
mal social relationships and daily activities as much as
possible and being able to control the illness experience are
vital for emotional well-being. Learning new ways of enjoy-
ing life despite disease-related limitations may reduce the
emotional burden [41].
 646 T. Saarto
56.6 Rehabilitation
There is a strong association between functional status and
health-related QoL in cancer patients [8, 11, 34].
Rehabilitation is aimed towards restoring and improving
functional abilities and physical independence and thus
maintaining quality of life. Even in the terminal phase of the
disease, the majority of patients express a strong desire to
retain independent mobility [42]. Yet, there is little evidence
describing the rehabilitation needs of advanced cancer
patients [43]. Some disability in physical functioning has
been demonstrated in the majority of the patients with
advanced breast cancer (55–90%) including compromised
walking capacity in half and reduced strength of the lower
extremities in one third of patients [11, 43]. Cachexia and
malnutrition are less common in metastatic breast cancer
than in many other advanced malignancies. The majority of
56 breast cancer patients are normal weight or overweight, but
slowly progressive sarcopenia and muscle weakness eventu-
ally develop which negatively affect disease course in the later
stages [11, 44].
Rehabilitation should be considered for patients with any
difficulties in activity of daily living (ADL); any new or sig-
nificant limitations in instrumental activity of daily living
(IADL), symptoms interfering with function, e.g. pain, dys-
pnoea and fatigue; or any new or significant deterioration in
mobility. The goal of rehabilitation changes throughout the
illness course from restorative (to return patients’ function-
ing to premorbid levels) and supportive (to optimize func-
tioning in patients with irreversible impairments) to palliative
(to reduce patients’ dependence in mobility and self-care
activities). Even in the terminal phase of the disease, there is
a need for rehabilitation [31].
56.7 End-of-Life Care
The terminal phase of the disease can be considered to start
when the patients’ functional status inevitably and irrevers-
ibly declines, and death is imminent in a near future (within
a few weeks or days). End-of-life care is the care of immi-
nently dying patients and their families. The goal of treat-
ment is purely palliative, focusing on QoL and the prevention
and treatment of suffering for both the patient and their fam-
ily. Planning of end-of-life care should be started early
enough to ensure that patients’ wishes and expectations can
be met, including specifying their preferred place of care (at
home, hospice or in some other institution), adequate symp-
tom control and psychosocial and spiritual care. Advanced
directives can assist in expressing patient preferences, help-
ing patients, families and healthcare providers to communi-
cate about end-of-life choices.
When the patient is imminently dying, her physical func-
tioning decreases rapidly, her food and fluid intake decrease,
and she spends more time in bed. Her ability to express her-
self reduces, and the need for careful symptom assessment
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and basic care is increased. Swallowing might be impaired,
which should be taken into consideration in the delivery
mode of medication. The subcutaneous route is often used in
end-of-life care. Social isolation progresses, and previous
roles vanish which may increase anxiety and impair the
patients’ emotional well-being with an increased need for
psychosocial and spiritual support. When death is imminent,
the importance of existential questions increases, emphasiz-
ing the need for spiritual counselling either within or outside
of religious practice.
The suffering of a dying patient is a complex issue, includ-
ing not only physical symptoms like pain or dyspnoea but
also emotional (depression, anxiety) and social concerns
(isolation, impaired self-identity), anger and bitterness,
hopelessness and meaninglessness of life, i.e. total pain.
Healthcare professionals who are taking care of dying patients
should understand the broad meaning of suffering and have
good communication skills to be able to help the patient and
their family in this unique moment in their life. Supporting
families and caregivers is essential not only during the course
of the illness but also at the time of death of their loved ones
and thereafter. Issues around death and dying are very emo-
tional and complex for the family, and the need for continu-
ous support and bereavement therapy is essential. This is
especially important for families with small children or ado-
lescents who need support to be able to continue their lives as
normally as possible after their loss.
Key Points
55 Palliative care intends to improve the quality of life
of patients and their families through the preven-
tion and relief of suffering such as pain and other
physical, psychosocial and spiritual problems.
55 Early integrated specialist palliative care improves
quality of life of patients with advanced cancer.
55 All healthcare professionals who are taking care of
patients with advanced cancer should have basic
knowledge and skills of palliative care.
55 Advanced breast cancer and ongoing treatments
impair physical functioning and disrupt patients’
social lives raising up rehabilitation needs.
55 Distressing symptoms should be systematically
assessed.
55 Repeated sensitive discussion and information
about the disease, psychosocial support delivered
by professionals and peer support from patient
groups may improve the emotional well-being.
55 Families are profoundly influenced by incurable
malignant disease of a family member, and psycho-
social support may also be helpful for family mem-
bers and caregivers.
55 Planning of end-of-life care, i.e. care of imminently
dying, should be started early enough to ensure
that patients’ wishes and expectations can be met.
Palliative Care
647 56
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34. Penttinen HM, Saarto T, Kellokumpu-Lehtinen P, Blomqvist C,

11. Kokkonen K, Saarto T, Mäkinen T, Pohjola L, Kautio H, Järvenpää S,
Huovinen R, Kautiainen H, et al. Quality of life and physical perfor-
Puustjärvi-Sunabacka K. The functional capacity and quality of life
mance and activity of breast cancer patients after adjuvant treat-
of women with advanced breast cancer. Breast Cancer.
ments. Psychooncology. 2011;20:1211–20.
2017;24(1):128–36.
35. Stricker CT, Drake D, Hoyer KA, Mock V. Evidence-based practice for
12. Färkkila N, Torvinen S, Roine RP, Sintonen H, Hanninen J, Taari K, Saa-
fatigue management in adults with cancer: exercise as an interven-
rto T.  Health-related quality of life among breast, prostate, and
tion. Oncol Nurs Forum. 2004;31:963–76.
colorectal cancer patients with end-stage disease. Qual Life Res.
36. Flechtner H, Bottomley A. Fatigue and quality of life: lessons from
2014;23(4):1387–94.
the real world. Oncologist. 2003;8(Suppl 1):5–9.
13. Teunissen SC, Wesker W, Kruitwagen C, de Haes HC, Voest EE, de
37. Bower JE, Ganz PA, Desmond KA, Rowland JH, Meyerowitz BE, Belin
Graeff A. Symptom prevalence in patients with incurable cancer: a
TR.  Fatigue in breast cancer survivors: occurrence, correlates, and
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impact on quality of life. J Clin Oncol. 2000;18(4):743–53.
4. Tubiana-Hulin M.  Incidence, prevalence and distribution of bone
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HP. Osteolytic bone metastases in breast carcinoma pathogenesis,
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1996;22:493–500.
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16. Coleman RE.  Skeletal complications of malignancy. Cancer.

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1997;80(Suppl 8):1588–94.
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17. Mercadante S.  Malignant bone pain: pathophysiology and treat-
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ment. Pain. 1997;69:1–18.
2001;345(24):1719–26.
18. Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the
41. Luoma ML, Hakamies-Blomqvist L. The meaning of quality of life in
treatment of cancer pain: evidence-based recommendations from
patients being treated for advanced breast cancer: a qualitative
the EAPC. Lancet Oncol. 2012;13:e58–68.
study. Psychooncology. 2004;13(10):729–39.
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42. Yoshioka H.  Rehabilitation for the terminal cancer patient. Am J
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2007;25(11):1423–36.
43. Cheville AL, Kornblith AB, Basford JR. An examination of the causes
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Bernstein L, McTiernan A, et al. Prevalence and prognostic effect of
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rares1geo@gmail.com
 649 57

Supportive Care
Renata Zaucha

57.1 Thromboembolic Complications – 650

57.1.1 Diagnosis – 650
57.1.2 Prophylaxis and Treatment – 651

57.2 Central Venous Catheter (CVC) – 652

57.2.1 CVC-Related Complications – 652
57.2.2 Catheter-Related Bloodstream Infections (CRBSI) – 652
57.2.3 Thrombotic Complications of CVCs – 653
57.2.4 Extravasation – 653

57.3 Axillary Cording – 653

57.4 Postmastectomy Pain Syndrome (PMPS) – 653

57.5 Use of Bone Marrow Support During Systemic Therapy – 654

57.6 Anti-Emetic Therapy During Chemotherapy – 654

References – 655

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_57

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 650 R. Zaucha

Supportive care (SC) includes different treatment methods
used to prevent, control or treat any side effects of antican-
cer therapy. It has been recognized as provision of the neces-
sary services for people living with cancer and its therapies.
The most frequent physical complications of breast cancer
surgery are thromboembolic events, lymphedema, axil-
lary cording and postmastectomy pain: these are largely
dealt with in other chapters (7 Chaps. 34, 58, and 62 ). For
 
systemic chemotherapy, the major supportive care issues
include central venous catheter-related problems, bone
marrow support and nausea and vomiting treatment and
prophylaxis.
57.1 Thromboembolic Complications
The incidence of the most morbid complications like
deep vein thrombosis (DVT) and pulmonary embolism
(PE) in patients undergoing any type of cancer surgery is
significantly higher than in the general population [11–13].
In breast cancer this risk is elevated in the first month after
surgery, although not as much as with many other forms of
cancer, especially in women receiving antioestrogens and/or
antiangiogenic therapy. The results of multiple prospective
trials have shown that the two- to threefold higher risk of PE,
DVT and superficial phlebitis seen in women taking tamoxi-
fen compared to tamoxifen-naïve women is probably related
to reduced plasma levels of antithrombin and protein C [13–
18]. The increase in risk commences 3 months after initiation
of therapy. Aromatase inhibitors are significantly less likely to
induce thrombosis compared with tamoxifen [19].

Thromboembolic complications are the most frequent

complications seen in cancer patient [1, 2]. Cancer-related
hypercoagulability may occur as a result of local venous
stasis, surgery, systemic anticancer therapies and the pres-
57 ence of a central venous catheter [3]. Breast cancer cells
have pro-inflammatory and anticoagulant fibrinolytic
potential responsible for causing a hypercoagulable state.
57.1.1 Diagnosis
The diagnosis of VTE should rely on clinical presentation sup-
ported by imaging. The estimation of thromboembolic compli-
cations and the need for further diagnostic tests can be based
on the Khorana and/or Wells scores (. Table 57.1) [12, 13, 20].

Due to their ability to shed microparticles containing tis-

sue factor (TF), mucin-1 and P-selectin, breast cancer cells
..      Table 57.1  Risk scores for thromboembolic complications
interact with leucocytes, platelets and endothelial cells
triggering intravascular coagulation. The mechanism of Khorana score for short-term risk of VTE Points
cancer-related alteration in coagulation factors is not fully
elucidated, but the reduction of antithrombin, protein S Type of cancer Stomach, pancreas 2
and protein C has been described. The antiphospholipid Lung, lymphoma, gynaecologic, 1
bladder, testis 0
syndrome may be important, although its role has not been
Others
confirmed [3, 4].
The increasing incidence of venous thromboembolic Platelet count <350 × 109/l 0
events (VTE) over the last couple of years has made it the ≥350 × 109/l 1
second leading cause of death among cancer patients [1, 2, 5]. Haemoglobin ≥10 g/dl and no therapy with 0
VTE risk depends on a variety of factors like the type and erythrocyte-stimulating factors 1
stage of cancer, accompanying diseases and therapy. Older <10 g/dl or therapy with
erythrocyte-­stimulating factors
age, a history of preexisting VTE or thrombosis and inher-
ited thrombophilia are well-known risk factors. Malignant White blood cell ≤11 × 106/l 0
diseases increase the VTE relative risk fourfold, while che- count >11 × 106/l 1
motherapy, hormone therapy (in particular tamoxifen), BMI <35 kg/m2 0
antiangiogenic therapy or some types of molecularly tar- ≥35 kg/m2 1
geted agents almost sevenfold [6, 7]. The incidence of VTE Total score Low risk (<1%) 0
in breast cancer depends on concomitant diseases, medica- Medium risk (2%) 1–2
tions, body mass index, lifestyle, etc. and varies in incidence High risk (7%) 3–6
between 0.1% and 45% but is significantly lower than in pan- Wells score for PE or VTE points
creatic cancer or myeloma. During chemotherapy VTE risk
is 10.8-fold higher (95% confidence interval [CI], 8.2–14.4; Active cancer 1
absolute rate, 59.6 per 1000 person-years) than in women Surgery or bedridden for ≥3 days during the past 4 weeks 1.5
not receiving chemotherapy [7]. Cyclophosphamide, cis-
History of PE, or DVT 1.5
platin and asparaginase have been identified as extremely
potent inducers of thrombosis [8, 9]. Cisplatin damages the Haemoptysis 1
endothelium and increases the level of von Willebrand factor Tachycardia, HR >100/min 1.5
[9]. Gemcitabine, mitomycin, anti-VEGF agents and mTOR
Clinical suspicion of PE 3
inhibitors are responsible for haemolytic microangiopathy
[10]. The mechanism of coagulation alterations caused by Clinical suspicion of DVT 3
other cytostatic drugs is not fully understood.

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Supportive Care
A Wells score >3 is an indication for duplex ultrasound
(US) for VTE and/or CT angiography for PE. Ultrasound is
better for the diagnosis of symptomatic proximal than calf
vein DVT [21, 22]. Magnetic resonance imaging is the inves-
tigation of choice for suspected abdominal thrombi [22].
Serum levels of d-dimers are not helpful (most cancer
patients have elevated d-dimers even without thrombosis),
excluding cases with a Wells score  <4, when low levels of
651 57
neoadjuvant chemotherapy/hormonal therapy, morbid obe-
sity, indwelling central venous catheter, the type of surgical
procedure, the type and length of anaesthesia, blood transfu-
sions and the type of reconstructions (expander/implant vs
myocutaneous flap) [24].
The Caprini risk score, which includes 20 weighted vari-
ables, may aid in VTE risk stratification in patients under-
going immediate reconstruction (. Table  57.2) [26]. Major

d-dimers have a negative predictive value [23].
57.1.2 Prophylaxis and Treatment
Thromboprophylaxis in cancer patients undergoing surgical
therapy should be a routine. The use of unfractionated hepa-
rin (UFH) reduces the risk of fatal DVT/PE by about 60%
and total surgical mortality by about 20%. The risk of VTE
after standard surgical treatment for breast cancer is well
below 1% [20]. Breast cancer surgery has a lower risk than
many other forms of cancer surgery because the performance
status of most breast cancer patients is very good. Many
breast cancer patients are discharged within 24 h of surgery
and early ambulation and mechanical anti-embolism devices
(intermittent pneumatic compression, foot pump, and gradu-
ated compression stockings – are regarded as the standard of
care, Grade 1A evidence) [24, 25]. Decisions regarding VTE
prophylaxis in breast surgery patients should be individual-
ized, based on VTE and bleeding complications related to
the history of DVT/PE, hypercoagulability disorders, limita-
tions in ambulation, a history of other recent major surgical
procedures, older age, heart failure, advanced stage of cancer,
myocutaneous flap procedures or lengthy reconstructive
surgery with a Caprini risk score above five should receive
pharmacological thromboprophylaxis, despite the increased
risk of haematomas, bruising or other postoperative bleeding
complications [27, 28].
The choice of prophylactic medication remains at the
discretion of the treating physician. Heparin derivatives are
most often recommended as oral vitamin K antagonists such
as warfarin need frequent laboratory assessment and may
interact with many other drugs likely to be used afterwards
[28–30]. Low molecular weight heparins (LMWH) like
dalteparin or enoxaparin remain the first choice of VTE pro-
phylaxis, being superior to unfractionated heparin (UFH)
in VTE reduction, major bleeding, fatal PE, death, wound
infection and haematoma rates [30, 31]. LMWH accumulate
in patients with renal impairment. Both LMWH and UFH
effectively treat thrombosis, but the risk of recurrence is
reduced by 32%, and the bleeding risk is reduced by 43% in
LMWH patients compared with UFH recipients [29, 32, 33].
Both LMWH and UFH may be responsible for heparin-­
induced thrombocytopenia (HIT). The best clinical HIT
probability scoring system is based on thrombocytopenia
(nadir and percentage reduction), the timing of the platelet

..      Table 57.2  The Caprini risk score

5 points 3 points 2 points 1 point

Stroke (in the previous Age ≥ 75 years Age 61–74 years Age 41–60 years

month)
Fracture of the hip,
pelvis or leg
Elective arthroplasty
Acute spinal cord injury
Prior episodes of VTE
Positive family history of VTE
Prothrombin 20210A
Factor V Leiden
Lupus anticoagulants
Anticardiolipin antibodies
High homocysteine in the
blood
HIT
Other congenital or acquired
thrombophilias
Arthroscopic surgery
Laparoscopy lasting >45 min
General surgery lasting
>45 min
Cancer
Plaster cast
Bed bound for >72 h
Central venous access
BMI > 25 kg/m2
Minor surgery
Oedema in the lower extremities
Varicose veins
Pregnancy
Post-partum
Oral contraceptive
Hormonal therapy
Unexplained or recurrent abortion
Sepsis (in the previous month)
Serious lung disease (pneumonia, acute
asthma, for example in the previous month)
Abnormal pulmonary function tests
Acute myocardial infarction
Congestive heart failure in the previous month
Bed rest
Inflammatory bowel disease

Score 0–1: Low risk of VTE

Score 2: Moderate risk of VTE
Score 3–4: High risk of VTE
Score ≥5: Highest risk for VTE

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 652 R. Zaucha

count fall, thrombosis and other causes of thrombocytopenia.
Patients with HIT require a different anti-embolic therapy,
and fondaparinux (7.5 mg SC daily) should be used instead.
The role of new oral non-vitamin K antagonists (NOACs)
in cancer patients is not established. The use of direct throm-
bin or factor Xa inhibitors (such as dabigatran, rivaroxaban,
apixaban and edoxaban) may substantially complicate breast
surgery. Planned breast surgery should be postponed until
24 h following the last dose. It is important to evaluate clot-
ting ability in patients taking NOACs, specifically aPTT, TT,
ECT and anti-Xa activity, but not INR. In cases of bleeding
while on NOAC recombinant factor VII (rFVIIa), activated
prothrombin complex concentrate and haemodialysis are
potentially effective. Idarucizumab  – a specific dabigatran
antidote  – is indicated only for emergency surgery or life-­
threatening bleeding [34]. NOACs may be reintroduced not
earlier than 6–8 h postsurgery [35].
Their risk depends on the experience of the surgeon, the type
of device, the technique, the place of insertion and finally
postoperative care. Patient-related factors such as age, per-
formance status, nutritional status, platelet counts and coag-
ulation system status are also very important. It is important
that these catheters are not placed in the arm where axillary
surgery (SLNB or ANC) has been performed to reduce the
risk of lymphedema.
The most frequent side effects of CVC placement are
infections such as exit-site infection, catheter-associated
septicaemia and endoluminal infection. Less frequent are
bleeding (especially in thrombopenic patients), extravasa-
tion, the pinch-off syndrome, catheter dislocation, occlusion
and leakage.
57.2.2 Catheter-Related Bloodstream
Infections (CRBSI)

57.2 Central Venous Catheter (CVC) Fever, suppurative discharge, pain, oedema, inflammation,
57 sepsis, port abscess or endocarditis constitute symptoms of
Long-term venous access devices are recommended in all catheter-related bloodstream infection [37]. Subcutaneous
breast cancer patients before starting systemic intravenous central vein ports are the least common cause of CRBSI
therapy [36]. They minimize pain and discomfort caused [38]. Before initiating antibiotics the same volume of blood
by venipuncture required for systemic chemotherapy, blood from the catheter and from the peripheral vein should be
products or other intravenous medications. Out of the many obtained for culture. Before collecting blood samples, the
sites available for placing CVC, only the femoral veins should skin should be prepared with alcohol, iodine or chlorhexi-
be excluded due to the high risk of infection and thrombo- dine (10.5%) to avoid contamination. In the case of catheter
sis. The site of insertion or the type of device depends on the exudate, a swab should be taken for culture. Diagnosis is
expected length of use, the patients’ anatomy and the type of made after more than one set of positive cultures. Empirical
planned future local therapy. antibiotic treatment with vancomycin (not linezolid) is
Short-term use CVCs are inserted directly (non-­ recommended until blood culture tests are available. The
tunnelled) into peripheral veins (basilic vein, brachial vein choice of therapy should always be based on antibiotic sus-
or cephalic vein). ceptibility data for each institution. Gram-positive bacillus
Longer use CVCs (>30 days) suitable for chemotherapy, infections are most frequent. In septic shock empirical use
parenteral feeding, blood products or other intravenous of antibiotic against Gram-negative bacilli such as fourth-
medicine infusions are inserted using tunnelling techniques generation cephalosporins, carbapenem with or without an
via central veins, or as fully implantable ports or port-a-caths. aminoglycoside is advocated. Fungal infections (primary or
Surgically implantable ports and port-a-caths: secondary to prolonged antibiotic therapy) usually occur in
55 Consist of a metallic, plastic, or both, fully implantable heavily pretreated patients, with coexisting risk factors such
subcutaneous chamber located subclavicularly, in the as prolonged neutropenia or a history of immunosuppres-
pouch in front of the pectoralis major muscle (on the sive therapy (everolimus). Clinically stable patients can be
unaffected side) and connected to the catheter. treated with fluconazole provided that azoles have not been
55 Are usually threaded through the subclavian (less com- administered in the last 3 months. In critically ill patients
monly jugular) vein. with candidaemia, the echinocandins are strongly recom-
55 Their use is associated with a low risk of infection or mended. A definitive diagnosis of CRBSI is made when the
thrombosis. same organism grows from percutaneous blood culture and
55 Their access requires specific needles. from the catheter tip. The most common method of CRBSI
55 They can be used for collecting blood samples. management is catheter removal. Salvage is contraindicated
in patients with severe sepsis or haemodynamic instability;
persistent bacteraemia despite 72  h of appropriate antibi-
57.2.1 CVC-Related Complications otic therapy; infections caused by Staphylococcus aureus,
Pseudomonas aeruginosa, fungi, mycobacteria, Bacillus spe-
The most common CVC-related complications are: cies, Micrococcus species or Propionibacterium; tunnel infec-
55 Infections tions, port abscesses or exit-site infections. The catheter may
55 Thromboembolism be retained only in stable patients with coagulase-negative
55 Mechanical defects Staphylococcus or Enterobacter infections provided antibi-

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Supportive Care
otic-lock therapy (ALT) is given. ALT is the instillation of
a concentrated antibiotic solution into the catheter lumen
with the intention of achieving a drug level high enough
to kill sessile bacteria within the biofilm of the catheter.
Thrombolytic agents are not routinely recommended but can
be used (cefazolin, vancomycin, ceftazidime and gentamicin
are stable in solution with heparin for many hours). ALT
should be administered concomitantly with systemic anti-
biotics. Suggested final concentrations of common antibiot-
ics are vancomycin, 2.0–5.0 mg/ml; ceftazidime, 0.5 mg/ml;
cefazolin, 5.0 mg/ml; ciprofloxacin, 0.2 mg/ml (due to pre-
cipitation at higher concentrations); and gentamicin, 1.0 mg/
ml, with 2500–10,000 IU/ml of heparin [39, 40].
Ideally, the dwell time should exceed 8 h per day. Seven to
14 days of such therapy is recommended depending on the
pathogen. Neutropenic patients with Staphylococcus aureus
may develop suppurative thrombophlebitis. Despite appro-
priate antibiotics the infected thrombus or intraluminal
abscess may remain intact even after catheter removal. This
condition is usually associated with erythema, oedema and
pain. In case of the central vein involvement, the neck, face,
chest or upper extremity may be swollen. The optimal choice
or duration of antibiotics and the use of anticoagulants or
thrombolytic agents have not been established. Repeated
blood cultures are recommended. Surgical drainage or exci-
sion of the affected vessel is required in a minority of patients,
with complicated necrosis [41].
57.2.3 Thrombotic Complications of CVCs
CVC thromboembolism occurs in 15–25% of patients. The
aetiology in cancer patients is multifactorial, as described
earlier in this chapter; however, colonization of the CVC is
the most frequent. Antiseptic care of CVCs is mandatory.
Suspected catheter-related thrombi have to be confirmed by
US.  Prophylactic instillation of UFH (5000  IU/ml) is rou-
tinely administered as a prevention of clotting. In case of CVC
occlusion, thrombus embolization by bolus flushing must be
avoided. Instead, low-dose urokinase may be tried although
this practice is not evidence-based. Prophylactic systemic
therapy is not indicated because of the increased risk of
bleeding. Catheter-related thrombosis should be treated with
LMWH. Progressive thrombosis during heparin therapy is an
indication for further diagnostic tests to exclude HIT.
57.2.4 Extravasation
Extravasation belongs to the most serious category of com-
plication of chemotherapy. It is diagnosed in about 6% of
patients with CVCs, usually as a result iatrogenic error.
Infusion of irritant drugs causes severe local inflammation or
soft tissue necrosis with non-healing ulceration if the punc-
ture is made close to but outside the reservoir. The tip of the
catheter placed in the distal part of the superior vena cava
may spontaneously migrate causing shoulder or neck pain,
rares1geo@gmail.com
653 57
phlebitis or thrombosis of the local veins. Patients should be
advised against extreme sports like rock climbing, mountain
biking or wearing heavy backpacks to decrease the risk of
needle dislocation or port damage.
Mechanical complications of CVCs may include the
pinch-­off syndrome, catheter fragmentation or disconnec-
tion or port catheter retraction. Placing the port medially
in the infraclavicular area causes compression of subclavian
central venous catheter between the clavicle and the first rib,
known as a pinch-off syndrome [42].
This complication is observed in 1–5% of patients, but
may be prevented by proper insertion of the catheter – either
laterally in the subclavian vein or directly into the internal
jugular vein. Removal of the port is required in each case
with such a complication.
57.3 Axillary Cording
Some women develop a series of tender, painful, cordlike
structures below the skin in the armpit area following axillary
surgery. This complication is known as cording or axillary web
syndrome [43, 44]. The exact cause of cording is not known.
The cords may be lymph channels or small veins that have
been damaged during surgery or may be fibrosis. Cording
causes pain and limits the range of arm motion. This may
complicate or delay postoperative radiotherapy. Daily stretch-
ing and supervised exercises, ideally supervised by an experi-
enced physiotherapist, are the best therapeutic methods.
57.4  ostmastectomy Pain Syndrome
P
(PMPS)
Postoperative pain is a common side effect of breast cancer
surgery leading to adhesive capsulitis of the shoulder (fro-
zen shoulder) or complex regional pain syndrome (causal-
gia) [45]. The definition of PMPS has not been standardized.
PMPS is a type of neuropathic pain, a complex chronic pain
state as a consequence of nerve damage during surgery or
the development of scarring involving the remaining breast
nerves. Altered sensation is usually observed along the
injured nerve and may last for several months, but eventually
goes away over time. It may have a burning, stabbing, sharp
or numb character. Young age and obesity are risk factors for
PMPS. Women who had breast pain before surgery are at risk
of feeling phantom pain after mastectomy.
Treatment for PMPS includes:
55 Anti-inflammatory drugs
55 Opioid analgesics
55 Neuropathic medications
55 Transcutaneous electrical nerve stimulation (TENS)
55 Massage
55 Capsaicin cream
PMPS should be managed based on widely available guide-
lines for pain control.
 654 R. Zaucha

57.5  se of Bone Marrow Support During

U ..      Table 57.3  MASCC score of the risk of serious complications
Systemic Therapy in patients with FN

Chemotherapy increases overall survival of breast cancer Factor Score

patient; however, in the adjuvant setting, this benefit is seen
Burden of symptoms No or mild symptoms 5
only in patients receiving at least 85% of the reference stan- Moderate symptoms 3
dard dose intensity. Unfortunately, even in early breast can- Severe symptoms 0
cer, chemotherapy cycles are delayed in about 45% of cases,
Blood pressure Systolic RR > 90 mmHg 5
and chemotherapy-induced neutropenia (CIN) is the cause Systolic RR ≤ 90 mmHg 0
of about 60% of dose modifications, especially in women
above 65  years of age. At least 1500 neutrophils/mm3 are Chronic obstructive No 4
pulmonary disease Yes 0
required for most of cytostatic agents active in breast cancer.
Standard regimens used in breast cancer are responsible for Previous fungal infection No 4
up to 35% of dose reductions of more than 15% and 25% Yes 0
of treatment delays of more than 7  days [46]. The depth Dehydration requiring No 3
and duration of neutropenia significantly impacts the risk parenteral fluids Yes 0
of complications. Those with an absolute neutrophil count Onset of fever In outpatient status 3
(ANC) of <500 cells/mm3 (Grade 3; G3) are at the highest In inpatient status 0
risk of developing febrile neutropenia defined as an oral tem-
Age <60 years 2
perature of >38.5 °C or two consecutive readings of >38.0 °C
57 for 2  h and an ANC  <  500 cells/mm3 or expected to fall
≥60 years 0

below this threshold [47, 48]. In the era of increasing antibi-

otic resistance, recommendations on antibiotic prophylaxis
in asymptomatic patients with Grade 3 neutropenia vary
from prophylaxis with a fluoroquinolone in intermediate-
risk (anticipated 7–10 days of G3 neutropenia) and high-risk
patients (NCCN) via fluoroquinolone in those anticipated to
be neutropenic (with an ANC < 100 cells/mm3) for >7 days
(American Society of Clinical Oncology) to no prophylaxis
at all (Australian Consensus Guidelines) [49–51].
Five to 30% of breast cancer patients experience FN,
most frequently during the first cycle of treatment. Febrile
neutropenia is fatal in approximately 8% of women; there-
fore, all symptomatic patients should undergo clinical inter-
view; full physical examination; laboratory tests including
complete blood count, electrolytes and creatinine; and a
radiological assessment according to clinical suspicions, in
order to maximize the possibility of a microbiologic diagno-
sis that may require specific antibacterial treatment. Up to
60% of episodes are due to a clinically or microbiologically
documented infection, with approximately 20–30% blood-
stream infection. Documented infections should be treated
with adequate antibiotics. Due to the high mortality rates
in Gram-negative rod (GNR) FN, early broad-spectrum
empiric therapy is recommended. Granulocyte colony-stim-
ulating factors (G-CSF) should be used in high-risk patients
with FN as adjunctive treatment with antibiotic therapy. The
risk can be assessed with a MASCC score (. Table 57.3). FN
 
patients with a MASCC score of >21 and without other clini-
cal warning signs can be safely managed with oral antibiotics
in the outpatient setting. [52].
In patients receiving chemotherapy associated with >20%
risk of FN or 10–20% FN risk in an individual with other
risk factors including ≥65 years of age, advanced disease, an
Eastern Cooperative Oncology Group (ECOG) PS  >  1 and
an albumin concentration  <35  g/l or significant comorbid
conditions, primary CIN prophylaxis with short- or long-
lasting GCSFs is recommended. The risk of neutropenic
complications is higher if an anthracycline/taxane- or an
anthracycline/gemcitabine-based regimens are administered
as these are associated with higher risk of severe mucositis,
longer duration of neutropenia, lymphopenia of <700 cells/
mm3 and monocytopenia of <150 cells/mm3.
Bone marrow suppression in the form of anaemia is
infrequent in breast cancer patients and should be managed
with red blood cell transfusions in accordance with local
guidelines and with iron, folic acid and vitamin B12 supple-
mentation if required.
Platelet transfusions are reserved for patients with symp-
tomatic thrombocytopenia or in cases of urgent surgical
intervention to maintain platelet levels above 50,000 cells/
mm3.
57.6 Anti-Emetic Therapy During
Chemotherapy
Patients beginning cancer treatment consistently list cancer
treatment-induced nausea and vomiting (CTINV) as one of
their greatest fears. Inadequately controlled emesis impairs
functional activity and quality of life for patients, increases
the use of healthcare resources and may occasionally com-
promise adherence to treatment. Therefore, effective pro-
phylaxis of CTINV has become one of the most important
supportive tasks. CTINV occurs in about 70% of patients.
The aetiopathogenesis of CTINV involves neurotransmitter-­
related activation of acetylcholine, histamine, dopamine,
gamma-aminobutyric acid, cannabinoid, serotonin (5HT3R)
and substance P (NK1) receptors present in the brain, in

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Supportive Care
655 57
treated with Cisplatin: a systematic review and meta-analysis. J Clin
..      Table 57.4  CTINV prophylaxis guidelines Oncol. 2012;30(35):4416–26.
10. Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN.  Drug-­
Acute CTINV induced thrombotic microangiopathy: a systematic review of pub-
lished reports. Blood. 2015;125:616–8.
Risk Recommendation 11. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM,

High 5HT3RA + dexamethasone + NK1RA Melton LJ.  Risk factors for deep vein thrombosis and pulmonary
embolism: a population based case-control study. Arch Intern Med.
Moderate (non-AC−/ 5HT3RA (palonosetron) + dexametha- 2000;160(6):809–15.
AC-like regimens) sone 12. Khorana AA, Connolly GC. Assessing risk of venous thromboembo-
lism in the patient with cancer. J Clin Oncol. 2009;27:4839–47.
Low Dexamethasone or DRA or 5HT3RA
13. Khorana AA.  Risk assessment and prophylaxis for VTE in cancer
Very low None patients. J Natl Compr Cancer Netw. 2011;9:789–97.
14. Mannucci PM, Bettega D, Chantarangkul V, Tripodi A, Sacchini V,
Delayed CTINV Veronesi U. Effect of tamoxifen on measurements of hemostasis in
healthy women. Arch Intern Med. 1996;156(16):1806–10.
High Dexamethasone + NK1RA
15. Pemberton KD, Melissari E, Kakkar VV. The influence of tamoxifen
AC/AC-like NK1RA in  vivo on the main natural anticoagulants and fibrinolysis. Blood
Coagul Fibrinolysis. 1993;4:935–42.
Moderate (non-AC−/ Dexamethasone 16. Jordan VC, Fritz NF, Tormey DC.  Long-term adjuvant therapy with
AC-like regimens) tamoxifen: effects on sex hormone binding globulin and antithrom-
bin III. Cancer Res. 1987;47:4517–9.
Low None
17. Mamby CC, Love RR, Feyzi JM. Protein S and protein C level changes
Very low None with adjuvant tamoxifen therapy in postmenopausal women.
Breast Cancer Res Treat. 1994;30(3):311–4.
AC anthracycline plus cyclophosphamide, 5HT3RA serotonin 18. Iqbal J, Ginsburg OM, Wijeratne TD, Howell A, Evans G, Sestak I,
receptor antagonist, NK1RA NK1 receptor antagonist, DRA Narod SA.  Endometrial cancer and venous thromboembolism in
dopamine receptor antagonist women under age 50 who take tamoxifen for prevention of breast
cancer: a systematic review. Cancer Treat Rev. 2012;38(4):318–28.
19. Walker AJ, West J, Card TR, Crooks C, Kirwan CC, Grainge MJ. When
are breast cancer patients at highest risk of venous thromboembo-
lism? A cohort study using English health care data. Blood.
the digestive system and/or in the vagus nerve. The risk of 2016;127(7):849–57.
CTINV depends on the emetogenic potential of the medi- 20. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Devel-
cations (breast cancer patients are frequently treated with opment and validation of a predictive model for chemotherapy-­
highly emetogenic cytostatics) and patient-related factors associated thrombosis. Blood. 2008;111:4902–7.
21. Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis
including age (<55 years), sex (female), alcohol consumption
of deep venous thrombosis: McMaster diagnostic imaging practice
(<100 g/day), a history of nausea and vomiting and anxiety. guidelines initiative. Ann Intern Med. 1998;128:663–77.
All types of CTINV may occur – acute, delayed and antici- 22. Streiff MB. Diagnosis and initial treatment of venous thromboem-
patory. The best therapeutic option is adequate prevention bolism in patients with cancer. J Clin Oncol. 2009;27:4889–94.
(. Table 57.4) [53].
 
