breast, skin, and soft tissue
BREAST CANCER
Lindi VanderWalde, MD, Alyssa D. Throckmorton, MD, FACS, and Stephen B. Edge, MD, FACS
Breast cancer is the most common malignancy in women in
the Western world. Its prevalence and public health impact
are increasing in developing countries, and breast cancer
leads to the death of hundreds of thousands of women world-
wide annually. In the United States, surgeons are involved in
the treatment of most women with breast cancer and are the
entry point for most women with breast cancer into the oncol-
ogy care delivery system. Surgical care must be coordinated
with other components of comprehensive breast cancer treat-
ment. Therefore, surgeons must have a thorough understand-
ing of the principles and current practices of overall breast
cancer medicine. This includes screening and evaluation of
benign disorders and suspicious findings, the use of imaging
and other diagnostic modalities, cancer risk modeling and
genetics, pathology, radiation therapy, systemic therapy, con-
cepts of treatment of metastatic cancer, surveillance follow-up,
and the emotional and social impact of a breast cancer
diagnosis.
This review provides an overview of most topics related to
breast cancer. It is extensively referenced with key past and very
recent literature through 2015 to give the reader a place to read
in more depth about most topics. It targets surgeons not primar-
ily specializing in breast disease, trainees, and students.
The review addresses treatment of malignancies of the ductal
and lobular epithelial components of the breast—what are com-
monly referred to as “breast cancer.” Malignancies of the non­
epithelial components of the breast, including mesenchymal
origin (phyllodes tumors and a variety of soft tissue sarcomas)
and lymphoma,1,2 are much less common and are not included
in this review.
Breast Evaluation
and Management of
Findings Suspicious
for Cancer
screening
All women should
undergo periodic screen-
ing for the presence of
breast cancer. This should
involve self- and profes-
sional physical examina-
tion and breast imaging.
Screening the general
population is proven to
reduce the risk of breast
cancer death. As is true
with all other health
screening, this comes at
some cost beyond the
financial cost. This
includes incorrect negative results of tests—screening is only
moderately sensitive for detecting cancer—known as false
© 2016 Decker Intellectual Properties Inc
negatives. It also suffers from a high false positive rate—results
that lead to further evaluation, often including needle or
surgical biopsy, that ultimately prove benign.
The age at which to start screening and the type of screening
are in part based on the individual’s level of risk. The key risk
factor for women is increasing age. Although breast cancer
can occur in some younger women, risk increases after age 40,
peaks in the late 50s, and remains at that level throughout the
remainder of life. This lower risk at a younger age is coupled
with somewhat reduced sensitivity of mammography in
younger women, making the test of extremely low or no value
for women without defined high risk factors who are under
age 40.
The American Cancer Society (ACS) and the United States
Preventive Services Task Force (USPSTF) provide the two pri-
mary guidelines for breast cancer screening. These are based
primarily on randomized and population studies of the impact
of breast cancer screening on breast cancer mortality and the
potential harms of screening stemming from the low specific-
ity (high false positive rate) that leads to many women requir-
ing a biopsy that proves benign.
Until recently, most guidelines called for mammography
annually beginning at age 40. However, based on review of
the available data by independent panels, both organizations
recently changed recommendations for the 90% or more of
women who are not among high–breast cancer risk groups.
Both groups recommend starting mammography at a higher
age and reducing the overall frequency of mammography.
The USPSTF guidelines recommend screening for women
without high-risk characteristics every 2 years beginning at
age 50 and that women age 40 to 49 make individual choices.3–5
The ACS guidelines revised in 2015 call for average-risk
women (who constitute about 90% of the population) to have
mammography annually from age 45 through age 54 and
every other year thereafter.6
There is no upper age limit for screening mammography.
Competing comorbidities and estimated life expectancy, but
not necessarily the age of the woman, should be the main con-
siderations in the decision regarding screening mammography
in older women. The ACS quantifies this by recommending
mammography every other year for older women with a
projected life expectancy of at least 10 years.
These changes have raised controversy, with some experts
still recommending annual mammography beginning at age
40. The ACS guidelines acknowledge this and advise practi-
tioners to discuss this with their patients, recommending that
women who want earlier mammography have this covered by
insurance. Surgeons should be aware of ongoing controversies
about the value of screening based on the variability in its
impact on mortality, the high rate of false positive examina-
tions, and the thesis that some lesions identified as “cancer”
may not have lethal potential but instead represent overdiag-
nosis and lead to overtreatment.7–9
Scientific American Surgery
DOI 10.2310/7800.2035
03/16
breast breast cancer — 2

Approach to the Patient with Breast Cancer

Assessment and Management

of Breast Findings

Screening Mass/skin change/

(No signs/symptoms) bloody discharge

History; physical examination;

diagnostic imaging
Average risk: High risk/
screening inherited susceptibility:
mammography screening
at age 40 + mammography
at < age 40;
consider screening
magnetic resonance imaging
Suspicious Negative
finding imaging

Suspicious:
complete diagnostic imaging

Biopsy or close
follow-up

BI-RADS 1 or 2: BI-RADS 4 or 5
continue screening BI-RADS 3
6-month
follow-up
imaging

Biopsy
Needle biopsy preferred
Image guided if not palpable

Scientific American Surgery

03/16
breast breast cancer — 3

Needle biopsy finding

Ductal carcinoma in situ (DCIS)

Atypical hyperplasia or
lobulat carcinoma in situ

History and physical examination

treatment options:
surgical wide excision
Surgical excision with/without radiation
or
mastectomy
Choice based on:
Not cancer: extent/size of involvement
consider antiestrogen
Cancer: see DCIS or invasive cancer

Wide excision: breast conserving therapy If mastectomy:

Assess margin and final pathology consider sentinel node biopsy;
consider reconstruction

DCIS and margin negative

consider radiation DCIS and margin positive: Invasive cancer:
re-excision to negative margin; go to appropriate
then consider radiation algorithm
or consider mastectomy ± reconstruction
If wide excision/
breast conserving therapy
consider antiestrogen drug

Invasive cancer

History and physical examination; identify clinical stage

Obtain biomarkers (ER, PR, HER-2)

Clinical stage I or II Clinical stage III Clinical stage IV

Perform staging studies:

Treatment options: if metastases, treat as stage IV
breast conserving therapy (BCT) or
mastectomy
Or neoadjuvant systemic therapy
Staging studies negative:
followed by surgery ± radiation
neoadjuvant systemic therapy
(chemotherapy or endocrine)
based on biomarker status

ER/PR(+) HER-2(−) ER/PR(−) HER-2(+/−)

Surgery first or Size > 2 cm: Operable: Inoperable:
neoadjuvant therapy neoadjuvant therapy preferred mastectomy or BCT change systemic
if large Size < 2 cm: surgery first based on response therapy and/or
then radiation radiation

BCT: wide excision to
negative margin and
sentinel node biopsy (SNB);
breast radiation
(may omit radiation age
70+, ≤ 2 cm, ER+)
0, 1, or 2 (+) nodes: no axillary
lymph node dissection
3 or more (+) nodes: AND
Mastectomy with sentinel node biopsy Initiate systemic
± reconstruction; treatment
axillary node dissection with (+) based on biomarkers
sentinel node biopsy Radiation for palliation
radiation with 4+ positive nodes Bone metastases
(Consider with 1− 3 nodes)
Breast surgery for
palliation if needed
Systemic therapy choice based on:
biomarkers; stage; age/comorbidity

Scientific American Surgery

03/16
breast breast cancer — 4
Screening for breast cancer for those at increased risk for
breast cancer may need to start at a younger age, be more
frequent, and include techniques other than mammography.
In total, this only applies to 10% or less of the population. Risk
factors include a strong family history of breast cancer and/or
known family mutations in breast cancer–related genes, a his-
tory of radiation to the chest (most commonly mantle radia-
tion for Hodgkin disease as a young adult), and specific
histologic findings on a previous breast biopsy. Women with
a lifetime risk of breast cancer greater than 20% should con-
sider mammography at a younger age as well as annual
screening magnetic resonance imaging (MRI). MRI detects
some cancers that are not evident on mammography, particu-
larly in those under age 40. For most situations, mammogra-
phy is still indicated, and MRI and ultrasonography are only
adjuncts to mammography. However, an emerging literature
suggests that when breast imaging screening is done for high-
risk women under age 30, there are few or no breast cancers
detected by mammography that are not detected by MRI, and
there are theoretical concerns that repeated radiation exposure
could be harmful in this age group.10,11
Breast density on a mammogram is another risk factor for
breast cancer. There are limited data that additional imaging
with ultrasonography or MRI is of value. This remains an area
of substantial debate.12,13 However, recent legislative mandates
in many US states require notification of women with mam-
mographically dense breasts of this fact, the potential increased
risk associated with dense breasts, and that additional screen-
ing imaging may be warranted, such as automated breast
ultrasonography or tomosynthesis.
There are tools (models) to estimate the future risk of breast
cancer and guidelines as to who should begin early screen-
ing.14,15 The most widely used is the Gail model, which assesses
risk for women with moderately increased risk based on age,
age at menarche, number of children, previous breast biop-
sies, and first-degree relatives with breast cancer (see http://
www.cancer.gov/bcrisktool/ for a Gail model breast cancer
risk calculator). However, the Gail model does not consider
paternal family history, maternal family history other than
first-degree relatives, or the age of cancer in family members
or other cancer types, making it less applicable to younger
women with a more extensive family history. Other risk
assessment tools include models such as the Tyrer-Cuzick
model and Pedigree Assessment Tool.16
Management of Clinical or Screening-Detected Findings
Women with a finding of concern on screening studies or
on self- or professional examination should undergo a thor-
ough evaluation. This includes a history and physical exam-
ination, diagnostic breast imaging if not previously done, and
possibly biopsy.
history and physical examination
History
Most women with breast cancer are asymptomatic at the
time of cancer diagnosis. The absence of findings on the history
and physical examination should not alter the need for further
evaluation or biopsy of nonpalpable findings on imaging stud-
ies. However, a complete history of breast-related symptoms
Scientific American Surgery
03/16
and evaluation for symptoms related to metastatic disease
should be performed on women with suspicious clinical or
imaging findings [see Table 1]. The patient may notice subtle
findings such as pain, early retraction of the nipple, skin ery-
thema or dimpling, or periodic nipple discharge. A previous
history of imaging findings and biopsies is important. The
physician should query for the presence of masses or lumps
in the breast, any apparent swelling, edema or thickening in
the breast tissue or skin, and the presence or absence of dis-
charge from the nipple (character, color, consistency, fre-
quency and mode of expression—spontaneous or elicited).
The patient should be queried regarding any changes in the
appearance of the nipple and the areola as well as the presence
of swelling, scaling, eczematous changes, or peeling of the
skin.
The physician should also document factors related to
breast cancer risk: age at onset of menarche and menopause,
age at first-term pregnancy, hormone use, and a detailed fam-
ily history of cancer. This history should include the type and
age at onset of cancer of all types (not just restricted to breast
and ovarian cancer) in all maternal and paternal first-degree
and second-degree relatives. Finally, a thorough history of
medication use should be recorded. In addition to common
prescription medications, the patient should be queried
regarding the use of exogenous hormone therapy as well as
supplements, other alternative medicine, and illicit drugs
because of their potential effects on hormone metabolism and
bleeding. Note that these findings are important to document
for long-term risk evaluation and management but do not sig-
nificantly impact the path for evaluation of a new breast find-
ing that must be managed on its own merit.
Some women have a family history suggesting a syndrome
of inherited susceptibility to breast and ovarian cancer or to
other inherited cancer syndromes. For these women, genetic
testing may be an option. If a geneticist or certified genetic
counselor is available, this is best managed by referral for for-
mal genetic counseling and consideration of testing. Current
indications for genetic counseling for breast and ovarian cancer
Table 1  Components of the Breast History
History of current problem
  Symptoms of presenting problem (presence of mass, pain, imag-
ing finding)
  Other breast symptoms
  Mass, pain, skin changes, swelling
  Nipple discharge
  Character (clear, green, red, dark)
  Frequency, duration
  Laterality (unilateral, bilateral)
  Symptoms of systemic problems
  New bony pain, constitutional symptom
Past and family history
  Past history of breast issues, including results of previous biopsies
  Family history
  Breast, ovarian, and other cancers in siblings, parents, parents’
siblings, grandparents
  Breast cancer risk factor information
  Age at menarche, menopause (natural or surgical)
  Age at first-term pregnancy
  Use, type, and duration of exogenous hormones
  Results of previous biopsies
  Results of genetic testing in self or family (if any)
breast breast cancer — 5
risk include a personal history of breast cancer under the age
of 50, triple-negative breast cancer under age 60, ovarian can-
cer at any age, male breast cancer, bilateral breast cancer, mul-
tiple first- or second-degree relatives with breast or ovarian
cancer, or a known mutation in a breast cancer–related gene
or other syndrome in the family.
Physical Examination
Examination of the breast and chest wall begins with maneu-
vers to accentuate skin puckering or retraction, including
extending the arms over the head and/or flexing the pectoral
muscles with the hands on the patient’s hips. Examination of
the axilla is best performed in the sitting position. The key to
successful examination of the axilla is relaxation of the muscles
of the shoulder girdle. This is best accomplished with the exam-
iner supporting the full weight of the arm abducted from the
body at about an angle of 60° while palpating the axilla with the
other hand. Care should be taken to examine the axilla fully
underneath the pectoral muscles and along the chest wall
toward the latissimus muscle. It is important to examine both
axillae. The supraclavicular region should be carefully exam-
ined for the presence of enlarged lymph nodes as well.
The most common technique for examining the breast for
mass lesions involves accentuating the skin of the breast by
placing the patient’s hand behind her head in the supine posi-
tion. The surgeon should develop a standard manner of exam-
ining the breast so that she or he consistently examines the
entirety of both breasts. It is generally best to begin the exam-
ination with the breast opposite the breast of concern so that
this examination is not forgotten. Most examiners use a pro-
cess of pushing the breast tissue back against the underlying
rib cage starting at the areola and working out in a circular
motion extending through the entire breast, recognizing that
the breast tissue extends into the axilla. The character, size,
and location of any masses identified should be noted. The
location should be noted using the face of a clock and distance
from the nipple. For example, the location of a mass in the
upper outer quadrant of the left breast might be designated as
at the 2 o’clock position, 6 cm from the nipple. The density and
glandularity of the breast should also be recorded. It is import-
ant to compare areas of dense glandular tissue with the con-
tralateral side to identify subtle differences in the size and
density of breast tissue. Although the primary examination is
performed in the supine position, frequently, patients will
self-identify a lesion in a position other than the supine posi-
tion. The patient should be queried as to whether the lesion is
palpable and should be examined in the position where she
noticed the lesion.
The skin of the nipple and areola should also be carefully
examined, and after warning the patient, the nipple may be
compressed to elicit a discharge. In cases where the woman
reports a discharge, sometimes only she can elicit this, and she
should be encouraged to do so. The character and color of the
discharge, the specific quadrant of origin, and the number of
ducts with a discharge should be noted. Cytologic examina-
tion of the nipple discharge for “atypical” cells is not useful
and may be misleading. It should not be considered a neces-
sary step for women with a nipple discharge.
imaging
Mammography
The mainstay of breast imaging is mammography. The
majority of breast cancers are detected by screening mammog-
raphy. With rare exceptions in very young women, evaluation
of a breast lesion is not complete without mammography.
Other imaging tools may add information, increase the sensi-
tivity of breast imaging, and enhance the accuracy and speci-
ficity of breast imaging but do not replace mammography.
A standard screening mammogram includes two views of
each breast: the craniocaudad view and the mediolateral
oblique view (oblique to ensure inclusion of the axillary tail of
the breast on the image). Concerning findings on a mammo-
gram include masses, asymmetry of the glandular tissue, dis-
tortion in the architecture of the breast tissue, and the presence
of calcifications grouped (“clustered”) in an area of breast tis-
sue. When an abnormality is identified, the patient should
have an extended mammographic examination known as a
diagnostic mammogram. Other images to supplement the
standard projections are obtained and may include accentu-
ated positions to change the perspective on a suspected lesion,
localized “spot” compression, and magnified images. Any
finding should be compared with previous mammograms to
determine if it is new.
The results of all mammograms in the United States must,
by Medicare regulations, be classified by a numerical score
called the Breast Imaging Reporting and Data System
(BI-RADS) [see Table 2].17 A score of 5 denotes an obvious can-
cer, 4 a suspicious lesion requiring biopsy, 3 a lesion that is
“probably benign” and warrants close follow-up, 2 an obvious
stable benign finding, and 1 a normal study. A score of 0 means
that additional imaging is required before a score of 1 to 5 is
assigned, and a score of 6 is used for a diagnostic mammogram
with a known biopsy-proven cancer. The scoring system and
criteria are used to classify the findings of other breast imag-
ing.18 This score and/or the specific language related to that
score are included on every mammogram report. A BI-RADS
score of 4 and 5 denotes a lesion that is of sufficient concern to
require biopsy.17 Mammography has a relatively low specific-
ity, with about 60 to 70% of all lesions classified as BI-RADS 4
or 5 proving to be benign. New technologies may improve the
sensitivity and specificity of mammography. Most notable is
breast tomosynthesis, which provides a quasi-three-­dimensional
reconstruction of the breast.19
A key point is that suspicious physical findings (e.g., lump
or discharge) should be evaluated and biopsied even if breast
imaging is normal. Mammography only detects 80 to 90% of
breast cancers and is less sensitive in women with dense glan-
dular tissue and for lobular cancer.
Ultrasonography
Ultrasonography is an adjunctive imaging tool to define the
characteristics of a lesion identified by other imaging modali-
ties. Ultrasonography itself has not been shown to be a useful
stand-alone screening tool. Ultrasonography primarily defines
whether a lesion is cystic or solid. Malignant lesions are solid
and tend to have irregular borders and inhomogeneous acous-
tic shadowing [see Figure 1a]. When a sonogram shows a
sharply defined lesion that transmits the sound completely
(fluid), the unequivocal characteristics of a simple cyst, no
Scientific American Surgery
03/16
breast breast cancer — 6
Table 2  BI-RADS Classification16
Category/Definition Optimal Management
0 Needs additional imaging Perform additional imaging
1 Negative Routine screening
2 Benign Routine screening
3 “Probably benign” Short-term follow-up (usually in 6 months)
4a, b, and c Suspicious Biopsy
5 Highly suggestive of cancer Biopsy
6 Biopsy-proven cancer Imaging done for treatment planning
BI-RADS = Breast Imaging Reporting and Data System.
further intervention is needed [see Figure 1b]. For breast lesions
that have solid components or are completely solid tissue (not
fluid), ultrasound features alone are insufficient to define if
the lesion is malignant. Biopsy is usually warranted for a solid
lesion. The exception may be a small mass in a young woman
that has the clear characteristics of a fibroadenoma for which
short-term follow-up in 6 months with ultrasonography may
be sufficient [see Figure 1c]. For solid lesions seen on ultraso-
nography, fine-needle aspiration (FNA), core-needle biopsy,
or vacuum-assisted needle biopsy may be guided by the same
ultrasonography.
Many surgeons use breast ultrasonography in their office as
an adjunct to the physical examination and to perform biop-
sies. This should be encouraged if the surgeon is qualified.
Surgeons who perform ultrasonography in the office need to
be fully familiar with its value and limitations and should
undergo appropriate training and certification of their skill.
Certification in the use of breast ultrasonography is available
through the American Society of Breast Surgeons and is man-
datory for surgeons performing ultrasonography as part of a
National Accreditation Program for Breast Centers (NAPBC)
center accreditation20 and for reimbursement from at least one
insurance company. Surgeon-performed ultrasonography may
or may not replace ultrasonography performed as part of the
radiologist’s diagnostic breast imaging.
Magnetic Resonance Imaging
MRI may be used in breast cancer screening and evaluation
of breast cancers.21 With the exception of screening in very
young women (under age 30), a key point is that MRI is an
adjunct to mammography and ultrasonography, not a replace-
ment. Specifically, MRI does not identify calcifications, one of
the key hallmarks of breast cancer on mammography. MRI
visualization of breast cancers requires contrast enhancement
using intravenous gadolinium. MRI may detect cancers that
are occult on mammography but suffers from a substantial
rate of false positive findings that leads to otherwise unneces-
sary biopsies and significant patient concern.22
Indications for breast MRI continue to evolve. MRI screen-
ing at annual intervals is useful in women at defined marked
increased risk for developing breast cancer, usually by virtue
of a family history of multiple affected close relatives or per-
sonal history of atypia or lobular neoplasia on previous
biopsy. Consider MRI screening for women with a lifetime
Scientific American Surgery
03/16
Probability of Cancer
Not applicable
Close to 0%
Close to 0%
≤ 2%
Low: 2–10% (a); intermediate: 10–50% (b);
moderate: 50–95% (c)
95%+
Not applicable
breast cancer risk of at least 20 to 25% as estimated using a risk
model that includes family history.23
MRI evaluation of the breast in a woman with a known
cancer has the dual purpose of screening the remainder of
breast tissue as well as providing additional information on
the extent of the known cancer.24 MRI detects mammographi-
cally occult breast cancer in the contralateral breast in as many
as 3% of women.22 MRI may also assist in surgical planning. It
is critical to recognize that surgical planning for cancer treat-
ment cannot be based on the MRI finding alone. A second
suspicious lesion seen on MRI generally requires biopsy con-
firmation before it is used to justify more extensive surgery.
Retrospective studies show that the surgical treatment plan-
ning is changed by MRI findings in as many as 20% of cases—
most commonly alteration from planned breast conservation
to mastectomy.
MRI should not be used automatically as a routine for all
cancers. It might seem intuitive that the added information is
helpful, but it may cause harm. Every study to date that has
examined the question has failed to show any difference in
outcomes, including local recurrence and breast cancer sur-
vival by virtue of having presurgical MRI.25,26 However, the
use of MRI may paradoxically unnecessarily increase the use
of mastectomy.
MRI may be useful in women with locally advanced breast
cancer for whom neoadjuvant chemotherapy is being consid-
ered to downsize the tumor to allow breast conservation. An
MRI-defined clinical response quantified as changes in enhance-
ment and in reduction in tumor volume may be prognostic of
ultimate cancer outcome.
Other Imaging Modalities for the Breast and for Screening for
Metastatic Cancer
Other breast imaging modalities include sestamibi imaging
and positron emission tomography (PET).27–29 Sestamibi
imaging remains investigational. PET is of minimal value in
evaluating the primary tumor. Whole body imaging using
PET–­ computed tomography (CT), CT, or bone scanning is
necessary in those patients presenting with locally advanced
breast cancer because they have a substantial chance of having
distant metastases, which may change treatment plans. How-
ever, imaging of the asymptomatic patient with clinical stage
I and II breast cancer is not appropriate unless there are symp-
toms suggestive of metastatic disease.30 The likelihood of find-
ing asymptomatic metastatic disease is very low, and the rate
breast breast cancer — 7