23. Carrier M, Lee AY, Bates SM, Anderson DR, Wells PS. Accuracy and
usefulness of a clinical prediction rule and D-dimer testing in
excluding deep vein thrombosis in cancer patients. Thromb Res.
2008;123:177–83.
References 24. Andtabacka RHI, Babiera G, Singletary SE, Hunt KK, Meric-­Bernstam
F, Feig BW, et al. Incidence and prevention of venous thromboem-
1. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology bolism in patients undergoing breast cancer surgery and treated
of cancer-associated venous thrombosis. Blood. 2013;122:1712–23. according to clinical pathways. Ann Surg. 2006;243(1):96–101.
2. Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in 25. Kakkos SK, Caprini JA, Geroulakos G, Nicolaides AN, Stansby GP,
patients with cancer: a systematic review and meta-analysis. PLoS Reddy DJ. Combined intermittent pneumatic leg compression and
Med. 2012;9(7):e1001275. pharmacological prophylaxis for prevention of venous thrombo-
3. Deitcher SR. Cancer and thrombosis: mechanisms and treatment. J embolism in high-risk patients. Cochrane Database Syst Rev.
Thromb Thrombolysis. 2003;16:12–31. 2008;4:CD005258.
4. Sud R, Khorana AA. Cancer-associated thrombosis: risk factors, can- 26. Caprini JA, Arcelus JI, Hasty JH, Tamhane AC, Fabrega F.  Clinical
didate biomarkers and a risk model. Thromb Res. 2009;123(Suppl assessment of venous thromboembolic risk in surgical patients.
4):S18–21. Semin Thromb Hemost. 1991;17(Suppl 3):304–12.
5. Sood SL.  Cancer-associated thrombosis. Curr Opin Hematol. 27. Friis E, Hørby J, Sørensen L, Pilsgaard B, Wille-Jørgensen P, Johansen
2009;16:378–85. L, et al. Thromboembolic prophylaxis as a risk factor for postopera-
6. Lee A, Levine M. The thrombophilic state induced by therapeutic tive complications after breast cancer surgery. World J Surg.
agents in cancer patients. Semin Thromb Hemost. 1999;25:137–45. 2004;28:540–3.
7. Khorana AA, Dalal M, Lin J, Connolly GC. Incidence and predictors of 28. Kim EK, Eom JS, Ahn HS, Son BH, Lee TK. The efficacy of prophylactic
venous thromboembolism (VTE) among ambulatory high-risk can- low-molecular- weight heparin to prevent pulmonary thromboem-
cer patients undergoing chemotherapy in the United States. Can- bolism in immediate breast reconstruction using the TRAM flap.
cer. 2013;119(3):648–55. Plast Reconstr Surg. 2009;123:9–12.
8. Falanga A, Rickles FR. The pathogenesis of thrombosis in cancer. N 29. Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR,
Oncol Thromb. 2005;1:9–16. et al. Prevention of venous thromboembolism: American College of
9. Seng S, Liu Z, Chiu SK, Proverbs-Singh T, Sonpavde G, Choueiri TK, Chest Physicians evidence-based clinical practice guidelines (8th
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30. Gould MK, Dembitzer AD, Sanders GD, Garber AM. Low-­molecular-­
weight heparins compared with unfractionated heparin for treat-
ment of acute deep venous thrombosis: a cost-effectiveness
analysis. Ann Intern Med. 1999;130:789–99.
31. Dolovich LR, Ginsberg JS, Douketis JD, Holbrook AM, Cheah G.  A
meta-analysis comparing low-molecular-weight heparins with
unfractionated heparin in the treatment of venous thromboembo-
lism: examining some unanswered questions regarding location of
treatment, product type, and dosing frequency. Arch Intern Med.
2000;160:181–8.
32. Mismetti P, Laporte S, Darmon JY, Buchmüller A, Decousus
H.  Meta-analysis of low-molecular-weight heparin in the preven-
tion of venous thromboembolism in general surgery. Br J Surg.
2001;88:913–30.
33. Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C,
Jahanzeb M, et al. American Society of Clinical Oncology guideline:
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treatment in patients with cancer. J Clin Oncol. 2007;25:5490–505.
34. Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein
RA, et  al. Idarucizumab for Dabigatran Reversal. N Engl J Med.
2015;373:511–20.
35. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J,
et  al. European Heart Rhythm Association Practical Guide on the
use of new oral anticoagulants in patients with non-valvular atrial
57 fibrillation. Europace. 2013;15:625–51.
36. Raad I, Hanna H, Maki DG. Intravascular-catheter-related infections:
advances in diagnosis, prevention and management. Lancet Infect
Dis. 2007;7:645–57.
37. Maki DG, Kluger DM, Crnich CJ. The risk of bloodstream infection in
adults with different intravascular devices: a systematic review of 200
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38. Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, Naomi P. Clinical
practice guidelines for the diagnosis and management of intra-
vascular catheter-related infection: 2009 update by the Infectious
Diseases Society of America. Clin Infect Dis. 2009;49:41–5.
39. Falagas ME, Vardakas KZ, Athanasiou S. Intravenous heparin combi-
nation with antibiotics for the treatment of deep vein septic throm-
bophlebitis: a systematic review. Eur J Pharmacol. 2007;557:93–8.
40. Fazeny-Dörner B, Wenzel B, Berzlanovich C, Sunder-Plassmann
AG, Greinix H, Marosi CC.  Central venous catheter pinch-off and
fracture: recognition, prevention and management. Bone Marrow
Transplant. 2003;31:927–30.
41. Cormier JN, Askew RL, Mungovan KS, Xing Y, Ross MI, Armer
JM.  Lymphedema beyond breast cancer: a systematic review and
meta-analysis of cancer-related secondary lymphedema. Cancer.
2010;116:5138–49.
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42. Meric F, Buchholz TA, Mirza NQ, Vlastos G, Ames FC, Ross MI, et al.
Long-term complications associated with breast-conservation sur-
gery and radiotherapy. Ann Surg Oncol. 2002;9:543–9.
43. Tilley A, Thomas-MacLean R, Kwan W. Lymphatic cording or axillary
web syndrome after breast cancer surgery. Can J Surg. 2009;52(4):
E105–6.
44. Macdonald L, Bruce J, Scott NW, Smith WC, Chambers WA.  Long-­
term follow-up of breast cancer survivors with post-mastectomy
pain syndrome. Br J Cancer. 2005;92:225–30.
45. Webster LR. Chronic pain and the opioid conundrum. Anaesthesiol
Clin. 2016;34(2):341–55.
46. Loibl S, Skacel T, Nekljudova V, Luck HJ, Schwenkglenks M, Brodo-
wicz T, Zielinski C, von Minckwitz G. Evaluating the impact of rela-
tive total dose intensity (RTDI) on patients’ short and long-term
outcome in taxane- and anthracycline-based chemotherapy
of metastatic breast cancer  – a pooled analysis. BMC Cancer.
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47. de Naurois J, Novitzky-Basso I, Gill MJ, Marti FM, Cullen MH, Roila F,
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48. Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kear-
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49. Baden LR, Bensinger W, Angarone M, et  al. Prevention and treat-
ment of cancer-related infections. J Natl Compr Cancer Netw.
2012;10:1412–45.
50. Flowers CR, Seidenfeld J, Bow EJ, et  al. Antimicrobial prophylaxis
and outpatient management of fever and neutropenia in adults
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prophylaxis for patients with neutropenia. Australian Consensus
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K, Leibovici L.  Oral versus intravenous antibiotic treatment for
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53. Basch E, Prestrud AA, Hesketh PJ. I wsp. Antiemetics: American Soci-
ety of Clinical Oncology clinical practice guideline update. J Clin
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 657 VIII

Survivorship
Contents

Chapter 58 Breast Cancer Survivorship: Chronic Post-operative

Pain and Sensory Changes – 659
Tuomo J. Meretoja

Chapter 59 Breast Cancer Survivorship: Psychological Distress,

Body Image, Sexuality and Importance of the
Clinical Consultation – 663
Louise Fairburn, Christopher Holcombe, and Helen Beesley

Chapter 60 Bone Health in Patients with Breast Cancer – 673

Amy Kwan and Janet E Brown

Chapter 61 Nursing Issues and the Role of the Specialist Nurse

in Breast Care – 681
Victoria Harmer

Chapter 62 Breast Cancer-Related Lymphedema – 689

Heli Kavola and Sinikka Suominen

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 659 58

Breast Cancer Survivorship:

Chronic Post-operative Pain
and Sensory Changes
Tuomo J. Meretoja

58.1 Incidence and Risk Factors – 660

58.2 Treatment of Persistent Pain – 660

References – 660

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_58

rares1geo@gmail.com
 660 T.J. Meretoja
58.1 Incidence and Risk Factors
Chronic persistent pain and sensory changes are surprisingly
common after breast cancer surgery and adjuvant systemic
therapy and radiotherapy. In excess of 50% of patients treated
for breast cancer that may have chronic pain in the breast,
axilla, upper arm or side of the chest at 1 year from surgery,
and consistently in about 15–20% of breast cancer patient,
this pain is clinically significant, being moderate to severe in
intensity [1, 2]. Moderate-to-severe intensity pain signifi-
cantly impairs the quality of life and is defined as being at
least 4 out of 10 on a numerical rating scale ranging from 0
(no pain) to 10 (worst imaginable pain) [3].
Persistent postsurgical pain is also encountered after
other types of surgery. The pathological mechanisms leading
to persistent pain after breast cancer treatments are likely
multifactorial, but the pain is often considered neuropathic
[4]. Several patient-specific, surgery-related and adjuvant
treatment-related factors have been associated with the
development of persistent pain after breast cancer treatment.
Persistent pain after breast cancer treatment is more com-
mon in younger patients, in patients with previous chronic
58 pain conditions, in depressed or anxious patients, in mor-
bidly obese patients and in patients with preoperative pain in
the breast, axilla or upper arm. Axillary clearance instead of
sentinel lymph node biopsy alone is one of the most impor-
tant risk factors for persistent pain, whereas the type of breast
surgery does not seem to affect the incidence of persistent
pain [1, 2, 5, 6].
The handling of the intercostobrachial nerve(s) during
axillary clearance has been studied extensively with regard to
persistent pain but with no conclusive results. Studies have
had mixed results regarding the potential benefit of preserva-
tion or planned transection of the nerve(s) [5, 7, 8]. It may
well be that even if the nerve is preserved during axillary
clearance, ischemic or thermal injury may have been inflicted
on it or the nerve may become impinged in the developing
scar in the dissected axilla. The optimal handling of the inter-
costobrachial nerve therefore remains somewhat ambiguous,
but it seems clear that there is no robust evidence for benefit
in preserving the nerve.
Also, more severe intensity of acute post-operative pain
seems a clear risk factor for persistent pain, and there is con-
vincing evidence for radiotherapy being another risk factor
[1, 7].
Sensory changes after breast cancer surgery are unsur-
prisingly even more common than clinically significant per-
sistent pain [2, 9]. These sensory alterations are more
common after axillary clearance and/or mastectomy than
after sentinel lymph node biopsy and/or breast-­conserving
surgery. The sensory changes may affect the breast, thoracic
wall, axilla or upper arm and cover a wide range of altered
sensations ranging from hypoesthesia to hyperesthesia and
pain [3]. The experience of altered sensation is subjective in
nature, and patients may describe the feeling using a multi-
tude of adjectives.
rares1geo@gmail.com
58.2 Treatment of Persistent Pain
Currently, there are no convincing evidence-based strategies
for preventing persistent pain in breast cancer patients,
although it has been hypothesized that effective treatment of
acute post-operative pain might reduce the risk of persisting
pain. Low-level evidence suggests that paravertebral blocks
might decrease the rate of persistent pain after breast cancer
surgery [10, 11]. Decreasing rates of axillary clearance in
breast cancer patients may well decrease the incidence of per-
sistent pain.
Moderate-to-severe post-operative pain should obviously
be recognized and effectively treated regardless of the risk of
persistent pain. Special care should be taken to distinguish
neuropathic pain for which commonly administered pain
medications are often ineffective. The best evidence in the
treatment of neuropathic pain following breast cancer sur-
gery is for tricyclic antidepressants that have been shown to
be efficient in postmastectomy pain [12]. Other possible
medications for neuropathic pain include dual-action anti-
depressants (e.g. duloxetine) and gabapentinoids (e.g. prega-
balin). All of these medications started at low doses that are
gradually increased with careful observation of side effects
and pain relief.
Also, weak opioids, such as codeine or tramadol, may be
effective especially in moderate intensity of persistent pain. If
the persistent pain is locally confined to a small restricted
area, topical anaesthetics, as well as capsaicin, may be helpful.
Surgical exploration or excision of the painful area is not
advised.
Breast cancer patients with moderate-to-severe persistent
pain should ideally be referred early to dedicated pain clinics
for multidisciplinary evaluation and treatment to minimize
the impact on quality of life.
References
1. Meretoja TJ, Leidenius MH, Tasmuth T, Sipilä R, Kalso E.  Pain at 12
months after surgery for breast cancer. JAMA. 2014;311(1):90–2.
2. Mejdahl MK, Andersen KG, Gärtner R, Kroman N, Kehlet H.  Persis-
tent pain and sensory disturbances after treatment for breast can-
cer: six year nationwide follow-up study. BMJ. 2013;346:f1865.
3. Langford DJ, Paul SM, West C, Levine JD, Hamolsky D, Elboim C, et al.
Persistent breast pain following breast cancer surgery is associated
with persistent sensory changes, pain interference, and functional
impairments. J Pain. 2014;15(12):1227–37.
4. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk fac-
tors and prevention. Lancet. 2006;367(9522):1618–25.
5. Bruce J, Thornton AJ, Powell R, Johnston M, Wells M, Heys SD, et al.
Psychological, surgical, and sociodemographic predictors of pain
outcomes after breast cancer surgery: a population-based cohort
study. Pain. 2014;155(2):232–43.
6. Gärtner R, Jensen MB, Nielsen J, Ewertz M, Kroman N, Kehlet
H. Prevalence of and factors associated with persistent pain follow-
ing breast cancer surgery. JAMA. 2009;302(18):1985–92.
7. Andersen KG, Duriaud HM, Jensen HE, Kroman N, Kehlet H. Predic-
tive factors for the development of persistent pain after breast can-
cer surgery. Pain. 2015;156(12):2413–22.
Breast Cancer Survivorship: Chronic Post-operative Pain and Sensory Changes
8. Warrier S, Hwang S, Koh CE, Shepherd H, Mak C, Carmalt H, et  al.
Preservation or division of the intercostobrachial nerve in axillary
dissection for breast cancer: meta-analysis of randomised con-
trolled trials. Breast. 2014;23(4):310–6.
9. Tasmuth T, von Smitten K, Kalso E. Pain and other symptoms during
the first year after radical and conservative surgery for breast can-
cer. Br J Cancer. 1996;74(12):2024–31.
10. Andreae MH, Andreae DA. Regional anaesthesia to prevent chronic
pain after surgery: a Cochrane systematic review and meta-analysis.
Br J Anaesth. 2013;111(5):711–20.
rares1geo@gmail.com
661 58
11. Ilfeld BM, Madison SJ, Suresh PJ, Sandhu NS, Kormylo NJ, Malhotra
N, et al. Persistent postmastectomy pain and pain-related physical
and emotional functioning with and without a continuous paraver-
tebral nerve block: a prospective 1-year follow-up assessment of a
randomized, triple-masked, placebo-controlled study. Ann Surg
Oncol. 2015;22(6):2017–25.
12. Kalso E, Tasmuth T, Neuvonen PJ. Amitriptyline effectively relieves
neuropathic pain following treatment of breast cancer. Pain.
1996;64(2):293–302.
 663 59

Breast Cancer Survivorship:

Psychological Distress, Body
Image, Sexuality
and Importance of the Clinical
Consultation
Louise Fairburn, Christopher Holcombe, and Helen Beesley

59.1 Breast Cancer Survival – 664

59.1.1 Survivorship – 664
59.1.2 Summary Points – 664

59.2 Psychological Distress Following a Breast

Cancer Diagnosis – 664
59.2.1 «Normal» Distress: Psychologically Adjusting
and Adapting to a Breast Cancer Diagnosis – 664
59.2.2 Summary Points – 666

59.3 Risk Factors for Enduring Psychological Distress – 666

59.3.1 Body Image and Sexuality – 666
59.3.2 Patient Characteristics and Early History – 667
59.3.3 Summary Points – 669

59.4 What do breast cancer patients value from

their clinical communications – 669
59.4.1 Summary Points – 669

References – 670

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_59

rares1geo@gmail.com
 664 L. Fairburn et al.
59.1 Breast Cancer Survival
Breast cancer survival rates have progressively increased but
vary greatly worldwide, ranging from 80% or over in some
European and North American cities, 60% in middle-income
countries and below 40% in low-income countries [1].
However, due to improvements in early detection and treat-
ment, women of developed countries are surviving longer
following a diagnosis of breast cancer. Women are, therefore,
living with the after-effects of breast cancer and its treatment,
which can have both physical and psychological conse-
quences.
59.1.1 Survivorship
Whilst the definition of a cancer survivor has varied to an
extent, in clinical terms, it has been any person diagnosed
with cancer, from the time of initial diagnosis until his or her
death. Over recent years, with cancer treatment improving
and the number of cancer survivors increasing, the concept
of cancer survivorship has evolved to acknowledge the phys-
ical, psychosocial, spiritual, social and economic conse-
quences of cancer diagnosis and its treatment, and there have
59 been steps to improve service delivery to support cancer
patients beyond the end of the acute phase of their treat-
ment. With much research and service development being
carried out in this area, the term ‘survivorship’ has become
familiar in the field of breast cancer, in both clinical and
research settings.
59.1.2 Summary Points
55 Due to improvements in detection and treatment, more
women are becoming «cancer survivors».
55 Living with the aftermath of breast cancer and its treat-
ment can have both physical and psychological conse-
quences.
55 The term «survivorship» refers to the physical, psycho-
social, spiritual, social and economic consequences of
breast cancer beyond the end of acute treatment.
59.2  sychological Distress Following
P However, this is the time point when people begin to live with
a Breast Cancer Diagnosis
Psychological distress following a cancer diagnosis is com-
mon, with one third of patients experiencing clinically sig-
nificant distress [2]. Breast cancer patients have been found
to be especially vulnerable to psychological distress in com-
parison to patients affected by other female cancers [3].
Distress can be understood on a continuum, ranging from
common feelings of vulnerability, sadness and fear to clini-
cally significant experiences of depression and anxiety [4].
rares1geo@gmail.com
Estimates of clinically significant distress within a breast can-
cer population are high; the prevalence of anxiety/depression
in the first year after a breast cancer diagnosis is approxi-
mately twice that of the general female population [5] and
10–30% in 5 years after diagnosis [6].
The impact of psychological distress on quality of life in
breast cancer patients can cause significant impairment to
functioning [7, 8]. Depression has a negative impact on phys-
ical functioning with several studies reporting an association
between distress and physical pain [9–11], number and
severity of treatment side effects reported [12] and the exac-
erbation of nausea and fatigue [13].
Due to the prevalence, and the deleterious effects of dis-
tress on the lives of people with breast cancer, the identifica-
tion of psychological distress is now acknowledged to be an
important component of good clinical care [14].
59.2.1 « Normal» Distress: Psychologically
Adjusting and Adapting to a Breast
Cancer Diagnosis
Cancer is one of the most feared life events [15] and distress
is a natural response. The task of adjusting and moving on
from a diagnosis can be considerable.
At diagnosis, a predominant initial reaction is shock
which often manifests as feelings of numbness or detachment
and carrying on as though on «autopilot». Shock can be
expressed in different ways, from overt emotional upset to
apparent lack of emotion [16]. Avoidance (from distraction
to apparent denial) can be noted at diagnosis and is a self-­
protective psychological defence mechanism operating as a
means of slowing down the rate at which the full implications
of the cancer diagnosis are absorbed. This is often manifested
through keeping busy or circumventing any discussion of the
cancer. These initial emotional reactions should be short
term and give way to different reactions once the cancer
begins to be incorporated into a person’s reality. Normal
emotional reactions can vary and can last from diagnosis to
well beyond the end of treatment. People can experience sad-
ness, anger, irritability, fear, helplessness and anxiety, result-
ing in loss of interest in activities, sleep disturbance and loss
of appetite. The end of treatment is often looked forward to as
the point when «normal» life and functioning can be resumed.
challenges such as treatment side effects (e.g. pain/fatigue),
changed body image/appearance and an increased awareness
of mortality. Distress, therefore, can often peak at the time
when people expect the worst to be over, causing confusion,
despair, hopelessness and a sense of not coping [17].
Strong emotional reactions are natural whilst assimilat-
ing a cancer diagnosis into life experience. Throughout life,
people make assumptions about themselves and the world
around them and form individual «mental models» whereby
the world can be viewed as a stable environment and people
Breast Cancer Survivorship: Psychological Distress, Body Image, Sexuality and Importance of the Clinical Consultation
can plan and anticipate a future [18]. Cancer can violate
people’s most deeply held assumptions regarding their health
and mortality, thus destabilising their assumptions and hopes
for the future. The process of adjusting to a cancer diagnosis
requires re-evaluation of assumptions to incorporate cancer
and its implications into the life experience. People can
report going through a process of re-evaluation, whereby pri-
orities are redefined and the important things in life become
clearer [19]. Post-traumatic growth [20], the experience of
positive growth from a traumatic event, has been reported in
cancer survivors and is associated with increased physical
well-being and decreased distress in breast cancer survivors
specifically [21].
As breast cancer patients move beyond diagnosis and
treatment into cancer survivorship, uncertainty regarding
the implications of their illness is a common cause of psycho-
logical distress. Uncertainty is common in relation to several
665 59
factors such as future employment and financial concerns,
social and family functioning and sense of identity and role.
However, the most commonly reported source of uncertainty
for cancer survivors is the possibility of future disease, with
many people experiencing fear of recurrence or metastases
[22]. This can make it difficult for people to plan ahead or
look to the future. The presence of physical symptoms (such
as fatigue, pain, treatment and/or surgical side effects) can be
associated with elevated fear of recurrence, where cancer sur-
vivors appraise physical symptoms as signs of recurrence or
progression of their disease [23]. In their large systematic
review, Simard and colleagues [24] found significant anxiety
and depression to be positively associated with fear of recur-
rence in cancer survivors. Whilst these experiences are com-
mon following a cancer diagnosis, they are not always
experienced and must not be assumed to be present for all
patients.

Case 1: A Lack of Reaction to Diagnosis

Lynne, aged 67.
Background
Lynne was diagnosed with screen-detected
breast cancer just two weeks ago. She is
retired and lives with her husband, Alan.
They both lead active lives, with Lynne
looking after her four grandchildren most
days whilst her son and daughter go to
work. In discussion with her consultant,
Lynne said that she «hasn’t got time for
cancer» due to her commitments with her
grandchildren. She explained that her fam-
ily was supportive, but she did not want
to discuss it with them as it would make it
«too real». Lynne’s consultant referred her
to clinical psychology as she was concerned
that Lynne was «in denial», did not under-
stand the gravity of the diagnosis and was
showing no emotion in response to the
situation.
Psychological Understanding
and Intervention
As Lynne was only diagnosed two weeks
ago, she is likely experiencing the initial
reactions of shock and managing this with
avoidance. Her comment that discussing
it with her family will make it «too real»
suggests that she is not yet at the stage
where she has absorbed the full impact of
the diagnosis, which would also account for
the detachment and lack of emotion. It is
unlikely that Lynne is experiencing denial
rather that she is taking on board her diag-
nosis gradually.
Intervening too much at this stage
can be unhelpful as Lynne is still naturally
processing the news that she has breast
cancer. Talking through normal reactions to
a diagnosis to help her understand her cur-
rent reaction, discussing common thoughts
and feelings she may experience in the
coming months and also encouraging
her to accept support from her family and
increase communication with her husband
when she feels able to would be the most
helpful for Lynne when she feels ready [25].

Case 2: Expecting to Be ‘Back to Normal’ After Treatment

Paula, aged 56.
Background
Paula was diagnosed with breast cancer
9 months previously after finding a lump.
She has undergone mastectomy with imme-
diate reconstruction, chemotherapy and
radiotherapy and currently takes tamoxifen.
Paula described managing the surgery and
treatment well, taking it «day by day» and
remaining positive throughout with the
support of her family, friends and clinicians.
She is married to Jason, with two teenage
sons, and works as a college lecturer. On
discussion with her breast care nurse at the
end of treatment, the nurse found Paula to
be tearful and low, and Paula was confused
as to why she felt like this. Paula reported
suffering from pain, fatigue and hot flushes
which were distressing for her. She also
talked about how she had been looking
forward to completing treatment and being
able to get back to work and back to normal,
but now she had reached that stage all she
wanted to do was «crawl under a rock and
hide» as she felt «like a different person».
Paula’s breast care nurse referred her to clini-
cal psychology to discuss ways forward.
Psychological Understanding
and Intervention
Paula had employed strategies which were
effective in managing the immediate chal-
lenge of the treatment regimens, taking
things «day by day» and accepting support.
She had focussed on the end of treatment
as being the point in she could «get back to
normal», when in reality, the end of treatment
is commonly the stage when the full implica-
tions of having had breast cancer can be
realised and Paula is likely to be feeling fright-
ened and anxious about her future. Paula
is also experiencing some treatment side
effects, thus challenging her desire to «get
back to normal», as Paula’s «normal» has not
before included pain, fatigue and hot flushes.
Though Paula’s reaction is natural,
people can often feel stuck, confused
and frightened at this stage. Psychologi-
cal intervention would facilitate Paula’s
natural adjustment by helping her navigate
through the different emotional challenges
she faces. Time talking with the clinical psy-
chologist would give Paula the opportunity
to reflect on her experience of cancer, her
current feelings and re-evaluation of her
future plans and priorities. Strategies would
be given for managing feelings of anxiety
and low mood whilst also normalising her
reaction to such a significant life event.

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 666 L. Fairburn et al.
59.2.2  Summary Points
55 Distress is a natural response to breast cancer, and the
experience of normal emotional reactions can occur
from diagnosis to well beyond the end of treatment.
55 Common feelings can include sadness, anger, irritability,
fear, helplessness and anxiety and can result in loss of
interest in activities, sleep disturbance and loss of appetite.
55 Strong emotional reactions are a natural when assimilat-
ing a cancer diagnosis into life experience.
55 Clinically significant psychological distress following a
cancer diagnosis is common, with breast cancer patients
even more vulnerable to experiencing depression and/or
anxiety.
55 The experience of significant psychological distress can
cause significant impairment to functioning and overall
quality of life.
55 The identification of psychological distress by clinicians
is now acknowledged to be a vital component of good
clinical care.
59.3  isk Factors for Enduring Psychologi-
R likely to opt for breast reconstruction following mastectomy
cal Distress
59 The experience of psychological distress is a normal, appro-
priate reaction to a breast cancer diagnosis and can dissipate
over time with the process of adjustment and with support of
family, friends and the clinical team. However, there are fac-
tors which can increase the likelihood of long-standing,
clinically significant distress which can persist even with the
support that many people have available to them. This chap-
ter will focus on two important areas: body image and sexu-
ality. It will then highlight patient factors which may make
clinically significant distress more likely to occur.
59.3.1 Body Image and Sexuality
Body image was originally defined as the picture of our own
body which we form in our mind [26]. It can be associated
with feminine identity, sexuality and attractiveness [27].
Bradbury [28] discussed that individuals who undergo
changes to their appearance in later life can experience
greater psychological distress than if the change had occurred
in early childhood, as they can then experience grief for the
loss of their previous appearance and sense of self.
Breast cancer treatment can include the loss of one or
both breasts, scarring, hair loss, weight loss or gain and early
menopause and as such negatively affect a woman’s body
image [29]. Breast cancer patients have reported feeling
mutilated by mastectomy and loss of their femininity [30].
Sexuality, intimacy and relationship with a partner are fre-
quently associated with body image concerns in the breast
cancer survivor [31]. Physically, breast cancer treatment can
induce a range of sexual difficulties such as loss of libido,
decreased sexual arousal and lack of sexual pleasure [32],
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with chemotherapy specifically thought to be a risk factor
for problems with arousal, lubrication, orgasm and sexual
pain [33].
Poor body image post-treatment has been linked to more
instances of anxiety, depression and fear of cancer recurrence
[34, 35], greater overall psychological distress and lowered
quality of life [36]. Younger women in particular (below
50 years of age) have been found to be at risk for poorer body
image than older women [31]. A longitudinal study [37]
found that younger women showed significantly greater
impairment in both emotional and social functioning, which
was still present 12 months post-treatment. The life stage of
the majority of younger women can be used to contextualise
these findings. Younger women often have small children to
care for. They can also face the prospect of infertility and the
symptomatic burden of the menopause. Women who are not
in a relationship with a partner may become concerned about
finding a future relationship due to their bodily changes.
Moreover, those who are in an intimate relationship can
experience loss of confidence in their own sexuality [38].
Surgery type particularly was found to have a large impact
on appearance satisfaction, with younger women being more
than older women [39, 40], with the primary motivation
given for breast reconstruction being the hope of boosting
women’s self-esteem [41, 42]. However, the evidence as to
whether breast reconstruction actually does this is mixed.
Some studies have shown that mastectomy-only patients are
more likely to have body image/sexuality concerns, in com-
parison to those who have undergone breast-conserving
treatment or reconstruction, and that they are more likely to
dislike their appearance naked [43], find it difficult to look in
the mirror [44] and feel «ugly» and self-conscious [45].
Conversely, other studies comparing those undergoing mas-
tectomy only versus breast reconstruction do not suggest that
having reconstruction improves quality of life, body image or
sexual function [46, 47]. Also, the higher likelihood of surgi-
cal complications following breast reconstruction can put
women more at risk of psychological distress [48]. Surgeons
therefore need to be able to guide patients in making
informed decisions about breast reconstruction, and in order
to do so, it is essential for the surgeon to understand how the
patient evaluates the procedure. It would be easy to assume
that satisfaction with reconstruction is simply related to cos-
mesis. In fact, satisfaction with reconstruction can often
involve a lot more than simply evaluating cosmesis, and can
include the role of reconstruction in completing the cancer
journey for some, and qualities of the relationship with the
surgeon [49].
One of the most consistent protective factors against poor
body image and sexual confidence in women following breast
cancer has been found to be the quality of partner support
[50, 51]. Indeed, partner support was linked to less overall
­psychological distress, with the quality of the relationship
being a stronger predictor of sexual functioning and satisfac-
tion than the physical effects of the cancer treatment [52].
Emilee and colleagues [32] discuss the importance of «sexual
Breast Cancer Survivorship: Psychological Distress, Body Image, Sexuality and Importance of the Clinical Consultation
667 59
renegotiation», the process whereby a couple renegotiate their and enables couples to manage the changes in their relation-
sexual practices when the type and frequency of intimacy ship. Open communication, partner empathy and support
they had precancer are no longer desirable or possible. This were all found to increase women’s psychological well-being
process can facilitate adjustment to a new level of functioning and perception of body image and sexuality [53, 54].

Case 3: Poor Body Image Following Reconstructive Surgery

Holly, aged 37.
Background
Holly was diagnosed with breast cancer
18 months ago. She underwent mas-
tectomy, implant-based reconstruction,
chemotherapy and radiotherapy. Unfor-
tunately, Holly suffered complications
following reconstructive surgery resulting
in implant loss. She is in the process of hav-
ing this rebuilt, but Holly reported to her
surgeon that she «hates» her appearance.
She avoids looking at herself in the mirror
as she is «repulsed». Holly has been married
to Damian for two years and reported that
they were still in the «honeymoon phase»
of their relationship when she was diag-
nosed. They have not been intimate since
the diagnosis, and Holly will not allow him
to see her without clothes. Though Damian
has been very supportive, they never talk
about sex, and Holly feels that he does not
find her attractive anymore as he does not
initiate any intimacy.
Psychological Understanding
and Intervention
Holly has had a challenging experience
with reconstructive surgery which is still
ongoing. The fact that the cancer and treat-
ment occurred at the life stage when Holly
was newly married makes her relationship
a key factor to her overall adjustment. Holly
reported that the relationship was in the
honeymoon phase and for them, sex and
intimacy had been central. The sudden loss
of this was naturally upsetting for them
both. Several factors will be exacerbating
the difficulties at the moment: Holly’s feel-
ings about her appearance, her perception
that Damian no longer finds her attractive
and their lack of communication.
Psychological intervention would aim
to increase their communication in the
first instance. Often couples engage in a
«conspiracy of silence» [55] whereby each
does not bring up a difficult subject for fear
of upsetting the other. A session for both
Holly and Damian to talk openly would be
helpful and facilitate the pathway for sexual
renegotiation at a level which feels appro-
priate for them both. Individual work with
Holly focussing on her feelings about her
body would also be advised.

59.3.2   atient Characteristics and Early

P about self) and shapes individuals’ expectations about rela-
History
A person’s life does not begin at the point they become a
«breast cancer patient». Each person brings with them (to
diagnosis and the clinical consultations they have) their own
individual history and values, and these shape how they
negotiate the challenges of breast cancer diagnosis, treatment
and survivorship.
A helpful framework for understanding how factors
which predate a cancer diagnosis can influence a person’s
response to the challenge of cancer, and influence the patient–
doctor relationship, is attachment theory. Bowlby [56, 57]
proposed the concept of «attachment relationships» which
are emotional bonds that lead an individual to seek proximity
to a person with the power to protect them (an «attachment
figure») in times of threat or danger. Bowlby proposed that
attachments are based on how an individual perceives them-
selves and other people around them; these perceptions are
formed from early childhood experiences with caregivers
(usually parents) and become generalised to other relation-
ships in adulthood [58, 59]. Attachment processes are likely
to be activated in the patient–doctor relationship, the «attach-
ment figure» being the surgeon, as theoretically, they hold the
power to remove the threat (the cancer). The four-category
model of attachment [60] (. Fig. 59.1) is frequently used in
healthcare literature to contextualise patient behaviour [61]
and describes four «mental models» of attachment.
Each mental model varies from positive (trust in others:
confidence in self) to negative (distrust of others: anxiety
tionships, with one «secure» attachment style and three
«insecure» attachment styles. In healthcare specifically, inse-
cure attachment style has been found to pose a threat to
physical health in terms of factors such as altered stress phys-
iology, unhelpful health attitudes [61, 62] and lowered treat-
ment adherence [63, 64].
Childhood Abuse: childhood abuse can impair the for-
mation of a secure attachment style. Unfortunately, child-
hood abuse (sexual, physical and emotional) is prevalent.
Worldwide, the prevalence of childhood sexual abuse in non-
clinical populations has been found to be as high as 53% for
women [65–67]. Physical and emotional abuse is also com-
mon. Research has reported an association between the
experience of childhood abuse and a wide range of adult
psychological difficulties including depression, anxiety, post-
traumatic stress disorder, personality disorder, alcohol and
substance abuse, obsessive compulsive disorder and low self-
esteem [68]. It has also been associated with considerable
interpersonal difficulties [69].
People with a history of childhood abuse are more vul-
nerable to psychological distress following a diagnosis of
breast cancer [70]. A study specifically investigated whether
childhood abuse explained some of the variability in emo-
tional problems following surgery for breast cancer [19].
Sexual, emotional and physical abuse were recalled by 10%,
25% and 28%, respectively. Overall emotional distress, post-
traumatic stress symptoms, self-blame and shame were pres-
ent in 49%, 8%, 22% and 13% of women, respectively, and
each problem was more common in women who recalled

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 668 L. Fairburn et al.

..      Fig. 59.1  Four-category model Positive Other

of attachment
Secure Preoccupied
Consistent and responsive early care- Inconsistently responsive early care-giving.
giving. Comfortable depending on, and Excessively vigilant of attachment relationships
can seek comfort and support, from and emotionally dependent on the approval of
others. others,but have poor self-esteem.

Positive self Negative self

Dismissing
Emotionally unresponsive early care-giving.
Developed self-reliant strategies, and are
uncomfortable being close to, or trusting,
others.
Fearful
Overly critical, harsh and/or rejecting early care-
giving. Desire social contact, but inhibited by fear
of rejection. Interpersonal pattern of approach-
avoidance in which they flee once a certain level of
closeness is attained.

Negative Other

one or more forms of abuse. Moreover, sexual and emotional
abuse were specific risk factors for emotional distress,
whereas emotional and physical abuse were specific risk fac-
59 tors for post-traumatic stress symptoms. These findings
imply that emotional problems following breast cancer can
arise partially from factors which predate the illness, suggest-
ing that the presence of childhood abuse is a significant risk
factor for emotional distress following breast cancer.
Social Support: Studies have consistently reported a
positive association between social support from friends/
family and psychological adjustment to breast cancer [71,
72], along with evidence to suggest that feeling supported by
the clinicians involved in their care is also a vital component
to psychological outcome in breast cancer [73–75]. However,
due to their early history and insecure attachment style,
patients with an adverse childhood history feel more isolated,
have difficulty forming trusting relationships and feel less
well supported by family [76], spouses [77] and friends [78].
In breast cancer patients, Salmon and colleagues [79] and
Clark and colleagues [70] specifically measured the patient–
surgeon relationship and found that women reporting child-
hood abuse were seven times more likely to feel incompletely
supported by their surgeon than other patients. In reciproca-
tion, surgeons reported experiencing these patients as more
difficult to help. Additionally, holding a negative attachment
model of self («I am not worthy of support») mediated their
perception of incomplete support, suggesting that attach-
ment processes are activated during the clinical relationship.
It can be theorised that when people feel threatened by mor-
tal disease, clinicians whom they regard as having the author-
ity and power to protect them evoke the attachment models
of self and others that have been shaped in early childhood.
This may also apply to the relationship with other clinicians
involved in the patient’s care [80].

Case 4: Difficulties in Supporting a Patient

Jane, aged 66.
Background
Jane was diagnosed with breast cancer
six months ago and had undergone
mastectomy, reconstruction and chemo-
therapy. Her clinical team reported that
she had been given what they perceived
to be a good level of support and informa-
tion. The team noted that Jane had asked
few questions and often they could feel
«dismissed» by her, but she had reported
no problems. However, Jane had attended
a clinic appointment and «out of the blue»
had reported dissatisfaction with her care,
the support received and the outcome of
her reconstruction. The clinical team con-
sequently felt «confused» and unsure how
to support her. Jane had a prior history of
severe depression and lived alone.
Psychological Understanding
and Intervention
Jane’s interpersonal functioning and depres-
sion history would be suggestive of dif-
ficulty prior to her breast cancer diagnosis.
Her relations with others, such as rejection
of support and dismissive attitude, can be
indicative of an insecure attachment style.
Psychological therapy could be offered
as an option for her to build an understand-
ing about interpersonal patterns and help
her access the care she needs. Interven-
tion could also potentially help guide the
clinical team as to how to best support
her. Joint working with her clinicians and
GP would also ensure that her emotional
needs were met alongside treatment for
breast cancer.

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Breast Cancer Survivorship: Psychological Distress, Body Image, Sexuality and Importance of the Clinical Consultation
59.3.3  Summary Points
55 There are patient factors which can increase the likeli-
hood of long-standing, clinically significant distress in
cancer survivorship. Two of these factors are poor body
image and early childhood abuse history.
55 Breast cancer treatment can negatively affect a woman’s
body image.
55 Sexuality, intimacy and relationship with a partner are
frequently associated with body image concerns in the
breast cancer survivor.
55 Poor body image post-treatment has been linked to
greater overall psychological distress and lowered quality
of life.
55 Open communication, partner empathy and support
were all found to increase women’s psychological well-
being and perception of body image and sexuality.
55 Each person brings their own life history to the breast
cancer diagnosis and consultations.
55 The experience of abuse in childhood is a significant
risk factor for emotional distress following breast cancer
and the inability to access support or feel supported by
professionals.
55 Attachment theory can provide a helpful framework for
understanding how factors which predate a cancer diag-
nosis can influence a person’s response to the challenge
of cancer and influence the patient–doctor relationship.
59.4  hat do breast cancer patients value
W the clinician) at a time of existential threat with a breast can-
from their clinical communications
Communication between physician and patient is complex
and goes beyond merely giving adequate information and
choice; both physician and patient play their part as the pro-
vider and receiver of care, respectively, but in addition bring
their own enduring characteristics into the consultation. This
complex interplay determines the ultimate outcome of a
patient-centred consultation which should leave the patient
feeling listened to, understood and supported by the clini-
cian. A large body of literature has examined, from the
patient perspective, what elements need to occur in a consul-
tation to enable this outcome. Some of the key areas are dis-
cussed briefly below.
Good interpersonal communication during consulta-
tions has been linked to less overall psychological distress
[81–83]. Research in this area has claimed that meeting
patients’ ­informational needs by providing information and
discussing treatment options is a standard and fundamental
aspect of cancer care [84]. However, some evidence suggests
that patients require clinicians to do much more in a consul-
tation than just meet their informational needs. Findings
from a large-scale study with breast cancer patients and clini-
cians suggested that patients valued a close relationship with
their clinician [85]. Indeed, 81% of patients in that study
indicate that trust in their physician was an important com-
ponent of their care.
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669 59
Meeting breast cancer patients’ communication needs
has been reported to be important to the success of the con-
sultation. One qualitative study reported that positive expe-
riences of communication were related to the clinician
taking the time to build a relationship, appearing unrushed,
a willingness to answer questions, responding sensitively to
feelings of vulnerability and distress, offering hope, recog-
nising the patient as an individual and an awareness of the
impact that cancer may have had on the patient’s psycho-
logical well-­being [86]. The authors highlighted that the
importance of a sense of collaboration and information
sharing facilitated the perception of a working relationship
leading to positive feelings of mastery and «control» over the
illness. The importance attached to communication skills
and «building» a relationship being what patients value has
varied in the literature. Findings from another qualitative
study of breast cancer patients [87] suggested that breast
cancer patients were not primarily concerned with doctors’
communication skills, but rather with doctors’ enduring
characteristics. Specifically, they valued doctors whom they
believed were technically expert, had formed individual
relationships with them and respected them. They therefore
valued forms of communication that are currently not
emphasised in training and research, whilst the «technical»
aspects of current communication training were valued less.
Recent research findings have also questioned the idea of
whether the relationship between breast cancer patient and
surgeon is «built» or rather is present from a very early stage,
based on the need for attachment (which can be provided by
cer diagnosis [88].
The responsibility for the success of the consultation, and
the degree to which patients are satisfied with the care they
receive, is often placed firmly with the doctor and their com-
munication skills. However, this view is oversimplistic as it
does not take into account the patient factors outlined in this
chapter which also influence the breast cancer patient–doc-
tor relationship. Additionally, it does not take into account
the role that the surgeon has from the start as the person who
can help the patient in such a fundamental way when they are
facing a life-threatening illness [88].
The key messages from these studies indicate that patients
value the interpersonal aspects of their consultations and the
behaviour of the clinical staff greatly contributes to how sup-
ported and cared the patients feel. Having their needs
responded appropriately can increase trust, having the option
to accept or reject treatment recommendations denotes
respect, and taking time to respond to emotional concerns or
engaging in what appears to be an individual act uniquely for
the patient can signify a personal connection.
59.4.1 Summary Points
55 The interaction between the patient and clinician during
clinical consultations has a significant influence on the
patient’s overall breast cancer experience.
 670 L. Fairburn et al.
55 Good interpersonal communication during consultations
has been linked to less overall psychological distress.
55 An important factor for patients is not just how clinicians
communicate but also their personal attributes and per-
sonality traits.
55 Some patients value a collaborative working relationship
during clinical consultations.
55 Interpersonal aspects of the consultation are valued, and
the behaviour of the clinical staff greatly contributes to
how supported and cared the patients feel.
55 The patient brings their life experience to a clinical con-
sultation which can affect how easy or difficult they find it
to be supported by the clinical team and how easy or diffi-
cult they find it to feel satisfied with the care they receive.
55 Doctors need excellent communication skills in order
to provide good clinical care, but the patient factors
outlined in this chapter also influence the breast cancer
patient–doctor relationship.
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 673 60

Bone Health in Patients

with Breast Cancer
Amy Kwan and Janet E Brown

60.1 Introduction – 674

60.1.1 What Is Bone Health? – 674
60.1.2 How Bone Health Is Monitored and Assessed – 675
60.1.3 Factors Affecting Bone Health in Breast Cancer Survivors – 675
60.1.4 Premature Ovarian Failure – 675
60.1.5 Pharmacology of Bone-Directed Therapy – 676
60.1.6 Suggested Algorithm for Monitoring and Treatment
for Cancer Treatment-­Related Bone Loss – 677

60.2 Summary – 678

References – 678

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_60

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 674 A. Kwan and J.E. Brown

60.1 Introduction bone mass and deterioration in the microarchitecture of

bone tissue. Individuals with osteoporosis are at high risk of
60.1.1 What Is Bone Health? fracture and long-term morbidity. The World Health
Organization (WHO) defines osteoporosis as a bone mineral
Increased understanding of the biology of breast cancer has density of less than 2.5 standard deviations from normal
led to the evolution of breast cancer treatments, particularly individuals [5], which is assessed by a dual energy x-ray
in the early setting. Endocrine treatment for hormone-­ absorptiometry (DEXA) scan. Osteoporosis in itself is
sensitive breast cancer has led to significantly fewer recur- asymptomatic; however there is increased morbidity and
rences and an increased number of breast cancer survivors. mortality in individuals sustaining an osteoporotic fracture
The 5-year relative survival for patients diagnosed with stage with a 10–20% increased risk of dying within the 12 months
1 and stage 2 disease is 99.1% and 87.6%, respectively [1]. following a hip fracture [6]. To try to identify which patients
However, the use of therapies which decrease oestrogen levels are at increased risk of fracture, various models have been
(aromatase inhibitors, ovarian suppression) is associated with developed. The most established is the FRAX tool (7 https://  

bone mineral density (BMD) loss. Even in women without www.shef.ac.uk/FRAX/). FRAX is a simple online tool that was
cancer, BMD loss occurs with increasing age, with a lifetime developed by the University of Sheffield with the WHO and
risk of 1 in 3 women over the age of 50 sustaining an osteopo- allows a calculation of fracture risk over the following
rotic fracture [2, 3]. It is therefore especially important that 10 years. It involves inputting 12 pieces of data related to a
bone health is considered in all breast cancer survivors. patient’s bone health (see . Fig. 60.1). The tool has been indi-
 

In normal bone, bone integrity is maintained through a vidualised based on population models from Europe, North
balance between osteoclastic bone resorption and osteoblas- America, Asia and Australia. Although it has not been vali-
tic bone formation. Oestrogen plays a key role in the negative dated in cancer patients, it can give some guidance to which
regulation of osteolysis, and low physiological levels of oes- patients need special consideration of bone health through
trogen significantly increase the risk of osteoporosis and its their cancer treatment. In the UK, bone health is managed
complications [4]. Osteoporosis is characterised by reduced primarily by general practitioners; however the initial

60

..      Fig. 60.1  Screenshot of FRAX assessment tool (© Centre for Metabolic Bone Diseases, University of Sheffield, UK. Used with permission from
the University of Sheffield)

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Bone Health in Patients with Breast Cancer
­ iagnosis of osteoporosis may be suspected by any medical
d 60.1.4 Premature Ovarian Failure
professional, and it is important that this information is com-
municated to primary care physicians to ensure patients are
appropriately followed up after commencing bone-directed
therapy.
60.1.2  ow Bone Health Is Monitored
H nent ovarian failure. Approximately 68% of patients, ranging
and Assessed
DEXA Scans
The standard for bone health monitoring is the use of DEXA
scans to assess bone mineral density. The principle behind
the DEXA scan is the measurement of difference between
penetrations of two photon beams of different energies
through the body. This allows the inference of the density of
two tissues (bone and soft tissue) and a real (not true volu-
metric) density to be estimated. Advantages of DEXA scans
are low doses of ionising radiation, good precision, short
scan times and stable calibration. The major disadvantage is
that changes in BMD often take many months or years to be
assessable by DEXA scan.
Bone Turnover Markers (BTMs)
BTMs can be divided into two groups, formation and resorp-
tion markers. Formation markers reflect the activity of osteo-
blasts and include bone-specific alkaline phosphatase (BALP)
and procollagen type 1 amino-terminal propeptide (P1NP).
Resorption markers reflect the activity of osteoclasts and
include type 1 collagen C-terminal telopeptide (CTX) and
type 1 collagen amino-terminal telopeptide (NTX).
BTM monitoring may allow for earlier identification of
patients with accelerated bone resorption and therefore
future BMD loss and may potentially provide a more
dynamic, non-invasive and cheaper assessment of skeletal
metabolism [7, 8]. In an exploratory subset analysis of the
patients who had BTM assessment in the Z-FAST trial
(Zoledronic acid-Letrozole Adjuvant Synergy Trial), an early
increases in NTX and BALP were predictive of clinically rel-
evant long-term bone loss [9]. However, further studies are
needed and BTMs are not routinely used in clinical practice.
60.1.3  actors Affecting Bone Health
F Tamoxifen is a selective oestrogen receptor modulator and is
in Breast Cancer Survivors
Bone health can be affected by cancer treatment irrespective
of menopausal status. In premenopausal women there is a
risk of accelerated bone loss due to oestrogen suppression
from adjuvant treatments including chemotherapy, aroma-
tase inhibitors and ovarian suppression or due to premature
ovarian failure [10]. In postmenopausal women the rate of
BMD loss is doubled in patients administered aromatase
inhibitors in the adjuvant setting [11]. Decrease in BMD
related to cancer treatment is usually described as treatment-­
induced bone loss (TIBL).
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675 60
Cytotoxic Chemotherapy
Combination cytotoxic chemotherapy is administered peri-
operatively to prevent disease recurrence and improve breast
cancer-related mortality. In premenopausal patients, the use
of such treatments can result in either temporary or perma-
from 20–100% depending on age, type and cumulative dose
of cytotoxic agent, will experience chemotherapy-induced
ovarian failure and amenorrhea [10, 12, 13]. This results in
rapid decrease in BMD of up to 7% within 1 year [14]. Bone
loss does not appear to be clinically significant in those that
retain their menses following treatment.
Ovarian Suppression/Ablation
Interruption of the hormonal axis, through the use of drugs
affecting the hypothalamic-pituitary-gonadal axis (e.g.,
GnRH/LHRH analogues), results in loss of menses and
potentially reversible ovarian suppression. Rapid bone loss
has been seen for the duration of amenorrhoea. Recent data
has suggested a decrease in disease-specific recurrence with
the addition of adjuvant ovarian suppression to either tamox-
ifen or exemestane in higher-risk patients who remain pre-
menopausal after chemotherapy [15]. In view of this, the use
of ovarian suppression and tamoxifen or exemestane may
play an important role in high-risk patients who have pre-
menopausal levels of oestradiol following chemotherapy. In
premenopausal breast cancer patients, a Phase 3 trial
(ABCSG-12) randomised 1803 patients with hormone
receptor-­positive breast cancer to receive endocrine treat-
ment (goserelin and tamoxifen or anastrozole), each with or
without zoledronic acid every 6 months for 3 years [16, 17].
Data from the bone sub-study (n  =  404) showed that in
patients who did not receive bone protective therapy with
zoledronic acid, there was a significant reduction in BMD at
3 years (trochanter, 7.3%; lumbar spine, 11.3%), with a larger
detrimental effect in those patients receiving anastrazole. At
5  years, there was only partial recovery with BMD levels
remaining less than baseline (trochanter, 4.1%; lumbar spine,
6.3%).
Tamoxifen
one of the most commonly used treatments in patients with
ER-positive breast cancer. In the premenopausal setting, it
has a predominantly antioestrogenic effect resulting in a
small (1–2%) increased loss of BMD.  This is not clinically
significant and no bone protection is recommended in this
setting. In the postmenopausal setting, tamoxifen has been
shown to increase BMD of the spine and hip.
Aromatase Inhibitors
In the postmenopausal setting, patients with ER-positive
breast cancer are increasingly treated with an aromatase
inhibitor (AI), and the most recent meta-analysis showed
 676 A. Kwan and J.E. Brown
that 5  years of treatment with an AI leads to 15% relative
reduction in the 10-year breast cancer mortality rates when
compared with 5  years of tamoxifen [18]. After the meno-
pause, circulating oestrogen results from the conversion of
androgens to oestrogen in the peripheral tissue by the enzyme
aromatase. Inhibition of aromatase, either by reversible non-­
steroidal inhibitors (anastrozole/letrozole) or the irreversible
steroidal inhibitor (exemestane), results in almost undetect-
able levels of circulating oestrogen. However, BMD loss with
an AI is double the normal physiological rate [11] resulting
increased fracture risk.
The bone sub-study in the «Arimidex, Tamoxifen alone,
or in combination» (ATAC) trial [19], reported the longer-­
term effects on BMD following hormone treatment for
5  years in patients with early breast cancer. A total of 308
women had baseline lumbar and hip BMD assessed by DEXA
and then on treatment at 1, 2, and 5 years. Following treat-
ment, 50 patients treated with anastrozole alone had further
assessment at years 6–7. Patients treated with anastrozole
alone showed a median decrease in BMD of 6.1% and 7.2% in
the lumbar spine and hip, respectively, compared to an
increase of 2.77% and 0.74% in the lumbar spine and hip,
respectively, in patients receiving tamoxifen. Of note, women
who had normal BMD at baseline did not develop osteopo-
rosis. DEXA measurements at 6 and 7 years showed increases
in BMD by 2.35% and 4.02% at the lumbar spine and 0.71%
and 0.5% at the hip suggesting that treatment-related bone
60 loss does not continue beyond treatment [20]. These results
were replicated in the Intergroup Exemestane Study [21].
Although BMD loss appears reversible after stopping AI
treatment, fracture risk increases throughout the duration of
AI use when compared to tamoxifen. At a median follow-up
of 100 months in the ATAC study, the incidence of fracture
during active treatment in the anastrozole arm was 12% com-
pared to 7.5% in patients receiving tamoxifen with annual
rates of 2.93% and 1.9%, respectively [22]. However, the dif-
ference in fracture rates between the two arms resolved after
AI treatment was discontinued, potentially explained in part
by the increase in BMD observed when patients were off
anastrozole treatment [22]. In the BIG 1–98 study, 4895
patients were randomised to receive 5  years of letrozole or
tamoxifen, and at a median follow-up of 5 years, the fracture
incidence was 9.3% and 6.5% in patients receiving letrozole
and tamoxifen, respectively [23]. Recognition and treatment
of patients at particular risk of fracture will therefore help to
select a patient group who would benefit from bone-directed
therapy.
60.1.5 Pharmacology of Bone-Directed
Therapy
Bisphosphonates
Bisphosphonates are the first line for treatment for patients
with established osteoporosis of any cause. Bisphosphonates
are stable synthetic analogues of pyrophosphate and have a
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P-C-P backbone that acts as a bone hook. Following either
oral or intravenous administration, they accumulate in the
bone and are selectively internalised by osteoclasts during
bone reabsorption. Osteoclast apoptosis is induced by the
metabolism of nonnitrogen-containing bisphosphonates to
ATP analogues [24] or inhibition of farnesyl diphosphate
synthase in the mevalonate pathway by nitrogen-containing
bisphosphonates which disrupts the prenylation of impor-
tant signalling GTPases [25]. Bisphosphonates can be
administered orally or intravenously. Intravenous bisphos-
phonates must be used with care in patients with renal insuf-
ficiency with dose reductions as per the manufacturer’s
guidelines.
Denosumab
Denosumab is a fully humanised IgG2 monoclonal antibody
administered subcutaneously that binds to RANK ligand
(Receptor Activator of Nuclear Receptor ĸ B) and prevents
activation of the RANK receptor on osteoclasts and their pre-
cursors and ultimately inhibits osteoclast formation, func-
tion and survival [26]. It does not require dose reduction in
renal or hepatic impairment and does not accumulate in the
bone.
Side Effects of Bone-Directed Therapy
Both bisphosphonates and denosumab are generally well tol-
erated, and side effects are related to mode of administration.
Oral bisphosphonates can cause gastrointestinal complica-
tions including gastrointestinal bleeding. Intravenous
bisphosphonates are associated with infusion reactions,
metabolic effects (hypocalcaemia) and renal toxicity.
Subcutaneous denosumab may cause local skin reactions and
hypocalcaemia. Due to the metabolic effects, all patients
must have adequate vitamin D levels and receive calcium
supplementations. A rare but serious side effect of bisphos-
phonate therapy and denosumab is the development of
osteonecrosis of the jaw [27]. The risk of developing this with
zoledronic acid is 0.12–0.7% if used biannually [28]. The
pathogenesis of this is unclear and may be largely avoided
with patient education and pretreatment dental evaluation. A
further rare but serious side effect are atypical fractures. At
present there are no consensus guidelines for the manage-
ment of such patients, and each case should be reviewed by a
specialist bone team.
Use of Bisphosphonates in TIBL
Both intravenous and oral bisphosphonates have been evalu-
ated for the treatment of AI-related TIBL [4]. The most
extensively studied bisphosphonate is zoledronic acid. In
three parallel-designed international trials (Z-FAST [9, 29],
ZO-FAST [30] and E-ZO-FAST [31]), and a fourth trial
N03CC [32], approximately 2750 postmenopausal women
with hormone receptor-positive breast cancer receiving
5  years of adjuvant letrozole were randomised to receive
either upfront or delayed zoledronic acid (both at a dose of
4 mg every 6 months). Delayed zoledronic acid was initiated
Bone Health in Patients with Breast Cancer
due to accelerated bone loss (T-score < −2.0) or fracture. The
primary end point for these trials was lumbar spine bone
mineral density change at 12  months. In all these trials,
upfront zoledronic acid effectively prevented letrozole-­
induced bone loss with an increase of mean percentage
change of bone mineral density at the lumbar spine of 4.3–
6.19% in the patients treated with upfront zolendronic acid
versus a decrease in bone mineral density of 2–5.4% in those
who received delayed treatment; this improvement was sus-
tained at ongoing follow-up of over 60 months.
A handful of smaller trials have shown efficacy of oral
bisphosphonates including the SABRE [33] and ARIBON
[34, 35] studies. In the SABRE study, 154 patients with a
moderate risk of fracture received either risedronate 35 mg
or placebo once a week alongside treatment with anastrazole.
The mean percentage change of bone mineral density was
2.2% at the lumbar spine and 1.6% at the hip compared to
decreases of 1.8% and 1.1%, respectively, in the placebo
group. The ARIBON study enrolled 131 postmenopausal
women of which 13 patients had osteoporosis, and 50
patients had evidence of osteopenia. All patients with osteo-
porosis received ibandronate, and those with osteopenia
were randomised to receive ibandronate 150  mg every
28 days or placebo in addition to anastrazole. At 24 months
of follow-up, patients in the bisphosphonate group showed a
mean increase in bone mineral density of 2.98% at the lum-
bar spine, compared to a decreased of 3.22% in the placebo
group. These trials do suggest that oral bisphosphonates
given in osteoporotic dosing regimens demonstrate efficacy
in AI-related TIBL; however follow-up was shorter, and
there are concerns about compliance with oral bisphospho-
nates.
In premenopausal patients undergoing ovarian suppres-
sion, the addition of zoledronic acid to endocrine therapy
alone was associated with stable BMD during the 3 years of
treatment with an increase seen at 5 years compared to base-
line (trochanter +3.9%, lumbar spine +4.0%). Recently pub-
lished data also show that it significantly reduces bone
turnover markers compared to significant increases in these
markers in placebo-treated patients [36]. Longer-term fol-
low-­up from these trials will be crucial to understand whether
the treatment-induced rapid bone loss observed in patients
without bone protection (with some evidence of partial
recovery after treatment stopped) translates into longer-term
fracture risk.
Use of Denosumab in TIBL
In the non-malignant setting, denosumab has been used as
an alternative to bisphosphonates as a treatment option to
prevent osteoporosis and fragility fractures with similar out-
comes to zoledronic acid. The ABCSG-18 trial [37] ran-
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677 60
domised 3420 postmenopausal early breast cancer patients
receiving aromatase inhibitors to either denosumab 60  mg
(n  =  1711) or placebo (n  =  1709) subcutaneously every
6 months. The primary end point was time to first fracture.
Patients in the denosumab group had a significantly delayed
time to first clinical fracture (hazard ratio [HR] 0.50 [95% CI
0.39–0.65], p  <  0.0001), and there was a reduction in the
overall number of fractures (92 vs 176 in the placebo group).
Treatment was well tolerated. This data suggests that deno-
sumab is an effective alternative to bisphosphsonates in this
setting.
60.1.6  uggested Algorithm for Monitoring
S
and Treatment for Cancer Treatment-­
Related Bone Loss
Over the past few years, a number of recommendations for
the management of cancer treatment-induced bone loss have
been published with expert consensus guidelines from the
UK and Europe. Patients receiving treatments which may
cause bone loss are advised to have a diet rich in calcium,
undertake regular weight bearing and resistance exercise and
take 1000–2000  IU of vitamin D daily [38]. Fracture risk
assessment scores are currently not designed to be used in
cancer patients. It is therefore recommended in women with
breast cancer that the potential risk of bone loss should be
discussed prior to initiating anticancer treatment and that
bisphosphonates are commenced when the BMD T-score is
below −2 (. Fig. 60.2) [38–40]. A bone questionnaire can be
given to patients before commencing treatment to identify
any coexisting causes of osteoporosis. For postmenopausal
women receiving an AI, with a T-score ≥ −2 and no other
risk factors for fracture, reassessment of BMD and risk fac-
tors is recommended after 1–2  years. If the patient experi-
ences an annual BMD decrease of ≥10%, or 4–5% annual
decrease if osteopenic at baseline, investigations for alterna-
tive causes of osteoporosis such as vitamin D deficiency,
hyperparathyroidism and hyperthyroidism, together with
initiation of bisphosphonate/denosumab therapy, are recom-
mended [4].
Once treatment is started, this should be continued for as
long as the patient is receiving an AI. Over 5 years, the cur-
rent data is strongest for zoledronic acid, 4 mg 6 monthly, but
other acceptable options are oral alendronate 70 mg weekly,
oral risedronate 35  mg weekly or oral ibandronate 150  mg
monthly.
The use of bisphosphonates as an anticancer treatment is
not discussed in this chapter; however emerging evidence for
the efficacy of bisphosphonates is likely to decrease the inci-
dence of osteoporotic events in breast cancer survivors.
 678 A. Kwan and J.E. Brown

Patient receiving anti-cancer therapy known to increase bone loss

Assess risk factors (consider use of FRAX tool) and perform DEXA scan

Patient on adjuvant
T score <–2.0 T score >–2.0
bisphosphonate

Presence of the following 2 Exercise

risk factors Calcium
• Age>65 Vitamin D
• T score<–1.5
• Smoking
Currently not recommended to
• BMI<24
monitor bone mineral density
• Family history of hip during treatment with
fracture bisphosphonates in the
• Personal history of fragility adjuvant setting
facture
• Oral glucocorticoid use for
>6 months

Exercise
Calcium and vitamin D
Bisphosphonate therapy
60

Monitor every 2 years, with DEXA scan, whilst on treatment

..      Fig. 60.2  Suggested algorithm for the management of bone health

60.2 Summary
Use of therapies which alter the balance of oestrogen in
women with breast cancer has led to deleterious effects on
bone health. This in turn leads to an increase risk of fracture
and morbidity with decreased quality of life. Recognition and
appropriate treatment of women at risk of developing bone
loss will help reduce the burden of TIBL. The use of bone-­
targeted treatments in breast cancer is still developing. These
agents are effect at improving bone mineral density but, even
more excitingly, have a potential role in the adjuvant setting
to improve breast cancer-related recurrences and survival.
Bone health should continue to be assessed and not be
neglected as cancer treatments evolve.
55 DEXA scans are the current gold standard for the
assessment of bone mineral density; however early
bone mineral density changes may take several
months to be assessable.
55 Bisphosphonates are the mainstay of treatment for
patients with bone mineral density loss secondary
to anticancer treatment.
55 Current guidelines for bone health management
include performing an assessment of bone health
prior to starting anticancer treatments, initiating
treatments dependant on T-score and risk factors
and reassessing after 2 years of initial therapy.