Scientific American Surgery

03/16
breast breast cancer — 8

Figure 1  Ultrasound images of representative breast lesions demonstrating key characteristics: (a) breast cancer showing irregular borders, inho-
mogeneous echogenicity (solid), and posterior acoustic shadowing; (b) simple cyst showing anechoic interior (fluid), sharp borders, and posterior
acoustic enhancement; (c) fibroadenoma showing homogeneous echogenicity (solid), sharp borders, and normal through transmission of sound, with
no posterior shadowing or enhancement. FN = from nipple.

of falsely positive studies with attendant invasive procedures subsequent cancer care. It may complicate the ability to do
is substantial. Avoiding overuse of staging studies in stage I breast-conserving surgery and eliminate the option for presur-
and II breast cancer is a national standard as codified in gical systemic drug therapy (neoadjuvant therapy). “Patient
guidelines and national quality measures, including the choice” is not a valid reason to justify surgical excisional biopsy
Choosing Wisely effort of the American Board of Internal in place of percutaneous biopsy. If the patient asks for surgical
Medicine Foundation.31 excision in place of needle biopsy, the surgeon should provide
careful counseling so that the woman understands that she
biopsy of suspicious may be harmed by unnecessary surgery.
findings Surgical biopsy without a previous percutaneous needle
A breast lesion suspi- biopsy should be performed only when needle biopsy cannot
cious for malignancy be performed for specific technical reasons. Technical reasons
requires tissue biopsy. that may preclude needle biopsy include the anatomic loca-
Percutaneous needle tion of the lesion close to the chest wall, in the far periphery
biopsy is preferred over of the breast, or very superficially in a small breast, which are
surgical excision. For the all locations that pose difficulty in positioning of the patient or
majority of cases where visualization with stereotactic biopsy equipment. Less than
the lesion proves benign 10% of nonpalpable lesions require surgical biopsy.
by needle biopsy, subse- The most widely used technique for percutaneous needle
quent surgery is com- biopsy is core-needle biopsy or vacuum-assisted needle biopsy
pletely unnecessary. In using a device with a rotating blade inside a needle. These
cases where the lesion is provide sufficient tissue for standard histology and for bio-
a cancer, initial surgical marker assessment. FNA provides cytology only; although
biopsy often leads to the used extensively in the past, FNA only allows cytologic eval-
need for a second reoper- uation. FNA is still widely used in the assessment of axillary
ation on the breast. Initial lymph nodes.
surgical biopsy ulti- Needle biopsy may be directed by surgeon palpation or
mately may compromise image guidance. Lesions that are clearly palpable may be

Scientific American Surgery

03/16
breast breast cancer — 9
accurately localized for biopsy by palpation without using
imaging equipment. However, it is best to use image guidance
if there is any question that the lesion is palpable or if the
lesion is not palpable. Core biopsy of the breast can be guided
by different imaging modalities (ultrasonography, stereotac-
tic, or MRI), depending on the character of the lesion, how it
is best visualized, and the expertise and preference of the pro-
vider. In general, if the lesion is seen on ultrasonography, this
is the easiest way to localize the lesion for the patient and the
physician. If not, then mammographic localization is used.
MRI localization for biopsy is tedious for the patient and the
physician and costly. Its use is reserved for those cases of
lesions seen only on MRI.
In most cases, a benign finding on core- or vacuum-assisted
needle biopsy is definitive, and surgical excision is not neces-
sary. In a few cases, surgical excision is required for lesions
defined as benign by needle biopsy. This is needed when the
pathology finding is “nonconcordant” with the imaging find-
ing (e.g., only adipose tissue when the imaging shows a solid
mass). Surgical excision is also generally done when the
biopsy shows certain otherwise benign lesions, the most com-
mon of which are atypical hyperplasia (ductal or lobular), lob-
ular carcinoma in situ (LCIS), radial scar, or intraductal
papilloma. With these lesions, there is a small chance that
there is cancer in the tissue immediately surrounding the
biopsy-sampled tissue.32,33 The need for surgical excision for
some of these benign findings on core biopsy remains an area
of active investigation and controversy.34 It is possible that in
the near future we should be able to identify patients in whom
the risk that a specific type of benign lesion found by core
biopsy harbors a cancer is low enough to allow it to be
followed without surgical excision.35
Management of Breast Cancer
Breast cancer management continues to evolve rapidly, and
a review can only provide a foundation to understand
principles of treatment and the basics of current approaches.
Surgeons must remain current with relevant literature and
should refer to national guidelines in making treatment
decisions. The most comprehensive guidelines that are
updated at least annually are supplied by the National
Comprehensive Cancer Network (NCCN) and are available at
http://www.nccn.org.30
Surgical care cannot be done in a vacuum and must be inte-
grated with adjuvant therapies, including radiation and sys-
temic therapy. In many cases, adjuvant systemic therapy is
best administered before surgery (“neoadjuvant therapy”).
Therefore, although it is not mandatory that every breast can-
cer patient have a preoperative consultation with specialists in
each relevant discipline, it is incumbent upon the surgeon to
ensure that the surgical care is appropriately coordinated and
integrated in an overall breast cancer care plan.
Breast cancer management must address two major issues.
The first is the treatment of the local disease in the breast itself
(“local therapy”). This is generally accomplished through surgi-
cal resection with or without radiation. The second is prevention
of distant recurrence using adjuvant systemic therapy (chemo-
therapy, immunotherapy, and endocrine therapy) because any
woman with invasive cancer has the risk of harboring occult
microscopic metastatic disease that can ultimately lead to
clinically apparent metastatic disease and death.
staging of cancer
Decisions about treatment require accurate information on
the extent of the cancer, the presence of certain biologic
markers and gene expression patterns, and other factors,
including age, performance status, and personal preference.
One of the key factors impacting treatment is the stage of the
cancer using systems that codify the anatomic extent of the
cancer at the time of diagnosis. The clinically used staging
system is the TNM system of the American Joint Committee
on Cancer (AJCC).36 This system categorizes the size and
extent of the primary tumor (T), the involvement of regional
lymph nodes (N), the presence or absence of distant metas-
tases (M) [see Table 3], and a “stage group” derived from the
T, N, and M categories [see Table 4]. The AJCC TNM system
is currently in its seventh edition, published for use in cases
diagnosed in 2010 and later [see Table 3]. The eighth edition
of the AJCC Cancer Staging Manual is planned for release in
late 2016 for use in cases diagnosed beginning January 2017.
Stage should be documented in the medical record at two
distinct points in treatment. Clinical stage is the initial cancer
stage used in treatment planning and includes information
gleaned from the history, the physical examination, and any
available imaging studies prior to the first course of treatment,
whether that is surgery, systemic therapy, or radiation. Clini-
cal stage is assigned on the available information; it is not
mandatory to do advanced scan imaging to determine clinical
stage. Pathologic stage is the clinical stage supplemented with
the findings from surgical resection (breast and lymph nodes).
When neoadjuvant therapy is used, the extent of disease after
treatment is the posttreatment stage. The degree of response
to neoadjuvant therapy may itself be a significant factor defin-
ing prognosis. The rules and specifics of the TNM staging sys-
tem are detailed in the AJCC Cancer Staging Manual.36
Primary Classes of Breast Cancer
Breast cancers are malignancy of the epithelial cells lining
the ductal and lobular system of the breast and emanate from
the terminal ductal lobular unit [see Figure 2]. Proliferation of
these cells that fill the duct but do not penetrate through the
intact basement membrane surrounding the duct or lobule is
called noninvasive, intraductal, or in situ cancer. These
account for about 20% of all cancers. Even with screening, by
the time of diagnosis, most cancers exhibit infiltration or inva-
sion of the malignant cells through the basement membrane
into the surrounding stroma of the breast. These cancers are
termed invasive or infiltrating cancers.
The significance of invasion through the basement mem-
brane is that these cancers have the potential to spread beyond
the breast. This is accomplished by invasion into surrounding
blood vessels and lymphatic channels that course through the
breast. Cancer cells may spread to lymph nodes in the region
(primarily in the axilla) or to other organs of the body
[see Figure 3].
Scientific American Surgery
03/16
breast breast cancer — 10

Table 3  American Joint Committee on Cancer (AJCC) TNM Staging System: T, N, and M Categories36
Primary tumor, clinical TX  Primary tumor cannot be assessed
(cT) and pathologic
T0  No evidence of tumor
(pT)
Tis  Carcinoma in situ
Tis  (DCIS) Ductal carcinoma in situ
Tis  (LCIS) Lobular carcinoma in situ
Tis  (Paget) Paget disease of the nipple with no tumor
T1 Tumor ≤ 2 cm
T1mic Tumor ≤ 0.1 cm
T1a  Tumor > 0.1–0.5 cm
T1b  Tumor > 0.5–1 cm
T1c  Tumor > 1–2 cm
T2  Tumor > 2–5 cm
T3  Tumor > 5 cm
T4  Tumor of any size with direct extension to chest wall and/or skin
T4a  Extension to chest wall, not including pectoralis muscle
T4b  Edema (including peau d’orange) or ulceration of the skin of the breast or satellite skin nodules confined to
the same breast
T4c  Both T4a and T4b
T4d  Inflammatory carcinoma
Regional lymph nodes, cNX  Regional lymph nodes cannot be assessed (e.g., previously removed)
clinical (cN)
cN0  No regional lymph node metastasis
cN1  Metastasis in movable ipsilateral axillary lymph node or nodes
cN2  Metastasis in ipsilateral axillary lymph nodes or in clinically detected ipsilateral internal mammary nodes in
the absence of clinically evident axillary lymph node metastasis
cN2a  Metastasis in ipsilateral axillary nodes fixed to one another (matted) or to other structures
cN2b  Metastasis only in clinically detected ipsilateral internal mammary nodes and in the absence of clinically
evident axillary lymph node metastasis
cN3  Metastasis in ipsilateral infraclavicular lymph node(s) or in clinically detected ipsilateral internal mammary
lymph node or nodes and in the presence of clinically evident axillary lymph node metastasis or metastasis in
ipsilateral supraclavicular lymph node or nodes with or without axillary or internal mammary lymph node
involvement
cN3a  Metastasis in ipsilateral infraclavicular lymph node(s)
cN3b  Metastasis in ipsilateral internal mammary lymph node(s) and axillary lymph node(s)
cN3c  Metastasis in ipsilateral supraclavicular lymph node(s)
Regional lymph nodes, pNX  Regional lymph nodes cannot be assessed (e.g., previously removed)
pathologic (pN)
pN0  No regional lymph node metastasis histologically
pN0(i−)  No regional lymph node metastasis histologically, negative IHC
pN0(i+)  Malignant cells in regional lymph node(s) ≤ 0.2 mm (detected by IHC, including isolated tumor cells)
pN0(mol−)  No regional lymph node metastasis histologically, negative molecular findings (RT-PCR)
pN0(mol+)  No regional lymph node metastasis by IHC or histology, positive molecular findings (RT-PCR)
pN1  Metastasis in one to three axillary lymph nodes and/or in internal mammary nodes with microscopic disease
detected by sentinel lymph node dissection but not clinically detected
pN1mi  Micrometastases (> 0.2 mm and/or > 200 cells, none > 2.0 mm)
pN1a  Metastasis in one to three axillary lymph nodes, at least one metastasis > 2 mm
pN1b  Metastasis in internal mammary nodes with micrometastases or macrometastases; microscopic disease
detected by sentinel lymph node dissection but not clinically detected
pN1c  Metastasis in one to three axillary lymph nodes and in internal mammary lymph nodes with micrometas-
tases or macrometastases detected by sentinel lymph node dissection but not clinically detected
pN2  Metastasis in four to nine lymph nodes or in clinically detected internal mammary lymph nodes in the
absence of axillary lymph node metastasis
pN2a  Metastasis in four to nine axillary lymph nodes (at least one tumor deposit > 2.0 mm)

Scientific American Surgery

03/16
breast breast cancer — 11

Table 3  American Joint Committee on Cancer (AJCC) TNM Staging System: T, N, and M Categories36
pN2b  Metastasis in clinically detected internal mammary lymph nodes in the absence of axillary lymph node
metastasis
pN3  Metastasis in 10 or more axillary lymph nodes, or in infraclavicular lymph nodes, or in clinically detected
ipsilateral internal mammary lymph nodes in the presence of one or more positive axillary lymph nodes or
­metastasis 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 detected or in ipsilateral supracla-
vicular lymph nodes
pN3a  Metastasis in 10 or more axillary lymph nodes (at least one tumor deposit > 2.0 mm) or metastasis to the
infraclavicular lymph nodes
pN3b Metastasis in clinically detected 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 detected
pN3c  Metastasis in ipsilateral supraclavicular lymph nodes
Distant metastases (M) M0  No clinical or radiographic evidence of distant metastases
cM0(+)  No clinical or radiographic evidence of distant metastases but deposits of molecularly or microscopically
detected tumor cells in blood, bone marrow, or nonregional nodes < 0.2 mm without symptoms or signs of m
­ etastases
M1  Distant detectable metastases as determined by classic clinical and radiologic means and/or histologically
proven > 0.2 mm
IHC = immunohistochemistry; RT-PCR = reverse transcriptase–polymerase chain reaction.
Clinical detection is defined as detection 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.
Classification is based on axillary lymph node dissection with or without sentinel lymph node dissection. Classification based solely on sentinel lymph node dissection without
subsequent axillary lymph node dissection is designated as “sn” for sentinel node (e.g., pN0(sn)).
“M” is classified as clinical M0 (cM0) unless there is clinical or radiologic evidence of metastases (classified as cM1) or pathologic confirmation of metastases (pM1). Imaging
staging tests are not required to classify a case as cM0. “MX” has no meaning and is not a category used in AJCC/TNM staging.