Key Points References

55 Loss of bone mineral density and osteoporosis
occurs with increasing age and the use of some anti-
cancer treatments.
1. CRUK. Cancer Research UK breast cancer statistics. [website] 2015.
Available from: http://www.cancerresearchuk.org.
2. Kanis JA, et  al. Long-term risk of osteoporotic fracture in Malmo.
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between the European Foundation for Osteoporosis and the
National Osteoporosis Foundation of the USA). 2000;11(8):669–74.
3. Melton LJ 3rd, et al. Perspective. How many women have osteopo-
rosis? J Bone Miner Res (The Official Journal of the American Society
for Bone and Mineral Research). 1992;7(9):1005–10.
4. Hadji P, et  al. Management of aromatase inhibitor-associated
bone loss in postmenopausal women with breast cancer: practi-
cal guidance for prevention and treatment. Ann Oncol (Official
Journal of the European Society for Medical Oncology/ESMO).
2011;22(12):2546–55.
5. Kanis JA. Assessment of fracture risk and its application to screening
for postmenopausal osteoporosis: synopsis of a WHO report. WHO
Study Group. Osteoporos Int (a journal established as result of coop-
eration between the European Foundation for Osteoporosis and the
National Osteoporosis Foundation of the USA). 1994;4(6):368–81.
6. Cummings SR, Melton LJ. Epidemiology and outcomes of osteopo-
rotic fractures. Lancet. 2002;359(9319):1761–7.
7. Burch J, et al. Systematic review of the use of bone turnover markers
for monitoring the response to osteoporosis treatment: the second-
ary prevention of fractures, and primary prevention of fractures in
high-risk groups. Health Technol Assess. 2014;18(11):1–180.
8. Lipton A, Costa L, Coleman RE.  Bone turnover markers: tools for
prognosis and monitoring response to bisphosphonates? Breast
Dis. 2011;33(2):59–69.
9. Brufsky AM, et al. Final 5-year results of Z-FAST trial: adjuvant zole-
dronic acid maintains bone mass in postmenopausal breast cancer
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10. Hadji P, et  al. Cancer treatment-induced bone loss in premeno-
pausal women: a need for therapeutic intervention? Cancer Treat
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11. Hadji P. Aromatase inhibitor-associated bone loss in breast cancer
patients is distinct from postmenopausal osteoporosis. Crit Rev
Oncol Hematol. 2009;69(1):73–82.
12. Bines J, Oleske DM, Cobleigh MA.  Ovarian function in premeno-
pausal women treated with adjuvant chemotherapy for breast can-
cer. J Clin Oncol (Official Journal of the American Society of Clinical
Oncology). 1996;14(5):1718–29.
13. Pfeilschifter J, Diel IJ. Osteoporosis due to cancer treatment: patho-
genesis and management. J Clin Oncol (Official Journal of the
American Society of Clinical Oncology). 2000;18(7):1570–93.
14. Lester J, et  al. The causes and treatment of bone loss associated
with carcinoma of the breast. Cancer Treat Rev. 2005;31(2):115–42.
15. Francis PA, Regan MM, Fleming GF. Adjuvant ovarian suppression in
premenopausal breast cancer. N Engl J Med. 2015;372(17):1673.
16. Gnant MF, et al. Zoledronic acid prevents cancer treatment-­induced
bone loss in premenopausal women receiving adjuvant endocrine
therapy for hormone-responsive breast cancer: a report from the
Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol
(Official Journal of the American Society of Clinical Oncology).
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17. Gnant M, et  al. Adjuvant endocrine therapy plus zoledronic acid
in premenopausal women with early-stage breast cancer: 5-year
follow-up of the ABCSG-12 bone-mineral density substudy. Lancet
Oncol. 2008;9(9):840–9.
18. Early Breast Cancer Trialists’ Collaborative, G, et al. Aromatase inhib-
itors versus tamoxifen in early breast cancer: patient-level meta-
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19. Eastell R, et al. Effect of anastrozole on bone mineral density: 5-year
results from the anastrozole, tamoxifen, alone or in combination
trial 18233230. J Clin Oncol (Official Journal of the American Society
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20. Eastell R, et  al. Long-term effects of anastrozole on bone mineral
density: 7-year results from the ATAC trial. Ann Oncol (Official
Journal of the European Society for Medical Oncology/ESMO).
2011;22(4):857–62.
21. Coleman RE, et  al. Reversal of skeletal effects of endocrine treat-
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2010;124(1):153–61.
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22. Forbes JF, et  al. Effect of anastrozole and tamoxifen as adjuvant
treatment for early-stage breast cancer: 100-month analysis of the
ATAC trial. Lancet Oncol. 2008;9(1):45–53.
23. Rabaglio M, et al. Bone fractures among postmenopausal patients
with endocrine-responsive early breast cancer treated with 5 years
of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol (Official
Journal of the European Society for Medical Oncology/ESMO).
2009;20(9):1489–98.
24. Rogers MJ, et  al. Cellular and molecular mechanisms of action of
bisphosphonates. Cancer. 2000;88(12 Suppl):2961–78.
25. Luckman SP, et al. Nitrogen-containing bisphosphonates inhibit the
mevalonate pathway and prevent post-translational prenylation of
GTP-binding proteins, including Ras. J Bone Miner Res (The Official
Journal of the American Society for Bone and Mineral Research).
1998;13(4):581–9.
26. Hanley DA, et al. Denosumab: mechanism of action and clinical out-
comes. Int J Clin Pract. 2012;66(12):1139–46.
27. Coleman R, et al. Safety of zoledronic acid and incidence of osteo-
necrosis of the jaw (ONJ) during adjuvant therapy in a randomised
phase III trial (AZURE: BIG 01-04) for women with stage II/III breast
cancer. Breast Cancer Res Treat. 2011;127(2):429–38.
28. Kourie HR, et al. Osteonecrosis of the jaw during biyearly treatment
with zoledronic acid for aromatase inhibitor associated bone loss in
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9.
29. Brufsky A, et al. Zoledronic acid inhibits adjuvant letrozole-­induced
bone loss in postmenopausal women with early breast cancer.
J Clin Oncol (Official Journal of the American Society of Clinical
Oncology). 2007;25(7):829–36.
30. Bundred NJ, et  al. Effective inhibition of aromatase inhibitor-­
associated bone loss by zoledronic acid in postmenopausal women
with early breast cancer receiving adjuvant letrozole: ZO-­ FAST
study results. Cancer. 2008;112(5):1001–10.
31. Llombart A, et  al. Immediate administration of zoledronic acid
reduces aromatase inhibitor-associated bone loss in postmeno-
pausal women with early breast cancer: 12-month analysis of the
E-ZO-FAST trial. Clin Breast Cancer. 2012;12(1):40–8.
32. Hines SL, et al. Immediate versus delayed zoledronic acid for pre-
vention of bone loss in postmenopausal women with breast cancer
starting letrozole after tamoxifen-N03CC.  Breast Cancer Res Treat.
2009;117(3):603–9.
33. Van Poznak C, et al. Prevention of aromatase inhibitor-induced bone
loss using risedronate: the SABRE trial. J Clin Oncol (Official Journal
of the American Society of Clinical Oncology). 2010;28(6):967–75.
34. Lester JE, et  al. Prevention of anastrozole induced bone loss with
monthly oral ibandronate: final 5 year results from the ARIBON trial.
J Bone Oncol. 2012;1(2):57–62.
35. Lester JE, et  al. Prevention of anastrozole-induced bone loss with
monthly oral ibandronate during adjuvant aromatase inhibitor
therapy for breast cancer. Clin Cancer Res (An Official Journal of the
American Association for Cancer Research). 2008;14(19):6336–42.
36. Hadji P, et al. Effects of zoledronic acid on bone mineral density in
premenopausal women receiving neoadjuvant or adjuvant thera-
pies for HR+ breast cancer: the ProBONE II study. Osteoporos Int (a
journal established as result of cooperation between the European
Foundation for Osteoporosis and the National Osteoporosis Foun-
dation of the USA). 2014;25(4):1369–78.
37. Gnant M, et al. Adjuvant denosumab in breast cancer (ABCSG-18):
a multicentre, randomised, double-blind, placebo-controlled trial.
Lancet. 2015;386(9992):433–43.
38. Coleman R, et al. Bone health in cancer patients: ESMO clinical prac-
tice guidelines. Ann Oncol (Official Journal of the European Society
for Medical Oncology/ESMO). 2014;25(Suppl 3):iii124–37.
39. Hadji P. Cancer treatment-induced bone loss in women with breast
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 681 61

Nursing Issues and the Role

of the Specialist Nurse in
Breast Care
Victoria Harmer

61.1 Background to Nursing – 682

61.2 The Specialist Nurse in Breast Care – 682

61.2.1 Clinical Nurse Specialist (CNS) – 682
61.2.2 Nurse Practitioners (NP) – 684
61.2.3 Consultant Nurses – 685

61.3 The Specialist Nurses Role in Influencing

the Community – 686

61.4 Caregivers and Family – 686

61.5 Cancer Survivorship – 686

61.6 Extending and Expanding Roles – 687

61.7 Words of Caution – 687

61.8 The Future and Leadership in Health Care – 687

References – 687

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_61

rares1geo@gmail.com
 682 V. Harmer
61.1 Background to Nursing
Nursing contributes the largest sector of the healthcare work-
force, and the nurse’s interaction with patients gives rise to an
enormous potential to increase the patient experience and
outcomes of care [1]. The population is aging which trans-
lates to patients having more comorbidities and complex
needs, each of which should be addressed [2]. This partnered
with the increase in numbers of people treated while working
with the backdrop of continual financial pressures means
nursing is becoming increasingly challenging, and a highly
tuned skill set is required. As with other healthcare profes-
sionals, nurses have experienced the opportunity to evolve,
extending and expanding their roles as healthcare provision
changes.
61.2 The Specialist Nurse in Breast Care
The role of the specialist nurse in breast care is an example of
nurses seeking new ways of working with the aim to serve
patients better. These senior nurses should have studied to
degree level and would be expected to be working towards a
masters or a PhD.  Not only should specialist nurses have
undertaken an additional course in breast cancer and be
experts in evidence-based nursing within breast care and
breast cancer, but there must also be an ability to problem-
solve, reflect, analyse and think critically [3] and most impor-
tantly have the skills to communicate all these aspects to
61 patients and their families. Patients receive a vast amount of
information from breast clinics at a time when they may feel
vulnerable. It is up to the specialist nurse to ensure all has
been understood and to assist the patient in their decisions
relating to potential treatment and the care pathway. The spe-
cialist nurse should be capable of assessing the patient and
skilled in detecting fears and concerns, highlighting these, as
appropriate, to the multidisciplinary team [4] where they
should act as the patient’s advocate.
In addition to clinical work, specialist nurses in breast care
should provide an element of service improvement, leadership
and positively impact the training, development and education
of staff in order that they meet, adapt and provide solutions to
the ever-changing demand for the provision of quality health
care. This chimes with the recent UK Francis Report into
health care [5], where the importance of strong leadership
skills, for nurses and other professionals, was emphasised to
ensure patient care is always the overriding priority.
Specialist nurses function at a highly sophisticated level
within defined patient populations and are responsible for
planning, assessing and evaluating patient care, effectiveness
of treatments and the consequences treatments may have on
the patient while ensuring continuity of care [6].
There are a myriad of titles and nuances for specialist
nurses working within breast care, but the main three will be
described in this chapter. These are clinical nurse specialist,
nurse practitioner and consultant nurse.
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61.2.1 Clinical Nurse Specialist (CNS)
Traditionally the role of CNS has been described as being
made up of four domains; clinical, education, research and
consultation [7, 8].
There are five central threads to this role:
55 Utilising and applying specialised intelligence of breast
cancer and its treatment with the aim of overseeing and
coordinating care delivery, disseminating complex infor-
mation, communication to the patient and their families
and personalising the treatment for each patient
55 Functioning as the patient advocate within the multidis-
ciplinary team
55 Performing proactive case management and applying
clinical insight and judgement to limit unwanted conse-
quences of treatment or disease progression
55 Applying skill and experience to assess any psychosocial
ramifications the patient may have as a consequence of
their cancer diagnosis and treatment and the ability and
judgement to refer on to other healthcare professionals
as appropriate
55 Assisting with service developments by drawing on
patient experiences in order to provide and promote
improvements in the patient pathway [9]
The UK Cancer Reform Strategy [10] illustrated the impor-
tance of the CNS, detailing this role as pivotal and vital to
patient outcomes, as timely interventions provided by this
cadre of nurses can deflect expensive care episodes [11].
There is evidence to show that patients who undergo treat-
ment at hospitals with more CNSs have a better experience,
receive better emotional support and benefit from healthcare
professionals working well as a team [12].
In the United Kingdom, the CNS in breast care is respon-
sible for providing information and support to patients and
their families throughout their breast cancer trajectory [13].
These nurses are introduced to the patient on their diagnosis
of cancer, and part of their technical expertise encompasses
assisting with decision-making regarding treatment.
Advances in modern health care have seen the development
of many refinements in the surgical and medical manage-
ment of the disease, and the specialist nurse in breast care
will disseminate information and proactively case manage
the patient and their families while they are undergoing these
treatments. Moreover the decision-making and discussion of
options of treatment can be complex; whether or not to have
an immediate breast reconstruction, for example, and while
this is generally a decision for the patient, the CNS will assist
by delivering additional information, practical advice and
support outside of consultations with the clinical team.
The CNS is in a unique position as they are often the one
constant throughout the patients’ care, as this relationship
straddles all treatment modalities (surgery, chemotherapy,
radiotherapy, endocrine and even into the palliative care set-
ting if needed). They triage telephone calls from patients,
provide vigilance and perform rescue work (detection of
Nursing Issues and the Role of the Specialist Nurse in Breast Care
683 61
..      Fig. 61.1  The Cassandra data
set (Reproduced from Ref. 14 with Context Outpatient Outpatient Telephone Inpatient Outreach MDT
Examples new Followup
permission from Prof Alison Leary
FRCN)
Psycological
Psychological assessment domain
Physical
domain Anxiety management
Supporting clinical choice and meeting
Physical assessment information needs
Symptom control (generalist) Anxiety rescue work
Symptom control (specialist) Dealing with distress
Requesting investigations Communicating significant news
Performing procedures Managing biographical disruption Social
domain
Rescue work (physical/drugs/latrogenic
Social assessment
reactions)
Mediation of relationship
Promoting self management
Advice (social)
Work and finance, vocational rehabilitation

Case
Non management
clinical domain
Advocacy
admin
Chasing up/tracking Referral
Other administration work (non clinical) Case management (continuity and rescue)

impending deterioration). On completion of treatment, the

CNS will continue their relationship with the patient and ..      Table 61.1  Clinical domains of practice associated with the
CNS
usually be the key accessible professional should any issues
regarding living with and beyond their cancer experience Family history and genetics (includes prevention, screening and
arise. prophylactic surgery)
The CNSs role concentrates on the person as they undergo
Benign breast conditions
a cancer diagnosis, treatment and beyond and focusses on
the impact of these on the patient and their holistic needs in National Health Service Breast Screening
addition to case managing and brokering the care bestowed. Patients newly diagnosed with breast cancer
The CNS in breast care delivers and facilitates the provi-
sion of expert quality care to women, men and their families Patients undergoing chemotherapy (and related side effects)
with breast disease both throughout the hospital within Patients undergoing radiotherapy (and related side effects)
which they work and extending into the community. This is
Patients on endocrine therapy (and related side effects)
achieved by linking practice with education and research
through multidisciplinary and multi-professional collabora- Breast surgery
tion. The CNS has a particular focus on care of patients with Breast reconstruction
breast cancer, the education of all staff, facilitation and imple-
mentation of evidence-based pathways, protocols and net- Prosthesis fitting
works of care in line with clinical governance and risk Management of menopausal symptoms
management. The CNS focusses on bridging gaps with other
Management of lymphoedema
disciplines involved in this speciality and facilitates the mod-
ernisation of the breast care service in line with national ini- Management of fungating wounds
tiatives, thereby leading to improved outcomes for patients Treatment-induced fertility issues
and their families.
The CNS provides expertise over a range of environments Metastatic disease
for a number of different domains of care as detailed by the Social issues and finance
Cassandra st [14] in . Fig. 61.1.
 
Recovery, rehabilitation and follow-up (including lifestyle
The clinical domains of a CNS can be seen in detail in changes)
. Table  61.1 [15]. This list is by no means exhaustive as the
 

CNS adapts, extending and expanding their role and the facets From Pennery [15] with permission from Wiley-Blackwell
of it in order to seamlessly adopt innovations in health care.

rares1geo@gmail.com
 684 V. Harmer
The impact of the CNS can be illustrated using four
domains, improving quality and experience of care, reinforc-
ing safety, increasing productivity and efficiency and demon-
strating leadership.
1. Improving quality of care and enhancing the patient
experience: managing the complex, individual and
changing information and support needs of patients and
carers, assisting patients in choices around treatment
and care, enhancing recovery and delivering care flex-
ibility and closer to home and facilitating the set-up of
support groups
2. Reinforcing safety: delivering safe, nurse-­led services,
identifying and taking action to reduce risks, performing
rescue work and facilitating rapid re-entry into acute
services as appropriate
3. Increasing productivity and efficiency: intervening to
manage the effects of treatment and symptom control,
preventing unplanned admissions, providing nurse-­led
services that free up consultant resource and empower-
ing patients to self-manage
4. Demonstrating leadership: educating the wider health-
care team and acting as a mentor, identifying and
implementing service improvements and efficiencies,
determining measureable outcomes, auditing practice
and sharing good practice and innovations [9, 16].
There is evidence that the workstrand of the CNS improves
outcomes through saving resources and promoting efficacy.
Their work overarches a number of different teams in order
61 to assist with the smooth running of individualised patient
care [17].
The cost-benefits of a CNS have been explored by the
Royal College of Nursing, and these include reducing waiting
times, avoidance of unnecessary and unplanned hospital
admissions, reduced post-operative length of stays, reduced
patient treatment drop-out rates, the freeing up of time
patients spent with consultants, the introduction of innova-
tive service delivery and improvements, direct specialist
advice being given to patients and families, delivering ser-
vices at the point of need and the education of health and
social care professionals [18].
More importantly perhaps in a national survey of health
advocacy groups, patients consistently ranked specialist
nurses higher than other health and social care professional
in regards to understanding their needs, being transparent
and honest, designing and implementing care pathways and
obtaining patient feedback [19].
Florence Nightingale said, «…medicine so far as we
know, assists nature to remove the obstruction, but does
nothing more. And what nursing has to do…, is to put the
patient in the best condition for nature to act upon him».
[20]. This may be interpreted to reflect many of the roles of
the CNS. They assist in complex decision-making by explain-
ing treatment choices, checking understanding, brokering on
behalf of the patient, providing support, vigilance, rescue
work, appropriate encouragement, co-ordination of care and
case management and ensuring timely referrals are made, for
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example, to clinical psychology, fertility or other depart-
ments both internal or external to the hospital setting. Family
and caregivers are also liaised with as guided by the patient,
and much time is spent ensuring the patient is indeed in the
best condition «for nature and the prescribed treatments to
act upon them.»
61.2.2 Nurse Practitioners (NP)
NPs focus on assessment, diagnosis and treatment as well as
health education and disease prevention [21]. Similarly these
nurses should demonstrate an up-to-date knowledge of the
speciality, be skilled in research, leadership, education and
function at a strategic and operational level within the breast
unit [6]. Although these specialist nurses incorporate educa-
tion, management and research in their work, the main
aspect of their role is in the delivery of direct patient care,
usually within the diagnostic setting. NPs have extended the
remit of their clinical care to incorporate additional func-
tions that were traditionally allocated to physicians such as
performing breast examinations, taking a patient’s history
and ordering appropriate diagnostic tests.
The UK Royal College of Nursing describes the level of
practice that a NP functions through the list below:
55 Making professionally autonomous decisions, for which
they are accountable
55 Receiving patients with undifferentiated and undiag-
nosed problems and making an assessment of their
healthcare needs, based on highly developed nursing
knowledge and skills, including skills not usually exer-
cised by nurses, such as physical examination
55 Screening patients for disease risk factors and early signs
of illness
55 Making differential diagnoses using decision-making
and problem-solving skills
55 Developing with the patient an ongoing nursing care
plan for health, with an emphasis on health education
and preventative measures
55 Ordering necessary investigations and providing treat-
ment and care both individually, as part of a team, and
through referral to other agencies
55 Having a supportive role in helping people to manage
and live with illness
55 Having the authority to admit or discharge patients from
their caseload and refer patients to other healthcare pro-
viders as appropriate
55 Working collaboratively with other healthcare profes-
sionals and disciplines
55 Providing a leadership and consultancy function as
required [22]
The evidence and literature evaluating the effectiveness and
safety of the NP role have been tremendously encouraging in
respect to the value of the role in addition to the ­satisfaction
from patients who have been seen by these specialist nurses
[23, 24].
Nursing Issues and the Role of the Specialist Nurse in Breast Care
While there are aspects of overlap for the CNS and NP in
relation to leadership, patient and staff education and service
improvements, the NP role tends to be grounded in the diag-
nostic pathway for breast patients. It is usual that once the
patient is diagnosed with breast cancer, the NP hands over
care to the CNS who will act as the first point of contact (Key
Worker) through modalities of the treatment trajectory and
onto aspects of survivorship.
61.2.3 Consultant Nurses
685 61
..      Table 61.2  The consultant nurse’s knowledge, skills and
expertise, personal qualities and attributes and processes
Knowledge, skills and expertise in integrated sub-roles
  Nursing practice as a generalist/specialist
  Research and evaluation in practice
   ractice development and the facilitation of structural, cultural
P
and practice change
  Education and learning in practice
  Consultancy: clinical to organisational

The titles consultant nurse and nurse consultant are used   Management, leadership and strategic vision
interchangeably within health care, although some argue that Personal qualities and attributes
nurse consultant can mean a nurse who is self-employed and
  Being patient centred
acting as a consultant in an arena of nursing for a project
when they may not in fact be working within a clinical arena   Being available, accessible, generous and flexible
or at an expert level [25]. Thus the title consultant nurse will   Being enthusiastic
be used in this chapter.   Being self-aware and attuned to others
The consultant nurse role developed in the 1980s and
  Being a collaborator and a catalyst
refers to a nurse who is at the pinnacle of their clinical career
ladder [25]. The genesis of this role was an attempt to retain   Having a vision for nursing and health care
senior nurses and their clinical expertise within nursing and   Being a strategist and demonstrating political leadership
at the bedside [26].
  Academic criteria
There are four components of the consultant nurse role
which are expert practice; professional leadership and con- Processes
sultancy; education, training and development and service   Transformational leadership processes
improvement and research and evaluation. Consultant     Developing a shared vision
nurses aim to possess skills and competencies similar to that
    Inspiring and communicating
of CNS’s but with greater breadth and complexity.
It is argued strongly [27, 28] that consultant nurses should     Valuing others
have extensive expertise and knowledge in their particular     Challenging and stimulating
speciality. They should also have a hands-on role in nursing
    Developing trust
practice, which enhances clinical credibility and enables
effective role modelling. The consultant nurse role is divided     Enabling
into clinical work, academic work and education. These   Processes of emancipation
nurses should have achieved or be studying towards a Clarifying
   and working with values, beliefs and assumptions
PhD. Consultant nurses focus on the whole service they pro- and challenging contradictions
vide for, assisting in the contribution to research, service
    Developing critical intent of individuals and groups
improvement activities while providing education to their
peers and patients and availing themselves as a resource pro-     Developing moral intent
moting expertise and quality care. Focussing
   on the impact of the context/system on practice as
The consultant nurse should be a transformational leader well as practice itself
who fosters a widening participation and collaboration. They Using
   self-reflection and fostering reflection in others
incorporate a complex and analytical reasoning process to
    Enabling others to ‘see the possibilities’
develop a shared vision and new approaches to running ser-
vices. They should contribute to national and international Fostering
   widening participation and collaboration by all
involved
strategies and policies and be seen as an expert in their field.
Consultant nurses should identify current gaps in practice    ractising expertly as a practitioner, researcher, educator,
P
and generate new areas of research that seek to increase consultant and practice developer
knowledge of the specialist area, enhance the effectiveness of     Role modeller
treatment interactions and improve the overall quality of care     Facilitating individual, collective and organisational learning
within breast care. The knowledge, skills and expertise, per-
    Facilitating change, practice and service development
sonal qualities and attitudes and processes of a consultant
nurse are illustrated in . Table 61.2.
 
From Manley and Tichen [25] with permission from the Royal
In addition to being a leader, the role of consultant nurse College of Nursing
in breast care fulfils the role of «responsible follower» also described in the Francis report. A responsible follower is an

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 686 V. Harmer
employee who is engaged, informed, a watchdog and able to
analyse a situation and support the leader [29]. A leader
without responsible followers cannot accomplish goals or
change because a responsible follower will take a stand, chal-
lenge the status quo, cooperate, take a risk and be aware of
his/her moral compass [29].
61.3  he Specialist Nurses Role
T The specialist nurse in breast care can encourage open-
in Influencing the Community
There is a sea change in the way health care is being delivered
and a migration of services from the hospital into the com-
munity. The enhanced recovery programme and open access
follow-up are just two initiatives that aim to relocate care.
Drug delivery methods have also changed, and some which
were traditionally delivered intravenously can now be given
via the subcutaneous route, moreover many new agents are
ingested orally. This lends itself to delivery closer to the
patient’s home and evolving healthcare provision, although
plans and channels of communication must be in place to help
implement these strategies [30]. It is usual that patients con-
tinue to take medication at home; thus it is imperative that the
specialist nurse undertakes a complete assessment of the
patient’s level of understanding in addition to any caregivers
relating to the storage, administration and potential effects of
treatment [3]. There therefore are no boundaries for the spe-
cialist nurse, and they need be armed with expert technical
skill and information in order to straddle hospital and com-
61 munity settings in addition to provide a slick and effective way
to hand over to community-based colleagues [30].
61.4 Caregivers and Family
Family dynamics are altered with a cancer diagnosis, and
healthcare professionals may underestimate the implications
this has in addition to the amount of support and care they
can pass on to the family [31]. For example, caregivers are
challenged with emotional and physical repercussions when
delivering care to someone with a potentially life-threatening
disease and that emotional distress they experience may be at
least as severe as that which the patient themselves encounter
[32]. The specialist nurse in breast care, if offering truly holis-
tic care, has a vital role in supporting the whole family which
will be at a level and depth specified by each individual
patient. If nurses help carers, they are helping the patient
[33]. As previously alluded, to patients are discharged more
promptly post-operatively, and more care is integrated into
the community setting. That being the case, the specialist
nurse needs to make sure the vulnerability of carers are
assessed and ensure they have all salient information they
need in order to confidently continue care at home and that
communication channels remain open. While we assume
most relatives would be eager to help care for a relative,
boundary or cultural issues may be apparent, and there needs
to be agreement from the patient and relative [30].
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Caregivers will need to process any previous experience
of cancer and reframe it, aligning it to the situation they and
the person they are caring for are in. Some carers may reap
satisfaction in caring for someone with cancer, while others
may feel it detrimental to their psychological and physical
well-being and to their personal relationships and that they
suffer additional economic consequences resultant from
their caregiving [34].
ness within families regarding discussing the patient’s breast
cancer which can assist them in understanding their indi-
vidual reactions and feelings with respect to potential grief,
fear and anxiety that surrounds such a diagnosis [35].
Although potentially challenging to achieve within the arena
of cancer, caregivers cope better if they are positive about
their situation [36], and the specialist nurse, among other
healthcare professionals, can assist, giving realistic hope,
expectation and information to all those involved. The issues
surrounding the family and caring for someone with breast
cancer are complex and fluctuate which means communica-
tion should be effective, continuous and at various touch-
points throughout someone’s treatment trajectory.
61.5 Cancer Survivorship
The concept of «cancer survivorship» has received consider-
able attention as increasing numbers of people live with and
beyond cancer. Previously, attention may have focussed more
on treatments for cancer and the likelihood of their success.
In recent years, interest has moved to the after-effects of
treatment and how people return to their lives while recover-
ing. As treatments become more successful and mortality
rates for cancers reduce, an increasing number of people liv-
ing in the community have completed cancer treatment; this
group, along with those living with cancer, is called cancer
survivors. Many cancer survivors experience long-term side
effects from previous treatment or from the cancer itself and
may have to overcome a number of psychological and medi-
cal issues [37]. There is evidence that many cancer survivors
are grappling with the effects of treatment and have unmet
needs [38], and certainly individual care needs vary. Specialist
nurses in breast care are in a privileged position with the
access they have to patients living with and beyond a breast
cancer diagnosis and remain the key accessible professional
and point of contact for cancer survivors. There is a continu-
ous need therefore for the specialist nurse to «upskil» them-
selves on potential consequences of treatment that individuals
may experience and aim to assist disseminating information
and practical advice. The utopian position is for the breast
cancer patient to adapt to their new normal (normalisation)
and engage with life as they previously did. Specialist nurses
need to arm the patient with the skills they require to self-­
manage, supporting the patient to self-care which should
enable independence, while ensuring they also understand
any red flag symptoms they should report promptly to their
healthcare provider.
Nursing Issues and the Role of the Specialist Nurse in Breast Care
61.6 Extending and Expanding Roles
The changing healthcare environment has facilitated the
development and opportunity for nurses to extend and
expand the remits of their practice and set the backdrop for
nurses to obtain more control as they take on roles that
encompass assessment, diagnosis, referral and prescribing
[39]. The crux of any role extension however must be that
safe care is delivered to patients and each practitioner is
accountable for their actions and should understand the legal
implications of role extension [40].
Specialist nurses have extended their scope of clinical
practice and taken responsibilities that were previously in the
domain of the physician. This trend is driven by local need,
looks likely to continue and seems appropriate and correct.
There are however no formal criteria that underpin the roles,
responsibilities or job titles of specialist nurses which could
lead to a blurring of understanding and an erosion of profes-
sional identity. The UK Nursing and Midwifery Council has
no official regulations for nurses in advanced roles, and there
is no legally specified training. Instead it is the responsibility
of the employer to examine standards of care delivered by
these nurses and provide vicarious liability [41]. Specialist
nurses will need the support of the multidisciplinary team
within which they work to practice and function effectively
and in order that any service developments or role extension
is adopted successfully.
61.7 Words of Caution
If additional responsibilities continue to be assigned to the
specialist nurse in breast care, the workload will increase.
This, partnered with the need for the nurses to case manage,
disseminating information and support relating to new and
sophisticated treatments, along with more ambitious breast
reconstructive options, means demands on time will be
heightened. Put simply specialist nurses have more in our
armoury to offer patients. Managing these continual modifi-
cations needs a strategy. The Independent Cancer Taskforce
in their «Achieving world-class cancer outcomes report» [42]
states the need for all cancer patients to have access to a CNS
or key worker to coordinate care and also mentions the
workforce implications of this goal. It states that plans should
be put in place incorporating a strategic review of workforce
deficits and the skill mix required to deliver a modern high-­
quality service. Moreover this problem may be magnified as
the number of people diagnosed with breast cancer is increas-
ing. The UK charity Breast Cancer Care highlighted that the
number of CNSs who work within the breast cancer arena
has remained the same (434 across England) since 2007 [43],
and yet there has been an 18% increase in the number of new
breast cancer cases (from 38,153 in 2003 to 44,831 in 2013) in
England. A similar rise has been seen in Scotland and Wales.
There is a therefore a definite need for the number of special-
ist nurses to be addressed, and the budget ring-fenced in
order that quality of care is not compromised.
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687 61
61.8  he Future and Leadership
T
in Health Care
The UK Francis Report [5] emphasised the need to develop
the right culture in the UK National Health Service (NHS),
through areas such as better leadership, ongoing professional
development and training. The report stated how important
it is for nurses and other professionals to exhibit strong lead-
ership skills to ensure patients are always put first. Creating
effective and compassionate leaders in cancer care and across
the NHS is a priority for the future and an element that forms
the core ethos of the specialist nurse in breast care’s role. The
face of health care will continue to change, and the profes-
sionals working within this arena will need to adapt to
demand and adopt new ways of working, straddling both
primary and secondary care settings. As a result the specialist
nurse in breast care’s role will need to incorporate adjust-
ments and nuances in order to continue to serve this cadre of
people to their best ability, working in partnership with them
to ensure they receive quality care and feel fully informed,
supported and safe throughout their breast cancer trajectory.
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5. Francis R.  Report of the mid Staffordshire NHS foundation trust
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7. Hamric AB, Spross JA, editors. The clinical nurse specialist in theory
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macmillan.org.uk/Documents/AboutUs/Commissioners/Excellen-
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10. Department of Health. Cancer reform strategy. London: Depart-
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11. Vidall C, Barlow H, Crowe M, Harrison I, Young A.  Clinical nurse
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12. Griffiths P, Simon M, Richardson A, Corner J. Is a larger specialist nurse
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13. Royal College of Nursing. Clinical standards for working in a breast
specialty: RCN guidance for nursing staff. London: Royal College of
Nursing; 2007.
14. Leary A. The Cassandra Matrix London, England is a registered trade
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15. Pennery E.  Specialist nursing roles: what are the challenges? In:
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Specialist Nurses. An HSJ Supplement. 2015 (Accessed April 2015).
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19. Royal College Nursing/National Voices. Local healthcare commis-
sioning: grassroots involvement? A National survey of health advo-
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61 29. Kellerman B. Followership: how followers are creating change and
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38. Armes J, Crowe M, Colbourne L, Morgan H, Murrells T, Oakley C,
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39. Mantzoukas S, Watkinson S. Review of advanced nursing practice:
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40. Barber D. The extended role of the nurse: practical realities. Hum
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2013;27(25):p18–20.
42. The Independent Cancer Taskforce. Achieving World-Class Cancer
Outcomes. A strategy for England 2015–2022. Executive summary.
NHS England. 2015.
43. Breast Cancer Care  – Breast cancer cases rise but number of spe-
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specialist-nurses-stays-same. Accessed 9 July 2016.
 689 62

Breast Cancer-Related
Lymphedema
Heli Kavola and Sinikka Suominen

62.1 Introduction – 690

62.2 Incidence of Breast Cancer-Related Lymphedema – 690

62.3 Pathophysiology – 690

62.4 Risk Factors – 690

62.4.1 Extent of Surgery – 690
62.4.2 Radiation – 691
62.4.3 Obesity – 691
62.4.4 Genetic Susceptibility – 691
62.4.5 Infection – 691