Noninvasive Cancer considerable discordance among pathologists—in other words,

(Carcinoma In Situ) a lesion called DCIS by one pathologist may be deemed atyp-
In situ lesions include ical hyperplasia by others.34 The standard treatment of these
ductal carcinoma in situ entities is vastly different despite the fact that there is overlap
(DCIS) and a benign in the histologic findings. This suggests that “stand­ard treat-
entity called lobular car- ment” leads some women to receive significant overtreatment.
cinoma in situ (LCIS). Surgeons should be aware of these issues and advise their
The hallmark is that the patients thoroughly.
neoplastic cells fill the lobular carcinoma in situ
duct or lobule and do
not penetrate the base- LCIS is not cancer in that it has no metastatic potential.
ment membrane. Rather, it is a benign lesion and does not require cancer treat-
The use of the term ment per se. Its presence indicates that an individual has a
carcinoma for these enti- higher risk than average of breast cancer in either breast over
ties is considered by a lifetime. The use of the term carcinoma to describe this entity
many to be misleading has long been challenged as it misleads physicians and causes
as the large majority of substantial unwarranted concern among patients. LCIS is
women with these enti- characterized by small uniform cells confined to the lobule of
ties will never progress the breast. It is generally a clinically and mammographically
to have an invasive can- occult lesion that is identified only incidentally when a biopsy
cer that has any meta- is performed for calcifications or a mass that proves to be
static or life-threatening some other benign lesion.
potential. They may be better classified as neoplastic lesions The primary issue for women with LCIS is that they have
analogous to the way carcinoma in situ of the uterine cervix an increased lifelong risk of subsequent invasive cancer of
has been classified as intraepithelial neoplasia. A recent approximately 0.5 to 0.75% per year.37 In addition, when LCIS
National Cancer Institute task force specifically called for is identified on a core-needle biopsy, there is some chance of
reclassification of these breast lesions without use of the term DCIS or invasive cancer in the surrounding tissue. Many
carcinoma.7 These controversies underscore the uncertainty advocate that women with a core biopsy showing LCIS should
regarding the natural history of these lesions and raise con- undergo surgical excision of the involved tissue, but others
cern that many of the standard treatments outlined below believe that this may be unwarranted.35,38,39
result in the overtreatment of many women with DCIS and Long-term follow-up shows that the large majority of
LCIS. Furthermore, within the spectrum of pathologic find- women with LCIS never develop invasive breast cancer.
ings of atypical hyperplasia (considered benign) and DCIS Therefore, ablative surgical therapy and radiation for LCIS are
(considered malignant), recent evidence shows that there is not necessary. Previously, LCIS was considered an indication

Scientific American Surgery

03/16
breast breast cancer — 12

Table 4  American Joint Committee on Cancer TNM Staging System: Anatomic Stage/Prognostic Groups36
Stage Group T N M
0 Tis N0 M0
1A T1 N0 M0
1B T0 or T1 N1mi M0
T0 N1 M0
IIA T1 N1 M0
T2 N0 M0
T2 N1 M0
IIB
T3 N0 M0
T0 N2 M0
T1 N2 M0
IIIA
T2 N2 M0
T3 N1 or N2 M0
IIIB T4 Any N M
IIIC Any T N3 M0
IV Any T Any N M1
1. Record clinical stage prior to initiation of treatment based on the physical examination and imaging. Advanced body imaging is not required to assign “clinical M0 (cM0).”
2. Record pathological stage based on clinical information prior to surgery and surgical findings, but only if surgery comes before systemic therapy or radiation.
3. Record posttherapy stage based on clinical and imaging information prior to treatment and on status after treatment for patients receiving presurgical (neoadjuvant) therapy.
4. Use clinical M status (cM0 or cM1) for both clinical stage group and pathologic stage group unless there is pathologic confirmation of distant metastases.

for bilateral mastectomy because of the risk of subsequent
cancer. However, mastectomy is not indicated solely because
of LCIS. The risk of cancer is low enough, and the likelihood
that it will be discovered on screening and successfully
treated is high enough, that observation without aggressive
intervention is the best option for women with LCIS. Mas-
tectomy may be performed in a few individuals in the con-
text of risk reduction for those at very high risk related to
additional factors such as inherited susceptibility (e.g., with
known mutations in breast cancer–related genes).40
Women with LCIS should be counseled regarding lifetime
breast cancer risk and may benefit from consultation with
genetics professionals especially if they have a family history
of breast and/or ovarian cancer. Women with a biopsy show-
ing LCIS may also consider risk-reducing chemoprevention
with one of the selective estrogen receptor modulators
(SERMs), tamoxifen or raloxifene, or the aromatase inhibitor
exemestane. These reduce the risk of subsequent invasive
cancer by about 50% with an acceptable toxicity profile.41–43
Tamoxifen is the only chemoprevention agent approved for
use in premenopausal women. Raloxifene and exemestane
are the preferred agents in postmenopausal women.
Pleomorphic LCIS is a very uncommon variant of LCIS
characterized by cells confined to the breast lobule with var-
ied size, shape, and nuclear configuration. It has many of the
histologic characteristics of DCIS but is clearly lobular in that
it does not express the transmembrane protein E-cadherin.
Pleomorphic LCIS may behave similarly to DCIS with a pre-
dilection for local recurrence and progression to invasive can-
cer. Because it is quite uncommon, there are limited data on
its behavior and outcome. However, many experts believe
that there is sufficient anecdotal evidence to support treating
pleomorphic LCIS as we treat DCIS (see below) with wide
excision to negative margins and consideration of adjuvant
radiation therapy.44,45
ductal carcinoma in situ
The histologic hallmark of DCIS is the presence of
malignant-­appearing cells confined to the lumen of the breast
ductal system without invasion through the ductal basement
membrane. DCIS is most often diagnosed because of the pres-
ence of calcifications clustered in one area of the breast. The
calcifications suspicious for DCIS are most often linear (not
round), clustered in a single location of the breast, and aligned
in a ductal distribution pattern. The area of involvement in
the breast with DCIS may not be limited to the extent of cal-
cifications, and not all DCIS manifests as microcalcifications.
It is uncertain whether all DCIS is a precursor to invasive
cancer and will therefore progress to invasive cancer if left
untreated.46 It is likely that some forms of what we call DCIS
are more akin to atypical ductal hyperplasia and serve pri-
marily as a marker of risk of developing a future breast can-
cer anywhere in the breast and not directly progressing to
invasive cancer at that specific site. It is hoped that research
will identify which lesions currently classified as DCIS
require ablative treatment and which are benign and require
no intervention. Unfortunately, despite extensive research, at
this point, there are no markers or other characteristics that
can accurately define which DCIS may progress to invasive
cancer.47,48 Therefore, most women diagnosed with DCIS still
undergo the current standard treatments, as outlined below.
However, there is intense interest in this issue because it is
likely that many women currently treated for DCIS do not
need aggressive treatment.7,49–51
DCIS encompasses a spectrum of histologic subtypes all
characterized by malignant-appearing cells confined to the
lumen of the breast ducts. However, the appearance ranges
from bland uniform cells growing from the wall of the duct
or bridging the duct (papillary, cribriform) to cells filling the
entire duct [see Figure 4]. These cells also vary in nuclear mor-
phology, ranging from low-grade, uniform-appearing nuclei

Scientific American Surgery

03/16
breast breast cancer — 13
Figure 2  Structure of breast.
to varying size and shape and large nuclei (high grade) and
also in the presence or absence of central necrosis within the
duct. The combination of high nuclear grade and central
necrosis is termed comedo DCIS or comedocarcinoma.
The primary clinical relevance of the DCIS subtypes is that
they may have different potential for local recurrence after
breast-conserving surgery. The presence of high-grade cells
or comedonecrosis is not an indication of any metastatic
potential and does not itself warrant systemic therapy or
lymph node staging but may denote a higher risk of future
recurrence in the breast. This may impact on the decision to
use radiation after breast-conserving surgery.
Treatment
The overall cancer-specific survival for women with DCIS
approaches 100% irrespective of the subtype of DCIS and the
type of treatment.46 Mastectomy is effective in DCIS, but in
most cases, breast-conserving therapy (BCT) is the most rea-
sonable and appropriate approach because it provides the
same very low risk of cancer-related death.
The primary purpose of breast surgery with DCIS is to
prevent progression of the DCIS to invasive cancer and the
recurrence of cancer at the original site—so-called local recur-
rence. Local recurrence can occur after mastectomy or BCT.
Recurrence in the skin of the mastectomy site or on the chest
Scientific American Surgery
03/16
breast breast cancer — 14

Figure 3  Impact of basement membrane invasion: invasive cancer.

Scientific American Surgery

03/16
breast breast cancer — 15
Figure 4  Histologic subtypes of ductal carcinoma in situ.
wall muscle (local recurrence) is very uncommon, with a risk
of about 0.5 to 3%.52 The risk of local recurrence with
breast-conserving surgery is related to a number of patient
factors, including age, the histologic features of the DCIS, the
size of the DCIS, the extent of surgery, and the use of radia-
tion and antiestrogen endocrine therapy. Younger women
have a slightly higher risk of local recurrence.
BCT for DCIS consists of surgical excision (lumpectomy or
wide excision) of the DCIS with some surrounding normal
breast tissue to achieve a negative margin. It is often supple-
mented by radiation therapy to the breast. The choice between
BCT and mastectomy is influenced by the size of the area of
involvement, the size of the breast, and the location of the
DCIS. There is no specific size of a lesion that mandates
Scientific American Surgery
03/16
breast breast cancer — 16
Figure 5  Specimen mammogram of breast cancer–localizing wire. Note the malignant-appearing calcifications in the center of the specimen and
unrelated vascular calcifications in the periphery of the tissue.
mastectomy, and the use of wide excision with a generous
resection of breast tissue can be accomplished in most women.
The use of breast-conserving surgery has been expanded to
women previously thought to require mastectomy for larger
or extensive DCIS through the use of so-called oncoplastic
surgery.53,54 This allows resection of larger sections of the breast
and rebuilding of the breast to provide an excellent cosmetic
outcome. Reconstruction of the breast mound is available to
most women who require or choose mastectomy for DCIS.
Breast reconstruction may be performed at the same time as
the mastectomy using implant techniques or tissue transfer
using a variety of tissue flaps (see below).
A key factor to successful BCT for DCIS is obtaining a neg-
ative surgical margin. The margin is defined as the distance
measured in millimeters between the edge of the surgical
specimen and the closest tumor cells. The margin status may
affect the risk of local recurrence in DCIS and invasive cancer.
Surgical Considerations
At surgery, it is imperative that the breast lumpectomy
excision specimen be properly handled to allow determina-
tion of whether the cancer abuts the edge of the resected tis-
sue (margin). The first step is proper identification of the area
to be removed. Because DCIS is not palpable, the mammo-
gram or other images must be used to identify the area to be
removed. This is most commonly done by inserting a fine
wire into the breast to the area of the cancer, termed wire
localization or needle localization. The surgeon removes the
Scientific American Surgery
03/16
tissue around the end of the wire. To confirm removal of the
area of concern, an x-ray image or specimen mammogram is
obtained during surgery [see Figure 5]. An alternate technique
for localizing the area for excision is placement of an iodine-
125-labeled seed that is identified with a radioactive detector
during surgery.55
The specimen then must be carefully oriented so that if the
cancer is close to one margin, the pathologist can identify the
specific margin (e.g., anterior, posterior, medial, lateral, supe-
rior, inferior). This is most commonly accomplished by paint-
ing the surface of the tissue with ink, using a separate color of
ink for each of the six margins [see Figure 6]. The pathologist
can see this thin line of ink microscopically and determine the
distance in millimeters of cancer cells from the margin.
Another surgical technique to evaluate margins is to
remove separate surgical specimens from each margin after
removal of the cancer. For each margin, a “shave” of the sur-
gical cavity a few millimeters thick is obtained. Any cancer in
these shave specimens defines a positive margin, and the
absence is defined as negative. One randomized trial with
invasive cancer showed a lower rate of reexcision and posi-
tive margins with this technique.56
A positive margin is one where cancer cells are present at
the edge of the resected tissue. Because the DCIS may extend
beyond the area of calcifications seen on mammography, the
rate of positive margins on the initial excision for DCIS range
is as high as 20 to 25%. Women who have a positive margin
on the initial excision for DCIS should undergo repeat surgery
breast breast cancer — 17
Figure 6  Breast cancer wide excision specimen painted with six colors of ink to orient the specimen for pathologic analysis of surgical margins.
to obtain a negative margin. On occasion, even with such
reexcision, the DCIS extends to the new margin, and further
reexcision is needed. Some of these women ultimately require
mastectomy.
The definition of a negative margin is an area of ongoing
discussion.57,58 The clinical trials of local therapy in DCIS from
the National Adjuvant Breast and Bowel Project (NSABP) dis-
cussed below used the definition of a negative margin as the
absence of the ink used to paint the surgical margin on any
cancer cells (no ink on the tumor). In women treated without
radiation, the lowest recurrence rates are among women with
a full 1 cm margin of normal tissue around the DCIS.59 How-
ever, removing this much breast tissue may leave a significant
breast defect. In conjunction with radiation, a margin of 2 mm
is required to obtain optimal rates of local recurrence with
DCIS.60 However, a recent guideline primarily focused on
invasive cancer reiterated that there are no concrete data
showing that any distance of tissue for a negative margin
greater than “no ink on the tumor” provides any lower risk
of recurrence.61 It is not clear if this recommendation applies
to DCIS or if a margin of 2 mm or greater is warranted.
Choice of Breast Surgery
Most women with DCIS can be treated with breast-­
conserving surgery—commonly referred to as “lumpec-
tomy”—often combined with breast radiation. Some women
require mastectomy for DCIS. The most common indication
for mastectomy is extensive DCIS involving a large portion of
the breast or documented in multiple locations in the breast.
However, the definition of “extensive” is not always clear-cut.
For many patients, the choice between mastectomy and
breast conservation may be difficult. As DCIS is rarely a
threat to life, the small long-term risk of a second breast
malignancy is inevitably incorporated into this decision.
Some women with disease treatable by breast conservation
still select mastectomy. The choice may also be influenced by
the risk of developing a subsequent second breast cancer
related to family history and biologically defined inherited
susceptibility. Some patients elect mastectomy to avoid radi-
ation as well. Patients should receive careful counseling
regarding surgical options, a personalized surveillance plan,
and reassurances regarding the long-term outlook for women
with DCIS.62
Scientific American Surgery
03/16
breast breast cancer — 18
Radiation Therapy
Large-scale randomized clinical trials in North America
and Europe demonstrated the effectiveness of BCT and the
impact of radiation in minimizing the risk of local recurrence
in DCIS.63 Trials conducted in the 1980s and 1990s by large
cooperative oncology research groups, including the NSABP
and the European Organization for Research and Treatment
of Cancer (EORTC), compared wide excision alone versus
wide excision plus radiation therapy.64–68 Every study reported
long-term overall cancer-specific survival approaching 100%
irrespective of treatment. However, women treated by
breast-conserving surgery without radiation had a higher rate
of recurrence in the same breast (local recurrence) than those
treated with radiation. The rate of local recurrence in the first
trial, conducted in the 1980s (NSABP B-17 study), was over
30% without radiation and about 12% with radiation.64 This
60% relative reduction in the risk of local recurrence with the
use of postoperative radiation is consistent across other stud-
ies. Recurrences are mostly in proximity to the site of the orig-
inal DCIS. In one half to two thirds of cases, the recurrence is
DCIS but is invasive cancer in the remainder.69,70
The standard radiation treatment is breast radiation ther-
apy to the entire breast to a dose of about 50 Gy coupled with
an additional 15 Gy administered to the site of the surgical
excision (termed a boost). The use of whole breast radiation
reduces the risk to a low level that may in some cases be
reduced even further by use of an antiestrogen hormonal
agent (tamoxifen or an aromatase inhibitor; see below).
Because most local recurrences occur in the breast tissue
close to the original DCIS, it is possible that radiation admin-
istered only to the affected region of the breast may be as
effective as whole breast radiation therapy. Techniques for
administering so-called accelerated partial breast irradiation
(APBI) therapy allow treatment to be delivered over a much
shorter period of time (as short as 5 days or even a single
intraoperative dose), making it an attractive alternative.71–73
However, as of 2015, there are limited long-term data demon-
strating the effectiveness of APBI in DCIS and some data
showing a higher rate of local recurrence with APBI, so its
use remains controversial.73–75
Substantial research has focused on identification of those
women with DCIS who may not require radiation after
breast-conserving surgery. Some evidence from nonrandom-
ized series suggests that for some subsets of women with
DCIS, most notably those with a small area (size) of DCIS
coupled with a low or intermediate nuclear grade and a
greater width of the resection margin, the risk of local recur-
rence with surgery alone is substantially less than 10%—a
rate low enough to warrant omission of radiation.76–78 How-
ever, subset analysis of the randomized trials has been unable
to identify any group of women for whom radiation does not
reduce the risk of local recurrence.63 This remains an area of
active research, with investigators trying to identify molecu-
lar profiles and other features that identify those cases of
DCIS likely to have a local recurrence and/or progress to
invasive cancer.79 The use of radiation or the decision to omit
radiation therapy with DCIS requires careful counseling of
the patient coupled with multidisciplinary input.80
Scientific American Surgery
03/16
Lymph Node Surgery
DCIS does not spread beyond the breast; therefore, lymph
node surgery is not necessary for DCIS. However, in 10 to
20% of cases where there are only calcifications seen on imag-
ing and DCIS on the needle biopsy, an invasive cancer will
be identified in the final surgical resection specimen. Because
lymph node surgery may be necessary for those for whom
the excision shows invasive cancer, some surgeons have
advocated lymph node surgery in all women with DCIS
found by needle biopsy.
This is not appropriate in most cases because women
undergoing BCT can undergo sentinel lymph node biopsy
(SLNB, described below under treatment of invasive cancer)
at a subsequent surgical procedure with the same level of
accuracy as if done at the time of excision if an invasive can-
cer is identified in the final surgical specimen [see the discus-
sion of SLNB in the section on invasive cancer, below]. SLNB
carries some risk of long-term morbidity. Every prospective
study demonstrates that women with SLNB have a signifi-
cant risk, averaging about 6%, of at least mild permanent
swelling of the arm called lymphedema.81–83 Therefore, with
breast-conserving surgery for DCIS, SLNB should not be per-
formed at the time of surgical excision and should be reserved
only for those for whom the excision reveals invasive cancer.
Exceptions to this rule include cases where initial evalua-
tion prior to excision shows the presence of a mass suspicious
for invasive cancer on imaging or on physical examination or
when the DCIS is in the axillary tail of the breast and excision
may preclude subsequent SLNB because of interruption of
lymphatic flow to the axilla. Another exception is when mas-
tectomy is used for DCIS, SLNB is appropriate because mas-
tectomy may preclude subsequent SLNB due to disruption of
lymphatic flow and would therefore commit women to full
axillary lymph node dissection (ALND) if invasive cancer
were identified in the mastectomy specimen.
Adjuvant Systemic Therapy
In women who undergo radiation with DCIS, clinical trials
have shown that adjuvant endocrine therapy reduces the risk
of local recurrence. The NSABP B-17 trial showed that tamox-
ifen reduced local recurrence by 40% after lumpectomy and
radiation.84 A subsequent trial (NSABP B-35) comparing the
aromatase inhibitor anastrozole with tamoxifen in postmeno-
pausal women after excision and radiation for DCIS showed
an additional 27% reduction in local recurrence and new
breast cancers with anastrozole.85 Therefore, anastrozole is a
clear option in place of tamoxifen in postmenopausal women.
The use of endocrine treatment in DCIS must be balanced
against the toxicity of the selected drug, recognizing that
endocrine therapy is not lifesaving in this situation. There are
no data supporting the use of endocrine therapy in women
treated for DCIS with mastectomy, but it may be considered
because of its potential impact on reducing the risk of a can-
cer in the contralateral breast.
paget disease of the breast
Paget disease of the nipple is an uncommon presentation of
breast cancer. The hallmark of Paget disease is eczematous
changes directly in the nipple, often with beet red and ulcerated
breast breast cancer — 19

skin on the nipple and surrounding areola. This is due to
malignant cells called Paget cells occurring in the nipple skin
that have a characteristic “fried egg” microscopic appearance.
In most cases of Paget disease, there is DCIS or invasive can-
cer in the underlying breast.
Women with pagetoid changes in the nipple are often mis-
diagnosed as having benign skin conditions and are treated
with topical steroids. If such treatments are used and the
lesion does not resolve, or if there is any clinical suspicion of
Paget disease, a biopsy of the affected skin is needed. If the
biopsy shows Paget disease, then the breast should be care-
fully imaged by mammography. MRI may be useful if the
breast is dense or the mammogram is negative. If a breast
lesion is found, it too should be biopsied.
Treatment is generally based on the type (in situ or invasive)
of primary tumor in the breast. Both the cancer in the breast
and the nipple should be treated. This may be accomplished
in many cases with removal of the nipple in continuity with
the breast cancer, followed by radiation.86 Mastectomy is still
often used but may be reserved for cases with more extensive
involvement.87 Lymph node surgery with SLNB is warranted
only with invasive cancer or mastectomy. Adjuvant systemic
therapy is administered by standard guidelines based on the
stage and biomarker expression found in the invasive cancer.
lobular carcinoma may be more insidious because of the infil-
trative nature of the disease, making it more difficult to detect
by mammographic or clinical means.
Molecular Classification
Breast cancers are also classified by biologic or molecular
characteristics. These provide information about the likeli-
hood of developing distant metastases and long-term prog-
nosis, as well as information on sensitivity to specific drugs
to help guide therapy. One of the key characteristics is the
microscopic grade of the cancer. Grade is generally classified
as 1, 2, or 3, corresponding, respectively, to low, intermediate,
and high grade. The pathologist classifies grade on the basis
of the microscopic appearance. The most reliable way of
defining grade that pathologists should use for all breast can-
cers is the modified Bloom-Scarf-Richardson grade, also
referred to as the Nottingham grade.88 In this system, the
pathologist assigns a level of 1, 2, or 3 to each of three char-
acteristics of the cancer: nuclear pleomorphism, tubule for-
mation, and mitotic count. The sum of these individual
features assigns a score from 3 to 9. A score of 3 to 5 is grade

Invasive Breast Cancer

classification
The majority of breast
cancers are classified as
invasive or infiltrating,
characterized by the epi-
thelial cells invading
through the basement
membrane of the duct or
lobule. Properties that
allow basement mem-
brane invasion also
allow the malignant
cells to invade surround-
ing blood vessels or
lymphatic channels and
therefore carry the pos-
sibility of spread to dis-
tant sites. Most have
probably not spread as
assessed by long-term survival without distant metastases.
However, the treatment of invasive breast cancer must
include both the local treatment of the breast and consider-
ation of adjuvant drug therapy because of the potential for
distant spread.
The majority of breast cancer arises from the ductal compo-
nent of the terminal ductal lobular unit and is termed inva-
sive ductal cancer. An additional 10 to 15% arise within the Figure 7  Microscopic appearance of invasive ductal and invasive
lobule, termed invasive lobular cancer, which is character- lobular cancer. (a) Invasive ductal cancer showing nests of tumor cells
with formation of tubules. Note two large ducts at the top of the image
ized by small cells infiltrating in a linear fashion through the
showing a component of cancer cells confined to the duct: ductal carci-
breast stroma [see Figure 7]. Invasive lobular carcinoma car-
noma in situ. (b) Invasive lobular cancer showing an infiltrating process
ries the same risk of distant metastases as invasive ductal of lines of small single cells (often termed Indian filing). These are lin-
carcinoma. Therefore, the treatment and prognosis are those ear groups of cells one cell layer–thick surrounding benign ducts in the
of a comparably staged invasive ductal carcinoma. However, center of the image.

Scientific American Surgery

03/16
breast breast cancer — 20
Table 5  Nottingham Grading System for
Invasive Breast Cancer
Feature of Cancer Assigned Score
Tubule formation
  Majority of tumor (> 75%) 1 decisions based on pathology reports assigning these sub-
  Moderate degree (10–75%) 2
  Little or none (< 10%) 3 before acting.
Mitotic count
  0–9 mitoses/10 HPF 1 cancer characterized by rapid onset and skin edema and ery-
  10–19 mitoses/10 HPF 2
  20 or more mitoses/10 HPF 3
Nuclear pleomorphism
  Small regular, uniform 1 inflammatory cancer is made clinically based on the skin
  Moderate size and variation 2 appearance. Skin biopsy showing dermal lymphatic involve-
  Marked nuclear variation 3
Combined Histologic Grade Total Score
  Low (I) 3–5
  Intermediate (II) 6–7
  High (III) 8–9
HPF = high-power field.
1, 6 to 7 is grade 2, and 8 to 9 is grade 3, with a corresponding
worsening prognosis with increasing grade [see Table 5].
The other key markers in breast cancer are the hormone
receptors for estrogen and progesterone and the level of
expression or amplification of the HER-2/neu gene.30 These
should be tested in all invasive breast cancers. They provide
key prognostic and predictive information about the sensitiv-
ity of the cancer to specific drugs. It is expected that biologic
classification of breast cancers beyond these three markers
will ultimately allow a higher degree of personalization of
both local and systemic treatment.89–94
In 2015, there was increasing use of genomic sequencing of
breast and other cancers to identify specific molecular defects
that may be targeted with drugs or other therapies. Although
currently clinical practice relies primarily on the hormone
receptors and HER-2, the surgeon is well advised to stay cur-
rent in this field as changes may impact the type of surgery
and the timing of surgery vis-à-vis systemic therapy.
Certain histologic subtypes of invasive ductal cancer that
account for about 15% of cases may have a higher or lower
propensity to spread and a different prognosis than that of
typical invasive ductal cancer. These include tubular carci-
noma, mucinous (colloid) carcinoma, medullary carcinoma,
metaplastic carcinoma, and inflammatory carcinoma. Tubular
and mucinous carcinomas may have a lower rate of lymphatic
metastases and a generally better prognosis than typical duc-
tal cancers.95,96 Medullary cancer, characterized by extensive
lymphoid cell infiltration within the tumor, was historically
considered a cancer with a better prognosis. However, the
term can be overapplied based on pathologic criteria, and
most cancers classified as medullary are actually high-grade
cancers with a poor prognosis. Standard guidelines do not
assign medullary cancer to a good prognosis subgroup.30 Met-
aplastic cancer is an epithelial cancer with elements of squa-
mous differentiation. It has a worse prognosis than typical
Scientific American Surgery
03/16
invasive cancer. Some pathologists may overuse assignment
of these subtypes in cases where only a small portion of the
tumor has the requisite characteristics. Because of the poten-
tial overuse of these subgroup terms and the therapeutic
implication, great care should be taken in making treatment
groups. The surgeon is best advised to review the findings
carefully and dialogue with the interpreting pathologist
Inflammatory breast cancer is a variant of invasive ductal
thema encompassing over one third of the breast.97 It has an
especially high likelihood of subsequent metastases and
death. It often correlates with the histologic finding of dermal
lymphatics clogged by tumor cells, but the diagnosis of
ment is not necessary to classify a cancer as inflammatory.36,97
A complete and understandable pathology report is the
cornerstone of breast cancer treatment. Ambiguity can lead to
misclassification and inappropriate treatment. Pathology
findings for breast and all cancers should be reported using
structured documents according to the templates provided
by the College of American Pathologists (http://www.cap.
org). Surgeons should be sure that testing for their patients is
performed and reported in accordance with these standards.
treatment
The treatment of invasive breast cancer includes treatment
of the breast itself with surgery or surgery and radiation
(termed local therapy) and consideration of drugs to reduce
the chance of death from distant metastases (termed systemic
therapy). Historically, surgery has been the initial step in
treatment. However, increasingly, treatment begins with sys-
temic chemotherapy or endocrine therapy before surgery
(termed neoadjuvant therapy). Coordinating the local and
systemic therapies is critical to achieve optimal outcomes.
Local Therapy: Surgery and Radiation
The primary goal of local therapy of breast cancer is erad-
ication of the primary tumor to prevent progression and fur-
ther dissemination of the disease and to minimize the risk of
local recurrence. In addition, surgery to remove regional
lymph nodes for pathologic examination provides staging
and prognostic information, guides systemic treatment, and
provides regional control in the common regional nodal
basins. Although surgery is still most often the initial treat-
ment of breast cancer, neoadjuvant therapy should be consid-
ered in cases of large tumors, those with lymph node
involvement, or cancers with particular aggressive features
such as HER-2 overexpression or amplification.
Breast surgery  Historically, local treatment for resectable
breast cancers meant mastectomy. One can argue that the
development of the operation of radical mastectomy was the
single most important advance in the treatment of breast
cancer. At the time it was developed in the late 1800s by pio-
neering surgeons including William Halsted, most women
presented with breast cancers that were locally advanced and
were likely to progress to painful and infected chest wall
tumors. Radical mastectomy provided temporary or even
breast breast cancer — 21
permanent control of the cancer in the breast. Although many
still progressed with metastatic cancer at some point, radical
mastectomy controlled symptoms, eradicated the cancer in
the breast, and provided most with a high-quality life for
some time free of the progressing, locally infiltrative cancer.98
The ability to treat breast cancer effectively led to women
presenting with smaller cancers. Today, the number of
women with these terrible advanced local tumors is small,
and the classic radical mastectomy is rarely required. How-
ever, it was not until the 1960s that the so-called “Halstedian”
thesis that breast cancers progressed in a stepwise fashion
from the breast (local) to lymph nodes (regional) to distant
disease (metastases) was proven incorrect and that the need
for the extended radical procedures was questioned.
In the 1970s and 1980s, landmark clinical trials demon-
strated that breast cancer is a systemic disease with the possi-
bility of disseminated disease even at the smallest size primary
tumor and that removal of the tumor without mastectomy
provided a long-term outcome equivalent to mastectomy. The
first of these studies, the NSABP B-04 study, compared radi-
cal mastectomy with removal of the breast, pectoralis muscle,
and all regional lymph nodes to simple mastectomy without
removal of the pectoralis muscle or lymph nodes. This study
showed that extended surgery and lymph node removal
do not improve survival. This was followed immediately in
100
80
Percent Surviving
60
40
20
0
2 5
Years from Diagnosis
Figure 8  Overall survival from the NSABP B-06 Study; p = .57 for three-way comparison among treatment groups. Adapted from Fisher
B et al.99
1978 by the NSABP B-06 trial on which women with cancers
4 cm or less in size were randomly assigned to receive mas-
tectomy, lumpectomy alone, or lumpectomy plus radiation
therapy.99 Long-term follow-up on this trial demonstrated no
difference in overall survival between the three groups [see
Figure 8]. However, with lumpectomy alone, the cancer
recurred in the same breast in 40% of women. Radiation
reduced the rate of local recurrence to approximately 12%.
On the basis of this finding, coupled with those of other stud-
ies, lumpectomy plus radiation therapy became an accepted
standard in the 1980s and was widely used thereafter.
Subsequent studies in more recent decades in which women
had therapy under current standards of pathology, surgery,
and radiation and received stage- and biomarker-appropriate
adjuvant systemic therapy have extended the initial findings
supporting breast conservation. As outlined below, local
recurrence with BCT is as low as, or even lower than, that
with mastectomy. Indeed, recent population studies suggest
that survival may be better with breast-conserving surgery
than with mastectomy.100
This review does not provide detailed information on the
technical performance of breast surgery. For this the reader
is directed to search this publication for breast procedures
and to the American College of Surgeons’ 2015 publication
Operative Standards for Cancer Surgery.101
Mastectomy
Lumpectomy
Lumpectomy+Radiation
8 12 16 20
Scientific American Surgery
03/16
breast breast cancer — 22
Table 6  Relative Indications for Mastectomy
Extensive invasive or in situ cancer with failed breast-conserving
surgery
Positive margins despite reexcision (no absolute limit on number
of reexcisions)
Multicentric cancer (more than one cancer) in separate
quadrants/separated by 5 cm
Diffuse microcalcifications related to cancer (e.g., extensive DCIS
component)
Large cancer in relation to size of breast (consider neoadjuvant
therapy)
Previous radiation to ipsilateral breast where radiation would
provide excessive dose to chest wall
Patient preference, especially with inherited susceptibility; careful
counseling required
DCIS = ductal carcinoma in situ.
Margins with BCT  Successful BCT requires surgical exci-
sion of the cancer to obtain negative margins of resection
around the tumor. As with DCIS, major clinical trials testing
BCT defined a negative margin as no ink on the tumor
[see Figure 6]. In 2013, a task force sponsored by the Society of
Surgical Oncology (SSO) and the American Society for Thera-
peutic Radiation Oncology (ASTRO) concluded a detailed
analysis of available data on the impact of margin width on
recurrence and published a guideline recommending that the
only margin width required to provide optimal low risk of
local recurrence is no ink on the tumor.61 The task force also
cautioned that aggressive surgery to obtain wider margins
provides no improvement in the risk of local recurrence and
may be harmful by requiring repeated surgeries, potentially
producing inferior cosmetic results and leading more women
to otherwise unnecessary mastectomy.
Therefore, BCT should provide a negative margin defined
by no ink on the tumor. If there is cancer (invasive or DCIS) at
the resection margin, additional surgery to remove more tissue
at this margin is necessary. A specific exception where a pos-
itive microscopic margin may be acceptable is at the chest wall
where the pectoralis fascia has been taken and anteriorly at
the skin. Otherwise, if a negative margin cannot be obtained
with lumpectomy, including with a second or occasionally a
third operation for reexcision, mastectomy is necessary.
Unfortunately, a substantial percentage of women require
more than one operation on the breast to achieve a negative
margin. Careful management and attention to detail limit the
need for reexcision. Factors that minimize the need for reex-
cision include obtaining a diagnosis before any surgery
through the use of needle biopsy, careful preoperative plan-
ning and imaging localization, and careful collaboration with
the radiologist and pathologist in intraoperative management
of the surgical specimen.
A majority of women with cancers less than 5 cm in size
may be treated with BCT. However, some require mastec-
tomy [see Table 6]. None of the indications for mastectomy are
absolute, but they need to be carefully considered in counsel-
ing women. These relative indications include the presence of
separate cancers in distinct parts of the breast separated by at
least 5 cm of normal breast tissue, termed multicentric cancer.
This occurs in 2 to 5% of cases. Other indications for mastec-
tomy include a very large tumor in relation to the size of the
breast that is not amenable to or does not respond sufficiently
Scientific American Surgery
03/16
to neoadjuvant systemic therapy and patients with a history
of previous radiation treatments to the breast, as with a pre-
vious breast cancer or other cancers, such as Hodgkin lym-
phoma. Mastectomy may also be needed if surgical margins
remain positive despite reexcision (often more than one reex-
cision). BCT is not advised for inflammatory breast cancer
because of the likelihood of microscopic multicentric cancer
within the breast and within the skin of the breast.
Oncoplastic breast surgery  One of the reasons often cited
for mastectomy is the need to resect a large area of the breast,
with the resulting poor appearance of the breast. Over the last
10 years, a new area of breast surgery has evolved that applies
plastic surgery principles to reconfiguring the breast after re-
section of a large specimen. This is called oncoplastic breast
surgery.53,54 A variety of techniques allow preservation of the
breast and its normal sensation and appearance where previ-
ously mastectomy was performed. This may be done inde-
pendently by a qualified and experienced breast surgeon or in
collaboration with a plastic surgeon.
Breast reconstruction  Women treated with mastectomy
may consider reconstruction of the breast mound performed
either at the time of mastectomy (immediate reconstruction)
or at a later time (delayed reconstruction).102 Immediate recon-
struction is reasonable in women with early-stage breast cancer.
However, the potential need for postmastectomy radiation
must be considered in reconstruction planning.103 Although
satisfactory cosmetic outcomes may be obtained even with
radiation to the implant, radiation increases the rate of painful
contracture. Decisions regarding immediate breast reconstruc-
tion should be made in collaboration with the entire multidis-
ciplinary treatment team. Conversely, delayed reconstruction
requires that the woman live without the reconstructed breast
for a period of 1 to 2 years and may be more difficult to per-
form because there is less skin remaining from the original
mastectomy to be used in reconstruction. However, more
advanced cancers, such as those invading the skin or chest
wall (T4) or extensive node involvement, are best treated by
mastectomy without immediate reconstruction.
Options for breast reconstruction include prosthetic recon-
struction with an implant or tissue expander generally placed
beneath the pectoralis major muscle or transfer of autologous
tissue from another region in the body.102 Implant reconstruc-
tion is generally simpler and quicker to perform but may not
leave as attractive an aesthetic result. Complications of
implant reconstruction include contracture around the
implant (that may be exacerbated if radiation is necessary)
and infection resulting in loss of the implant.
Autologous tissue reconstruction often leaves a superior cos-
metic result but at the cost of more complex surgery, longer
recovery, and the potential for complications at the site of the
donor tissue. The most common donor sites are the rectus
abdominis muscle (transverse rectus abdominis myocutaneous
[TRAM] flap), the more superficial fat and skin from the
abdominal wall (deep inferior epigastric perforator [DIEP]
flap), and the lattissimus dorsi muscle flap. These flaps may be
used in conjunction with complete sparing of most of the skin
of the breast (skin-sparing mastectomy), which provides for a
superior cosmetic outcome. In general, the nipple and areola
are resected with mastectomy. In select circumstances such as
breast breast cancer — 23

Figure 9  Anatomy of the axilla. (a) The levels of the axilla are defined by the surrounding muscles and the axillary vein. Level I are nodes later-
al to the pectoralis muscle. Level II nodes reside between the lateral to medial border of the pectoralis minor muscle. Level III nodes are those
medial to the pectoralis minor muscle to the thoracic inlet. Most but not all sentinel nodes are in level I. (b) Key structures to recognize and protect
in axillary surgery.

small tumors located in the periphery of the breast or for breast
cancer risk-reducing surgery, mastectomy that preserves the
nipple (nipple-sparing mastectomy) is reasonable.104–107
Many factors impact the choice to do reconstruction, the
timing of reconstruction, and the type of reconstruction.
Patient factors affecting reconstruction planning include breast
size, body habitus, recent or ongoing tobacco use, diabetes,
and obesity. In addition, factors related to the cancer itself,
such as stage, risk of recurrence, and the likelihood of the need
for postmastectomy radiation, also impact these decisions.
Lymph node surgery  The presence of metastases in
regional lymph nodes is a key prognostic factor used in
making treatment decisions. In addition, removing lymph
nodes prevents recurrence risk in the regional lymph node
basin. However, treatment of lymph nodes does not itself affect
survival. Surgery for removal of regional lymph nodes is the
only accurate way to determine if nodes are involved with
cancer. Noninvasive testing of the regional lymph nodes with
PET, MRI, and ultrasound imaging has insufficient sensitivity
and specificity to replace surgical resection.108 Therefore, if the
nodal status is needed for staging to plan subsequent systemic
or radiation treatment, surgical evaluation of regional nodes
remains a key component of breast cancer care.109
Lymph from the breast drains primarily through the axil-
lary lymph nodes.110 A small fraction of lymph drainage from
the breast is through other pathways, including direct drain-
age through the supraclavicular nodes and the internal mam-
mary chain.111 Because the majority of drainage is through the
axilla, and because of the potential morbidity of internal
mammary lymph node dissection, surgical evaluation of
women with breast cancer is generally limited to the axilla.
The axilla contains an average of 15 to 20 lymph nodes
extending under the axillary vein medially toward the thoracic
inlet [see Figure 9]. Until 15 years ago, evaluating these nodes
required dissection of the entire axillary contents. Although
ALND is a safe operation, it carries substantial risk of long-
term morbidity related to disruption of the lymphatic flow
from the arm and permanent swelling, termed lymph-
edema,112–114 as well as paresthesias due to irritation or inter-
ruption of the intercostobrachial nerves in the axilla.
Lymphedema is a chronic lifelong condition that ranges from
minimal effects to disabling swelling. The risk of lymphedema
is 10 to 15% with axillary dissection alone and substantially
higher when radiation is also required after node dissection.82,115
Sentinel lymph node biopsy  During the 1990s, investiga-
tors tested the hypothesis that lymphatic flow from a tumor
drained through a definable pathway and that drainage to the
axilla could be mapped using radioactive or large colloidal
particle tracers. The premise is that the tracers are trapped in
the first few lymph nodes identified by these mappings, that
these are the same nodes to which cancer spreads, and that the
presence or absence of cancer in these sentinel nodes defines
the status of the entire axillary lymph node basin. Testing
proved this hypothesis correct.116,117 Therefore, to determine if
the axillary nodes are positive, only a few lymph nodes must
be removed, and full ALND is not necessary for those with