62.5 Signs and Symptoms – 691

62.6 Diagnosis – 691

62.6.1 Volume Measurements – 692
62.6.2 Measurements of Tissue Water Content – 692
62.6.3 Imaging Techniques – 692

62.7 Conservative Treatment – 693

62.7.1 General Measures – 693
62.7.2 Compression Garments – 693
62.7.3 Decongestive Lymphatic Therapy – 693

62.8 Surgical Treatment – 693

62.8.1 Liposuction – 694
62.8.2 Other Mass Reduction Methods – 694
62.8.3 Lymphatico-Venous Anastomosis – 694
62.8.4 Lymphatic Vessel Transplantation – 695
62.8.5 Vascularized Lymph Node Transfer – 695
62.8.6 Combined Autologous Breast Reconstruction and Lymph Node
Transfer – 696

62.9 Prevention – 696

62.9.1 Preventive Surgery – 696

62.10 Future Perspective – 697

References – 697

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_62

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 690 H. Kavola and S. Suominen
62.1 Introduction
As a result of more advanced breast cancer treatment modal-
ities, the number of breast cancer survivors is increasing.
Late effects of cancer treatment include, among others,
chronic lymphedema, an accumulation of protein-rich fluid
in interstitial spaces due to disruption of the lymphatic circu-
lation. Lymphedema can have a significant impact on quality
of life long after the malignant disease is cured. Lymphedema
is also associated with an increased incidence of recurrent
episodes of cellulitis with potentially life-threatening conse-
quences. Early detection is a key element in preventing the
progression of breast cancer-related lymphedema.
62.2 I ncidence of Breast Cancer-Related
Lymphedema
Lymphedema is a relatively common and often feared com-
plication of breast cancer surgery. There is a wide variation in
the reported incidence of breast cancer-related lymphedema
(BRCL) depending on the diagnostic criteria used, the treat-
ment of breast cancer and the duration of follow-up.
According to recent studies, it has been estimated that
20–50% of breast cancer survivors eventually develop lymph-
edema [1–6]. The incidence is highest during the first years
after operation. Approximately 80% of BCRL patients mani-
fest lymphedema within first 3  years, but the risk remains
lifelong at the rate of 1% per year [3, 6]. Although the use of
sentinel node biopsy (SNB) has been shown to reduce the
risk of lymphedema, the incidence after SNB still is 4–7% [1,
4, 7–9]. As long as there are no uniform definitions for
62 lymphedema, reliable assessment methods and long-term
follow-up studies, the true incidence of BCRL remains hard
to evaluate.
62.3 Pathophysiology
The lymphatic system is essential for maintaining the body’s
fluid homeostasis, immune response and transportation of
nutrients and waste products.
Hydrostatic pressure in arteries pushes plasma into the
interstitial space to provide nutrition to the surrounding tis-
sues. Under normal circumstances 90% of interstitial fluid
returns to the blood circulation through venous capillaries.
The remaining 10% of interstitial fluid consists of high-molec-
ular-weight proteins that are too large to enter venous capil-
laries. Lymphatic capillaries lack a basement membrane, and
therefore they can absorb these larger particles. Lymphatic
capillaries are then connected to collecting lymphatic vessels.
Unlike lymphatic capillaries, collecting lymphatic vessels are
lined by basement membrane and contractile pericytes, and
they possess valves to facilitate lymph flow to lymph nodes
and eventually back to the blood circulation [10, 11].
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When lymphatic vasculature is injured, due to, for
example, cancer surgery, lymphatic return is no longer able
to transport protein-rich fluid from interstitial spaces. This
leads to accumulation of high-molecular-weight proteins in
the interstitium, which, in turn, increases oncotic pressure
and draws additional water into the interstitium. Clinically,
swelling at this phase presents as classical pitting oedema.
Prolonged stagnation of protein-rich excess interstitial fluid
leads to progressive chronic inflammation that is consid-
ered as having a major role in progression of lymphedema
[12]. Persistent inflammation activates a cascade resulting in
fibrotic changes in lymphatic vessels and surrounding soft
tissue. Clinically, at this stage, pitting becomes less apparent
or non-existent [13, 14].
Accumulation of interstitial fluid also activates the differ-
entiation and proliferation of adipocytes leading to local adi-
pose deposition and even massive adipose tissue hypertrophy.
At the end stage of lymphedema, the increased volume of the
extremity is largely dominated by excess fat [15, 16].
Obstruction in the venous outflow by constricting axil-
lary scarring might be an additional factor in postoperative
lymphedema sequelae [17].
62.4 Risk Factors
62.4.1 Extent of Surgery
Having any kind of axillary lymph node surgery, with or
without radiation, places a patient at risk to develop arm
lymphedema. Axillary lymph node dissection (ALND) has
been strongly shown to be a major risk factor for BCRL [1, 4,
18–20]. Although wide adoption of SNB for staging of clini-
cally node-negative breast cancer has reduced the incidence
of breast cancer-related lymphedema [4, 19–21], the risk still
exists. SNB is considered less traumatic, although there can
be quite a large variation in the number of lymph nodes
removed in a procedure classified as a sentinel node biopsy
[4, 7]. There is no clear consensus whether the number of
lymph nodes removed has a correlation to the risk of lymph-
edema. Several studies have shown that the number of nodes
removed determines the risk [5, 22–24], but some studies
show conflicting findings [7, 25, 26]. It has been proposed
that the amount of surgical trauma and disrupted lymphatic
pathways is the key element rather than simply the number
of nodes removed [7].
Anatomical variations and the existence of alternative
lymphatic pathways, like the cephalic (the Mascagni) path-
way draining to supraclavicular nodes and the tricipital (the
Caplan) pathway draining to the posterior scapular nodes,
might explain why not all patients undergoing ALND
develop lymphedema [27–29].
Also the extent of local surgery affects the risk of lymph-
edema. Mastectomy has been reported to have a higher risk for
lymphedema compared to breast-conserving therapy [1, 30].
Breast Cancer-Related Lymphedema
691 62
62.4.2 Radiation symptoms are indicative for developing progressive lymph-
edema. Chronic lymphedema is usually gradual and can
Postoperative radiation therapy significantly increases the occur in a delayed fashion months or years after initial sur-
risk for lymphedema [18, 31–33]. The exact mechanism is gery. Although pain is not a major feature of lymphedema,
still unknown, but it has been suggested that radiation-­ some patients experience discomfort or a feeling of unease.
induced soft tissue fibrosis especially in combination with Sensory disturbances after ALND (see 7 Chap. 58) are com-
 

surgery contributes to development of lymphedema. mon, and some patients may perceive numbness as a sensa-
Radiation therapy has been shown to decrease the number of tion of swelling, although objectively lymphedema cannot be
dermal capillary lymphatic vessels and lymphatic endothelial observed.
cells causing further lymphatic dysfunction [34]. As the condition progresses, arm size discrepancy
becomes more noticeable and swelling firmer. The heaviness
of the arm may cause problems in daily living. Episodes of
62.4.3 Obesity cellulitis may be frequent.
Lymphedema can have a significant psychological effect
Being overweight or obese at the time of breast cancer diag- on a woman’s life [44–46]. The appearance of the arm may
nosis is a well-supported risk factor for BCRL. According to lead to negative self-image and feelings of shame and embar-
a prospective study by Helyer and colleagues, patients with a rassment. Women often find difficulty in finding well-fitting
body mass index >30 had a nearly threefold risk of develop- clothing due the size discrepancy of the arms. A heavy and
ing lymphedema compared to patients with a BMI <25 [25]. clumsy arm can cause difficulties in daily activities, which
There is evidence that obesity itself causes impaired lym- causes further frustration and anxiety. Even breast cancer
phatic flow [35], and it is hypothesized that obese women patients, who do not have lymphedema, may experience
have higher risk for BCRL because their baseline lymphatic anxiety and emotional distress in anticipation of future pos-
function is already impaired before surgery [36, 37]. sible lymphedema.

62.4.4 Genetic Susceptibility 62.6 Diagnosis

According to recent studies, a number of lymphaticogenic
and angiogenic genes play an important role in the develop-
ment of lymphedema. Mutations in certain genes are linked
to an increased risk of BCRL [38–40]. These findings suggest
that some patients have a genetic predisposition for lymph-
edema after breast cancer surgery.
62.4.5 Infection
Diagnosis of BCRL is usually based on physical examination.
In the early stages the lymphedema manifests itself as pitting
oedema. In the later stages, the increased arm volume is
dominated by hypertrophic adipose tissue, and the arm
shows little or no pitting at all.
A few staging systems for defining lymphedema have
been proposed, but currently the staging system of the
International Society of Lymphology [47] is most widely
adopted (. Table 62.1) (. Fig. 62.1).

Infections are closely linked to the risk of lymphedema. The

lymphatic system is important to immune surveillance, and ..      Table 62.1  Lymphedema staging according to the
impaired lymphatic function due to axillary lymph node dis- International Society of Lymphology [47]
section weakens the protection against infections. Recurrent
Stage 0 Latent/subclinical stage
infectious episodes further damage the lymphatic flow and
Swelling not yet evident
are a significant risk factor for development of lymphedema Impaired lymph transportsubtle changes in imaging
[6, 41].
Stage I Clearly visible swelling with soft pitting
Swelling temporarily reduced by elevation/during
night-time
62.5 Signs and Symptoms
Stage II Increasing fibrosis and excess fat
Pitting is less pronounced/not detectable
Early signs of lymphedema include complaints of slight puff- Swelling not reduced by elevation
iness, feeling of fullness and indentations from jewellery.
Swelling might subside during night-time. Stage III Extremely swollen
Fibrotic and hard tissues
Some patients, especially those receiving taxane-based
Pressure does not leave any pitting
chemotherapy, may experience some degree of transient Skin changes (papillomas, hyperkeratosis, blisters
swelling of the arm in the initial phase after surgery with leaking lymphatic fluid)
spontaneous resolution within months [23, 42, 43]. Persistent

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 692 H. Kavola and S. Suominen
..      Fig. 62.1  Lymphedema stage III: hard fibrotic tissues. Extremely
swollen arm with hard fibrotic tissues and excess fat [47]
62.6.1 Volume Measurements
So far, there is no standard method for quantitative assess-
ment of lymphedema. Arm circumference or volume differ-
ence compared to the unaffected arm or preoperative
measurements of the ipsilateral arm can be used to describe
the amount of lymphedema. However, diurnal variation and
temporal changes due to diet and external temperature as
well as weight change can affect the arm volume results. Also,
there is natural asymmetry, with the dominant arm usually
1.6% larger than the non-dominant arm [48]. The generally
adopted diagnostic criteria for lymphedema are a 10% or
200 ml limb volume difference/change or a 2 cm circumfer-
62 ential difference/change [49, 50]. In very slim patients,
smaller arm circumferential differences can be noteworthy.
Moreover, in a very obese patient, 2  cm change in the cir-
cumference may not be a relevant definition for lymphedema.
Probably the most commonly used method is circumfer-
ential tape measurements at defined intervals (e.g. 4 cm) and
using specific anatomical landmarks (e.g. styloid process of
the ulna at the wrist) as a starting point.
The water displacement method is considered to be the
gold standard for measuring arm volume. In this method the
arm is immersed in a water tank, and using Achimedes’ law,
the volume of the arm is calculated from the amount of water
displaced. The benefit of the method is that it has proven
to be very reliable, and also the volume of the hand can be
measured. Still, it is rarely used due to impracticalities in the
clinical setting.
Perometry is an optoelectronic measuring device that
uses infrared light beams in a form of a square frame. The
arm is placed inside the frame, and the frame is moved along
the arm calculating the volume of the arm from the cross-­
sectional area. Perometry is considered to have high inter-
and intra-rater reliability [51, 52]. Perometry is also very
hygienic since there is no direct contact with the extremity
and the measuring device. However, it is rather expensive
and space-consuming equipment.
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62.6.2 Measurements of Tissue
Water Content
Bioimpedance spectrometry (BIS) is a non-invasive method
for measuring water content in tissues. The device passes a
small electrical current through the limb and measures the
resistance to current. The higher the water content (lymph-
edema) in the interstitial tissue, the lower the resistance
(impedance). Bioimpedance spectrometry can be helpful in
detecting early-phase lymphedema, but is not accurate for
advanced stages when lymphedema has progressed to a more
fibrotic and fatty consistency [53, 54].
The tissue dielectric constant (TDC) can also be used
to measure water content. The method utilizes a handheld
non-­invasive device that passes an electrical current to a local
point when the probe touches the skin. The reflected signal
determines water content at that specific anatomical point.
Being easy to use and low cost, TDC-devices are a practical
asset in the clinical setting. Like bioimpedance spectrometry,
tissue dielectric constant is most useful in tracking subclini-
cal lymphedema [55, 56].
62.6.3 Imaging Techniques
Although the diagnosis of lymphedema is usually made
clinically, imaging techniques can be used to confirm the
diagnosis of lymphedema in uncertain cases. In assessment
of breast cancer-related upper extremity lymphedema, espe-
cially if presenting in a delayed fashion, recurrence of previ-
ous breast cancer needs to be ruled out by routine imaging
methods.
Advanced imaging techniques are valuable to obtain
more detailed understanding of lymphatic function and to
monitor the results of lymphedema treatment.
Lymphoscintigraphy is currently the main imaging
modality for diagnosing lymphedema [8, 47, 57]. In this
technique, a small amount of 99  m technetium-labelled
tracer (e.g. nanocolloid) is injected intradermally into the
interdigital space. The injected radiotracer is filtered to lym-
phatics and transported to lymph nodes. Visualization with
a gamma camera provides a two-dimensional qualitative
evaluation of lymphatic function and pathways. Also semi-­
quantitative information in the form of a transport index can
be obtained based on clearance rates and dermal backflow
parameters [58, 59].
Contrast-enhanced magnetic resonance lymphan-
giogram (MRL) using gadolinium contrast media provides
more detailed three-dimensional image of the lymphatic
system. It is non-invasive and involves no ionizing radiation.
MRL shows good potential having higher spatial and tempo-
ral resolution and therefore being more sensitive in defining
the anatomical and functional status of lymphatics [60–62].
With limited availability, relatively high costs and need for
special expertise, MRL is not yet a standard diagnostic tool
for lymphedema.
Breast Cancer-Related Lymphedema
The most promising advance in the field of lymphatic
imaging is indocyanine green (ICG) lymphography [63, 64].
In this method, a small amount of ICG, a fluorescent mol-
ecule, is injected intradermally. When the skin is illuminated
by near-infrared light, the light emitted by fluorescent ICG in
the lymph vessels is detected by using a special camera, and
the lymphatics can be visualized. The ICG lymphography
pattern changes from a normal linear pattern to an abnor-
mal dermal backflow pattern depending on the severity of
lymphedema. Yamamoto and colleagues proposed a staging
method based on different ICG lymphography patterns [65].
ICG lymphography is useful in preoperative planning and
provides real-time observation of functioning lymph vessels
during surgery. Its disadvantage is that it can only detect ves-
sels if they are less than 2 cm deep [63].
62.7 Conservative Treatment
Conservative treatment should be started as soon as the early
signs of lymphedema start to develop. Early treatment can
limit progressive arm volume increase and thus prevent irre-
versible tissue changes [66].
62.7.1 General Measures
On obese or overweight patients with lymphedema, weight
loss is essential. These patients should be offered referral to a
dietician as a part of lymphedema treatment. Weight reduc-
tion has been shown to decrease excess arm volume [67].
Patients with normal weight should be strongly encouraged
to avoid weight gain.
Adequate hygiene and skin care are important to prevent
cracking of dry skin and help to avoid infections that might
exacerbate lymphedema.
Flexibility exercises are beneficial in maintaining the range
of movements in the affected arm. Patients should be encour-
aged to have a physically active lifestyle that also supports weight
control. Slowly progressive resistance exercises and lightweight
training can be performed safely [68, 69]. By activating the
musculoskeletal pump and increasing muscle strength, exer-
cises may alleviate lymphedema symptoms [70, 71].
62.7.2 Compression Garments
Elastic compression garments (sleeve and glove/gauntlet) are
the mainstay of lymphedema treatment. The aim is to limit
fluid accumulation in the tissues and reduce arm volume.
Compression garments should be fitted by properly trained
personnel since poorly fitting compression garments are
uncomfortable and can even aggravate lymphedema. Some
patients may need custom-made garments if ready-made
garments are not suitable. Compression garments are usually
worn during the daytime, and the patient should always have
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693 62
at least two sets of garments: one to wear and one to wash.
Compression garments are renewed every 6 months or when-
ever they lose elasticity. Compression garments are the first-
line therapy in mild (stage 0–1) lymphedema [66, 70, 72].
62.7.3 Decongestive Lymphatic Therapy
Decongestive lymphatic therapy (DLT) or complex/complete
decongestive therapy (CDL) is the standard of care for mod-
erate to severe (stage II–III) lymphedema. Some of the
patients with mild (stage I) lymphedema might also need
more intensive treatment if the symptoms are not controlled
by compression garment alone [66, 72, 73]. DLT consists of
manual lymphatic drainage (MLD), multilayer compression
bandaging, therapeutic exercises, skin care and properly fit-
ted compression garment.
DLT starts with an intensive period aiming to reduce the
amount of fluid in the tissues. MLT is performed preferably 5
times a week by a specially trained physiotherapist, and after
each session, the arm is wrapped in a multilayer bandage.
Therapeutic exercises are repetitive «pumping» movements
that, combined with external compression, aim to enhance
fluid flow.
After an intensive period of MLD and bandaging when
the arm volume is reduced (usually 2–4 weeks), a compres-
sion sleeve and glove/gauntlet are fitted. During this mainte-
nance phase, the patient wears compression garments at least
during the day. Some patients may also require night-time
compression garments or bandaging to control fluid accu-
mulation. The intensive phase of DLT is repeated if necessary
at the time of renewing the compression garments.
The evidence for the benefits of manual lymphatic drain-
age apart from DLT is conflicting [70, 74]. Although it
might have some additional effect on compression therapy
and especially as a part of DLT, manual lymphatic drainage
should not be used as a stand-alone therapy [75, 76].
62.8 Surgical Treatment
Although conservative therapy continues to be first-line
treatment for lymphedema, surgical management aiming to
improve function and quality of life can be considered in
selected patients. Severe or recurrent episodes of cellulitis
may indicate surgical treatment is appropriate.
In obese patients, weight reduction should be a prereq-
uisite for operative consideration. Surgical management
options can be divided grossly in two categories: mass reduc-
tion (debulking) techniques and reconstructive (physiologic)
techniques. Mass reduction techniques, such as liposuction,
offer a palliative remedy, whereas reconstructive techniques,
including lymphatico-venous anastomosis, vascularized
lymph node transfer and lymphatic vessel transplantation,
aim to restore lymphatic function. Despite of the recent
advancements in surgical techniques, none of the operations
 694 H. Kavola and S. Suominen
can definitely cure lymphedema. There are no standardized
protocols for surgical management of lymphedema, and
objective long-term results are scarce. Neither are there com-
parative studies of different treatment options.
The choice of operative treatment should be evaluated
individually. Different techniques can be also combined
depending on the patient’s condition and the surgeon’s pref-
erences.
62.8.1 Liposuction
At present liposuction is the most common mass reduction
technique. Long-term lymphedema results in the deposition
of adipose tissue and even massive local fat hypertrophy.
Especially in the late stage of non-pitting lymphedema, when
the arm volume is largely dominated by excess fat, compres-
sion therapy has limited impact on volume reduction. In
these cases liposuction can provide a clear improvement in
the patient’s arm function and quality of life. Strict adherence
to compression garment use is mandatory before and after
operation. Permanent use of compression garments is neces-
sary to prevent fluid reaccumulation after liposuction. If the
patient is not compliant to preoperative compression therapy,
liposuction is not indicated [77]. Liposuction is performed
through small skin incisions with a vibrating power-assisted
or ultrasound-assisted liposuction cannula since traditional
liposuction may not be sufficient to break up the fibrotic adi-
pose tissue. A preoperatively measured compression garment
is applied in the operation room immediately after liposuc-
tion to prevent hematomas. Compression therapy is contin-
62
Veins
Magnification
Lymph
vessels
..      Fig. 62.2  Lymphatico-venous anastomosis
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ued lifelong after liposuction. Liposuction is effective in
volume reduction, and with rigorous use of a compression
garment, it can provide stable long-term results [78].
Liposuction does not, if properly performed, further reduce
the already impaired lymphatic transport [79, 80].
62.8.2 Other Mass Reduction Methods
Brachioplasty, as in postbariatric surgery, can be performed
to remove excess non-retracted skin in the upper arm when/
if oedema is settled after reconstructive procedures.
More ablative operations, such as the Charles procedure
(excising the skin and soft tissue on a fascial level and using
the skin as a skin graft to cover the defect), are very rarely
used in upper extremity lymphedema due to disfiguring
­outcomes.
62.8.3 Lymphatico-Venous Anastomosis
Lymphatico-venous anastomosis (LVA) or bypass is a tech-
nique of connecting multiple distal subdermal lymphatic
vessels to superficial nearby venules (. Fig. 62.2). This allows
lymph to drain directly to the venous system, and the
obstructive part of the lymphatic pathway is bypassed. The
LVA technique is minimally invasive since the anastomoses
are performed through small skin incisions, and the opera-
tion can even be performed under local anaesthesia. ICG and
patent blue can be used to localize suitable lymph vessel.
Identifying healthy functioning lymphatic vessel as well as a
Cut end of Disrupted
vein proximal part of
lymph vessel
Vein anastomosed
to lymph vessel
Breast Cancer-Related Lymphedema
venule without venous backflow is necessary for a function-
ing anastomosis.
LVA is most suitable for patients with early-stage
lymphedema that has not yet progressed into the fibrotic,
fat-­dominating stage. The technique is highly demanding,
requiring a skilled microsurgeon and special supermicrosur-
gery equipment to handle thin-walled, fragile lymph vessels.
Patency of the recreated lymphatic pathway is difficult to
evaluate postoperatively.
Studies on the long-term effects of LVA report subjective
improvement of lymphedema symptoms in the majority of
patients [81, 82]. The effect on volume reduction is variable,
but approximately half of the patients have been able omit
wearing pressure garments [83]. A decreased incidence of
cellulitis has also been reported [82, 84].
LVA appears to be a safe procedure with no severe com-
plications reported. Neither has it been shown to impair lym-
phatic flow or exacerbate lymphedema.
62.8.4 Lymphatic Vessel Transplantation
Lymphatic vessel transplantation or lymphatico-lymphatic
bypass uses a lymph vessel as a graft to connect a distal part
of the affected extremity to more proximal lymph vasculature
[85]. A lymph vessel graft harvested, for example, from the
thigh is tunnelled under the skin to bypass the obstructed
axilla and sutured distally in the arm and proximally on the
neck to reconnect lymphatic vessels. Like LVA, this technique
requires microsurgical expertise and supermicrosurgical
instrumentation.
..      Fig. 62.3  Vascularized lymph node transfer from the groin (sche-
matic drawing and photograph) (Reproduced from Greene et al. Ed,
Lymphedema, pp. 269–278, Lymph Node Transfer to Proximal Extremity,
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695 62
62.8.5 Vascularized Lymph Node Transfer
Vascularized lymph node transfer (VLNT) is a microsurgi-
cal method, in which lymph nodes from a healthy lymph
basin, most commonly from the groin (. Fig.  62.3), are
transferred to a lymphedematous extremity, and the artery
and vein of this lymph node flap are anastomosed to local
vessels to maintain vascularity [86]. Lymph vessels are not
anastomosed since they are expected to form spontane-
ously from the transferred lymph nodes. The exact mecha-
nism by which VLNT improves lymphatic flow is still
unclear. It is hypothesized that axillary scar tissue release
opens the obstructed lymphatic vessels, and replacing the
scar with a well-­vascularized flap bridges the distal lym-
phatics with the healthy proximal system [87]. Experimental
studies have demonstrated that lymphatic vessels have an
enormous capacity to regenerate after tissue transfer by
regrowth of lymphatic vessels and spontaneous reconnec-
tions of existing lymphatics [88, 89]. Direct connection
with lymph nodes and veins inside the flap allows drainage
directly to the venous system [90]. It has also been proposed
that the lymph node flap acts as a «pump» that draws fluid
from the surrounding interstitium to the transferred lymph
node flap by a gradient between arterial inflow and venous
outflow [91].
Obstruction in the venous outflow being one factor in
postoperative lymphedema sequelae is supported by clini-
cal observations that releasing the compressing scar around
the axillary vein may sometimes provide immediate relief of
symptoms well before the lymphatics have, even theoreti-
cally, regenerated.
Heli Kavola, Sinikka Suominen, Anne Saarikko © Springer International
Publishing Switzerland 2015. With permission from Springer)
 696 H. Kavola and S. Suominen
VLNT can be transferred to either proximal (axilla) or
distal (wrist or elbow) recipient sites. The axillary recipient
site may be preferable because it allows scar release. Some
authors advocate for the distal site based on the pumping
effect being more efficient distally [91]. So far, there are no
objective studies comparing different recipient sites.
VLNT is considered to be most effective in the early
stages of lymphedema when adipose tissue hypertrophy and
fibrosis have not yet developed.
In cases of chronic infections or recurrent episodes of
erysipelas related to lymphedema, VLNT might be use-
ful since transplanted healthy lymph nodes are expected
to improve the local immune response [87]. VLNT to the
axilla seems to be beneficial in the treatment of chronic pain,
neuromas and brachial plexus neuropathies associated with
breast cancer surgery [92, 93]. This is possibly due to wide
scar release combined with VLNT, and vascularized soft tis-
sue with active lymph nodes might prevent recurring fibrosis
and scarring.
The most common donor site for a lymph node flap is the
inguinal area [94], where superficial lymph nodes are har-
vested based in the superficial circumflex vessels. The contra-
lateral thoracic lymph node flap consisting lymph nodes from
the lower axilla along the anterior border of latissimus dorsi
muscle [95], the cervical (supraclavicular) lymph node flap
based on the transverse cervical artery [96, 97] and submen-
tal lymph node flap based on the submental artery arising
from the facial artery [98] have also been described for the
donor site. The risk of developing postoperative iatrogenic
lower limb lymphedema is a major concern for the groin area
donor site [99, 100], but with adequate preoperative plan-
ning, a delicate surgical technique and with the use of reverse
62 lymphatic mapping [101], the risk can be minimized. None
of the donor sites are without risk of postoperative complica-
tion. Therefore, all patients must be carefully evaluated and
properly advised about possible harms and benefits.
Recent reports of VLNT show promising results,
although systematic large-scale studies are still lacking. Most
of the studies report a reduction of arm circumference [87,
91, 102]. A decrease in infectious episodes has been observed
[87, 91], and approximately 60% of patients have been able
to discontinue wearing compression garments [83, 87, 103].
VLNT also seems to significantly improve quality of life
among patients with BCRL [102, 103].
62.8.6  ombined Autologous Breast
C SNB (from diagnostic to therapeutic), minimizing the extent
Reconstruction and Lymph Node
Transfer
Lymph node transfer can be conveniently combined with
microvascular abdominal wall breast reconstruction [104–
106]. For postmastectomy patients suffering from upper
extremity lymphedema, breast reconstruction with lymph
node transfer is an optimal choice. Any soft tissue flap from
the lower abdominal wall, either based on the deep inferior
epigastric vessels (traditional TRAM-flap, muscle-sparing
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TRAM-flap or DIEP flap) or superficial inferior epigastric
vessels (SIEA flap), can be used as a carrier of lymph node
flap. If the abdominal tissue is insufficient for breast recon-
struction, transverse myocutaneous gracilis (TMG)-flap with
lymph nodes is another option [107].
62.9 Prevention
Any patient undergoing breast cancer surgery is at risk of
developing lymphedema at some point in his/her life.
Therefore all these patients should be advised about possible
adverse effects. Patient education with self-monitoring plays
an important role in prevention. Patients should be informed
about the early symptoms of lymphedema and encouraged to
seek treatment as soon as they recognize these early signs.
They should be advised about proper skin care and to avoid
infections. Weight reduction in obese patients and maintain-
ing optimal weight is essential since obesity is one of the
main risk factors for lymphedema.
Early postoperative physiotherapy and progressive active
and action-assisted shoulder exercises combined with educa-
tion seem to be effective in prevention of lymphedema after
ALND [108].
Many other preventative practices (e.g. avoidance of
blood pressure measuring or blood sample taken from the
ipsilateral arm) have been advocated, although there is no
evidence supporting these practices [109].
Early detection of lymphedema should be incorporated
in breast cancer follow-up routines. It is recommended to
have preoperative measurement of both arms before breast
cancer surgery to serve as baseline measurements for further
follow-up. Regular monitoring of high-risk patients facili-
tates early detection and can reduce lymphedema incidence
[66, 110]. Measurements based on tissue water content, such
as bioimpedance spectrometry or tissue dielectric constant,
could possibly predict the onset of lymphedema earlier than
volumetric measurements [53, 56].
62.9.1 Preventive Surgery
The use of SNB for axillary staging instead of ALND is the
main method of primary prevention, although the risk of
lymphedema is not completely absent with SNB. Since ALND
is the main risk factor for BCRL, widening indications for
of axillary surgery as well as more advanced techniques such
as reverse axillary mapping (see 7 Chap. 27) might further
reduce the risk. Still, these methods need to be carefully
evaluated in terms of oncological safety.
Direct lymphatico-venous microsurgery (performing
immediate LVAs between the arm lymphatics and collateral
branches of the axillary vein at the time of ALND) has been
proposed as a promising technique in primary prevention of
lymphedema [28], but the need for microsurgical skills may
be a limiting factor.
Breast Cancer-Related Lymphedema
Including lymph nodes in the abdominal flap with simul-
taneous LVAs in immediate breast reconstruction seems a
fascinating way to immediately restore not only breast shape
but also lymphatic function for simultaneous prevention of
lymphedema [111]. Long-term results of this method are
pending.
10. Alitalo K.  The lymphatic vasculature in disease. Nat Med.
11. Maclellan R. The lymphatic system. In: Greene A, Slavin S, Brorson
62.10 Future Perspective
With growing numbers of breast cancer survivors, BCRL is
becoming an increasingly important issue for healthcare
systems and the patients themselves. Objective research on
the efficacy of different treatment modalities is urgently
needed. The lack of a consistent definition of lymphedema,
heterogeneity of measurement techniques as well as variable
outcome measures presents a major obstacle to objectively
evaluating different treatment options. Advanced imaging
techniques might offer more precise diagnostic tools in the
future. Patient selection and timing of surgical interven-
tions need to be evaluated to find the most cost-effective
treatment.
As early detection and timely interventions may reduce
the incidence of debilitating late-stage lymphedema, increas-
ing awareness among breast cancer patients as well as health-
care professionals is crucial. Also future research is needed
to identify high-risk patients. Genetic profiling may offer a
target for closer monitoring of patients with a genetic predis-
position for BCRL.
One interesting future prospect is the development of
growth factors and gene therapy with aim to rebuilding the
lymphatic vasculature and to restore lymphatic function as a
definitive cure for lymphedema [112].
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 701 IX

Quality Assurance
Contents

Chapter 63 Research and Audit in Advancing the Quality

of Breast Cancer Care – 703
Petra G. Boelens, Elma Meershoek-Klein Kranenbarg,
Esther Bastiaannet, Cornelis van de Velde,
and Riccardo A. Audisio

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 703 63

Research and Audit
in Advancing the Quality
of Breast Cancer Care
Petra G. Boelens, Elma Meershoek-Klein Kranenbarg, Esther Bastiaannet,
Cornelis van de Velde, and Riccardo A. Audisio

63.1 Introduction – 704

63.2 Trial Design – 704

63.3 Study Types – 704

63.4 Specific Research Methodologies
and Research Quality Standards – 705
63.4.1 Randomised Trials and ­Meta-Analyses – 705
63.4.2 Observational Studies (Cohort, Case Control) – 705
63.4.3 Case Reports – 706

63.5 Clinical Trials and Bias – 706

63.6 Clinical Trials and Funding – 706

63.7 Quality Assurance in Breast Cancer Care:

The Role of National and International Registries,
Audits and Quality Standards – 708
63.7.1 Guidance – 708

63.8 Cancer Registries and Auditing – 708

63.9 The Older Breast Cancer Patients in 

Observational Studies – 710

63.10 Summary – 710

References – 710

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_63

rares1geo@gmail.com
 704 P.G. Boelens et al.

63.1 Introduction methods, has the ability to perform critical evaluation of

Breast cancer has been leading the way in adopting an evi-
dence-based approach to improving outcomes. Breast can-
cer survival rates have increased substantially in the last
40  years, and the quality of life of survivors has been
increased by better quality treatment following advances in
breast surgery (breast conservation, oncoplastics, sentinel
node biopsy and reconstruction), screening, radiotherapy
and systemic therapies. All of these advances have been sup-
ported by research evidence highlighting its primacy in can-
cer care optimisation. This chapter will review research and
audit methods and give examples of key studies that exem-
research data and keeps abreast of the latest trials and
research to ensure they stay up to date. This chapter will focus
on these issues giving examples of breast cancer research and
audit to demonstrate each research type.
63.3 Study Types
There are many different types of research, and all may play
an important role in improving the outcomes for women
with breast cancer. The different types, their definitions and a
classical example are shown below (. Table 63.1) [1–18].

plify them. Another common way to classify trials is according to

63.2 Trial Design
There are many different types of research that may inform
best practice in the field of breast cancer. It is of vital impor-
their phase as they progress from testing the basic physiolog-
ical impact of the new intervention in vitro, in animal models
(preclinical) and humans, to dose finding and ultimately
confirmatory studies of safety and efficacy, at which point
regulatory approval is usually granted. Refinements of use
are then made in late phase studies (. Table 63.2). All have a

tance that the modern breast surgeon is aware of research role in the evaluation of new treatments.

..      Table 63.1  Trial classification according to purpose

Trial purpose Aim Design Breast cancer-specific examples

Breast cancer To identify ways to reduc- Cohort studies of lifestyle IBIS I and II
prevention ing the incidence of breast impacts, use of drugs in ran- NSABP P1 [1–4]
cancer domised trials

Breast screening To identify effective ways to Randomised trials, cohort study Swedish Two-County and other screening trials
increase early diagnosis with bias correction MARIBS trial of breast MRI screening
FH01 trial of screening in high-risk women [5–7]

63 Diagnostic To evaluate the efficacy of

diagnostic tests, predictive
and prognostic biomarker
studies
Observational cohort or ran-
domised trials to evaluate accu-
racy, sensitivity and specificity of
new diagnostic tests
TAILORx and MINDACT are good examples of
biomarker evaluation trials. Radiology trials to
evaluate new means of staging the axilla such
as that by Memarsadeghi 2006 [8, 9]

Treatment To assess the efficacy of
new drugs, surgical tech-
niques and radiotherapy
regimes
In surgery: often observational
studies of case series and cohorts,
some randomised studies [10, 11].
RCTs widely used in systemic
therapy trials often with large
meta-analyses to confirm findings
The AMAROS trial comparing axillary clearance
and radiotherapy
The ALMANAC trial comparing axillary clearance
and SLNB
The Early Breast Cancer Trialists’ series of meta-
analyses [12–15]

Quality of life To look at ways of improv- Quantitative questionnaire Often integrated into many of the above trial
and supportive ing the quality of life of design, validated quality of life designs. Good examples are the PRIME trial and
care cancer patients during and tools, PROMs and qualitative the ALMANAC trial [16–18]
after treatment research

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Research and Audit in Advancing the Quality of Breast Cancer Care
705 63
why so many informative non-randomised hospital or per-
..      Table 63.2  Table describing the common phases of clinical
trials
sonal series are published. RCTs in surgical oncology are
therefore less common than cohort studies. Surgical versus
Phase Aim non-surgical comparative trials also suffer from problems of
lack of equipoise both on the part of the surgeon and the
Preclinical studies In vitro and animal studies patient as the differences between treatments are often
Phase 0 First in human studies to define pharma- extreme. It is also difficult to blind the patient and surgeon to
codynamics and pharmacokinetics the intervention which may introduce bias.
Phase 1 Safety screening There are some examples of well-designed trials compar-
ing two surgical modalities or surgical versus non-surgical
Phase 2 Efficacy and dose finding interventions. Trials such as those conducted by pioneering
Phase 3 Comparative efficacy surgeons Umberto Veronesi in Europe and Bernard Fisher in
the USA, comparing mastectomy versus breast-conserving
Phase 4 Use optimisation in clinical practice
therapy several decades ago, are excellent examples which
lead to a massive change in practice in the field of breast can-
cer care [10, 11]. Trials that have successfully compared surgi-
cal and non-­surgical options have also been conducted in
Metaanalysis breast care. An innovative, highly impactful and controversial
trial compared standard axillary completion clearance with no
Randomised
controlled trials further surgery in the ACOZOG 0011 trial [21]. This trial,
whilst methodologically imperfect, has again changed global
Cohort studies
practices concerning axillary clearance in patients with low-
risk clinically positive lymph nodes. Similarly the AMAROS
Case control studies
trial, in which patients with T1–2 primary breast cancer and no
Case reports palpable lymphadenopathy were randomised to receive either
axillary lymph node dissection or axillary radiotherapy in cases
Expert opinion with a positive sentinel node, concluded that radiotherapy gave
excellent oncological results with less axillary morbidity [12].
As with trials in other surgical disciplines, breast surgery trials
..      Fig. 63.1  Hierarchy of research evidence have also sometimes included a learning curve phase to ensure
technical competency in the new technique. A good example
of this was the ALMANAC trial of SLNB in breast cancer [1, 2,
63.4  pecific Research Methodologies
S 18, 22]. There have been many advances in trial methodology
and Research Quality Standards in the past decade to ensure that data generated is valid and
may be compared between studies. These have been formalised
63.4.1 Randomised Trials into trial guidelines such as the CONSORT statement for RCTs
and ­Meta-Analyses [23] and the PRISMA standards [24] for systematic reviews
and meta-­analyses. There are numerous other quality stan-
Randomised controlled trials (RCTs) and meta-analyses of dards in action. It is essential that breast surgeons have a good
data from such trials are considered the highest levels of evi- understanding of how to assess the quality of research evidence
dence supporting clinical practice in oncology (. Fig. 63.1).   so they can decide what is worthy of clinical adoption. There
The quality of the design and the quality control of these are a number of excellent overviews of how to critically assess
trials are of the utmost importance to warrant the safety, effi- the quality of research, a skill that should be an integral part of
cacy and reproducibility of the data and conclusions drawn an oncologists’ training [25–28].
from them. Surgical trials however have a number of chal- In addition to randomised trials and meta-analyses, there
lenges when compared to non-surgical trials. Choosing a are valid reasons why some research questions cannot be
homogenous patient population and an equivalent control answered using this methodology. In the field of breast
group is challenging. Surgery, unlike a pill, is not a stan- ­cancer, there are many such examples of where a cohort
dardised, reproducible entity, but rather a unique product methodology is advantageous or the only feasible option.
whose details are defined by variables, which include the skill
of the surgeon. The skill level will not only vary among sur-
geons, but will increase for the same surgeon whilst he/she 63.4.2  bservational Studies (Cohort,
O
gains experience (surgical procedures have a learning curve) Case Control)
[19]. Furthermore, surgeons with a specific interest in a pro-
cedure will perform better [20]. These surgeons are also well Data from observational studies are increasingly used to fill
disposed to develop new techniques in their own centre and knowledge gaps [29]. However, several challenges exist in
subsequently analyse their series. This is one of the reasons the use of observational data: bias due to confounding by

rares1geo@gmail.com
 706 P.G. Boelens et al.
i­ndication is one of the major obstacles. This could poten-
tially be tackled by using comparative effectiveness research
if careful design and analysis is applied. For those research
questions where randomised controlled trials are unethical,
impractical or simply too lengthy for timely decisions, obser-
vational research may be used. The main problem with
observational studies is treatment allocation bias which is
difficult to fully adjust for in analysis. Patients who received
a certain treatment typically differ from patients in whom
that treatment is omitted. Excellent examples are patients
treated non-­surgically with primary endocrine therapy for
operable cancer due to age, frailty or comorbidity will have
higher morbidity and mortality rates than the fitter cohort
who undergo the surgical option. Although it may be possi-
ble to adjust for factors that were measured, there will always
remain certain factors that were unmeasured, so-called
residual confounders [30]. The best example is frailty which
is rarely formally assessed in studies but has a profound
impact on treatment allocation and outcomes. Direct com-
parison of treatments can result in overestimation of treat-
ment efficacy, and it is very likely that this problem occurs in
most studies that have used this methodology. Although
randomisation does not guarantee that treatment groups are
equal across all possible confounding factors, it does guaran-
tee that residual differences between groups are due to
chance [30].
One of the more appropriate alternative methods that can
be used to study treatment effectiveness in observational data
is the use of instrumental variables. The instrumental vari-
able is a factor that is associated with the allocation of a cer-
tain treatment, but is not directly associated with the
outcome. For example, if two countries with comparable
patients have a very different treatment strategy, the country
may be used as the instrumental variable. Instead of compar-
63 ing the outcome of patients with and without a certain treat-
ment, differences in outcome between the two countries are
compared, which eliminates bias due to confounding by
indication [30]. There are three conditions that must be ful-
filled for the use of an instrumental variable:
1. The instrumental variable must be related to the
probability of receiving the treatment under investiga-
tion.
2. It should not be related to the prognosis of the patient.
3. It should not affect the outcome in any other way than
through the treatment given [31].
The use of an instrumental variable is particularly useful in
populations where randomisation is not feasible or not ethi-
cal [31], but it can be challenging to identify a proper instru-
mental variable that fulfils all three criteria. Still, when a
good instrumental variable is available, it is considered to be
the best method that can be used to study treatment effects in
observational research [30].
Excellent examples of where observation studies have
value are in areas where there are high levels of patient vari-
ability such that stratification with a randomised trial would
be unfeasible. Research into the elderly is an excellent exam-
rares1geo@gmail.com
ple of where observational data may be of value. Randomised
trial inclusion of patients over the age of 70 is very limited
with only 1–5% of the included patients older than 70 years,
and there are a number of valid reasons for this. Not all older
patients are suitable for standard treatments administrated to
younger patients, and heterogeneity of the older population
may complicate inclusion criteria [32]. Furthermore, early
mortality  – directly resulting from comorbid conditions  –
could reduce the apparent effectiveness, and shorter follow-
­up time will decrease statistical power to detect differences
between treatment and control arms. Besides these method-
ological barriers, the participation and preferences of older
patients and the willingness of otherwise of their clinicians
may be considered another barrier. For all of these reasons,
observational studies with appropriate adjustment for patient
characteristics may be the only avenue to determine best
practice in this age group.
63.4.3 Case Reports
For exceptionally rare conditions, running trials or even
large observational studies may be impossible, and case
reports may be the appropriate level of evidence to support
best practice. In the field of breast cancer surgery, publication
of case reports may ultimately lead to better understanding
of rare associations, for example, the link between angiosar-
coma and radiotherapy or the newly described but excep-
tionally rare breast implant-associated anaplastic large cell
lymphoma (BIA-ALCL) (7 Chap. 29, breast implants).
63.5 Clinical Trials and Bias
A full understanding of bias and how it influences study
results is essential for the practice of evidence-based medi-
cine. Bias is defined as any factor of influence which pre-
vents objective consideration of a question. Bias can occur
at any phase of a study, including study design or data col-
lection, as well as in the process of data analysis and publi-
cation. Breast surgeons must be trained to critically interpret
study results and must also evaluate chosen endpoints,
study design (patient population/controls) and identify
study biases.
In clinical trials some forms of bias are always present; the
issue is to what degree bias influences a favourable outcome
for the test group (. Table 63.3) [33–35].
63.6 Clinical Trials and Funding
Cancer research in general is funded by different sources
such as drug companies, charities, national governments and
the European Union. Running randomised (double-blind),
prospective clinical trials is time-consuming and costly.
Costs involved in executing high-quality trials need to cover
treatments, research staff to run the trial and collect the data,
Research and Audit in Advancing the Quality of Breast Cancer Care
707 63

..      Table 63.3  Different types of bias which may affect clinical research

Trial period Bias Definition How to avoid

Planning the Flawed study design Many errors can occur in study design. Meticulous study design, power analysis,
trial Sample size should meet the power. publish clinical trial study design, register trials,
Study groups should be equal, con- medical ethical committee approval before
trol treatment as equal as possible, starting the trial
endpoints adequate to answer to the
hypothesis, time point adequate to test
the hypothesis, etc.

Selection bias [33] Comparing two different groups Prospective design with unknown outcome
reduces the likelihood of selection bias. Clear
defined study population with inclusion and
exclusion criteria for patients most at risk

Randomisation or allo- Use blinded treatment allocation Researchers should not have a hand in alloca-
cation bias tion of treatments preferably by using comput-
erised external randomisation

Bias during the Interviewer bias Questions to be asked should be stan- Use blinding for group/outcome.
trial execution dardised to avoid any suggestion of Use validated questionnaires to avoid
interviewers ‘researcher’s influence’

Recall bias Influence of the question in the recall of Only use validated tools (questionnaires); use
events happened in the past objective interviewers blinded to group and
outcome

Chronology bias Historical data as control Prospective design consecutive patients

Performance bias Variation in performance can influence Standardise surgical techniques to minimise
outcome results variation between surgeons

Bias from misclassifica- Misclassification of results or outcome Blinding for outcome, standardisation of data
tion due to variation in interpretation to clas- collection and outcome
sify results

Transfer bias Missing information due to subjects lost Reduce lost to follow-up as much as possible
to follow-up

After the trial Publication bias [34] The tendency of investigators to submit Reviewers and editors’ responsibility to accept
or the reviewers and editors to accept all decent quality research regardless of posi-
manuscripts based on the direction or tive or negative findings
strength of the study results

Citation bias Tendency of negative results not to be Also publish negative results of studies
published and positive results to be Preregister trials
published

Confounders Any factor that correlates with depen- Control for confounders in the study design.
dent and independent variables Use stratification. Use double blinding and
randomisation

Internal vs external Internal validity denotes to the reliability
validity [35] or correctness of the study results
External validity of study design refers
to the degree to which findings are able
to be generalised to other groups or
populations
A study’s internal validity reflects the investi-
gator’s and reviewer’s confidence that study
design, execution and data collection and
analysis have reduced bias and that the find-
ings are representative of the true association
between exposure and outcome

costs of specific tests and laboratory analysis, costs of com-
puter technology to analyse the results and administrative
costs. The recently presented investigator-initiated
MINDACT trial had a budget of €47 million [36]. Costly,
large adjuvant trials with long-term follow-up and ‘strong’
endpoints are increasingly being replaced by cheaper,
quicker, neoadjuvant trials with surrogate endpoints. The
FDA instituted its Accelerated Approval Program to allow
for earlier approval of drugs for the treatment of serious con-
ditions and to fill an unmet medical need based on a surro-
gate endpoint. A surrogate endpoint is defined as a marker,
such as a laboratory measurement, radiographic image,
physical sign or other measures, that is thought to predict
clinical benefit, but is not itself a measure of clinical benefit.

rares1geo@gmail.com
 708 P.G. Boelens et al.
The use of surrogate endpoints can considerably shorten the
time required to receive (preliminary) FDA approval. Drug
companies are still required to conduct studies to confirm
the anticipated clinical benefit. These studies are known as
phase 4 confirmatory trials. If the confirmatory trial shows
that the drug actually provides a clinical benefit, then the
FDA grants traditional approval for the drug. If the confir-
matory trial does not show that the drug provides clinical
benefit, FDA has regulatory procedures in place that could
lead to removing the drug from the market [37]. Studies on
surgical procedures are however generally not financed in a
similar fashion. The lack of funds can also have a negative
impact on the quality of the data. In financially supported
drug trials, other issues are encountered. The main question
to be answered is whether there is a reason for concern that
pharmaceutical companies sponsor clinical trials which may
introduce bias. Trial design might be optimised to gain regu-
latory approval, and staff may be selected who have a vested
interest in seeing a positive result. In addition there is increas-
ing concern about publication and citation bias with only tri-
als showing positive results being published, whereas negative
trial results are not published [34]. After a drug developing
period, in which the companies invest in the new drug, the
stakes are high to market newly designed drugs. Sponsorship
of clinical trials by corporate industries can be as high as
75%. Pharmaceutical companies fund a large amount of can-
cer research and run their own trials looking at drugs they
have developed [38].
Unfortunately, examples show that sponsors in the past
have delayed publications or even stopped publications of
unfavourable or negative outcomes. Moreover, the integrity
of multiple scientists has been questioned for their unfair
presentation of trial outcomes, even leading to withdrawal of
publications in high-end journals and termination of aca-
63 demic careers [39]. The money involved in certain
­industry-­financed projects can be huge. Conflict of interest
statements must declare these links to enable the scientific
community to be aware of potential bias.
Bias and errors in design and methodology should be
screened for in industry-sponsored research for an objective
representation of the study by journal reviewers, editors and
readers. Many issues may obscure the study outcomes such
as selection bias, inappropriate power calculation, sample
size congruence, reasonable follow-up times, use of (invali-
dated) surrogate endpoints or the choice of the control agent
or group. Selection can be detected by studying exclusion and
inclusion criteria to see whether the included patients form a
more favourable patient population, thereby contrasting with
the ‘real-world’ patient population, excluding older patients
and patients with comorbid diseases, or higher stages. In
breast cancer investigation, follow-up time is of utmost
importance to reveal true effects, and short follow-up times
might be inappropriate. This is especially true in low-grade
ER-positive breast cancer where outcomes such as local
recurrence or death from breast cancer may not occur for
well over a decade.
rares1geo@gmail.com
63.7  uality Assurance in Breast Cancer
Q
Care: The Role of National and
International Registries, Audits and
Quality Standards
Breast cancer is the leading cause of cancer-related death
among women [40]. Ensuring it is optimally treated is there-
fore of huge significance to female cancer mortality rates.
There is wide variation in outcomes across European mem-
ber states [41] due to differing rates of early diagnosis and
different treatment protocols, and it is important that breast
units have a systematic approach to critically reviewing the
quality of their service against local, national and interna-
tional standards. Service audits against these standards are an
essential part of understanding where improvements can be
made.
63.7.1 Guidance
There are a number of excellent quality standards and proto-
cols that may be audited against, and all breast surgeons
should be familiar with these. They include the St. Gallen
Consensus Guidelines, the European Society of Breast
Cancer Specialists (EUSOMA) and ESMO guidelines,
National Guidelines such as the Dutch Breast Cancer
Guidelines and the UK NICE guidelines. All of these are
regularly updates by expert panels who synthesise the latest
evidence in the field. It is also important that not only process
and practice is audited but also outcomes which should be
compared to national and international norms. Cancer inci-
dence and mortality outcomes are collected by a range of
national and international bodies. Internationally, the WHO
collates these and publishes these as the GLOBOCAN data.
Nationally, many European countries have mandatory
reporting of cancer incidence and mortality rates via a series
of cancer registries, many of which collect very detailed data
about treatment, stage and outcomes. These may be used to
undertake comparative audits between European countries.
One of the international quality assurance initiatives, devel-
oped under the wings of the European Society of Surgical
Oncology (ESSO) and the European Cancer Organisation
(ECCO), is EURECCA, which is the acronym of European
Registration of Cancer Care. EURECCA has a unique col-
laborative network of epidemiologists, patients and health-
care professionals.
63.8 Cancer Registries and Auditing
Registry of patient characteristics and therapeutic effects has
been recognised as an extremely valuable source of informa-
tion. Cancer registries have been collecting data for many
decades, and their disease surveillance has shown distinct
regional variations in breast cancer management and out-
comes [42, 43].
Research and Audit in Advancing the Quality of Breast Cancer Care
..      Fig. 63.2  Displays all patients receiving radiotherapy after breast-conserving surgery stratified to age groups, showing that the oldest
patients received less radiotherapy after breast-conserving surgery
Auditing is combining data collection with feedback on
performance to learn from best practice. In the last couple of
decades, auditing cancer performance has been shown to be
a powerful tool to improve regional and national healthcare
infrastructures, for example, in rectal cancer [44, 45].
EURECCA was founded in 2007 by Prof Cornelis van de
Velde, Professor of Surgical Oncology at Leiden University,
the Netherlands, and EURECCA started with a colorectal
working group. The main goals of EURECCA are to improve
cancer outcomes by harmonising cancer data collection, pro-
viding feedback and developing guidelines and educational
tools and sharing data across countries in prospective obser-
vational databases [46].
EURECCA Breast in collaboration with the European
Society of Breast Cancer Specialists (EUSOMA) aims to
improve and standardise the level of breast cancer patient
care throughout Europe. The aim of this collaborative study
rares1geo@gmail.com
709 63
was to assess age-specific compliance to the EUSOMA qual-
ity indicators (QIs) regarding treatment for patients across
Europe [47]. Twenty-seven consented EUSOMA certified
breast units from Austria, Belgium, Germany, Italy and
Switzerland participated, and a dataset of 41,871 patients
with a mean age of 59.6 years was available for analysis. The
primary outcome measure was compliance with EUSOMA
quality indicators (QIs) by age, selecting 13 QIs and using
multivariable logistic regression analysis. This exceptional
dataset demonstrated a low compliance to quality indicators
among the youngest (<40 years) and the oldest (⩾75 years)
patients (see example of one of the QIs in . Fig.  63.1).  
Younger women were treated more than the guidelines rec-
ommended, whilst older patients less than recommended
(see . Fig.  63.2 [47]). . Figure  63.1 shows the selection of
patients who underwent breast-conserving surgery per
breast unit. Of all patients in the dataset 88.6% underwent
 710 P.G. Boelens et al.
BCS, ranging from 72% to 97% between breast units.
. Figure  63.2 shows examples of radiotherapy offered to
 
patients undergoing breast-conserving therapy in the differ-
ent breast units.
63.9  he Older Breast Cancer Patients
T 63.10 Summary
in Observational Studies
EURECCA has a specific focus on older patients, which is a
challenging heterogeneous subgroup of patients due to their
wide variance in age, frailty and comorbidities. Forty per cent of
breast cancer occurs in women 65 years and older. Most studies
on therapeutic agents are selective in the inclusion of subjects
and more often exclude women over a certain age and/or those
with comorbidity. Irrespective of age, patients with breast can-
cer participating in trials had fewer comorbid diseases, smaller
tumours and a higher socioeconomic status in comparison to
unselected breast cancer patients from the Netherlands Cancer
Registry [35]. Moreover, overall mortality of patients aged
65 years and older was lower for patients in trials as compared
with patients of similar ages in the general population.
Taking into account that randomised controlled trials
(RCTs) tend to exclude older women, prediction tools like
Adjuvant! Online might lack validity to be used in medical
decision-making in the older subset of patients with breast
cancer. De Glas and colleagues entered data from the
population-­ based cohort of all consecutive patients aged
65  years and older with breast cancer (n  =  2012) into
Adjuvant! Online with average for age comorbid status or
individualised comorbid status. Primary outcome measures
were a 10-year overall survival and 10-year cumulative recur-
rence, defined as locoregional recurrence, distant recurrence
or contralateral breast cancer, in line with the definition of
63 Adjuvant! Online. Adjuvant! Online did not predict these
outcome measures accurately and is not representative of
unselected older breast cancer population [3, 48].
In an international comparison of population-based data
of older women with breast cancer, large differences in treat-
ment approach were found with more guideline adherence
on locoregional treatment in the Netherlands and more pre-
scription of systemic therapy in Ireland. Authors concluded
that their findings should be a strong recommendation to
perform more international studies, with the ultimate goal of
equalising survival rates for breast cancer patients across
Europe [49]. A EURECCA International comparison is ana-
lysing treatment strategies and relative survival in more than
120.000 patients aged 70 years and older with non-metastatic
breast cancer coming from the Netherlands, Belgium,
Ireland, Portugal, Poland and the UK. Preliminary data pre-
sented at the European Cancer Conference in Amsterdam
2015 showed huge variations of treatment approaches in
these age groups [50].
EURECCA Breast is planning to analyse data relating to
changing axillary surgical practice subsequent to the recent
groundbreaking Z11 [21] and AMAROS trials [12] and is
rares1geo@gmail.com
recruiting patients in a prospective database for patients
undergoing nipple-sparing mastectomies (INSPIRE), which
will hopefully finally put to rest concerns about the oncologi-
cal safety (or otherwise) of this technique.
The modern breast surgeon must keep up to date with the
rapidly changing evidence base supporting optimal breast
care to ensure patient outcomes maintain parity with the best
in Europe. This requires the modern breast surgeon to
develop critical appraisal skills so they may make their own
judgements about the quality of new evidence and whether
proposed changes in practice are justified. They must also
continually evaluate their outcomes against national and
European datasets to ensure they meet the highest standards,
and if they find they do not, they must be responsive and
change. Only in this way will they be able to ensure that they
are delivering the very best care in this rapidly evolving field
of cancer care.
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41. Thomson CS, Forman D. Cancer survival in England and the influ-
ence of early diagnosis: what can we learn from recent EUROCARE
results? Br J Cancer. 2009;101(Suppl 2):S102–9.
42. DeSantis CE, Bray F, Ferlay J, Lortet-Tieulent J, Anderson BO, Jemal
A.  International variation in female breast cancer incidence and
mortality rates. Cancer Epidemiol Biomark Prev. 2015;24(10):
1495–506.
43. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coe-
bergh JW, Comber H, et  al. Cancer incidence and mortality pat-
terns in Europe: estimates for 40 countries in 2012. Eur J Cancer.
2013;49(6):1374–403.
44. Breugom AJ, Boelens PG, van den Broek CB, Cervantes A, Van CE,
Schmoll HJ, et al. Quality assurance in the treatment of colorectal
cancer: the EURECCA initiative. Ann Oncol. 2014;25(8):1485–92.
45. Van GW, Van den Broek CB, Mroczkowski P, Dziki A, Romano G,
Pavalkis D, et al. The EURECCA project: data items scored by Euro-
pean colorectal cancer audit registries. Eur J Surg Oncol. 2012;38(6):
467–71.
46. Van GW, Van de Velde CJ. Improving quality of cancer care through
surgical audit. Eur J Surg Oncol. 2010;36(Suppl 1):S23–6.
47. Kiderlen M, Ponti A, Tomatis M, Boelens PG, Bastiaannet E, Wilson
R, et  al. Variations in compliance to quality indicators by age for
41,871 breast cancer patients across Europe: a European Soci-
ety of Breast Cancer Specialists database analysis. Eur J Cancer.
2015;51(10):1221–30.
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48. de Glas NA, van de Water W, Engelhardt EG, Bastiaannet E, de
Craen AJ, Kroep JR, et  al. Validity of adjuvant! Online program in
older patients with breast cancer: a population-based study. Lancet
Oncol. 2014;15(7):722–9.
49. Kiderlen M, Walsh PM, Bastiaannet E, Kelly MB, Audisio RA, Boelens
PG, et  al. Treatment strategies and survival of older breast cancer
patients  – an international comparison between the Netherlands
and Ireland. PLoS One. 2015;10(2):e0118074.
50. Derks M, Kiderlen M, Hilling D, Bastiaannet E, Boelens PG, Siesling S,
et al. Treatment patterns for older patients with non-metastatic breast
cancer in four European countries - preliminary data from a EURECCA
international comparison. Eur J Cancer. 2015;51:S297. Ref Type: Generic

63

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 713 X

Appendix
Contents

Chapter 64 MCQ Self-Test – 715

Lynda Wyld and Christos Markopoulos

rares1geo@gmail.com
 715 64

MCQ Self-Test
Lynda Wyld and Christos Markopoulos

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_64

rares1geo@gmail.com
 716 L. Wyld and C. Markopoulos
The European Board of Surgery Qualification (EBSQ)
Examination in Breast Surgery is organised by the UEMS-
EBS Division of Breast Surgery and consists of two parts: Part
A (written part) and Part B (oral part) (7 https://www.
 
uemssurg.org/divisions/breast-surgery/ebsq-examination). A
candidate has to «pass» both parts in order to be qualified for
the «EBSQ in Breast Surgery» Diploma. The written exami-
nation consists of 50 multiple choice questions. Each ques-
tion has five alternative answers, of which only one answer is
correct.
A series of 20 sample questions is shown below. The key
to the answers is on the following page for readers wanting
self-assessment.
1. A 64-year-old gentleman with bilateral diffuse non-
tender breast enlargement. Examination reveals grade 2
gynaecomastia bilaterally but no focal lump. Which of
the items below is not necessary for workup of this
patient?
a. Taking thorough history for drug intake
b. Clinical testicular examination
c. Measuring serum luteinising hormone, testosterone
and oestradiol levels
d. Measuring serum beta human chorionic gonadotro-
pin levels
e. Bilateral mammography
2. A 42-year-old lady with a 1 cm area of pleomorphic
lobular carcinoma in situ (PLCIS) identified from
screening on stereotaxic vacuum-assisted core biopsy.
What is the best next step for management?
a. Genetic counselling
b. MR imaging to rule out invasive cancer
c. Excisional biopsy with a clear margin
d. Unilateral mastectomy
e. Follow-up with yearly surveillance mammograms
and consideration of chemoprevention
64
3. According to the ACOSOG Z0011 trial, which one of
the criteria below is not appropriate for omitting
completion axillary dissection in sentinel lymph
node-positive patients who received breast-conserving
surgery (BCS)?
a. Having a tumour less than 5 cm
b. Having no palpable suspicious lymph node at
presentation
c. Having metastases in two sentinel lymph nodes
d. Not receiving whole breast radiation in addition to BCS
e. Having adjuvant systemic treatment
4. Which of the statements below is false regarding breast
cancer in male?
a. The risk appears to be higher in males with a BRCA2
rather than a BRCA1 gene mutation.
b. The median age of diagnosis is higher than for females.
c. Almost all male breast cancers are of ductal origin.
d. The majority are oestrogen receptor negative.
e. It has a similar stage distribution as female cancers.
rares1geo@gmail.com
5. Which one of the following statements about women
carriers of the BRCA1 gene mutation is incorrect?
a. Median age for the development of breast cancer is 42.
b. 65% of all breast cancers are triple-negative cancers.
c. Screening with annual MRIs should commence at the
age of 25–30.
d. HRT after bilateral risk-reducing salpingo-oophorec-
tomy is always contraindicated.
e. Risk of contralateral breast cancer after a first breast
cancer diagnosis is ~2% per year.
6. In women with breast pain, which one of the following
statements is ­correct?
a. First-line treatment is with a non-steroidal anti-
inflammatory gel and a well-fitting bra.
b. Cyclical breast pain has been proven to respond to oil
of evening primrose derivatives.
c. Postmenopausal breast tenderness is usually a sign of
underlying breast malignancy.
d. Women with cyclical breast tenderness should be
advised not to wear a bra.
e. Tamoxifen should be prescribed for women with
cyclical breast pain.
7. When comparing immediate and delayed breast
reconstruction, which of the following statements is
incorrect?
a. Patient reported cosmetic satisfaction is higher with
delayed reconstruction.
b. Objective cosmetic satisfaction is higher with
immediate reconstruction.
c. The majority of women having mastectomy have
immediate reconstruction.
d. Implant-based immediate reconstruction is higher
risk for implant loss and capsule formation if chest
wall radiotherapy is given.
e. Immediate skin-sparing mastectomy is not associated
with a significantly higher rate of local recurrence.
8. With regard to neoadjuvant chemotherapy in breast
cancer, which one of the following statements is correct?
a. It improves prognosis in all patients.
b. Works best in lobular cancers.
c. May make surgery easier.
d. Should not be used in inflammatory breast cancer.
e. Is not useful in triple-negative cancers.
9. You are planning a mastectomy for a 45 mm area of
high-grade DCIS. How do you manage the axilla?
a. There is no need for axillary staging as this is DCIS.
b. Sentinel node biopsy should be performed.
c. Frozen section of the lesion during surgery and
sentinel node biopsy if proof of invasive cancer is seen.
d. Axillary clearance should be offered due to the size
and grade of the DCIS.
e. No staging but a sentinel node biopsy be performed if
final histopathology shows invasive cancer.
MCQ Self-Test
10. A 13 mm screen-detected lesion, BIRAD 4, with a B4
core biopsy result is presented at your multidisciplinary
meeting. What is the optimal next step in management?
a. Fine needle aspiration biopsy
b. Repeat core needle biopsy
c. Wide local excision and sentinel node biopsy
d. Vacuum-assisted biopsy
e. Early screening recall at 6 months
11. Therapeutic mammoplasty is not an appropriate option
in which one of the following scenarios?
a. Moderate-sized tumour in a moderate-­sized breast
b. Following a complete imaging response to neoadju-
vant systemic therapy for a previously T3 tumour
c. Small tumour in a very large breast
d. Multifocal disease confined to a single quadrant
e. Recurrent cancer following previous wide local
excision and radiotherapy
12. Which one of the following epidemiological statements
is true?
a. High alcohol intake does not increase the risk of
developing breast cancer.
b. African-American/Afro-Caribbean women have a
worse breast cancer prognosis, when compared to
Caucasian women.
c. Asian women have a high incidence of developing
breast cancer.
d. Breast cancer survival is higher in women from
lower socio-economic classes.
e. Childbearing does not alter the lifetime risk of
developing breast cancer.
13. The aim of the MINDACT trial was to assess:
a. Survival among patients with high-risk clinical
features and a low-risk 70-gene-expression profile in
whom chemotherapy was avoided
b. Regional control in sentinel node-positive patients
in whom axillary radiotherapy versus axillary
dissection was performed
c. The use of chemotherapy in women with ER(+)
HER2(−) breast cancer with mid-range 21-gene
assay
d. Safety of sentinel node biopsy after neoadjuvant
chemotherapy
e. Dual anti-HER2 blockade
14. Which one of the following statements regarding
phyllode tumours is incorrect?
a. Frequently metastasise to the axillary lymph nodes;
hence, surgical axillary staging is necessary.
b. Wide local excision is preferred.
c. Local surgical excision with a tumour-free margin is
indicated.
d. Total mastectomy may be necessary if negative
margins cannot be obtained.
e. Can be benign, borderline or malignant.
rares1geo@gmail.com
717 64
15. What is red breast syndrome?
a. Clinical entity characterised by non-­infectious
erythema associated with the use of acellular dermal
matrix ADM
b. Inflammatory breast cancer
c. Paget’s disease
d. Fat transfer-associated complication
e. Infectious disease
16. A 32-year-old female presents with a palpable lump in the
right breast. The workup reveals a 15 mm unifocal breast
cancer. She underwent mantle radiotherapy aged 17 for
Hodgkin’s lymphoma. There is a breast cancer history in
the family, which affected her grandmother aged 65. The
most likely aetiology for this breast cancer is:
a. p53 gene.
b. PTEN gene.
c. CDH1 gene.
d. BRCA2 gene.
e. None of the above. The patient’s cancer is a result of
radiotherapy.
17. In adjuvant breast radiotherapy in elderly patients,
which one of the following statements is correct?
a. Improves overall survival in the good biology group
(hormone receptor positive).
b. Has been shown to improve local control of the disease.
c. Partial breast irradiation (PBI) is not suitable for
these patients.
d. Hypofractionated whole breast irradiation is not an
option for these patients.
e. The PRIME II trial found a sixfold increased rate of
5-year local recurrences if radiotherapy is omitted in
elderly women after breast conservation.
18. An absolute contraindication for breast-­conserving
surgery is:
a. Multifocality
b. Retro-areolar tumour
c. Tumour of the lower inner quadrant
d. Inflammatory breast cancer
e. Age over 80 years
19. Tomosynthesis of the breast is associated with:
a. Better detection of small masses
b. Lower detection of microcalcifications
c. Better detection of architectural distortion
d. Detection of deep lesions
e. Less exposure radiation than standard mammography
20. Based on the 2005 Early Breast Cancer Trialists’
meta-analysis, how many local recurrences need to be
avoided to avoid one breast cancer death?
a. One
b. Two
c. Three
d. Four
e. Five
 718 L. Wyld and C. Markopoulos

zz Answers
1. E
2. C
3. D
4. D
5. D
6. A
7. C
8. C
9. B
10. D
11. E
12. B
13. A
14. A
15. A
16. E
17. B
18. D
19. A
20. D

64

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 E1 

Erratum to: The Breast

and Oncoplastic
Multidisciplinary Team
Fiona MacNeill, Marios Konstantinos Tasoulis, Melissa Ley Hui Tan,
and Andreas Karakatsanis

Erratum to
L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-
3-319-56673-3_16

In the original version of chapter 16, the author Andreas Karakatsanis was missed.