Scientific American Surgery

03/16
breast breast cancer — 24
negative sentinel nodes. Morbidity, including the risk of
lymphedema and paresthesias, is markedly lower with SLNB
than with axillary dissection. However, SLNB is not risk free.
Lymphedema still occurs even with SLNB, with rates of mea-
surable lymphedema on average about 6% compared with
15 to 20% with axillary dissection.81,83
SLNB is appropriate for any woman with an invasive can-
cer and clinically negative nodes. Those with clinically posi-
tive nodes are not candidates for SLNB and should have full
ALND or neoadjuvant therapy. If there is a question about
the clinical status of lymph nodes, involvement of nodes may
be confirmed before surgery using ultrasound-guided needle
biopsy (core-needle biopsy or FNA). It may also be consid-
ered for women with local recurrence after previous
breast-conserving surgery and radiation who had a previous
SLNB, although the accuracy of SLNB in this setting has
never been fully proven.
SLNB is performed by injecting a radiolabeled sulfur col-
loid and/or blue dye (isosulfan blue or methylene blue) into
the breast either into the periareolar skin and under the are-
ola or around the tumor (peritumoral). Many surgeons per-
form SLNB with either radioactive colloid or blue dye tracer,
and others recommend using both in all cases. Over a few
minutes, this drains to and is trapped in the first few lymph
nodes that drain the breast lymph. The tracer(s) are found in
an average of three lymph nodes that are removed and exam-
ined for metastases.
The agents used for SLNB are safe. Isosulfan blue adminis-
tration has about a 0.5% risk of immediate anaphylaxis with
hypotension and an occasional case with rapid onset of hives.
Methylene blue may cause skin necrosis in a few cases. These
blue dyes should not be used in pregnancy because of the
potential teratogenic effects. However, radioactive sulfur col-
loid is generally considered safe to use in pregnancy because
the radiation dose to the fetus is exceedingly low, although
safety data are relatively limited.
Management of patients with a positive SLNB has histori-
cally been to perform complete axillary dissection. This is still
the standard when performing a mastectomy, although this
may change in the next few years. The practice has changed
because of randomized trials of axillary dissection compared
with no further axillary surgery for those with limited axil-
lary node involvement. The most notable trial is American
College of Surgeons Oncology Group (ACOSOG) Z0011.118 In
this study, women treated with breast-conserving surgery
who had one or two positive sentinel nodes were random-
ized between completion ALND and no additional axillary
surgery. The large majority of these patients received adju-
vant radiation to the breast as well as adjuvant endocrine
therapy and/or chemotherapy. There was no difference in
local, axillary, or distant recurrence or in survival between
these groups. Primarily on the basis of this study, it is now
accepted that axillary dissection is not necessary for women
with one or two positive sentinel nodes treated with
breast-conserving surgery, systemic therapy, and whole
breast radiation.117 Women treated with breast-conserving
surgery with more than two positive sentinel nodes or those
with bulky or matted axillary nodes should still have full
axillary dissection.
Scientific American Surgery
03/16
It is unclear to what extent the low rate of axillary recurrence
in the ACOSOG Z0011 study was due to radiation of part of
the axilla. In 2014, the findings of a review of the extent of
radiation administered to the breast on the study were pub-
lished showing that about 20% of the patients had radiation to
the axilla beyond what was allowed in the protocol.119 It is
unlikely that this could impact the overall findings of the study,
but the editorial accompanying the article recommended more
detailed analysis of the ACOSOG Z0011 findings.120
Microscopic lymph node involvement  A key factor for surgeons
is to understand the prognostic significance of the microscopic
lymph node involvement. The prognosis in breast cancer is
better when there is minimal cancer in the lymph nodes com-
pared with larger and more extensive deposits. There are two
classes of microscopic lymph node involvement as codified in
the AJCC staging system: isolated tumor cells (ITCs) defined
as small clusters of cells measuring 0.2 mm or less and
micrometastases defined as tumor deposits from 0.2 to 2 mm.
ITCs have minimal or no prognostic impact and are classified
as negative nodes (N0(i+)).121,122 Micrometastases are classified
as positive with a “mi” descriptor (N1mi).
SLNB with neoadjuvant therapy  SLNB can be performed ei-
ther before neoadjuvant chemotherapy is initiated or after
completion of chemotherapy. With both approaches, sentinel
nodes that are identified appear to provide accurate informa-
tion on node status. Most surgeons perform SLNB after neo-
adjuvant therapy in those with clinically negative nodes and
omit axillary dissection when the sentinel lymph node is neg-
ative. At the current time, ALND remains the standard when
sentinel lymph nodes are positive after neoadjuvant therapy.
As discussed below, neoadjuvant chemotherapy may result in
a major shrinkage or in some cases complete eradication of
the cancer in the breast and nodes (termed a pathologic com-
plete response [pCR]). A recent ACOSOG study examined the
feasibility of SLNB after neoadjuvant chemotherapy in
patients initially presenting with positive lymph nodes.123 In
women with a negative sentinel node after chemotherapy,
12% had other positive lymph nodes (12% false negative rate).
Additional studies are ongoing to determine if omission of
axillary dissection is appropriate when a pCR in the nodes is
obtained with neoadjuvant therapy.
Radiation  Radiation to the area of the breast is necessary
in most cases of cancers treated by BCT to reduce the chance
of recurrence in the breast area (local recurrence). Radiation is
also necessary for select cases treated with mastectomy.
Radiation with mastectomy  Mastectomy should be supple-
mented with radiation when the cancer is over 5 cm in size,
when surgical resection margins are close or positive, or when
lymph nodes are involved.124 The “textbook” standard is that
radiation is indicated with four or more positive nodes. How-
ever, radiation should be considered even when only one to
three nodes are involved. Meta-analyses of available random-
ized trials published in 2014 showed improved survival with
postmastectomy radiation therapy even with one to three
positive nodes, although the absolute level of improvement
may be very small, with very limited nodal involvement.125,126
The potential need for radiation after mastectomy may
affect decisions regarding immediate breast reconstruction.103
breast breast cancer — 25
Reconstruction may complicate radiation dosimetry and
uniform dose delivery over the entire field and increase the
volume of treated tissue, including the lung and heart. In addi-
tion, radiation may compromise the cosmetic result of recon-
struction through contracture of the scar capsule around an
implant and/or loss of tissue volume within an autologous
tissue flap. The potential need for radiation after mastectomy
should be discussed with all women having mastectomy for
invasive breast cancer. Referral to a plastic surgeon specializ-
ing in reconstruction and to a radiation oncologist before sur-
gery can allow for detailed discussion about the risks and
benefits to immediate versus delayed reconstruction for the
patient who is likely to require postmastectomy radiation.
Radiation with BCT  Radiation is generally administered in
all cases with BCT. Radiation reduces the risk of local recur-
rence compared with lumpectomy alone by as much as 70%.
This is true regardless of the size of the cancer. Subset analysis
of large clinical trials and limited clinical trials in women with
small cancers have not identified any group of small cancers
for which radiation does not reduce the risk of local recur-
rence. Although the initial studies of BCT showed no impact of
radiation on survival, more recent data suggest that radiation
with BCT improves both local recurrence and survival.43,100,127
One group where radiation may be omitted after breast-­
conserving surgery is women age 70 and over with cancers
that are hormone receptor positive and 2 cm or smaller and
who have clinically negative axillary lymph nodes. Two clin-
ical trials demonstrated that radiation offers little or no clini-
cal advantage in this situation. A Cancer and Leukemia
Group B (CALGB) study in the 1990s randomly assigned
women meeting these criteria to lumpectomy with radiation
and tamoxifen or to lumpectomy with tamoxifen only.128,129
There was no difference in long-term survival at a median
follow-up of 12 years. Local recurrence occurred in 2% with
radiation and 10% without radiation. However, ultimately,
the outcome was not impacted by this slightly higher rate of
local recurrence. Most women treated initially without radia-
tion could be treated with a repeat lumpectomy (with or with-
out radiation), whereas those who received radiation initially
all had mastectomy. Therefore, omission of radiation is rea-
sonable in this group. A trial of lumpectomy with adjuvant
hormone therapy with or without radiation in the United
Kingdom for women age 65 and over with estrogen receptor–
positive tumors under 3 cm showed a local recurrence rate of
4% without radiation and 1.3% with radiation.130 There was
no difference in survival. A similar trial conducted in Canada
for women age 50 and over demonstrated local recurrence
rates of about 15% among women between ages 50 and 70,
lending caution to omitting radiation for younger women.131
Historically, the standard radiation treatment after
breast-conserving surgery is treatment of the entire breast to
a dose of about 50 Gy, with an additional boost of radiation
to the primary tumor site of 15 Gy, taking about 7 weeks
overall. For women with relatively smaller breasts and body
habitus, an alternative is administration of the entire radia-
tion dose in 16 fractions over about 3 weeks, termed hypo­
fractionation.132–134 Hypofractionated whole breast radiation
has equivalent efficacy and provides substantial time and
cost savings for the patient and for the health care system.
Partial breast radiation  Recent clinical research has focused
on limiting the extent and time required to deliver radiation to
the breast. Most recurrences occur at or near the primary
tumor site. Only about 15% of new events in the treated breast
occur outside this area and are most likely a new second pri-
mary cancer. Limiting radiation to the site of the primary
cancer might provide local control equivalent to whole breast
radiation therapy. APBI has a key advantage: it may be deliv-
ered in a much shorter time frame, generally two fractions a
day over only 5 days. Another purported advantage is that if
there is a second disease event in the affected breast, this may
be treated by a repeat lumpectomy rather than mastectomy,
although there are no data to support this thesis.
There are a number of techniques to deliver APBI.135 The
technique with the longest-term follow-up, albeit in a limited
number of patients, is multicatheter brachytherapy.136 This tech-
nique is cumbersome, unsightly, and seldom used. Alternative
techniques for delivery of APBI include three-­ dimensional
CT–directed external-beam radiation or brachytherapy using a
radiation seed in a multilumen catheter placed in the lumpec-
tomy site. A single dose of radiation administered during
surgery (intraoperative radiation therapy [IORT]) may also be
sufficient.137,138
Long-term data from controlled clinical trials demonstrat-
ing the safety and effectiveness of these techniques are lim-
ited.72,133,135,139 Data from noncontrolled series with relatively
short-term follow-up show promising findings, albeit per-
haps with a slightly higher local recurrence compared with
standard radiation.74,75 Large clinical trials are ongoing,
including a study by the NSABP. As of 2015, APBI or IORT
is being used by many surgeons but is often limited to those
with lower risks of local recurrence based on guidelines from
the American Society of Breast Surgeons, American
Brachytherapy Society, or ASTRO.140–142 There are reports
from some analyses of administrative and other data that the
cosmetic outcome may be inferior with APBI.143 The use of
APBI has decreased in the last few years. The overall safety
and efficacy of APBI are uncertain, and we must await fur-
ther trial results before broad application of this technique.
Whole breast radiation therapy is safe and well tolerated and
remains the gold standard.30,144–146
Side effects of breast radiation  The immediate effects of radi-
ation include skin reaction and occasional skin breakdown.
This is generally readily managed. Fatigue is another com-
mon issue during radiation. The most serious long-term effect
is a slight increased risk in coronary artery disease presenting
years or decades after breast radiation for left-sided cancers,
but this added risk is very low. Less significant effects include
tenderness and potentially volume loss in the treated breast,
breast lymphedema, pneumonitis, and an increase in the risk
of rib fractures in the treated field. In addition, a serious but
very rare effect is an angiosarcoma in the treated field.
management of the contralateral breast
Women with breast cancer have a risk of second malignan-
cies, including the risk of developing a contralateral primary
breast cancer. Outside the setting of inherited susceptibility
(mutations in the BRCA1 or BRCA2 or other breast cancer–
related genes), the chance of developing a contralateral pri-
mary breast cancer is about 10% over 20 to 30 years.99
Endocrine therapy for treatment of hormone-positive breast
Scientific American Surgery
03/16
breast breast cancer — 26
cancer further reduces the risk of a contralateral breast. Since
the average woman diagnosed with breast cancer is in her 50s
or 60s, and most of these contralateral breast cancers will be
effectively treated, the risk that a woman with a breast cancer
will succumb to a new contralateral breast cancer in her life-
time is far outweighed by both the risk of death from the
current breast cancer and the long-term risk of death from
other causes. Therefore, prophylactic treatment of the contra-
lateral breast is generally not necessary.
Lobular cancer was historically thought to convey a much
higher risk of a contralateral breast cancer compared with
ductal cancer. However, any added risk of contralateral can-
cer in a woman with lobular cancer is relatively small. A
recent population study from the Netherlands showed that
over 10 years, the risk of a contralateral breast cancer was
3.5% with ductal cancer and 4.1% with lobular cancer.147
Therefore, the presence of lobular compared with ductal can-
cer should have little bearing on the consideration of contra-
lateral prophylactic treatment.147,148
Careful counseling can largely allay a woman’s fears of the
impact of the risk of a second cancer. For young women, or
those with a family history suggesting inherited susceptibil-
ity, referral for genetics evaluation and possible testing is
warranted to help identify those who may benefit from con-
tralateral prophylactic mastectomy and/or risk management
and preventive measures for other cancer types (e.g., ovarian,
gastric).
However, some women, especially those undergoing mas-
tectomy for the index cancer, may request contralateral mas-
tectomy regardless of a defined low risk and despite careful
counseling. Recent observational studies demonstrate that
the number of women undergoing prophylactic contralateral
mastectomy increased significantly over the last decade. For
example, in New York State, the rate of contralateral mastec-
tomy among those treated with mastectomy rose from about
4% of women treated in 1995 to 15% in 2005.149 The rising rate
of contralateral prophylactic mastectomy has been the subject
of recent study, with proposed reasons including improved
reconstruction outcomes, increasing use of breast MRI, and
increased awareness of hereditary cancer syndromes.
choice of breast surgery in women with breast
cancer inherited susceptibility
The issues in selection of breast cancer surgery are different
for women with inherited susceptibility from breast cancer–
related genes. The most common are BRCA1 and BRCA2, but
recent research and the use of next-generation sequencing
tools are showing a broader spectrum of breast cancer genes
involved in breast cancer inherited susceptibility.11 Women
with inherited susceptibility are generally younger at the
time of the initial breast cancer diagnosis and have a higher
risk of developing a second cancer in the same (ipsilateral) or
contralateral breast. The risk of a contralateral breast cancer
is dependent on the age at which they are diagnosed with
their first breast cancer: 25 to 50% for those under age 50 at
the initial diagnosis, 15 to 20% for those over age 50, and
lower for those over age 60.150
Women who have inherited susceptibility with a known
mutation in BRCA1, BRCA2, or other breast cancer–related
genes also often choose mastectomy or bilateral mastectomy.
The overall survival for women treated with BCT in this
Scientific American Surgery
03/16
situation is the same as for women without inherited suscep-
tibility.151 However, the women are at increased risk for
developing a second primary cancer in the same breast, a risk
that approaches 50%, especially in women under age 50 at the
initial diagnosis.150 There are some emerging data that women
with inherited susceptibility who undergo bilateral mastec-
tomy when treated for a breast cancer may have slightly
improved long-term survival.152 The choice of bilateral mas-
tectomy must be carefully considered in the context of the
risk of metastases from the index cancer (e.g., those with
advanced cancers may have less to gain from mastectomy)
and the patient’s age. Women in their 60s or above with a
BRCA1 or BRCA2 mutation have a substantially lower risk
of a contralateral breast cancer over their lifetime than women
in their 30s or 40s and gain little or no advantage from
mastectomy.
treatment of local recurrence after mastectomy
or breast-conserving surgery
Local recurrence after surgical treatment of breast cancer
occurs with both mastectomy and BCT. When performed by
experienced surgeons with careful pathologic control, appro-
priate radiation, and stage-appropriate adjuvant systemic
therapy, the rate of local recurrence with BCT is as low as 1 to
5%. Biomarker-appropriate adjuvant systemic therapy is also
a key factor in minimizing the risk of local recurrence.153
Local recurrences are also a significant issue among women
treated with mastectomy. This risk is about 2 to 5% for
women with negative lymph nodes and ranges as high as
25% for women with multiple positive lymph nodes who do
not receive radiation.154,155 In general, mastectomy provides
no benefit over breast-conserving surgery measured by the
risk of local recurrence.
Local recurrence is a serious event regardless of the type of
initial surgery. These women have a higher risk of develop-
ing distant metastases compared with women with similar-­
stage cancer who do not suffer local recurrence. It has
previously been generally cited that radiation only impacts
the risk of local recurrence and not overall survival. How-
ever, meta-analysis of all available data for women treated
with BCT and mastectomy demonstrates that radiation ther-
apy not only reduces the risk of local failure but also improves
survival.127 The best estimate is that radiation saves one life
for every four local recurrences prevented. Radiation is there-
fore recommended for women who have a risk of local failure
over 10% regardless of the type of primary surgery.
The accepted treatment for local recurrence after BCT is
mastectomy. This is because the recurrence may be multifocal
and because full-dose radiation is difficult to administer
safely a second time due to cumulative tissue toxicity. In care-
fully selected patients, repeat lumpectomy with additional
whole breast or partial breast radiation may be performed,
but most consider this an investigational approach.
Local recurrence after mastectomy is more difficult to treat
and carries a more serious prognosis. Treatment usually
includes resection of a local recurrence in the skin, muscle, or
regional nodes if possible, followed by radiation to the chest
wall and regional nodes. If previously treated with radiation,
targeted radiation may be used despite the very high cumu-
lative dose with related toxicity.
breast breast cancer — 27
The role for additional adjuvant systemic therapy after
local recurrence is uncertain, although there are some limited
data supporting its use.156 Many oncologists will deliver addi-
tional systemic treatment based on the type of previous treat-
ment and the nature and extent of the local recurrence.
selection of breast-conserving therapy versus
mastectomy
The decision between BCT and mastectomy is a complex
and difficult one for women with breast cancer. From a tech-
nical standpoint, BCT is possible in the large majority of
women with breast cancer: more than 90% of women with
tumors under 2 cm in size (T1) may undergo BCT. However,
many other factors in addition to the technical ability to per-
form BCT affect the decision. Ultimately, the individual
patient is the determinant of whether or not she will have a
mastectomy. Her choice may be influenced by perceptions or
values based on personal or family experiences, real or per-
ceived increased risks of recurrent cancer based on the family
history, willingness to pursue radiation treatment, ability to
comply with imaging surveillance, and other factors.62
Counseling women regarding the choice of surgery is one
of the most important tasks for the treating surgeon.157 Sur-
geons need to learn the skills of nondirective counseling and
must incorporate other professionals and resources into their
practice. Careful study of the decision-making process has
shown that physicians are not necessarily fully sensitive to
their patient’s concerns or to their styles of decision mak-
ing.158,159 This has led to the development of decision aid sup-
port tools and to the recognition of the need for
multidisciplinary counseling, especially in more complex sit-
uations or those associated with questions surrounding
inherited susceptibility and genetics.160
One of the key factors in this process is the recognition that
breast cancer treatment is not an emergency. There are no
data that treatment initiated within a few days of diagnosis
improves outcome compared with treatment delayed a rea-
sonable period of time, measured in a number of weeks or
even months. Women should be provided with the opportu-
nity to seek additional counseling, research information on
their own, and obtain second opinions if they so desire. Inclu-
sion of professionals of other disciplines, including radiation
oncology, plastic surgery, medical oncology, radiology, psy-
chology, social work, nursing, and genetics, may be war-
ranted. Unfortunately, there are data suggesting that surgeons
do not appropriately coordinate services with other disci-
plines in breast cancer care.161
adjuvant systemic therapy
Women with invasive cancer need to consider systemic
drugs in addition to treating the breast because of the risk of
developing distant metastases. These metastases develop
from microscopic dissemination of cancer cells prior to diag-
nosis. The decision depends on both the estimated risk of
developing metastatic disease and the degree of benefit that
treatment may provide. These risks are estimated by analyz-
ing features of the cancer, including the size of the invasive
component of the cancer, the presence or absence of regional
lymph node metastases, the grade of the cancer, and the pres-
ence or absence of specific biomarkers associated with prog-
nosis and response to treatment. The three clinically used
markers are the estrogen receptor, the progesterone receptor
(collectively referred to as hormone receptors), and HER-2/neu
protein expression or gene amplification. Other markers are
described, but their utility in defining prognosis and treatment
is unproven. These include Ki-67 and the androgen receptor. In
making these assessments, it must be recognized that a sub-
stantial fraction of women with negative lymph nodes will
develop metastatic disease and require systemic therapy.36
In stage I and stage II cancer, it is not necessary to perform
staging studies such as bone scanning, CT, PET, and MRI in
all women. These are not sensitive at detecting this micro-
scopic metastatic disease; they are negative in most cases, yet
these individuals have the same risk of future development
of metastatic cancer as those who do not have scans. Further-
more, there is a substantial chance of false positive scans,
requiring extensive evaluation, further invasive studies, and
a delay in initiation of treatment.
Adjuvant systemic therapy for breast cancer consists of two
major classes of drugs: endocrine drugs that block synthesis
(aromatase inhibitor) or the effect of circulating estrogen
(SERM) on breast cancers that express estrogen and proges-
terone receptors and systemic cytotoxic chemotherapy. The
discussion below provides general concepts of the use of
adjuvant systemic therapy based on stage and biomarker sta-
tus. Specific treatment recommendations change regularly
with accumulating evidence, so advice regarding the exact
regimens appropriate for a given case is not possible in a
review such as this. The best available treatments are codified
in widely accepted and regularly updated practice guidelines
developed and updated annually by the American Society of
Clinical Oncology (ASCO), NCCN, and others.30
Timing of Adjuvant Systemic Therapy: Before or After
Surgery?
The standard treat-
ment for breast cancer
has been to perform
breast and axillary sur-
gery as the initial step in
treatment and use the
information from surgery
(pathologic stage) to
define the best adjuvant
systemic therapy. How-
ever, mounting evidence
supports delaying surgery
until after completion of
systemic therapy. Presur-
gical therapy—so-called
neoadjuvant therapy—
was first investigated in
the 1970s and 1980s
mostly for those with
large, potentially unre-
sectable cancers. Neoad-
juvant chemotherapy often reduced the size and extent of the
cancer more than 50%, with 15 to 25% having complete dis-
appearance of cancer clinically. Half of those women had no
viable tumor identified pathologically (pCR). Neoadjuvant
chemotherapy is now the accepted standard treatment for
locally advanced and inflammatory breast cancers (stage III).
Scientific American Surgery
03/16
breast breast cancer — 28
These findings with locally advanced breast cancer led to
studies of neoadjuvant chemotherapy with smaller cancers.162
Large-scale studies, most notably the NSABP B-18 study,
demonstrated similar cancer responses.163 Neoadjuvant ther-
apy did not convey any survival advantage over chemother-
apy administered postoperatively. However, women treated
with neoadjuvant chemotherapy were more likely to have
BCT, and the rate of local recurrence was not increased. Fur-
thermore, the degree of response to neoadjuvant therapy is
itself of significant prognostic importance.163–165 Those women
who achieve a major response, especially those who achieve
a pCR in the tumor, are more likely to have long-term sur-
vival compared with those who do not.162 Because of the
prognostic significance of response to neoadjuvant therapy,
in 2013, the Food and Drug Administration approved the use
of pCR as an end point for clinical trials to assess the effec-
tiveness of new drugs or drug combinations in breast cancer.
This may speed the process of identifying effective drugs in
breast cancer therapy.166
Neoadjuvant endocrine therapy may also be of value in
select cases.167,168 A response to neoadjuvant chemotherapy is
most likely among women with high-grade and endocrine
receptor–negative cancers. Cancers that are endocrine recep-
tor positive are less likely to respond to neoadjuvant chemo-
therapy. However, these tumors may respond to neoadjuvant
endocrine therapy with similar benefits in terms of surgical
treatment. With endocrine therapy, the time to maximal
tumor response is longer than with chemotherapy; it may
take 6 months to achieve a maximum tumor response prior
to surgery.
It is also reasonable to administer neoadjuvant therapy to
any woman who would otherwise receive systemic treatment
for breast cancer. In general, neoadjuvant therapy is adminis-
tered to those with larger T2 cancers (those over 3 to 4 cm in
size) and T3 cancers in an effort to allow breast-conserving
surgery. Increasingly, it is also used with even smaller tumors,
especially those that are HER-2 positive or triple negative. In
addition, neoadjuvant therapy is the treatment of choice for
those with cancer that involves the skin or chest wall (T4), who
have extensive lymph node involvement clinically, or who
have inflammatory cancer. Regardless of the final surgery type
and the degree of tumor response, women with locally
advanced breast cancer should receive surgery and radiation.169
adjuvant therapy with hormone receptor–positive
cancer
Most women with hormone receptor–positive breast cancer
should receive antiestrogen (endocrine) therapy for up to
10 years, with some women also benefiting from chemotherapy.
Endocrine therapy reduces mortality and the risk of second or
contralateral breast cancer. Endocrine therapy has less imme-
diate toxicity and is a good option for some women as their
only systemic therapy. However, adjuvant endocrine therapy
is effective only for women whose tumors express hormone
receptors. This includes premenopausal women and post-
menopausal women with hormone receptor–positive cancers.
The latter still have low levels of circulating estrogens from
nonovarian sources (adipose tissue and adrenal glands).
There are two primary classes of endocrine drugs: SERMs
(e.g., tamoxifen), which are competitive inhibitors of the
estrogen receptor in breast cancer, and aromatase inhibitors
Scientific American Surgery
03/16
(e.g., anastrozole, letro-
zole, exemestane),
which block peripheral
synthesis of estrogen.
Because ovarian pro-
duction of estrogen is
not affected by aro-
matase inhibitors, these
drugs are only effective
in postmenopausal
women.170 Recent clini-
cal trials in postmeno-
pausal women
demonstrated that aro-
matase inhibitors are
superior to tamoxifen in
preventing recurrence
of breast cancer and
have a slightly improved
safety profile over
tamoxifen. Tamoxifen
remains the drug of
choice in premenopausal women. These drugs are remark-
ably safe and effective, with only rare serious side effects.
With only a few exceptions, all women with hormone recep-
tor–positive breast cancers should receive prolonged endo-
crine therapy. At least 5 years of therapy is warranted. There
is an increasing body of evidence that many should continue
therapy for at least 10 years.171–173
Some women with hormone receptor–positive breast can-
cers should also consider adding systemic chemotherapy to
the endocrine therapy. A large body of evidence from clinical
trials shows that survival in some cases may be improved by
the addition of chemotherapy to endocrine therapy.174,175
However, the magnitude of benefit over the benefit of endo-
crine therapy alone may be small. For otherwise healthy
women who have positive lymph nodes, additional chemo-
therapy may be strongly considered. For those with negative
nodes, the benefit varies according to the characteristics of
the cancer. It must be clearly recognized that for women with
hormone receptor–positive breast cancer, chemotherapy is
used in addition to endocrine therapy and not instead of
endocrine therapy.
Genomic profiling of cancers or evaluation of the expres-
sion of multiple genes allows for the stratification of women
with hormone receptor–positive breast cancer by risk of dis-
tant disease. It also identifies some who get no benefit and,
conversely, those who get a major benefit from adding che-
motherapy to endocrine therapy.176–178 The most widely used
genomic profiling system in breast cancer in 2015 is Onco-
typeDx. Those women with a low OncotypeDx recurrence
score benefit from adjuvant endocrine therapy and get no
further improvement from adding chemotherapy. Conversely
those with a high recurrence score have a dramatic reduction
in recurrence risk by adding chemotherapy. Ongoing studies
are examining the chemotherapy benefit in the intermediate-­
risk group. This profiling test is validated for use in women
with invasive cancer that is hormone receptor positive,
HER-2/neu negative, and lymph node negative. A small
body of retrospective data suggests that it provides similar
predictive information in those with positive nodes. As of
breast breast cancer — 29
2015, major clinical trials are under way to determine the
utility of this assay in those with positive nodes.
There are other genomic profiling tests available on the
market that are less widely used in the United States, includ-
ing the 70-gene assay marketed under the name MammaPrint
and the PAM50 gene expression signature, which may also
prove useful in a variety of breast cancers.179,180 Other genomic-­
based prognostic and predictive systems in development are
likely to further identify those requiring chemotherapy, those
that will not, and the specific drug or targeted agents that will
likely be effective for a given cancer.
adjuvant therapy with hormone receptor–negative
and/or her-2-positive cancer
Endocrine therapy is not effective in women with hormone
receptor–negative breast cancer. For these women, the only
treatment to reduce the risk of distant metastases is cytotoxic
chemotherapy. Unless otherwise contraindicated by serious
comorbidities, women with cancers over 1.0 cm and negative
hormone receptors should receive chemotherapy.30 Although
those with tumors under 1 cm have a lower risk of distant
metastases, they still derive some benefit from added chemo-
therapy, and it should be considered based on the full spec-
trum of patient and tumor characteristics. Women with
negative hormone receptors and positive nodes should receive
chemotherapy unless otherwise contraindicated. Women
with hormone receptor–negative and/or HER-2-positive can-
cers should be considered for neoadjuvant therapy for any
cancer at least 2 cm in size or with clinically positive nodes.
Breast cancers that express the HER-2/neu protein have a
higher risk of developing distant metastases in the absence of
treatment. Agents have been developed that target this pro-
tein and have a significant therapeutic effect. When given in
conjunction with chemotherapy in both the adjuvant setting
and in patients with metastatic cancer, they improve the out-
come for those with HER-2-positive cancers. The first and
most widely studied and used of these drugs is the monoclo-
nal antibody trastuzumab. It is safe and effective when given
in combination with chemotherapy. The administration of
standard chemotherapy coupled with a year of trastuzumab
reduces the risk of distance metastatic disease by about half
over the rate seen with chemotherapy alone and reduces can-
cer mortality by about 30%.181,182 Women with HER-2-positive
breast cancer should receive chemotherapy and trastuzumab.
A number of other anti-HER-2 agents are available and may
be used in conjunction with trastuzumab or in those whose
tumors recur or progress after trastuzumab. Combining these
with trastuzumab may increase the efficacy with a higher rate
of pCR with neoadjuvant chemotherapy.183 Based on this, the
standard accepted regimens for neoadjuvant therapy in
HER-2-positive cancers include the combination of chemo-
therapy drugs and dual anti-HER-2 drugs with trastuzumab
and pertuzumab. Similarly, in the treatment of metastatic dis-
ease, use of combined anti-HER-2 therapy improves survival
over trastuzumab alone, as demonstrated in the CLEOPLA-
TRA study, which recently demonstrated that chemotherapy
plus the combination of trastuzumab and pertuzumab
improves survival for women with metastatic cancer.184
The most difficult situation is when estrogen receptor,
progesterone receptor, and HER-2/neu are negative (triple
negative cancers). This type of breast cancer is more common
in younger women, those of African American ancestry, and
those with inherited susceptibility. These cancers have an
increased risk of both local and distant recurrence. Women
with these cancers should receive neoadjuvant or adjuvant
chemotherapy, but it may not be as effective as it is in other
cancers. There is active ongoing clinical research to define
improved approaches in this setting, including the use of
platinum-based chemotherapy drugs (e.g., cisplatinum).
Clinical trials over the last three decades have defined the
most effective drugs in breast cancer. Chemotherapy drugs
are most effective when used in combination with other
drugs. The most effective drugs in breast cancer are the anth-
racyclines, of which the most widely used agent is doxorubi-
cin, cyclophosphamide, and the taxanes (paclitaxel and
docetaxil). Readers are referred to large-scale meta-analysis
of the value of adjuvant chemotherapy and endocrine ther-
apy, to recent reviews on the subject, and to updated practice
guidelines for the current recommended therapies.174,175,185
Decisions regarding adjuvant systemic therapy are complex
for both patients and their physicians. To aid these decisions,
there are mathematical models that incorporate relevant prog-
nostic factors and provide individualized risk of distant recur-
rence and benefit from treatment. The most widely used
models are Adjuvant! (https://www.adjuvantonline.com) and
CancerMath.net (http://cancer.lifemath.net/).186–188 Finally,
women should be offered the opportunity to participate in one
of the many ongoing clinical trials that will help define even
better adjuvant therapies, improve outcomes, and reduce the
short- and long-term toxicity of therapy.
stage iv breast cancer and metastatic breast
cancer
A small fraction of
breast cancers have dis-
tant metastases (stage
IV) at the time of initial
cancer presentation. A
much larger number of
women develop meta-
static breast cancer years
after initial treatment.
When a patient presents
with stage IV cancer at
the initial diagnosis, it is
generally necessary to
obtain tissue from both
the primary tumor and
the suspected metastatic
site to confirm the diag-
nosis and obtain hor-
mone receptor and
HER-2/neu information.
For those who develop
metastatic cancer after
initial treatment, it is best to biopsy a metastatic site to con-
firm the diagnosis and to repeat estrogen receptor, progester-
one receptor, and HER-2 staining on the metastatic cancer. In
15% of distant recurrences, the metastasis will have different
receptor status from the primary tumor. This is even more
important now that next-generation genomic sequencing on
Scientific American Surgery
03/16
breast breast cancer — 30
the tumor may identify a specific target for which a proven
or investigational drug is available.
Metastatic breast cancer is generally incurable, and treat-
ment is targeted at preventing disease progression for the
longest time possible while maintaining a high quality of life.
Those with metastatic cancer must know and understand
that, ultimately, the goal of treatment of metastatic cancer is
palliative: to prolong high-quality life. They must understand
that they will need to balance the potential benefits with the
symptoms of therapy and recognize that they will eventually
reach a point where treatment is likely futile. However, cur-
rent treatments for metastatic cancer now often provide many
years of quality of life. It is clearly worth considering ongoing
systemic therapy and to switch sequentially to different ther-
apies to achieve this goal.
First-line treatment of stage IV and recurrent metastatic
cancer is generally systemic therapy.30 In the absence of symp-
tomatic or aggressive visceral disease, those with hormone
receptor–positive tumors are best treated with oral endocrine
therapy or in some cases intramuscular endocrine therapy
with the estrogen receptor blocker fulvestrant. Many may have
long progression-free intervals and a high quality life with
limited treatment-related toxicity. Those with hormone recep-
tor–negative cancers may begin with systemic chemotherapy.
For those with stage IV cancer at presentation and where
the metastases are identified before the primary tumor in the
breast is removed, there is generally no reason to do surgery.
Systemic treatment often provides a major response in the
breast and achieves sufficient local control for the duration of
the woman’s life. For those women fortunate to have pro-
longed survival but in whom the primary tumor does prog-
ress, surgery and/or radiation may be used for local control
and to preserve quality of life.
Data from population cancer registries suggest that women
who present with metastatic disease who undergo surgery at
the time of diagnosis have longer survival than those who do
not have surgery.189–191 However, this finding is most likely a
selection bias in that women with a lower burden of disease
are more likely to have undergone surgery before discovery
of the metastatic cancer and are therefore more likely to sur-
vive longer. There are two small randomized trials showing
that surgery in those with metastatic disease provides no
improvement in survival. A randomized trial in the United
States examining whether surgery for the primary tumor in
the breast impacts survival in women with stage IV breast
cancer completed accrual in 2015 and will be reported in a
number of years.192
surgical treatment of local recurrence and
distant metastases
Surgical resection of local or regional recurrence of breast
cancer in the absence of distant metastases is generally per-
formed when feasible. Breast local recurrence after BCT is
generally amenable to surgical resection. Recurrent cancer in
the axillary nodes can be resected and is useful if metastatic
evaluation shows no other disease. Resection of supraclavic-
ular nodes is generally not of value. Treatment of local recur-
rence after mastectomy generally includes resection of visible
disease if it is limited and treatment with radiation whether
the disease is or is not resected. Radiation is also an important
tool with regional lymph node recurrences.
Scientific American Surgery
03/16
Surgery for distant metastases, including liver and lung
metastases in breast cancer, is usually futile, although it is
sometimes considered in young women. Unfortunately, these
metastases are seldom isolated, and virtually all will recur
without any survival advantage from the resection.
Finally, it is important to communicate clearly with the
patient about the overall palliative goal of therapy and to
help her deal with symptoms and the psychological issues of
this diagnosis. Early consultation with a palliative care spe-
cialist and a palliative care team helps many women. Pallia-
tive care consultation does not preclude the use of aggressive
therapy for metastatic cancer, and the partnership of the pal-
liative specialist and oncology treatment team is of great
value to the patient. Hospice services are also critical for
patients as they approach the end of life. Honest communica-
tion about the potential benefits of treatment is critical to eas-
ing the suffering and burden of end-of-life care.
Special Circumstances
There are a number of special circumstances that are
uncommon but occur frequently enough to deserve separate
discussion. These include adenocarcinoma presenting in axil-
lary lymph nodes with no obvious known primary tumor,
breast cancer in pregnancy, and breast cancer in men.
axillary node with adenocarcinoma cancer,
primary unknown
A small number of women present to their physician with
an axillary node containing metastatic adenocarcinoma and
no detectable primary cancer in the breast (occult breast pri-
mary). This is almost always breast cancer. Mammography
will often reveal the primary breast cancer, and MRI finds
many of these cancers not seen on mammography.193 How-
ever, in a few cases, even MRI will be negative. In a woman,
this is still virtually always a breast cancer despite the negative
breast imaging, even if the hormone receptors are negative.
Extensive whole body imaging to search for another source
of adenocarcinoma is not indicated. The woman should
receive therapy assuming that this is a breast cancer.
In the past, mastectomy was used for all women with an
occult breast primary presenting with a positive axillary
node. Recent data show that mastectomy is not necessary.
These patients can undergo ALND with stage- and biomarker-­
appropriate adjuvant systemic therapy and radiation to the
breast.194,195 The systemic therapy may be administered before
(neoadjuvant) or after surgery. Those with large or bulky
axillary nodes should receive neoadjuvant chemotherapy
before surgery. In place of mastectomy, whole breast radia-
tion is administered after completing systemic therapy, as
with other women undergoing breast-conserving surgery.
breast cancer in pregnancy
Breast cancer is uncommon in young women but may
occur during childbearing years. Therefore, breast cancer
may occur during pregnancy and is the second most common
cancer associated with pregnancy. Women in this age group
are generally not undergoing routine breast cancer screening,
and changes in the breast associated with pregnancy can
mask the presence of a mass. Therefore, breast cancer diag-
nosis is often delayed. Women with a suspicious mass during
breast breast cancer — 31
pregnancy should be evaluated aggressively. Imaging can
generally be done with mammography and ultrasonography,
and biopsy should be performed as in any other woman with
a suspicious breast lesion.
The principles of treatment are the same as in any woman
with breast cancer.196–198 The only limitation is that chemo-
therapy cannot be administered during the first trimester and
radiation cannot be administered until after delivery. How-
ever, neither of these issues limits aggressive treatment of
women with breast cancer during pregnancy. Termination of
the pregnancy is not necessary, although some women diag-
nosed early during the pregnancy choose to do so.
Older texts suggested that mastectomy is the preferred
treatment in women with breast cancer during pregnancy.
However, now the same choices are available to women with
cancer during pregnancy because the radiation is generally
delayed until after chemotherapy and therefore is timed to
occur after delivery of the child. Therefore, breast conserva-
tion can be used safely during pregnancy. Similarly, chemo-
therapy may be used safely during pregnancy after the first
trimester. There are extensive data demonstrating the safety
of chemotherapy for both the mother and the fetus. SLNB
may also be performed during pregnancy using radioactive
sulfur colloid alone. The estimated radiation dose to the fetus
is exceedingly low and considered safe.199 Isosulfan blue and
methylene blue have potential teratogenic effects and are
contraindicated during pregnancy.
Women who have breast cancer at a young age or during
pregnancy may wish to have additional children. Decades
ago, they were advised against this because of concern that
hormonal changes associated with pregnancy could promote
recurrence. Studies have shown that women who choose
to have children after breast cancer treatment have no
additional risk of breast cancer recurrence and death.200,201
Fertility preservation options, including oocyte and embryo
cryopreservation, are available, and consultation with a
reproductive endocrinologist should be offered to any woman
diagnosed with breast cancer who has not completed her
childbearing.200,202–204
breast cancer in men
Breast cancer occurs in men, but with an incidence less
than 1% that of women (lifetime risk for men about one in
1,000). No screening for men is warranted. Any mass in the
breast should be fully evaluated. Most masses prove to be
gynecomastia. Breast cancer in a younger man may be indic-
ative of inherited susceptibility from breast cancer–associated
genes within that family, particularly related to BRCA2. Care-
ful family history and counseling regarding this risk should
be provided with strong consideration of genetic testing for
any man with breast cancer.
The treatment of breast cancer in men follows the same
principles as in women.205,206 Surgery is generally mastectomy
because often the tumor is directly under the nipple-areola
complex and overall smaller breast size. However, studies
have been published demonstrating similar outcomes with
breast conservation.207
Radiation indications are the same as for women: large
tumors, skin and/or chest wall involvement, and nodal
involvement. SLNB and ALND should be performed using
the same indications as in women. Men should also receive
adjuvant systemic therapy using the same criteria as for
women. Most breast cancers in men are hormone receptor
positive, and endocrine therapy is effective. Chemotherapy
should be added based on the same criteria as with women.
Survival when matched stage for stage with women is the
same, although, overall, men have a worse prognosis because
men tend to present with cancer at a higher stage.
Follow-up after Breast Cancer Treatment
Patients who have been treated for invasive breast cancer
are at risk for developing distant metastases, local recurrence,
and a contralateral or ipsilateral new breast cancer. Most recur-
rences occur within the first 5 to 10 years, with the peak at 4 to
6 years. Recurrences with estrogen receptor–negative cancers
on average are earlier than with estrogen receptor–positive
cancers. Occasionally, women develop distant metastases well
beyond 10 years after diagnosis.
Follow-up for breast cancer only requires periodic careful
history, physical examination, and breast imaging. Women
with breast cancer often assume that careful and aggressive
imaging screening is warranted to allow early detection of
metastases on the assumption that early detection will pro-
vide a better chance of a successful outcome. Unfortunately,
there is no such entity as early metastatic cancer. Once breast
cancer metastases are established to the extent that they are
detectable, there is no therapy that is curative, and treatment
is largely palliative, as discussed previously above. Because
of this, national guidelines recommend against imaging or
serologic testing for metastatic disease on a periodic basis as
it does not provide any survival advantage to a woman with
breast cancer. This question has been tested in randomized
clinical trials of extensive testing versus simple follow-up for
local recurrence only combined with evaluation of any symp-
toms suggestive of metastatic disease. These studies showed
no survival advantage to the extensive testing group despite
detection of metastatic disease an average of 3 months earlier
than in the simple follow-up group.208,209
Screening women for evidence of local recurrence with
both invasive and in situ cancer may be of value. This should
include mammography of the ipsilateral breast in women
treated with breast conservation, contralateral mammogra-
phy for all women, and a careful history and physical exam-
ination. Mammography should be done annually, with the
history and physical examination done every 6 to 12 months.
The role of breast MRI in breast cancer follow-up is unclear.
Women should maintain a primary care provider to be sure
that other regular medical care is provided.
cancer survivorship
In addition to covering medical issues in cancer follow-up,
surgeons should provide ongoing resources to help women
adjust to the cancer diagnosis, deal with psychological issues,
address cancer genetic and family concerns, and identify
other long-term sequelae of cancer.210 Patients should be pro-
vided with a written treatment summary and a “survivorship
care plan” for their ongoing care. Patients should be encour-
aged to seek individual counseling and participate in support
groups as they see the need and to gain the value of engagement
in the vast array of support and advocacy activities available
in most communities.211 Long-term effects of cancer care are
Scientific American Surgery
03/16
breast breast cancer — 32
common. Recently, a number of organizations established  
guidelines for many domains of survivorship care that pro-
vide a guide to the many dimensions of survivorship care
and their management.212–216  
Financial Disclosures: Lindi VanderWalde, MD, Alyssa D. Throckmorton, MD, FACS,
and Stephen B. Edge, MD, FACS, have no relevant financial relationships to disclose.  
References
 