The updated original online version for this chapter can be found at
­https://doi.org/10.1007/978-3-319-56673-3_16

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3_65

rares1geo@gmail.com
 719

Supplementary
Information
Index – 721

© Springer International Publishing AG 2018

L. Wyld et al. (eds.), Breast Cancer Management for Surgeons, https://doi.org/10.1007/978-3-319-56673-3

rares1geo@gmail.com
 721 A–B

Index

A
Ageing, changes associated with  530 –– neoadjuvant setting  299
Aggressive fibromatosis. See Desmoid –– with node-negative disease  292–293
­fibromatosis (DF) Axillary clearance (AC)  660
Abdominal advancement flap  384
AIs. See Aromatase inhibitors (AIs) –– history 286
Accelerated partial-breast irradiation
ALCL. See Anaplastic large cell lymphoma (ALCL) –– indications 286
(APBI)  472, 476
Alcohol risk  25 –– pathological analysis  289
Acellular dermal matrices (ADM)  316
–– consumption  37, 38 –– staging 286
–– delayed breast reconstruction (DBR)  326, 345,
Allergy 420 –– surgical technique  288–289
346
ALMANAC trial  280 Axillary dissection (AD)  256
–– Goldilocks procedure  397
ALND. See Axillary lymph node dissection (ALND) Axillary efferents  6
–– immediate breast reconstruction (IBR)  320
Amastia 13 Axillary lymph node (ALN)  464, 469, 470
–– implant-based reconstructions  370
Amenorrhoea, chemotherapy-induced  522, 525 Axillary lymph node dissection (ALND)  276,
–– Alloderm 369
American Cancer Society  60, 152 279–282, 286, 292–298, 304, 690
–– benefits of  369
American College of Medical Genetics and –– axillary reverse mapping (ARM)
–– complications 371
Genomics (ACMG)  44 –– lymphatics and nodes, identification  306
–– nipple-areola complex (NAC) reconstruc-
American Society of Clinical Oncology (ASCO) –– nodes involvement, patients with  307
tion 407
Clinical Practice Guideline  45, 286 –– lymphatic’s pathways  304
–– seromas 416
Amphiregulin 14 Axillary lymph nodes  6
–– wound complication  418
Analgesics  643, 644 Axillary metastases, preoperatively detec-
Achimedes’ law  692
Anaplastic large cell lymphoma (ALCL)  377, 562 tion 286
ACOSOG Z1071 study  293, 295
Anastrozole 122 Axillary reverse mapping (ARM)
Adenomatous polyposis  560
Androgens 14 –– crossover 306–307
ADH. See Atypical ductal hyperplasia (ADH)
Angiogenesis, inhibitor  448 –– lymphatics and nodes, identification  306
Adipose tissue  36
Angiosarcoma (AS)  477, 554, 555 –– lymphoedema rates, impact
Adiposity 35
–– diagnosis of  556 –– oncological safety  309, 311
Adjuvant breast radiotherapy  717, 718
–– secondary 555 –– upper extremity lymphoedema, incidence
Adjuvant chemotherapy  93–94, 535–536
Anterior intercostal artery perforator (ICAP) of 309
–– chemotherapy regimens  442–443
flap 386 –– metastatic involvement
–– p53 442–443
Anthracycline  440, 441, 448 –– neoadjuvant setting  309
–– TOPO2A 443
Antibiotic-lock therapy (ALT)  652–653 –– node location  305, 306
–– endocrine responsive breast cancer  440–441
Anti-HER2 agents  516 –– pathologically positive axilla  307
–– HER2 positive  441–442
APBI. See Accelerated partial-breast irradiation (APBI) –– patients with positive SLN and ALND  307
–– immediate breast reconstruction (IBR)  318
Apparent diffusion coefficient (ADC)  137–140 –– SLN-ARM nodes  307
–– luminal A tumours  441
Archimedes’ formula  336 Axillary staging, locally recurrent breast
–– luminal B tumours  441
Adriamycin 448 cancer 268
–– male breast cancer  546–547
ARM Axillary reverse mapping (ARM) Axillary surgery  398, 533–534
–– triple-negative breast cancer (TNBC)  442
Aromatase inhibitors (AIs)  84, 432, 650 Axillary web syndrome  653
Adjuvant Dynamic Marker-Adjusted Personalized
–– ovarian function suppression (OFS)  429
Therapy Trial (ADAPT)  456, 460

B
–– side effects  433
Adjuvant endocrine therapy  9, 27
–– vs. tamoxifen  433, 434
–– algorithm 435
–– treatment 432
–– estrogen receptors  428 Background parenchymal enhancement
Arzoxifene 82
–– menopause, definition of  428 (BPE) 137
Ataxia telangiectasia mutated (ATM)  50
–– postmenopausal women Baker scale  360
Atypical ductal hyperplasia (ADH)  104, 118
–– AIs, side effects of  433 Basal subtypes  187–188
–– histology 106–107
–– tamoxifen 432–434 Base excision repair (BER)  504
–– significance 107
–– premenopausal women Batwing mastopexy  233–236
Atypical lobular hyperplasia (ALH)  107
–– ovarian function suppression (OFS)  428– Batwing technique  233
Auditing 709
432 BCP. See Breast cancer during pregnancy (BCP)
Autologous fat grafting (FG)  374
–– tamoxifen 428–430 BCS. See Breast conserving surgery (BCS)
–– DBR, 336, 340, 345
Adjuvant HER2 blockade  449–450 BCT. See Breast-conserving therapy (BCT)
–– history of  246
Adjuvant hormonal therapy  535, 547 Benign lesions  130, 134, 137
Autologous grafts  407
Adjuvant Lapatinib and/or Trastuzumab Benign phyllodes tumors  554
Autologous reconstruction  74
Treatment Optimisation (ALTTO) Trial  457 Berg’s classification  6
Autologous tissue reconstruction  382
Adjuvant paclitaxel and trastuzumab trial Bi-allelic mutations  50
Automated breast ultrasound system
(APT) 451 Biannual mammograms  154
(ABUS) 64, 134
Adjuvant radiotherapy  298, 319–320, 327, 330, Bias  706, 707
Axilla
340, 468–470, 537 Bilateral oophorectomy  428
–– anatomy 287
Adjuvant systemic treatment  491–494 Bilateral salpingectomy with ovarian retention
–– evaluation of  135–136
Adjuvant therapy  448, 574–575 (BSOR) 75
–– management
Adjuvant VEGF/HER2 inhibition  450 Bilateral salpingo-oophorectomy (BSO)  71,
–– with initial node-positive disease  293
ADM. See Acellular dermal matrices (ADM) 74–75, 504
–– isolated tumour cells  295–296
Adriamycin 454 Biofouling 360
–– male breast cancer  546
African-American/Afro-Caribbean women, breast Bioimpedance spectrometry (BIS)  692
–– micrometastases 295–296
cancer  717, 718 Biomarkers 459

rares1geo@gmail.com
 722 Index

Biopsy(ies) –– whole brain radiotherapy  607–608 –– punch biopsy  167

–– DCIS 117–118 BRCA1/BRCA2-associated breast cancer  48, 51, –– radiologists and pathologists  179–180
–– diagnostics, difficulties of  180 60–64, 70, 71, 178, 500, 716, 718 –– staging  167–174, 182–183
BIRAD 4  717, 718 –– mutation-associated, systemic treat- –– ultrasound 165–166
Birth control and fertility  494 ment 504–505 –– WHO classification  185
Bisphosphonates 643–644 –– mutation carriers  256 Breast Cancer Detection Demonstration Project
BMD. See Bone mineral density (BMD) –– risk-reducing bilateral mastectomy in (BCDDP) 51
Bone cement (polymethyl methacrylate)  597 healthy women  502–503 Breast cancer during pregnancy (BCP)  512
Bone health –– surgical approach to BC in BRCA carri- –– anti-HER2 agents  516
–– BMD loss  674, 675 ers 503 –– chemotherapy 515–516
–– bone-directed therapy –– PARP inhibitors in  505 –– diagnosis and staging  513–514
–– bisphosphonates 676 –– platinum analogues as therapy in  505–507 –– endocrine therapy  516
–– denosumab 676 –– risk-reducing strategies for  501–502 –– long-term outcomes of children  517–518
–– side effects  676 BRCAPro model  51 –– management algorithm  512
–– bone turnover markers (BTMs)  675 Breast –– obstetric care  517–518
–– DEXA scans  675 –– anterior chest wall  5 –– radiotherapy 514–515
–– diet 677 –– axilla  6, 7 –– supportive care  516–517
–– FRAX assessment tool  674 –– blood supply  3–4 –– surgical management  514
–– management of  677, 678 –– development Breast Cancer Index  93, 95
–– osteoporosis 674 –– adult 14–16 Breast cancer-related lymphedema (BRCL).
–– in postmenopausal women  675 –– congenital anomalies  13 See Lymphedema
–– in premenopausal women  675 –– infant 13–14 Breast conserving surgery (BCS)  117, 120, 121,
–– tamoxifen 675 –– peripubertal 14 204, 215, 256, 464–468, 533, 628, 716–718
–– TIBL (see Treatment-induced bone loss (TIBL)) –– post menopausal  16 –– checklist for planning of  215
–– zoledronic acid  677 –– prenatal 12–13 –– contour defects after  247
Bone marrow suppression  654 –– epithelium 14 –– ipsilateral breast tumour recurrence
Bone metastases  162, 641 –– fascial and ligamentous structure  2–3 after 264–267
–– anaesthetic assessment  600–601 –– innervation 4 –– local recurrence after  215
–– biopsy 597 –– lesions 130 –– margins 223–224
–– bone-directed therapy  588 –– lymphatic drainage  5–7 –– MRI in patient selection for  217
–– clinical presentation  596 –– nerve supply  4 –– neoadjuvant systemic treatment  218–219
–– description 596 –– progenitor cells  12 –– oncoplastics 218
–– incidence 596 –– reconstruction –– patient selection  709
–– Mirels’ scoring system  596 –– autologous 74 –– previous breast surgery  217
–– pathological fracture treatment –– implant based  74 –– radiotherapy  217, 709, 710
–– amputation 597 –– superficial fascia  2 –– rates 230
–– bone cement  597 Breast and Ovarian Analysis of Disease Incidence –– technical considerations in  219–220
–– endoprosthetic/modular surgery  599 and Carrier Estimation Algorithm (BOADICEA) Breast-conserving therapy (BCT)  464, 466
–– long bones  598–599 model 51 Breast density  63, 128–129
–– pelvis and acetabulum  598 Breast angiosarcoma, radiation-induced  555, Breast Imaging Reporting and Data System
–– proximal femur  598 557 (BI-RADS®)  128, 141, 142
–– spine 599–600 Breast cancer  428 Breast-implant-associated anaplastic large cell
–– upper limb  599 –– aetiology  717, 718 lymphoma (BIA-ALCL)  358–359
–– radioisotopes 588 –– biopsies 166–167 Breast implants
–– standards of care  597 –– care (see Cancer care) –– capsule formation  360–362
Bone mineral density (BMD)  535, 674, 675 –– clinical examination  163 –– complications 359–360
Bone turnover markers (BTMs)  675 –– common clinical manifestations  160–161 –– composition 356
Boomerang flap  346 –– core biopsy  167 –– history of  356
Boost RT  467 –– diagnosis  163–167, 179 –– safety issues
Brachioplasty 694 –– ductoscopy 167 –– BIA-ALCL 358–359
Brachytherapy 267 –– early imaging  164–166 –– PIP implants  359
Brain metastases  162, 643 –– excision biopsy  167 –– systemic disease  358
–– decision model  610, 611 –– galactography 167 –– shapes 357
–– evidence 609 –– history of presenting complaint  163 –– surface 357
–– incidence 604 –– incisional biopsy  167 –– tissue expanders  356
–– neurosurgical treatment benefits  608 –– inspection 163 –– use, indications for  362
–– pathology 604–606 –– mammography 164–165 Breast irradiation, for locally recurrent breast
–– screening 606 –– medical history  163 cancer 267
–– stereotactic radiosurgery  609–610 –– micro-and macrobiopsies  179 Breast lesion excision system (BLES, Intact®)  142
–– surgical excision  608–609 –– molecular biology assays  187–189 Breast mass  160–161
–– symptoms –– molecular/intrinsic subtypes  187–188 Breast multidisciplinary team  196–197
–– focal symptoms and signs  606 –– MRI 166 Breast pain, first-line treatment  716, 718
–– headache 606–607 –– multigene signatures  188–189 Breast parenchyma  222
–– seizures 606 –– palpation 163–164 Breast reconstruction (BR)  716, 718
–– treatment approaches –– pathology input  179 –– bilateral reconstruction  389–390
–– definitive therapy  607 –– physical examination  163–164 –– DBR (see Delayed breast reconstruction (DBR))
–– medical 607 –– proliferation 186 –– decision making  382, 383

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Index
723 B–C
–– implant-based reconstructions (see Implant- –– nipple necrosis  418–419 –– non-oestrogenic pathways
based reconstructions) –– oncoplastic conserving surgery flaps  418– –– Cox-2 inhibitors  85
–– lipomodelling with  247 419 –– EGFR-directed therapies  85
–– local transposition flaps –– PE 419 –– metformin 85
–– abdominal advancement flap  384 –– postoperative 412–413 –– PARP inhibitors  85
–– thoracodorsal transposition flap  384 –– scar tissue formation  412 –– retinoids 85
–– microvascular flaps (see Microvascular flaps) –– seroma  416, 417 –– risk level for  83
–– pedicled and local flaps  383–384 –– shoulder, range of motion and cord- –– risk stratification techniques  84
–– pedicled perforator flaps ing 416–417 –– SERMs
–– AICAP flap  386 –– skin flora, contamination with  412 –– arzoxifene 82
–– LICAP flap  386 –– surgical infections  414 –– lasofoxifene 82
–– TDAP flap  386 –– tissue fluid accumulation  412 –– raloxifene 82
–– types  384, 385 –– vessel injury  412 –– tamoxifen 81–82
–– and radiotherapy  477–478 –– wound dehiscence  417–418 Chemotherapy
–– surgical complication  419 –– complications after neoadjuvant chemo- –– anti-emetic therapy  654–655
Breast sarcomas  552 therapy (NACT)  260 –– breast cancer during pregnancy (BCP)  515–
–– clinical outcomes  552 –– development of  260 516
–– clinical presentation and diagnosis  552 Breast surgical specimen, inking  180 –– early breast cancer  493–494
–– phyllodes tumors  552–554 Breast symmetry  218 –– febrile neutropenia  654
–– primary 554–555 British Association of Surgical Oncology –– induced amenorrhoea  522, 525
–– radiation-induced sarcoma  555–557 (BASO)  121, 596 –– ovarian suppression with GnRH agonists
–– treatment 552 British Orthopaedic Association (BOA)  596 during chemotherapy  523–525
Breast screening British Orthopaedic Oncology Society Chemotherapy-induced neutropenia (CIN)  654
–– costs 150 (BOOS) 596 Chest wall
–– early stage Bruising 249 –– muscles of  7
–– detection 148 BSO. See Bilateral salpingo-oophorectomy (BSO) –– radiation therapy to  468–469
–– test 149 Childhood abuse  667–668

C
–– treatment 148 Chronic inflammation  36
–– in Europe  154 Claus model  51
–– evidence 152 Clavien-Dindo classification  413
Caffeine 38
–– health service provision  149 Clinical breast examination (CBE)  60, 62, 150
Cancer and Leukaemia Group B (CALGB) trial  536
–– mammography Clinical nurse specialist (CNS)
Cancer care
–– age range of  153–154 –– in breast care  682, 683
–– auditing 709
–– overdiagnosis 152–153 –– Cassandra data set  683
–– case reports  706
–– modalities 150–152 –– clinical domains  683–684
Cancer detection rate  61
–– natural history of breast cancer  148 –– cost-benefits 684
Cancer Genome Atlas  45
–– principles 148–150 –– decision-making 684
Cancer stem cells (CSCs)  634
–– programmes 154 –– patient care  682, 683
Cancer susceptibility genes  489
–– risks 149–150 –– role  682, 683
Cancer treatment-induced nausea and vomiting
–– surgical considerations  154–155 Columnar cell lesions  104
(CTINV) 654–655
Breast self examination (BSE)  150–152 Complex oncoplastic surgery  218
Caprini risk score  651
Breast surgery Composite nipple graft  408
Carbon dye injection  221
–– after PST Comprehensive geriatric assessment (CGA)  531
Cardiac toxicity  474, 530
–– diagnostic implications  256 CONCORD data  25
Caregivers 686
–– interdisciplinary cooperation  256 Congenital anomalies  13
Catalogue Of Somatic Mutations In Cancer
–– pathologic evaluation  260 Connective tissue disease  465
(COSMIC) 45
–– radiotherapy 260 Conservative mastectomies
Catheter-related bloodstream infections
–– in suspected BRCA carriers  256 –– incisions  206, 207
(CRBSI) 652–653
–– therapeutic implications of  256 –– marking 206
Cavalieri formula  336
–– timing of  260 –– oncological safety  206–209
Cavity marking  232
–– complications –– technique 206
CDH1 germline mutations  49
–– allergy 420 Constitutional mutation  44, 46–47
Central adiposity  35–36
–– bleeding 413–414 Consultant nurse  685–686
Central venous catheter (CVC)
–– breast reconstruction  419 Contralateral reduction mastopexy  340
–– complications 652
–– Clavien-Dindo system  413 Contralateral risk-reducing mastectomy
–– CRBSI 652–653
–– delayed wound healing  417–418 (CRRM)  70, 71, 75
–– extravasation 653
–– DVT 419 Contralateral symmetrisation surgery  366
–– longer use  652
–– elongated fibrous cords formation  417 Contrast-enhanced spectral mammography
–– short-term use  652
–– haematoma 413–414 (CESM) 132
CGA. See comprehensive geriatric assessment (CGA)
–– lymphatic flow, disruption of  412 Cooper’s ligaments  4
CHEK2 mutation  50, 542
–– lymphoedema and associated infec- Copy number variations (CNVs)  44
Chemo brain  495
tions 418 Cording 653
Chemoprevention
–– mastectomy skin flaps, necrosis of  418–419 Core needle biopsy  118, 142
–– agents 81
–– medications, reaction to  420 Coronary heart disease (CHD)  82
–– aromatase inhibitors  84
–– muscle weakness  414–416 COSMIC 45
–– indications 84
–– nerve damage  412 Cowden syndrome (CS)  49, 498
–– induced premature menopause  80–81
–– neuropathic pain  414–416 Cox-2 inhibitors  85

rares1geo@gmail.com
 724 Index

Cross-sex hormonal treatment  34 Delayed-immediate breast reconstruction –– recurrence

CV flap  403, 406 (D-IBR)  327, 345 –– clinical factors  123
Cyclophosphamide, methotrexate and –– oncological considerations  327, 329–331 –– future perspectives  124
5-fluorouracil (CMF)  440, 441 Delayed wound healing  417–418 –– pathology factors  123
Cysts 134 Denosumab  676, 677 –– prognostic scores  123–124
Cytotoxic chemotherapy  675 Dermal flap  395–399 –– survival 124
Cytotoxic regimens  454 Dermal sling technique  371–373 –– surgery 120
Dermatofibrosarcoma protuberans (DFSP)  –– treatment 119

D
554–555 Ductoscopy 167
Desmoid fibromatosis (DF)  560 DVT. See Deep vein thrombosis (DVT)
–– histopathological (biopsy) assessment  561 Dyspnoea 644
DBCG 82c trial  469
–– management
DCIS. See Ductal carcinoma in situ (DCIS)

E
–– natural history/active observation  561
Decongestive lymphatic therapy (DLT)  693
–– nonoperative treatment  562
Deep inferior epigastric perforator (DIEP)
–– strategy 561
flap  327, 335, 346, 352, 386–388, 413, 416, Early breast cancer  464, 465, 468–471
–– surgery 561–562
419 –– adjuvant systemic treatments  491–494
–– MRI imaging  560
De-epithelialised dermal flaps –– biology 488
–– radiological assessment  560–561
–– implant breast reconstruction surgery  397 –– chemotherapy 493–494
Desmoid tumors  555. See also Desmoid
–– in plastic surgery  396 –– diagnostic procedures, staging and
fibromatosis (DF)
Deep vein thrombosis (DVT)  419, 650 follow-up 489–490
DF. See Desmoid fibromatosis (DF)
De-escalating regimens  450–451 –– endocrine therapy  491–493
D-IBR. See Delayed-immediate breast reconstruc-
Delayed breast reconstruction (DBR) –– epidemiology 488
tion (D-IBR)
–– autologous flap  346–349, 383 –– genetic predisposition and testing  488–489
DIEP flap. See Deep inferior epigastric perforator
–– contralateral symmetrization surgery  349 –– neoadjuvant treatment  490
(DIEP) flap
–– delayed-immediate breast reconstruction –– psychosocial issues  495
Diet  24, 251
(D-IBR), oncological considerations  327, –– radiotherapy 491
–– alcohol consumption  37
329–331 –– surgery 490–491
–– caffeine 38
–– disadvantages 326 –– targeted therapy  494
–– food items  37
–– flap donor site  351–352 Early Breast Cancer Trialist, meta-analysis  717
–– macronutrients 37
–– free-flap complication  350 Early Breast Cancer Trialists’ Collaborative Group
–– micronutrients 37
–– high satisfaction rates  351 (EBCTCG)  448, 465, 466
–– non-alcoholic beverages  38
–– vs. IBR  326 Eastern Cooperative Oncology Group (ECOG)  97,
–– patterns 37
–– implant-related complications  349–350 637
Diffusion-weighted sequence (DWI)  137
–– multiple-step approach  327 E-cadherin  107, 109
Digital breast tomosynthesis (DBT)  63, 132, 151
–– pain management  350 Electrocautery 74
Digital mammographic imaging screening trial
–– partial mastectomy defects  345 Embryo cryopreservation  523, 525
(DMIST) 63
–– patient-related factors  330–336 Emotional abuse  667
Disease-free survival (DFS)  264, 268, 271
–– post-discharge complications  350 Endocrine therapy (ET)  122, 448, 674
Distant metastatic disease  547
–– psychological support  351 –– breast cancer during pregnancy  514
DNA damage  44, 45, 47, 48, 50
–– radiotherapy 327 –– early breast cancer  491–493
Doughnut mastopexy  234, 236
–– reoperation rates  349 –– metastatic breast cancer  584
Downstaging 292
–– risk profiles  349 –– primary 536–537
Dual energy x-ray absorptiometry (DEXA)
–– secondary reconstructive procedures  349 Endogenous oestrogens  32
scans 674
–– technical assessment EndoPredict® (EP)  93, 189
Ductal carcinoma in situ (DCIS)  60, 62, 63, 105,
–– allogenic volume replacement  340 EndoPredict® clinical score (EP Clin)  189
116, 138, 148, 152–153, 186, 544
–– autologous pedicled flaps  336, 338 Epidemiology
–– diagnosis
–– BCS 336 –– alcohol 25
–– biopsy 117–118
–– breast size and initial parenchyma –– diet 24
–– mammogram 116–117
defect 340–343 –– exogenous hormones  23
–– MRI 117
–– breast volume, percentage of  339 –– intervention strategies  27
–– ultrasound 117
–– cut-off values  338 –– obesity 24–25
–– differential diagnosis  118–119
–– final shape and volume  336 –– physical activity  24
–– endocrine therapy  122
–– free flap  336, 338 –– prevention 25
–– epidemiology 116
–– glandular flaps  340 –– risk factors  21–23
–– high-grade  118, 119
–– LD flap transfer  340 –– smoking 25
–– intermediate grade  119
–– local flap  340 –– survival
–– lymph nodes  121
–– mastectomy and SLNB  335, 337 –– developing countries  25, 27
–– margins 121
–– mastopexy techniques  340 –– patterns over time  27
–– natural history  116
–– postoperative 340 –– rate 62–63
–– neoadjuvant-targeted therapy  122–123
–– preoperative 340 –– western countries  25
–– overdiagnosis 120
–– radiation-damaged skin  335 Epidermal growth factor receptor (EGFR)  85
–– overtreatment 120
–– scar tissue  335 ERs. See Estrogen receptor (ER)
–– pathology 118
–– tools and software  338 Erythema 477
–– radiation 121–122
Delayed-delayed breast reconstruction ESO-ESMO consensus guidelines  620
–– receptor status  119
(D-DBR) 345 Estrogen receptor (ER)  119, 428, 440

rares1geo@gmail.com
Index
725 C–H
ET. See Endocrine therapy (ET) Free transverse myocutaneous rectus abdominis Hereditary breast cancers
Ethinyloestradiol  33, 34 myocutaneous (TRAM) flap  387, 388 –– DNA sequence alterations  44–45
EURECCA  708, 709 Full-field digital mammography (FFDM)  151 –– gene panel testing  52–53
EUROCARE data  25 –– gene sequencing technologies  51–52
European Board of Surgery Qualification (EBSQ)
examination 716 G –– genetic testing  500–501
–– high penetrance genes
European Cancer Observatory (EUCAN)  20, 25 Gadolinium contrast media  136 –– BRCA1 48
European Organisation for Research and Gail model  51 –– BRCA2 48
Treatment of Cancer (EORTC)  466 Galactography 167 –– CDH1 49
European School of Oncology (ESO)  620 Gardner syndrome  555, 560 –– PTEN 49
European Society for Medical Oncology (ESMO)  620 Gene expression (GE) analysis  187 –– STK11 49
European Society of Breast Cancer Specialists Gene panel testing  52–53 –– TP53 49
(EUSOMA)  708, 709 Genetic testing, hereditary breast cancer  500–501 –– immunophenotype 501
European Union Commission project Horizon Genome-wide association studies (GWAS)  44, 47 –– low penetrance alleles  50
2020 27 Genomic hybridization array (CGH)  501 –– moderate penetrance mutations
EUSOMA recommendations  64 German Consortium of Hereditary Breast and –– ATM 50
Exemestane 84 Ovarian Cancer (GC-HBOC)  61, 63, 64 –– CHEK2 50
Exogenous hormone administration Glands of Montgomery  4 –– PALB2 50
–– feminizing therapy  34–35 Global Burden of Cancer Study (GLOBOCAN)  20, 25 –– oncogenesis
–– HRT 34 Gluteal flaps –– constitutional mutations  46–47
–– oral contraceptive (OC)  33 –– I-Gap 389 –– mechanisms 44
–– ovarian-stimulating agents  33–34 –– S-Gap 389 –– somatic mutations  45–46
Extraskeletal osteosarcoma  554 Glycoprotein E-cadherin  49 –– risk prediction  50–51
Goldilocks procedure –– susceptibility 47–48

F –– advantages 395 High-familial-risk women

–– aesthetic outcomes  399 –– breast MRI
–– autologous breast reconstruction tech- –– cancer detection rate  60–62
False-negative rate (FNR)  292–298
nique 400 –– interval cancer rates  62
Fat grafting
–– complications 399 –– mortality rate  62–63
–– autologous 246
–– contraindication 397 –– sensitivity 60–62
–– complications 249–250
–– costs 400 –– specificity 60–62
–– indications 246
–– de-epithelialised dermal flaps –– survival rate  62–63
–– Informed consent  250
–– implant breast reconstruction surgery  397 –– EUSOMA recommendations  64
–– lipomodelling (see Lipomodelling)
–– in plastic surgery  396 –– future perspectives  64–65
–– preoperative assessment  250–251
–– disadvantages 395 –– mammography 63
–– radiotherapy 251
–– flap vascularity  399 –– pregnancy and lactation  64
–– technique 250–252
–– history of  395 –– ultrasound 63–64
Febrile neutropenia  654
–– indications 397 High risk breast lesions
Feminizing therapy  34–35
–– intraoperative  395, 396 –– atypical ductal hyperplasia (ADH) 
Fertility
–– NAC preservation  398 106–107
–– and birth control  494
–– patient selection  397 –– flat epithelial atypia (FEA)  105
–– breast cancer on, impact of  522
–– postmastectomy imaging  400 –– intraductal papilloma  111
–– preservation
–– post-operative  395, 396 –– lobular neoplasia  107–109
–– strategies and outcomes  523, 524
–– preoperative 395 –– management 112–113
–– techniques 522–525
–– radiotherapy 399 –– radial scars  110
18F-FDG-positive lymph node  298
–– second-stage surgeries  399 Histopathological (microscopic) analysis  178
FFPE. See Formalin-fixed paraffin-embedded (FFPE)
–– surgery 398–399 Holmström’s flap  384
FG. See Autologous fat grafting (FG)
–– symmetrising surgery  399 Homologous recombination (HR)  504
Fibroglandular tissue  128
–– wise pattern marking  396, 398 Horizon 2020  27
Fibromatosis 555
Gonadotropin-releasing hormone (GnRH) Hormone receptor  184
Fibrous septum  5
agonists  80, 523–525 Hormone replacement therapy (HRT)  23, 34
Fine needle aspiration (FNA)  117, 166
Grade 2 gynaecomastia  716, 718 Human epidermal growth factor receptor type 2
Fine needle aspiration biopsy (FNAB)  135, 142
Guideline concordant care (GCC)  119 (HER2)  90–93, 441–442, 449, 585
Flap vascularity  399
Guidewire 220 –– blockade
Flat epithelial atypia (FEA)  104
Gynecomastia 13 –– concurrent/sequential 449
–– histology 105
–– dual adjuvant, role of  449–450
–– significance 105

H
–– extended, role of  450
Fluconazole 652
–– HER2-enriched subtype  188
5-Fluorouracil, epirubicin and cyclophosphamide
–– HER2-negative breast cancer  458–459
(FEC) 449 Haematoma 413–414
–– HER2-positive breast cancer  457–458
Formalin-fixed paraffin-embedded (FFPE)  90–93 Health economics (HE) analysis  96
–– pCR rates of  457
Frailty 530 Health Insurance Plan  152
–– status  184, 185
FRAX assessment tool  674 Heparin-induced thrombocytopenia (HIT)  651
–– tumours  efficacy in small  451
Free flap reconstructions. See Autologous Hepatectomy 614
Hyperthermia 556
reconstruction HER2. See Human epidermal growth factor
Hypofractionation  464, 472
Free nipple grafting  209–210 receptor type 2 (HER2)