  1. Telli ML, Horst KC, Guardino AE, et al. Phyllodes tumors
of the breast: natural history, diagnosis, and treatment.
J Natl Compr Canc Netw 2007;5:324–30.
  2. Lum YW, Jacobs L. Primary breast sarcoma. Surg Clin
North Am 2008;88:559–70, vi.
  3. U.S. Preventive Services Task Force. Screening for breast  
cancer: U.S. Preventive Services Task Force recommenda-
tion statement. Ann Intern Med 2009;151:716–26, W-236.  
  4. Smith RA, Cokkinides V, Brawley OW. Cancer screening in
the United States, 2009: a review of current American
Cancer Society guidelines and issues in cancer screening.
CA Cancer J Clin 2009;59:27–41.
  5. Smith RA, Cokkinides V, Eyre HJ. Cancer screening in the  
United States, 2007: a review of current guidelines, prac-
tices, and prospects. CA Cancer J Clin 2007;57:90–104.
  6. Oeffinger KC, Fontham ETH, Etzioni R, et al. Breast cancer  
screening for women at average risk; 2015 guideline update
from the American Cancer Society. JAMA 2015; 314:
1599–1614.
  7. Esserman LJ, Thompson IM Jr, Reid B. Overdiagnosis and  
overtreatment in cancer: an opportunity for improvement.
JAMA 2013;310:797–8.
  8. Berry DA. Breast cancer screening: controversy of impact.
Breast 2013;22:S73–6.  
  9. Harding C, Pompei F, Burmistrov D, et al. Breast cancer
screening, incidence, and mortality across US counties.
JAMA Intern Med 2015;175:1483–9.  
 10. Chiarelli AM, Prummel MV, Muradali D, et al. Effective-
ness 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
2014;32:2224–30.
 11. Euhus D. Genetic testing today. Ann Surg Oncol  
2014;21:3209–15.
  12. Wang AT, Vachon CM, Brandt KR, et al. Breast density and
breast cancer risk: a practical review. Mayo Clin Proc
2014;89:548–57.  
  13. Ray KM, Price ER, Joe BN. Breast density legislation: man-
datory disclosure to patients, alternative screening, billing,  
reimbursement. AJR Am J Roentgenol 2015;204:257–60.
 14. Green VL. Breast cancer risk assessment, prevention, and
the future. Obstet Gynecol Clin North Am 2013;40:525–49.  
  15. Nelson HD, Fu R, Goddard K, et al. Risk assessment, genetic
counseling, and genetic testing for BRCA-related cancer:
systematic review to update the U.S. Preventive Services
Task Force recommendation. U.S. Preventive Services Task  
Force Evidence Syntheses, formerly Systematic Evidence
Reviews. Rockville (MD): Agency for Healthcare Research
and Quality (US); 2013. Report No.: 12-05164-EF-1.  
  16. Howell A, Anderson AS, Clarke RB, et al. Risk determination
and prevention of breast cancer. Breast Cancer Res 2014;16:446.
Scientific American Surgery
03/16
17. Eberl MM, Fox CH, Edge SB, et al. BI-RADS classification
for management of abnormal mammograms. J Am Board
Fam Med 19:161–4, 2006.
18. Erguvan-Dogan B, Whitman GJ, Kushwaha AC, et al. BI-­
RADS-­ MRI: a primer. AJR Am J Roentgenol 2006;187:
W152–60.
19. Peppard HR, Nicholson BE, Rochman CM, et al. Digital
breast tomosynthesis in the diagnostic setting: indications
and clinical applications. Radiographics 2015;35:975–90.
20. The American Society of Breast Surgeons. The American
Society of Breast Surgeons Performance and Practice Guide-
lines for Breast Ultrasound. Available at: https://www.
breastsurgeons.org/statements/Performance_and_Practice_
Guidelines_Breast_Ultrasound.pdf (accessed January 26,
2016).
21. Lehman CD, Smith RA. The role of MRI in breast cancer
screening. J Natl Compr Canc Netw 2009;7:1109–15.
22. Brennan ME, Houssami N, Lord S, et al. Magnetic resonance
imaging screening of the contralateral breast in women with
newly diagnosed breast cancer: systematic review and
meta-analysis of incremental cancer detection and impact on
surgical management. J Clin Oncol 2009;27:5640–9.
23. Saslow D, Boetes C, Burke W, et al. American Cancer Soci-
ety guidelines for breast screening with MRI as an adjunct
to mammography. CA Cancer J Clin 2007;57:75–89.
24. McLaughlin S, Mittendorf EA, Bleicher RJ, et al. The 2013
Society of Surgical Oncology Susan G. Komen for the Cure
Symposium: MRI in breast cancer: where are we now? Ann
Surg Oncol 2014;21:28–36.
25. Houssami N, Hayes DF. Review of preoperative magnetic
resonance imaging (MRI) in breast cancer: should MRI be
performed on all women with newly diagnosed, early stage
breast cancer? CA Cancer J Clin 2009;59:290–302.
26. Pilewskie M, King TA. Magnetic resonance imaging in
patients with newly diagnosed breast cancer: a review of
the literature. Cancer 2014;120:2080–9.
27. Singh V, Saunders C, Wylie L, et al. New diagnostic tech-
niques for breast cancer detection. Future Oncol 2008;4:501–13.
28. Lee JH, Rosen EL, Mankoff DA. The role of radiotracer
imaging in the diagnosis and management of patients with
breast cancer: part 1—overview, detection, and staging.
J Nucl Med 2009;50:569–81.
29. Lee JH, Rosen EL, Mankoff DA. The role of radiotracer
imaging in the diagnosis and management of patients with
breast cancer: part 2—response to therapy, other indica-
tions, and future directions. J Nucl Med 2009;50:738–48.
30. Gradishar WJ, Anderson BO, Blair SL, et al. Breast cancer
version 3.2014. J Natl Compr Canc Netw 2014;12:542–90.
31. American Board of Internal Medicine Foundation. Choosing
wisely. Available at: www.choosingwisely.org (accessed
January 26, 2016).
32. Eby PR, Ochsner JE, DeMartini WB, et al. Frequency and
upgrade rates of atypical ductal hyperplasia diagnosed at
stereotactic vacuum-assisted breast biopsy: 9-versus
11-gauge. AJR Am J Roentgenol 2009;192:229–34.
33. Menes TS, Rosenberg R, Balch S, et al. Upgrade of high-risk
breast lesions detected on mammography in the Breast
Cancer Surveillance Consortium. Am J Surg 2014;207:24–31.
34. Elmore JG, Longton GM, Carney PA, et al. Diagnostic con-
cordance among pathologists interpreting breast biopsy
specimens. JAMA 2015;313:1122–32.
breast breast cancer — 33
  35. Middleton LP, Sneige N, Coyne R, et al. Most lobular carci-  
noma in situ and atypical lobular hyperplasia diagnosed on
core needle biopsy can be managed clinically with radiologic
follow-up in a multidisciplinary setting. Cancer Med  
2014;3: 492–9.
  36. Edge SB, Byrd DR, Compton CC, et al. AJCC cancer staging
manual. 7th ed. New York: Springer; 2010.  
  37. Chuba PJ, Hamre MR, Yap J, et al. Bilateral risk for subse-
quent breast cancer after lobular carcinoma-in-situ: analysis
of surveillance, epidemiology, and end results data. J Clin  
Oncol 2005;23:5534–41.
 38. Hussain M, Cunnick GH. Management of lobular carci-
noma in-situ and atypical lobular hyperplasia of the
 
breast—a review. Eur J Surg Oncol 2011;37:279–89.
  39. Karabakhtsian RG, Johnson R, Sumkin J, et al. The clinical
significance of lobular neoplasia on breast core biopsy. Am
 
J Surg Pathol 2007;31:717–23.
  40. Anderson BO, Calhoun KE, Rosen EL. Evolving concepts in
the management of lobular neoplasia. J Natl Compr Canc
Netw 2006;4:511–22.
  41. Vogel VG. Recent results from clinical trials using SERMs  
to reduce the risk of breast cancer. Ann N Y Acad Sci
2006;1089:127–42.
  42. Vogel VG. The NSABP Study of Tamoxifen and Raloxifene
(STAR) trial. Expert Rev Anticancer Ther 2009;9:51–60.  
  43. Cigler T, Richardson H, Yaffe MJ, et al. A randomized, pla-
cebo-controlled trial (NCIC CTG MAP.2) examining the
effects of exemestane on mammographic breast density,
bone density, markers of bone metabolism and serum lipid
levels in postmenopausal women. Breast Cancer Res Treat  
2011;126:453–61.
  44. Masannat YA, Bains SK, Pinder SE, et al. Challenges in the
management of pleomorphic lobular carcinoma in situ of  
the breast. Breast 2013;22:194–6.
  45. Pieri A, Harvey J, Bundred N. Pleomorphic lobular carci-
noma in situ of the breast: can the evidence guide practice?  
World J Clin Oncol 2014;5:546–53.
  46. Aberle DR, Allegra CJ, Ganschow P, et al. NIH state-of-the-
science conference statement: diagnosis and management
of ductal carcinoma in situ (DCIS). NIH Consens State Sci  
Statements 2009;26:1–27.
 47. Kuerer HM, Albarracin CT, Yang WT, et al. Ductal carci-
noma in situ: state of the science and roadmap to advance
the field. J Clin Oncol 2009;27:279–88.
  48. Duggal S, Robin J, Julian TB. Ductal carcinoma in situ: an
overview. Expert Rev Anticancer Ther 2013;13:955–62.
 49. Cowell CF, Weigelt B, Sakr RA, et al. Progression from
 
ductal carcinoma in situ to invasive breast cancer: revisited.
Mol Oncol 2013;7:859–69.
 50. Alvarado M, Ozanne E, Esserman L. Overdiagnosis and
overtreatment of breast cancer. Am Soc Clin Oncol Educ
 