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 726 Index

I –– mammography 569
–– management 626–627
Lateral intercostal artery perforator (LICAP)
flap  384, 386
IBCSG SOFT trials  491–493 –– vs. non-IBC  570 Latissimus dorsi (LD) flap  383–384
IBR. See Immediate breast reconstruction (IBR) –– prognosis 571 Latissimus dorsi muscle flap (LDm)  340, 346
IHC4 assay  93 –– radiotherapy 572 Latissimus dorsi myocutaneous (LDmc) flap  337,
IMAP flap. See Internal mammary perforator –– surgery 571–572 340, 346
(IMAP) flap Inframammary fold (IMF)  326, 386, 397–399 LICAP flap. See Lateral intercostal artery
Immediate breast reconstruction (IBR) Inking surgical specimen  180 perforator (LICAP) flap
–– adjuvant chemotherapy  318 Insomnia 643 Li-Fraumeni syndrome (LFS)  49, 465, 489, 500
–– aesthetic outcome  321 Instrumental variable  706 Lipomodelling
–– and DBR  326, 330, 335, 346, 349 Insulin  35, 36 –– after extended latissimus dorsi reconstruc-
–– decision algorithms Insulin-like growth factor-I (IGF-I)  36 tion 247
–– large and ptotic breasts  322 Intensity-modulated radiotherapy (IMRT)  470 –– breast reconstruction with  248, 249
–– minimal/no ptosis  322 Intercostal artery perforators  3–5 –– in conjunction with implant-based
–– small-and medium-sized breast  322 Internal mammary nodes (IMNs)  469 reconstruction 248
–– history of  316 Internal mammary perforator (IMAP) flap  384, 386 –– indications 247–249
–– indication 316–317 International Agency for Research on Cancer Liposuction 694
–– neoadjuvant chemotherapy  318 (IARC) 152 Liver metastases  172, 173, 642
–– QoL 320–321 Internationally normalised ratio (INR)  413 –– case-matched control study  615
–– radiotherapy 319–320 Interstitial brachytherapy  267 –– description 616
–– surgical and oncological safety  317–318 Interventional techniques  141–143 –– radioembolisation 616–617
Immunohistochemical markers  440 –– imaging guidance  141–142 –– resection 614–616
Immunophenotype, hereditary breast –– tissue biopsy  141 –– stereotactic body radiation therapy  617
­cancer  501 Intracytoplasmic vacuoles  107, 108 LMWH. See Low molecular weight heparin (LMWH)
IMPACT trial  456 Intraductal papilloma Lobular carcinoma in situ (LCIS)  107, 108
Impalpable tumour localization  220–222 –– histology 111–112 –– histology 107
Implant-based reconstructions –– significance 112 –– necrosis 109
–– ALCL 377 Intraoperative margin assessment  224 –– pleomorphic  107, 109
–– complication Intraoperative radiotherapy (IORT)  472, 473 –– significance of  109
–– implant loss, risk factors of  374–375 Intraoperative ultrasound (IOUS)  221, 222 Locally advanced breast cancer (LABC)  160–161,
–– infection 375 Intratumoural heterogeneity  45 345, 568
–– radiotherapy, impact on  375–376 Intrinsic breast cancer, classification  187 –– adjuvant therapy  574–575
–– skin necrosis  375 Invasive breast cancer –– algorithm 571
–– delayed approach  373–374 –– gross examination  180–181 –– axillary surgery  629
–– local recurrence –– identification 180 –– clinical presentation  568
–– risk of  376 –– microscopic findings  181–187 –– clinical response  574
–– surveillance of  376–377 –– no special type  185 –– conserving surgery vs. mastectomy  628
–– one stage  366 –– pathology report  187 –– CT and MR images  569, 570
–– patient selection and preoperative counsel- Invasive disease-free survival (IDFS)  449 –– definition 626
ling Invasive lobular cancer  178 –– epidemiology 569
–– breast size  366 Involution 15 –– HER2-positive 573–574
–– contralateral symmetrisation surgery  366 Ipsilateral breast tumour recurrence (IBTR) –– histopathology 570
–– one-stage vs. two-stage reconstruc- –– after conservative breast surgery  264, 265 –– luminal/HER2-negative tumours  573
tion 366–367 –– after mastectomy  264–267 –– management 626–627
–– ptosis degree of 366 –– reconstructive surgery for  267–268 –– mastectomy 627–628
–– revision surgery  366 Ischaemic necrosis  419 –– prognostic factor  570
–– risk factors  366 –– radiotherapy 572

J
–– unilateral procedures  366 –– risk factors  569
–– sub-muscular technique –– surgery 571–572
–– dermal sling  371–373 –– systemic neoadjuvant treatment  572
Japanese Clinical Oncology Group (JCOG
–– lower pole sling technique  369–371 –– treatment options  571
1017) 637
–– partial sub-muscular technique  368–369 –– treatment results  629
–– triple-negative 572–573
K
–– pre-pectoral/subcutaneous implant
placement  373, 374 –– tumour-node-metastasis stage  626
–– total sub-muscular technique  368 Locally advanced disease  547
Kaplan-Meier survival curves  188 Locally recurrent breast cancer
–– systemic recurrence, risk of  376
Khorana score  650 –– axillary staging  268, 270
–– two stage  366
Klinefelter’s syndrome  543 –– breast irradiation for  267
Imprint cytology  280
Knudson’s model  47 –– indications to systemic therapy  268, 270–271
IMRT. See Intensity-modulated radiotherapy (IMRT)
Independent Cancer Taskforce  687 –– prognosis 264
Indocyanine green (ICG)  305–307
–– lymphography 693
L –– surgery for  267
Loco-regional radiation therapy  469–470
Infection 375 LABC. See Locally advanced breast cancer (LABC) Loco-regional recurrence (LRR)  162, 468
Inflammatory breast cancer (IBC)  161, 179, 330, Lactation  15, 64 Locoregional therapy (LRT)  634
568, 627 Lactiferous ducts  2 Lower abdominal flaps
–– clinical presentation  569 Lapatinib  450, 516 –– DIEP flap  387–388
–– diagnosis 570 Lasofoxifene 82 –– free TRAM flap  387

rares1geo@gmail.com
Index
–– pedicled TRAM flaps  387
–– SIEA 387–388
Lower pole sling technique
–– ADMs 370
–– Alloderm 369
–– benefits of  369
–– complications 371
–– alternative materials  371
Low molecular weight heparin (LMWH)  413,
419, 651
Luer lock syringes  251
Lumbar artery perforator flap  389
Luminal subtypes  187
Lumpectomy 219
Lung metastasectomy. See Pulmonary
­metastasectomy
Lung metastases  162. See also Pulmonary
­metastases
Lung toxicity  476
Luteinizing hormone-releasing hormone
(LHRH) 428
Lymphatic drainage  5–7
Lymphatico-lymphatic bypass  695
Lymphatico-venous anastomosis (LVA)  694–695
Lymphatic’s pathways  304
Lymphedema  477, 690
–– arm volume measurements  692
–– bioimpedance spectrometry  692
–– brachioplasty 694
–– conservative treatment
–– decongestive lymphatic therapy  693
–– elastic compression garments  693
–– flexibility exercises  693
–– indocyanine green (ICG) lymphography  693
–– liposuction 694
–– lymphatico-lymphatic bypass  695
–– lymphatico-venous anastomosis  694–695
–– lymph node transfer  696
–– lymphoscintigraphy 692
–– magnetic resonance lymphangiogram  692
–– pathophysiology 690
–– perometry 692
–– prevention 696–697
–– risk factors for lymphoedema
–– extent of surgery  690
–– genetic predisposition  691
–– infections 691
–– obesity 691
–– radiation therapy  691
–– signs and symptoms  691
–– stages  691, 692
–– tissue dielectric constant  692
–– vascularized lymph node transfer  695–696
–– water displacement method  692
Lymph node  121, 135, 182, 184, 296–298
Lymphoedema  309–311, 418.
See also Lymphedema
Lymphoma 358–359
Lymphoscintigraphy 692
–– frontal and lateral view  277
–– preoperative 277
Lymphovascular invasion (LVI)  186
M
Macromastia  231, 396–398
Macronutrients 37
Magnetic resonance imaging (MRI)  60, 71
–– abnormal findings  137–138
–– breast cancer in  138
–– clinical considerations
–– diagnostic performance  138
–– multimodality approach  138–139
–– preoperative evaluation  139–141
–– reporting system  141
–– contraindications 136
–– DCIS, 117
–– evaluation 137
–– guidance 142
–– high-familial-risk women  60–63
–– indications 136
–– limiting factors  137
–– preoperative marking  143
–– protocols 136–137
–– technical considerations  136–137
–– typical imaging findings  138
Magnetic resonance lymphangiogram (MRL)  692
Male breast cancer (MBC)  161, 542, 716, 718
–– aetiology and risk factors
–– age 542
–– endocrine risk factors  543
–– family history  543
–– genetics 542
–– race 543
–– risk factors  543
–– clinical presentation  543
–– differential diagnosis  544
–– genetic counselling  544
–– histopathology 544–546
–– imaging and tissue diagnosis  544
–– mammographic features of  544
–– prognosis  547, 548
–– psychological impact and support  548
–– staging 544
–– treatment
–– adjuvant chemotherapy  546–547
–– adjuvant hormonal treatment  547
–– axilla management  546
–– breast surgery  546
–– radiation 546
–– targeted 547
Malignant lesions  130, 134
Malignant phyllodes tumor  554
MammaPrint®, 91–92, 188, 189
Mammary band  12, 13
Mammary glands  12
Mammography  63, 149
–– abnormal findings  130–131
–– age range  153–154
–– breast cancer in  131
–– breast density  128–129
–– DCIS, 116, 117
–– in dense breasts  128
–– for ductal carcinoma  130
–– factors improving  130
–– future perspectives  131–133
–– guidance 128
–– high-familial-risk women  63
–– image acquisition  128
–– image evaluation  129–130
–– indications 128
–– overdiagnosis 152–153
–– pathological features in  141
–– previously treated breast  131
rares1geo@gmail.com
727 I–M
–– typical malignant lesions  130
Mammostrat®  93, 94
Manchester scoring system (MSS)  50, 51
Margins 223–224
–– ASCO guidelines
–– breast conservation  215–223
–– DCIS 121
–– invasive 223
–– LCIS 107
–– pathology 181
MASCC score  654
Mastectomy  71–74, 204–205, 264, 533, 627–628
–– adjuvant radiation therapy after  468–470
–– bilateral, risk-reducing  502
–– breast-conserving therapy with  466
–– conservative (see Conservative
mastectomies)
–– DBR  326, 330, 331, 335, 336, 340, 345–346,
349, 350
–– definitions pertaining to  204
–– indications 205
–– ipsilateral breast tumour recurrence
after 264–267
–– nipple-sparing 206
–– non-conservative 205–206
–– reconstructive surgery after  534–535
–– skin-sparing 206
Mastectomy skin flaps, necrosis of  418–419
Mastopexy techniques  340, 345
MBC. See Male breast cancer (MBC)
Medio-lateral oblique (MLO)  128
Medullary breast carcinoma  178
Memorial Sloan Kettering Cancer Center
(MSKCC) 615
Menarche signals  32
Menopause  16, 32
Metastatic breast cancer (MBC)
–– bone metastases  596–601
–– brain metastases  644–645
–– clinical manifestations  160–161
–– diagnosis 580–581
–– endocrine therapy  584
–– HER2-positive 585
–– anti-HER2-therapy 587
–– luminal 587–588
–– pertuzumab 585–586
–– trastuzumab 585
–– incidence and mortality  580
–– liver metastases  614–617
–– local treatments  589–590
–– lung metastases  620–622
–– luminal HER2-negative  582–585
–– pain
–– analgesics  643, 644
–– bisphosphonates 643–644
–– causes 643
–– radiotherapy 643
–– RANK-ligand inhibitor denosumab 
643–644
–– palliative care (see Palliative care)
–– symptom burden  643
–– systemic endocrine therapy  583
–– treatment  581, 582
–– triple-negative 588–589
Metformin 85
Microcalcifications  116, 117, 130, 132, 134
Micrometastasis 295
 728 Index

Micronutrients 37
Microvascular anastomosis  311
–– risk assignment  95–96
–– risk classification  95 O
Microvascular flaps Multigene signatures  188–189 Obesity  24–25, 38, 359, 362, 382, 395, 397, 400
–– gluteal flaps Muscle sparing LD (msLD) flap  384 –– bimodal role of adiposity  35
–– I-Gap 389 Muscle sparing TRAM (MS-TRAM) technique  387 –– central adiposity  35–36
–– S-Gap 389 Muscle weakness  414–416 –– weight change  35
–– lower abdominal flaps Mutation carrier  70, 71, 74–76 Observational studies  705–706, 710
–– DIEP flap  387 Myoepithelial cells  12, 15, 111 Occult breast cancer  161
–– free TRAM flap  387 Oedema 249
–– pedicled TRAM flaps  387
–– SIEA 387–388 N Oestradiol 32
Oestrogen  13–16, 80
–– lumbar artery perforator flap  389 National Comprehensive Cancer Network (NCCN) Oestrogen exposure  36
–– thigh flaps guidelines  50, 52, 117, 317 –– endogenous
–– PAP flap  389 National Health Service Breast Screening –– childbearing 33
–– TMG flap  388–389 Programme (NHS BSP)  118, 195 –– early age at menarche  32
MINDACT trial  91, 92, 94, 717, 718 National Institute of Health and Care Excellence –– late age at menopause  32
Mirels’ scoring system  596 (NICE)  47, 50, 51, 53, 117 –– exogenous hormone administration  33–35
Moderate-to-severe intensity pain  660 National Surgical Adjuvant Breast and Bowel –– obesity and exercise  35–36
Modified Charlson Comorbidity Index Project (NSABP) clinical trials  268 Oestrogen receptor (ER)  90, 119, 123
(MCCI) 531 National Surgical Quality Improvement Program Older patients, breast cancer
Molecular biomarkers  459 (ACS-NSQIP) database  332 –– adjuvant chemotherapy  535–536
Molecular profiling Nausea 654–655 –– adjuvant hormonal therapy  535
–– adjuvant chemotherapy  93–94 Nd:YAG laser technique  622 –– adjuvant radiotherapy  537
–– clinical management uncertainties  96 Near-infrared fluorescence imaging  305 –– axillary surgery  533–534
–– cost-benefit analysis  96 Neoadjuvant chemotherapy (NAC)  256, 309, –– breast-conserving surgery  533
–– DCIS 318, 717, 718 –– disease stage  531–532
–– clinical management uncertainties  96 Neoadjuvant endocrine therapy  455–456 –– fitness assessment  531
–– Oncotype DX® Breast DCIS Score  96–97 Neoadjuvant systemic treatment  218–219 –– mastectomy 533–535
–– decision impact  96 Neoadjuvant-targeted therapy  122–123 –– patient factors  530
–– future tools  97 Neoadjuvant therapy  95, 454, 460 –– primary endocrine therapy  536–537
–– international BC treatment guidelines  94, 95 Neoadjuvant treatment (NAT)  186 –– screening 532
–– MGAs Nephrotoxicity 530 –– surgery, management  533–535
–– Breast Cancer Index  93 Neuropathic pain  414–416 –– tumour biology  532–533
–– EndoPredict® 93 Neutropenia 654 Oncogenesis
–– IHC4 assay  93 Next-generation sequencing (NGS)  52 –– constitutional mutation  46–47
–– MammaPrint® 91–92 Nipple-areola complex (NAC)  2–4, 320, 326, 327, –– mechanisms 44
–– Mammostrat® 93 336, 341–343, 396, 398, 502 –– somatic mutations  45–46
–– Oncotype DX® Breast Recurrence Score –– areola reconstruction techniques  408–410 Oncological safety  231
Assay 90–91 –– indication for  402 Oncoplastic breast surgery (OPBS)  218, 326
–– Prosigna® (PAM50)  92–93 –– local flap –– definition 200
–– neoadjuvant therapy  95 –– augmentation 407 –– education and training  200
–– risk assignment  95–96 –– CV flap  403, 406 –– procedures 200
Mortality rate  62–63 –– nipple sharing  408 –– benefits 201
Multicentric cancer  216 –– S-flaps  403, 407 –– limitations 201
Multicentric disease  231 –– skate flaps  403, 404 –– setting up  200–201
Multidisciplinary meetings (MDMs)  197 –– nipple position marking  402 Oncoplastic conserving surgery flaps  418–419
–– barriers and challenges  198–199 –– prosthetics 410 Oncoplastic multidisciplinary team (OPBS)  200
–– benefits  198, 199 –– temporary nipple tattoos  410 Oncoplastics  120, 218
–– future of  199 Nipple discharge  135 Oncoplastic surgery  218, 464
–– infrastructure 197 Nipple grafting, free  209–210 –– batwing technique  233
–– organization and format  197 Nipple involvement  209 –– cavity marking  232
–– requirements 197 Nipple loss  209–210 –– classification 232–236
Multidisciplinary team (MDT)  112 Nipple necrosis  418–419 –– clear resection margins  231–232
–– definition 195 Nipple preservation  402 –– cosmetic outcomes  242–243
–– and services  195–196 Nipple reconstruction. See Nipple-areola –– doughnut mastopexy  236
Multifocal cancer  216 complex (NAC) –– indications 230–231
Multi-gene assays (MGAs) Nipple sharing  408 –– oncological safety  231
–– currently available  91, 92 Nipple-sparing mastectomy (NSM)  71, 72, 120, –– relative contraindications  241–242
–– Breast Cancer Index  93 206, 320, 402, 502 –– round block mastopexy  236
–– cost-benefit analysis  96 Nipple-sparing techniques  491 –– specimen marking  232
–– decision impact  96 Non-conservative mastectomy  205–206 –– technical atlas
–– EndoPredict® 93 Non-epithelial malignant tumours  162 –– of level 1 techniques  232–236
–– IHC4 assay  93 Non-steroidal anti-inflammatory drugs –– of level 2 techniques  232, 233, 236,
–– MammaPrint® 91–92 (NSAIDs) 413 239–241
–– Mammostrat® 93 Non-vitamin K antagonists (NOACs)  652 –– volume replacement  232
–– Oncotype DX® Breast Recurrence Score NSM. See Nipple-sparing mastectomy (NSM) Oncotype DCIS® score  124
Assay 90–91 Nulliparous women  33 Oncotype DX®  188
–– Prosigna® (PAM50)  92–93 Nurse practitioners (NP)  684–686 Oncotype DX® Breast Assay  96

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Index
One-step nucleic acid amplification (OSNA)  280 –– TDAP flap  386
Oocyte cryopreservation  523, 524 –– thoracodorsal and intercostal flap plan-
Oophorectomy  80, 84 ning 385
Oral contraceptives (OCs)  23, 33 –– types 385
Osteoporosis 674 Pedicled transverse myocutaneous rectus
Osteosarcoma abdominis myocutaneous (TRAM) flap  387,
–– extraskeletal 554 388
–– radiation-induced  555, 556 Perometry 692
Ovarian cancer (OC)  70, 71, 74, 75, 503–504 Persistent pain
Ovarian function suppression (OFS)  428, –– axillary clearance  660
430–431, 492, 494 –– pathological mechanisms  660
–– AIs 429 –– treatment 660
–– benefits of  491 Pertuzumab  450, 458, 516
–– efficacy of  428 Peutz-Jeghers syndrome (PJS)  49
–– side effects  431 Phyllodes tumors (PTs)  162, 554, 717, 718
–– vs. tamoxifen  430 Physical abuse  667
Ovarian-stimulating agents  33–34 Physical activity  24, 36
Ovarian suppression, with GnRH agonists during Physician Data Query (PDQ)  316
chemotherapy 523–525 Pinch-off syndrome  653
Ovarian tissue cryopreservation  523, 524 PIP. See Poly Implant Prothèse (PIP) implants
Oxytocin 15 Platinum analogues  505–507
Platinum-based regimens  506
P Platinum salts  458, 460
Pleomorphic lobular carcinoma in situ
PABC. See Pregnancy-associated (PLCIS)  716, 718
breast cancer (PABC) POETIC trial  456
Paget’s disease  161–162 Poland’s syndrome  13
Pain Poly ADP-ribose polymerase inhibitors
–– moderate-to-severe intensity  660 (PARPi)  85, 489
–– relief 249 Poly Implant Prothèse (PIP) implants  359
PALB2, 50 Postmastectomy pain syndrome (PMPS)  653
Palliative care Post-mastectomy radiation therapy (PMRT)  319,
–– brain metastases  644–645 468
–– in cancer disease trajectory  642 POSYTIVE trial  637
–– definition 642 Predictive testing  51
–– dyspnoea 644 Pregnancy  64, 465
–– end-of-life care  642, 646 –– after breast cancer  525–526
–– goals 642 –– during and after breast cancer  494–495
–– liver metastases  645 –– breast cancer during
–– loco-regional and skin problems  644 –– anti-HER2 agents  516
–– psychosocial support  645 –– chemotherapy 515–516
–– quality of life  643 –– diagnosis and staging  513–514
–– rehabilitation 646 –– endocrine therapy  516
–– treatment goals  642 –– long-term outcomes of children  517–518
PAP flap. See Profunda artery –– management algorithm  512
perforator (PAP) flap –– obstetric care  517–518
Parkinson’s disease  464 –– radiotherapy 514–515
PARP inhibitors  505 –– supportive care  516–517
Pathological complete remission (pCR) –– surgical management  514
–– prognostic relevance of  455 Pregnancy-associated breast cancer
–– rates in HER2-directed therapy  457 (PABC) 512
Pathology Premature ovarian failure
–– fixation 181 –– aromatase inhibitors  675–676
–– frozen section  181 –– cytotoxic chemotherapy  675
–– gross examination  180 –– ovarian suppression/ablation  675
–– inking surgical specimen  180 –– tamoxifen 675
–– margin assessment/status  181 Premenopausal women  32, 36
–– specimen orientation  180 Preoperative marking  143
–– specimen slicing  181 Primary chemotherapy (PST)  292
Patient-centred treatment planning  197 –– complete pathological response
PE. See Pulmonary embolism (PE) (pCR) 292
Pectoralis major muscle  2–6 –– NCCN guidelines  292, 293
Pectoralis minor muscle  5 –– node-negative disease  292–293
Pedicled flaps  338, 340, 346, 350, Primary site locoregional therapy
418, 419 –– prospective registry trial  637
Pedicled perforator flaps –– randomized trials
–– AICAP flap  386 –– completed trials  636–637
–– LICAP flap  386 –– ongoing trials  637
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729 M–P
–– retrospective studies
–– advantages 634–635
–– potential biases  635
Primary systemic chemotherapy
–– future concepts in  460
–– general considerations  456
–– indications for  454
–– modern approaches  459
–– predictive markers for benefit of  459
–– principle 454–455
–– surgery after PST  257–259
Primary systemic therapy (PST)  256–257
Primary tumour
–– resection 634
–– survival vs. local therapy  634, 635
Primordium  12, 13
Profunda artery perforator (PAP) flap  388, 389
Progenitor cells  12
Progesterone 13–16
Progesterone receptor (PR)  119, 123, 428
Progestins 34
Progestogen 34
Prolactin 15
Prophylactic contralateral mastectomy
(PCM) 502
Prophylactic mastectomy  70
Prosigna®  92–93, 189
PRs. See Progesterone receptor (PR)
Pseudo-positive margin  223
PST. See Primary systemic therapy (PST)
Psychological distress
–– common feelings  665
–– emotional reactions  664
–– interpersonal communication  669
–– interpersonal functioning and depression
history 668
–– physical and emotional abuse  667
–– poor body image  666–668
–– post-traumatic growth  665
–– psychological intervention  665
–– psychological therapy  668
–– quality of life  664
–– self-protective psychological defence
mechanism 664
–– sexual and emotional abuse  668
–– sexuality  666, 667
–– shock  664, 665
PTEN gene  49
pTNM classification  182–183
PTs. See Phyllodes tumors (PTs)
Pulmonary embolism (PE)  419, 650
Pulmonary metastasectomy  620
–– indications 621
–– preoperative assessment  621
–– preoperative imaging  621
Pulmonary metastases
–– CT scan  620
–– diagnosis 621
–– ESO-ESMO consensus guidelines  620
–– lung-sparing resection  622
–– Nd:YAG laser technique  622
–– non-surgical techniques  622
–– percutaneous ablation  622
–– PET scan  621
–– radiofrequency ablation  622
–– resection 620
–– thoracotomy 621
–– video-assisted thoracic surgery  621–622
 730 Index

Q Risk-reducing salpingo-oophorectomy
(RRSO)  489, 502
–– composition 356
–– PIP 359
Quality-adjusted life year (QALY)  150 Risk reducing surgery –– sercoma 416
Quality of life (QoL)  320 –– bilateral salpingo-oophorectomy  71 –– surface 357
–– breast reconstruction –– surgical infections  414
–– autologous 74 –– wound complication  418

R –– implant based  74
Radial scars
–– histology 110
–– significance  110, 111
Radiation-induced toxicity  473–474, 476–477
Radiation therapy  23, 121, 122
–– induced breast angiosarcoma  555, 557
–– induced osteosarcoma  555, 556
–– induced sarcoma  555–557
Radioactive seed localization  221, 223
Radiocolloid 294–295
Radioembolisation 616–617
Radioguided occult lesion localization
(ROLL)  220–221, 223
Radiological localisation  155
Radiotherapy (RT)
–– adjuvant 298
–– boost dose  222
–– breast cancer during pregnancy  514–515
–– breast implants  361
–– breast reconstruction and  477–479
–– to chest wall  468–469
–– contraindications to  464–465
–– delayed breast reconstruction (DBR)  326, 327,
330, 332, 335, 336, 338, 340, 345, 346
–– early breast cancer  491
–– fat grafting  251
–– flap 382
–– general and specific contraindications to  464
–– Goldilocks procedure  399
–– implant-based reconstructions  375–376
–– indications for  469, 470
–– inflammatory breast cancer  572
–– locally advanced breast cancer  572
–– male breast cancer  546
–– metastatic breast cancer  589
–– planning and delivery  470–476
–– trastuzumab 573–574
–– whole breast and tumour bed (boost)  465–468
–– whole breast, tumour bed and regional
nodes 467–468
Raloxifene 81
Randomised controlled trial (RCT)  123, 152, 705
Recurrence  122, 123
Recurrence Score assay  90, 91
Red breast syndrome  717, 718
Redo conservation surgery  231
Regional node irradiation (RNI)  467, 468, 472
Registries (cancer)  708
Residual Cancer Burden (RCB) scoring sys-
tem 455
Retinoblastomas 46
Retinoids 85
Risk of recurrence (ROR) score  92–94, 189
Risk prediction  50
Risk-reducing bilateral mastectomy (RRBM)  S-flaps  403, 407
502–503
Risk-reducing bilateral salpingo-oophorectomy
(RRBSO) 503–504
Risk-reducing mastectomy (RRM)  70–76, 489, 490
–– interventions 70
–– mastectomy 71–74
–– psychosocial considerations  75
–– skin incisions  71–74
–– surveillance 76
RNI. See Regional node irradiation (RNI)
Round block mastopexy  236, 238
RRBSO. See Risk-reducing bilateral
salpingo-oophorectomy (RRBSO)
S SN FNAC study  293
Sappey’s subareolar plexus  7
Sarcomas of the breast. See Breast sarcomas
Scarff-Bloom-Richardson (SBR) grade  184
Second breast-conserving surgery  267
Selective estrogen receptor modulators
(SERMs) 432
–– arzoxifene 82
–– lasofoxifene 82
–– raloxifene 82
–– tamoxifen 81–82
Selective Use of Postoperative Radiotherapy
After Mastectomy (SUPREMO)  469
Self-protective psychological defence mecha-
nism 664
Sensory innervation  6
Sentimag© technique  222
SENTINA study  293, 296
Sentinel lymph node biopsy (SLNB)  276, 304
–– accuracy of  278–279
–– after primary systemic therapy (PST)  295
–– axillary reverse mapping (ARM), lymphatics
and nodes  306
–– axillary clearance  286
–– clinical decision-making after  281–282
–– definition 276
–– detection methods  276–278
–– development 276
–– indications 278
–– morbidity after  280–281
–– before primary systemic therapy (PST)  296
–– rationale 276
–– timing of  296
Sentinel nodes  277
–– biopsy  533–534, 716, 718
–– detection of  276–278
–– distribution of  278
–– intraoperative analysis  279–280
–– metastasis 286
–– surgical procedure  278
Septum fibrosum  4, 5
Seroma  416, 417
Sex hormone-binding globulin (SHBG)  36
SIEA flaps. See Superficial inferior epigastric
artery (SIEA) flap
Silicone implant-based reconstruction  418
Silicone implants  316, 356, 358
Silicone lymphadenopathy  360
Single-fraction radiotherapy  644
Single gene testing  52
Single nucleotide polymorphism (SNP)  44, 542
Skate flaps  403, 404
Skin flap necrosis  209–210
Skin incisions  71–74
Skin necrosis  375, 420
Skin-reducing techniques  366
Skin sparing mastectomy (SSM)  71, 120, 206,
320, 360, 397, 398, 402, 412
SLNB. See Sentinel lymph node biopsy (SLNB)
Society of Surgical Oncology  71
SOFT trials  491–493
Solitary pulmonary nodule  620
Somatic mutations  45–46
Specialist nurse
–– in breast care  682–686
–– CNS (see Clinical nurse specialist (CNS))
–– communication 682
–– drug delivery methods  686
–– education 682
–– evidence-based nursing  682
–– leadership skills  687
–– quality of care  687
–– responsibilities 687
–– role of  682
Specimen marking  232
Spinal metastases  599–600
SSMs. See Skin sparing mastectomy (SSM)
Stage IV breast cancer  634
–– overall survival  636
–– registry trial  637
Star flap  403, 405
Stereotactic body radiation therapy (SBRT)  617
Stereotactic radiosurgery (SRS)  609–610
Stereotaxic vacuum-assisted core biopsy  716,
718
STK11 49
Subdermal flaps  403
Sub-muscular technique
–– dermal sling  371–373
–– lower pole sling technique  369–371
–– partial sub-muscular technique  368–369
–– pre-pectoral/subcutaneous implant
placement  373, 374
–– total sub-muscular technique  368
Suckling 15
Superficial fascia  4, 5
Superficial inferior epigastric artery (SIEA)
flap 387–388
Superparamagnetic iron oxide (SPIO)  222, 276,
277, 281
Suppression of Ovarian Function (SOFT) trial  429
Surgical follow-up  250
Surveillance  Epidemiology and End Results
(SEER) programme database  205
Survivorship (cancer)  664, 686
Susceptibility genes  breast cancer  500
Swiss Federal Statistical Office  153

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Index
731 Q–Z

T Treatment-induced bone loss (TIBL)

–– bisphosphonates 676–677
Variants of unknown significance (VUS)  44, 52
Vascular endothelial growth factor (VEGF)  448–
Tailoring therapy  460 –– denosumab 677 449
Tamoxifen  80, 90, 93, 96, 97, 122, 123, 448, 491, Trials (clinical) Vascularized lymph node transfer (VLNT)  695–
675 –– bias  706, 707 696
–– chemoprevention 81–82 –– classification 704 Venous thromboembolic events (VTE)
–– postmenopausal women –– common phases  704, 705 –– Caprini risk score  651
–– CYP2D6 polymorphism  432 –– funding 706–708 –– diagnosis 650–651
–– side effects of  432–433 –– meta-analyses 705 –– incidence 650
–– premenopausal women –– observational studies  705–706, 710 –– Khorana score  650
–– ATLAS trial  428 –– quality assurance  708 –– prophylaxis 651–652
–– with chemotherapy  428, 429 –– randomised controlled trials  705 –– risk factors  650
–– IBCSG13–93 trial  428 –– registries 708 Volume displacement  233
–– side effects  429 Trial Assigning Individualized Options for VTE. See Venous thromboembolic events (VTE)
–– treatment with  432 Treatment (TAILORx)  90, 91, 94, 440

W
Tata Memorial trial  636 Triple-negative breast cancer (TNBC)  512
Taxane 440–442 –– adjuvant chemotherapy  442
T-box transcription factor (TBX3) gene  13 –– metastatic 588–589
Water displacement method  692
TDAP flap. See Thoracodorsal artery perforator Triple-negative tumours (TNT)  48, 50
WBRT. See Whole brain radiotherapy (WBRT)
(TDAP) flap TUG flap. See Transverse upper gracilis (TUG) flap
West German Study Group (WSG)  91
TDLUs. See Terminal duct lobular units (TDLUs) Tumour cell proliferation  459
Whole brain radiotherapy (WBRT)  607–608
TE. See Tissue expander (TE) Tumour-infiltrating lymphocytes (TILs)  178, 459
Whole breast and tumour bed, radiotherapy
Technetium-99 (99Tc)  305 Tumour node metastases (TNM) classifica-
to 465–468
Temporary nipple tattoos  410 tion 182–183
Whole-breast irradiation (WBI)  464, 467,
Terminal duct lobular units (TDLUs)  14, 104, 105, Tumour size (pT)  182
470–472
107, 207 Tumour suppressor genes (TSGs)  45, 46
Whole exome sequencing (WES)  52
TEXT trial  491–493 Tumour-to-nipple distance (TND)  209–210
Whole genome sequencing (WGS)  52
Therapeutic mammoplasty  717, 718 Turkish Federation of Breast Diseases  636
Winged scapula  9
Thigh flaps Turner’s syndrome  35
Wire-guided localization (WGL)  223
–– PAP flap  389 Tyrer-Cuzick model  51
Wise pattern incision  72, 73
–– TMG flap  388 Wise pattern mastectomy  396, 398
Thoracic irradiation  465
Thoracoacromial artery  5–7 U Witch’s milk  13
Women’s Health Initiative (WHI)  34, 35
Thoracodorsal artery perforator (TDAP) flap  386 UK Cancer Reform Strategy  682 World Health Organization (WHO)  20, 148, 185
Thoracodorsal transposition flap  384 UK charity Breast Cancer Care  687 Wound dehiscence  417–418
Thoracotomy 621 UK Nursing and Midwifery Council  687

X
TH3RESA trial  586 Ulnar-mammary syndrome  13
Time to chemotherapy (TTC)  317 Ultrasound 155
Tissue dielectric constant (TDC)  692 –– abnormal findings  134–135
X ray mammography  60, 63, 64
Tissue expander (TE)  317–319, 356, 362, 414 –– axilla, evaluation of  135–136
TMG. See Transverse myocutaneous gracilis (TMG) –– DCIS 117
TNBC. See Triple-negative breast cancer (TNBC)
Tomosynthesis  133, 717, 718
–– examination 133–134
–– guidance 141
Y
–– versus digital mammography  133 –– high-familial-risk women  63–64 Young age  216
Topoisomerase IIa (TOPO2A) gene  443 –– indications 133 Young women, breast cancer in  488
Total skin-sparing mastectomy (TSSM)  502 –– lymph nodes  135 –– biology 488
Toxicity, radiation-induced  473, 474, 476–477 –– preoperative marking  143 –– diagnostic procedures, staging and follow-
TRAM. See Transverse rectus abdominus –– typical imaging findings  134–135 up 489–490
myocutaneous (TRAM) Utah Population Database  47 –– epidemiology 488
Translational Breast Cancer Research Group –– genetic predisposition and testing  488–489

V
(TBCRC 0313)  637 –– treatment 490–491
Transverse myocutaneous gracilis (TMG)  388

Z
Transverse rectus abdominus myocutaneous
Vacuum-assisted biopsy (VAB)  118, 142
(TRAM)  332, 346, 416, 419
Vancomycin 652
Transverse upper gracilis (TUG) flap  388
Van Nuys Prognostic Index (VNPI)  96 Z0011 trial  297
Trastuzumab (TCH)  449–451, 458, 516

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