Book 2012:e40–5.
 51. Esserman LJ, Thompson IM, Reid B, et al. Addressing
overdiagnosis and overtreatment in cancer: a prescription
for change. Lancet Oncol 2014;15:e234–42.  
  52. Carlson GW, Page A, Johnson E, et al. Local recurrence of
ductal carcinoma in situ after skin-sparing mastectomy.
J Am Coll Surg 2007;204:1074–8; discussion 1078–80.
  53. Silverstein MJ, Mai T, Savalia N, et al. Oncoplastic breast  
conservation surgery: the new paradigm. J Surg Oncol
2014;110:82–9.
54. Haloua MH, Krekel NM, Winters HA, et al. A systematic
review of oncoplastic breast-conserving surgery: current
weaknesses and future prospects. Ann Surg 2013;257:609–20.
55. Barentsz MW, van den Bosch MA, Veldhuis WB, et al.
Radioactive seed localization for non-palpable breast
cancer. Br J Surg 2013;100:582–8.
56. Chagpar AB, Killelea BK, Tsangaris TN, et al. A random-
ized, controlled trial of cavity shave margins in breast
cancer. N Engl J Med 2015;373:503–10.
57. Blair SL, Thompson K, Rococco J, et al. Attaining negative
margins in breast-conservation operations: is there a consen-
sus among breast surgeons? J Am Coll Surg 2009;209:608–13.
58. Azu M, Abrahamse P, Katz SJ, et al. What is an adequate
margin for breast-conserving surgery? Surgeon attitudes
and correlates. Ann Surg Oncol 2010;17:558–63.
59. Macdonald HR, Silverstein MJ, Lee LA, et al. Margin width
as the sole determinant of local recurrence after breast con-
servation in patients with ductal carcinoma in situ of the
breast. Am J Surg 2006;192:420–2.
60. Dunne C, Burke JP, Morrow M, et al. Effect of margin status
on local recurrence after breast conservation and radiation
therapy for ductal carcinoma in situ. J Clin Oncol 2009;27:
1615–20.
61. Moran MS, Schnitt SJ, Giuliano AE, et al. Society of Surgical
Oncology-American Society for Radiation Oncology con-
sensus guideline on margins for breast-conserving surgery
with whole-breast irradiation in stages I and II invasive
breast cancer. J Clin Oncol 2014;32:1507–15.
62. Throckmorton AD, Esserman LJ. When informed, all
women do not prefer breast conservation. J Clin Oncol
2009;27:484–6.
63. Recht A. Are the randomized trials of radiation therapy for
ductal carcinoma in situ still relevant? J Clin Oncol
2014;32:3588–90.
64. Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and
radiation therapy for the treatment of intraductal breast
cancer: findings from National Surgical Adjuvant Breast
and Bowel Project B-17. J Clin Oncol 1998;16:441–52.
65. Bijker N, Meijnen P, Peterse JL, et al. Breast-conserving
treatment with or without radiotherapy in ductal carcino-
ma-in-situ: ten-year results of European Organisation for
Research and Treatment of Cancer randomized phase III
trial 10853—a study by the EORTC Breast Cancer Coopera-
tive Group and EORTC Radiotherapy Group. J Clin Oncol
2006;24:3381–7.
66. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk
reductions for local recurrence after postoperative radio-
therapy after sector resection for ductal carcinoma in situ of
the breast. J Clin Oncol 2008;26:1247–52.
67. Goodwin A, Parker S, Ghersi D, et al. Post-operative radio-
therapy for ductal carcinoma in situ of the breast—a system-
atic review of the randomised trials. Breast 2009;18:143–9.
68. Warnberg F, Garmo H, Emdin S, et al. Effect of radiother-
apy after breast-conserving surgery for ductal carcinoma in
situ: 20 years follow-up in the randomized SweDCIS Trial.
J Clin Oncol 2014;32:3613–8.
69. Arvold ND, Punglia RS, Hughes ME, et al. Pathologic char-
acteristics of second breast cancers after breast conservation
for ductal carcinoma in situ. Cancer 2012;118:6022–30.
Scientific American Surgery
03/16
breast breast cancer — 34
  70. Wapnir IL, Dignam JJ, Fisher B, et al. Long-term outcomes
of invasive ipsilateral breast tumor recurrences after
lumpectomy in NSABP B-17 and B-24 randomized clinical
trials for DCIS. J Natl Cancer Inst 2011;103:478–88.
  71. Keisch M, Vicini F, Beitsch P, et al. American Society of Breast
Surgeons MammoSite Radiation Therapy System Registry
Trial: ductal carcinoma-in-situ subset analysis—4-year data
in 194 treated lesions. Am J Surg 2009;198:505–7.
  72. Shah C, Badiyan S, Ben Wilkinson J, et al. Treatment effi-
cacy with accelerated partial breast irradiation (APBI): final
analysis of the American Society of Breast Surgeons Mam-
moSite((R)) breast brachytherapy registry trial. Ann Surg
Oncol 2013;20:3279–85.
 73. Vicini F, Shah C, Ben Wilkinson J, et al. Should ductal
carcinoma-­in-situ (DCIS) be removed from the ASTRO con-
sensus panel cautionary group for off-protocol use of accel-
erated partial breast irradiation (APBI)? A pooled analysis
of outcomes for 300 patients with DCIS treated with APBI.
Ann Surg Oncol 2013;20:1275–81.
  74. Marta GN, Macedo CR, Carvalho Hde A, et al. Accelerated
partial irradiation for breast cancer: systematic review and
meta-analysis of 8653 women in eight randomized trials.
Radiother Oncol 2015;114:42–9.
 75. Liu Y, Schloemann DT, Lian M, et al. Accelerated partial
breast irradiation through brachytherapy for ductal carcinoma
in situ: factors influencing utilization and risks of second
breast tumors. Breast Cancer Res Treat 2015;151:199–208.
 76. Silverstein MJ, Lagios MD, Craig PH, et al. A prognostic
index for ductal carcinoma in situ of the breast. Cancer
1996;77:2267–74.
  77. Silverstein MJ, Buchanan C. Ductal carcinoma in situ: USC/
Van Nuys Prognostic Index and the impact of margin
status. Breast 2003;12:457–71.
  78. McCormick B, Winter K, Hudis C, et al. RTOG 9804: a pro-
spective randomized trial for good-risk ductal carcinoma in
situ comparing radiotherapy with observation. J Clin Oncol
2015;33:709–15.
  79. Solin LJ, Gray R, Baehner FL, et al. A multigene expression
assay to predict local recurrence risk for ductal carcinoma
in situ of the breast. J Natl Cancer Inst 2013;105:701–10.
  80. McCormick B. Radiation therapy for duct carcinoma in situ:
who needs radiation therapy, who doesn’t? Hematol Oncol
Clin North Am 2013;27:673–86, vii.
  81. Lucci A, McCall LM, Beitsch PD, et al. Surgical complica-
tions associated with sentinel lymph node dissection
(SLND) plus axillary lymph node dissection compared with
SLND alone in the American College of Surgeons Oncology
Group Trial Z0011. J Clin Oncol 2007;25:3657–63.
  82. McLaughlin SA, Wright MJ, Morris KT, et al. Prevalence of
lymphedema in women with breast cancer 5 years after sen-
tinel lymph node biopsy or axillary dissection: objective
measurements. J Clin Oncol 2008;26:5213–9.
  83. Gebruers N, Verbelen H, De Vrieze T, et al. Incidence and
time path of lymphedema in sentinel node negative breast
cancer patients: a systematic review. Arch Phys Med Reha-
bil 2015;96:1131–9.
  84. Fisher B, Dignam J, Wolmark N, et al. Tamoxifen in treat-
ment of intraductal breast cancer: National Surgical Adjuvant
Breast and Bowel Project B-24 randomised controlled trial.
Lancet 1999;353:1993–2000.
Scientific American Surgery
03/16
 85. Margolese RG, Cecchini RS, Julian TB, et al. Preliminary
results, NRG Oncology/NSABP B-35: a clinical trial of anas-
trozole (A) versus tamoxifen (tam) in postmenopausal
patients with DCIS undergoing lumpectomy plus radiother-
apy [abstract]. J Clin Oncol 2015;33 Suppl:abstr LBA500.
 86. Marshall JK, Griffith KA, Haffty BG, et al. Conservative
management of Paget disease of the breast with radiother-
apy: 10- and 15-year results. Cancer 2003;97:2142–9.
 87. Chen CY, Sun LM, Anderson BO. Paget disease of the
breast: changing patterns of incidence, clinical presentation,
and treatment in the U.S. Cancer 2006;107:1448–58.
 88. Rakha EA, Reis-Filho JS, Baehner F, et al. Breast cancer
prognostic classification in the molecular era: the role of his-
tological grade. Breast Cancer Res 2010;12:207.
  89. Cianfrocca M, Gradishar W. New molecular classifications
of breast cancer. CA Cancer J Clin 2009;59:303–13.
  90. Martin M, Gonzalez Palacios F, Cortes J, et al. Prognostic
and predictive factors and genetic analysis of early breast
cancer. Clin Transl Oncol 2009;11:634–42.
  91. Kittaneh M, Montero AJ, Gluck S. Molecular profiling for
breast cancer: a comprehensive review. Biomark Cancer
2013;5:61–70.
  92. van de Vijver MJ. Molecular tests as prognostic factors in
breast cancer. Virchows Arch 2014;464:283–91.
  93. Ma CX, Ellis MJ. The Cancer Genome Atlas: clinical appli-
cations for breast cancer. Oncology (Williston Park)
2013;27:1263–9, 1274–9.
  94. Rakha EA, Ellis IO. Modern classification of breast cancer:
should we stick with morphology or convert to molecular
profile characteristics. Adv Anat Pathol 2011;18:255–67.
  95. Rakha EA, Lee AH, Evans AJ, et al. Tubular carcinoma of
the breast: further evidence to support its excellent progno-
sis. J Clin Oncol 2010;28:99–104.
  96. Barkley CR, Ligibel JA, Wong JS, et al. Mucinous breast car-
cinoma: a large contemporary series. Am J Surg 2008;196:
549–51.
  97. Dawood S, Merajver SD, Viens P, et al. International expert
panel on inflammatory breast cancer: consensus statement
for standardized diagnosis and treatment. Ann Oncol
2011;22:515–23.
  98. Sakorafas GH, Safioleas M. Breast cancer surgery: an histor-
ical narrative. Part II. 18th and 19th centuries. Eur J Cancer
Care (Engl) 2010;19:6–29.
  99. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up
of a randomized trial comparing total mastectomy, lumpec-
tomy, and lumpectomy plus irradiation for the treatment of
invasive breast cancer. N Engl J Med 2002;347:1233–41.
100. Hwang ES, Lichtensztajn DY, Gomez SL, et al. Survival
after lumpectomy and mastectomy for early stage invasive
breast cancer: the effect of age and hormone receptor status.
Cancer 2013;119:1402–11.
101. Nelson H, Hunt KK, Veeramachaneni V, et al. Operative
stand­ards for cancer surgery. Chicago: Wolters Kluwer; 2015.
102. Kronowitz SJ, Kuerer HM. Advances and surgical deci-
sion-making for breast reconstruction. Cancer 2006;107:
893–907.
103. Kronowitz SJ, Robb GL. Radiation therapy and breast
reconstruction: a critical review of the literature. Plast
Reconstr Surg 2009;124:395–408.
breast breast cancer — 35
104. Brachtel EF, Rusby JE, Michaelson JS, et al. Occult nipple
involvement in breast cancer: clinicopathologic findings in
316 consecutive mastectomy specimens. J Clin Oncol
2009;27:4948–54.
105. Gerber B, Krause A, Dieterich M, et al. The oncological
safety of skin sparing mastectomy with conservation of the
nipple-areola complex and autologous reconstruction: an
extended follow-up study. Ann Surg 2009;249:461–8.
106. Edge SB. Nipple-sparing mastectomy: how often is the
nipple involved? J Clin Oncol 2009;27:4930–2.
107. Coopey SB, Tang R, Lei L, et al. Increasing eligibility for
nipple-­ sparing mastectomy. Ann Surg Oncol 2013;20:
3218–22.
108. Hwang SO, Lee SW, Kim HJ, et al. The comparative study
of ultrasonography, contrast-enhanced MRI, and (18)F-FDG
PET/CT for detecting axillary lymph node metastasis in T1
breast cancer. J Breast Cancer 2013;16:315–21.
109. Quan ML, McCready D. The evolution of lymph node
assessment in breast cancer. J Surg Oncol 2009;99:194–8.
110. Estourgie SH, Nieweg OE, Olmos RA, et al. Lymphatic
drainage patterns from the breast. Ann Surg 2004;239:
232–7.
111. Chen RC, Lin NU, Golshan M, et al. Internal mammary
nodes in breast cancer: diagnosis and implications for
patient management—a systematic review. J Clin Oncol
2008;26:4981–9.
112. Hayes SC, Janda M, Cornish B, et al. Lymphedema after
breast cancer: incidence, risk factors, and effect on upper
body function. J Clin Oncol 2008;26:3536–42.
113. Warren AG, Brorson H, Borud LJ, et al. Lymphedema: a
comprehensive review. Ann Plast Surg 2007;59:464–72.
114. Tsai RJ, Dennis LK, Lynch CF, et al. The risk of developing
arm lymphedema among breast cancer survivors: a
meta-analysis of treatment factors. Ann Surg Oncol
2009;16:1959–72.
115. Hinrichs CS, Watroba NL, Rezaishiraz H, et al. Lymph-
edema secondary to postmastectomy radiation: incidence
and risk factors. Ann Surg Oncol 2004;11:573–80.
116. Lyman GH, Giuliano AE, Somerfield MR, et al. American
Society of Clinical Oncology guideline recommendations
for sentinel lymph node biopsy in early-stage breast cancer.
J Clin Oncol 2005;23:7703–20.
117. Lyman GH, Temin S, Edge SB, et al. Sentinel lymph node
biopsy for patients with early-stage breast cancer: American
Society of Clinical Oncology clinical practice guideline
update. J Clin Oncol 2014;32:1365–83.
118. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissec-
tion vs no axillary dissection in women with invasive breast
cancer and sentinel node metastasis: a randomized clinical
trial. JAMA 2011;305:569–75.
119. Jagsi R, Chadha M, Moni J, et al. Radiation field design in
the ACOSOG Z0011 (Alliance) trial. J Clin Oncol
2014;32:3600–6.
120. Zellars RC. New information prompts old question: is sen-
tinel lymph node sampling equivalent to axillary lymph
node dissection? J Clin Oncol 2014;32:3583–5.
121. Weaver DL, Ashikaga T, Krag DN, et al. Effect of occult
metastases on survival in node-negative breast cancer.
N Engl J Med 2011;364:412–21.
122. Giuliano AE, Hawes D, Ballman KV, et al. Association of
occult metastases in sentinel lymph nodes and bone marrow
with survival among women with early-stage invasive
breast cancer. JAMA 2011;306:385–93.
123. Boughey JC, Suman VJ, Mittendorf EA, et al. Sentinel lymph
node surgery after neoadjuvant chemotherapy in patients
with node-positive breast cancer: the ACOSOG Z1071 (Alli-
ance) clinical trial. JAMA 2013;310:1455–61.
124. Fernando SA, Edge SB. Evidence and controversies in the
use of post-mastectomy radiation. J Natl Compr Canc Netw
2007;5:331–8.
125. Li Y, Moran MS, Huo Q, et al. Post-mastectomy radiother-
apy for breast cancer patients with t1-t2 and 1-3 positive
lymph nodes: a meta-analysis. PLoS One 2013;8:e81765.
126. EBCTCG Early Breast Cancer Trialists’ Collaborative Group,
McGale P, Taylor C, Correa C, et al. Effect of radiotherapy
after mastectomy and axillary surgery on 10-year recur-
rence and 20-year breast cancer mortality: meta-analysis of
individual patient data for 8135 women in 22 randomised
trials. Lancet 2014;383:2127–35.
127. Clarke M, Collins R, Darby S, 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;366:2087–106.
128. Hughes KS, Schnaper LA, Berry D, et al. Lumpectomy plus
tamoxifen with or without irradiation in women 70 years of
age or older with early breast cancer. N Engl J Med
2004;351:971–7.
129. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy
plus tamoxifen with or without irradiation in women
age 70 years or older with early breast cancer: long-term
follow-­up of CALGB 9343. J Clin Oncol 2013;31:2382–7.
130. Kunkler IH, Williams LJ, Jack WJ, et al. Breast-conserving
surgery with or without irradiation in women aged 65 years
or older with early breast cancer (PRIME II): a randomised
control trial. Lancet Oncol 2015;16:266–73.
131. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with
or without breast irradiation in women 50 years of age or
older with early breast cancer. N Engl J Med 2004;351:963–70.
132. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results
of hypofractionated radiation therapy for breast cancer.
N Engl J Med 2010;362:513–20.
133. McCormick B. Hypofractionated whole breast radiation
and partial breast radiation for early-stage breast cancers:
an update on progress. J Natl Compr Canc Netw
2012;10:1161–4.
134. Eblan MJ, Vanderwalde NA, Zeman EM, et al. Hypofrac-
tionation for breast cancer: lessons learned from our neigh-
bors to the north and across the pond. Oncology (Williston
Park) 2014;28:536–46.
135. Offersen BV, Overgaard M, Kroman N, et al. Accelerated
partial breast irradiation as part of breast conserving ther-
apy of early breast carcinoma: a systematic review. Radio-
ther Oncol 2009;90:1–13.
136. Kamrava M, Kuske RR, Anderson B, et al. Outcomes of
breast cancer patients treated with accelerated partial breast
irradiation via multicatheter interstitial brachytherapy: the
Pooled Registry of Multicatheter Interstitial Sites (PROMIS)
experience. Ann Surg Oncol 2015;22:404–11.
137. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted
intraoperative radiotherapy versus whole-breast radiother-
apy for breast cancer: 5-year results for local control and
Scientific American Surgery
03/16
breast breast cancer — 36
overall survival from the TARGIT-A randomised trial.
Lancet 2014;383:603–13.
138. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraopera-
tive radiotherapy versus external radiotherapy for early
breast cancer (ELIOT): a randomised controlled equiva-
lence trial. Lancet Oncol 2013;14:1269–77.
139. McCormick B. Partial breast radiation for early-stage breast
cancer. Curr Opin Obstet Gynecol 2012;24:31–7.
140. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated par-
tial breast irradiation consensus statement from the Amer-
ican Society for Radiation Oncology (ASTRO). J Am Coll
Surg 2009;209:269–77.
141. Wilkinson JB, Beitsch PD, Shah C, et al. Evaluation of cur-
rent consensus statement recommendations for accelerated
partial breast irradiation: a pooled analysis of William
Beaumont Hospital and American Society of Breast Sur-
geon MammoSite Registry Trial Data. Int J Radiat Oncol
Biol Phys 2013;85:1179–85.
142. Shah C, Vicini F, Wazer DE, et al. The American Brachyther-
apy Society consensus statement for accelerated partial
breast irradiation. Brachytherapy 2013;12:267–77.
143. Liss AL, Ben-David MA, Jagsi R, et al. Decline of cosmetic
outcomes following accelerated partial breast irradiation
using intensity modulated radiation therapy: results of a
single-institution prospective clinical trial. Int J Radiat
Oncol Biol Phys 2014;89:96–102.
144. Carlson RW, Allred DC, Anderson BO, et al. Breast cancer.
Clinical practice guidelines in oncology. J Natl Compr Canc
Netw 2009;7:122–92.
145. Dirbas FM. Accelerated partial breast irradiation: where do
we stand? J Natl Compr Canc Netw 2009;7:215–25.
146. Theberge V, Whelan T, Shaitelman SF, et al. Altered frac-
tionation: rationale and justification for whole and partial
breast hypofractionated radiotherapy. Semin Radiat Oncol
2011;21:55–65.
147. de Glas NA, Engels CC, Bastiaannet E, et al. Contralateral
breast cancer risk in relation to tumor morphology and
age—in which patients is preoperative MRI justified?
Breast Cancer Res Treat 2015;150:191–8.
148. Vo TN, Meric-Bernstam F, Yi M, et al. Outcomes of
breast-conservation therapy for invasive lobular carcinoma
are equivalent to those for invasive ductal carcinoma. Am
J Surg 2006;192:552–5.
149. McLaughlin CC, Lillquist PP, Edge SB. Surveillance of pro-
phylactic mastectomy: trends in use from 1995 through
2005. Cancer 2009;115:5404–12.
150. Graeser MK, Engel C, Rhiem K, et al. Contralateral breast
cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin
Oncol 2009;27:5887–92.
151. Bordeleau L, Panchal S, Goodwin P. Prognosis of BRCA-as-
sociated breast cancer: a summary of evidence. Breast
Cancer Res Treat 2010;119:13–24.
152. Evans DG, Ingham SL, Baildam A, et al. Contralateral mas-
tectomy improves survival in women with BRCA1/2-associ-
ated breast cancer. Breast Cancer Res Treat 2013;140:135–42.
153. Mamounas EP, Tang G, Liu Q. The importance of systemic
therapy in minimizing local recurrence after breast-con-
serving surgery: the NSABP experience. J Surg Oncol
2014;110:45–50.
Scientific American Surgery
03/16
154. Buchanan CL, Dorn PL, Fey J, et al. Locoregional recurrence
after mastectomy: incidence and outcomes. J Am Coll Surg
2006;203:469–74.
155. Nielsen HM, Overgaard M, Grau C, et al. Study of failure
pattern among high-risk breast cancer patients with or
without postmastectomy radiotherapy in addition to adju-
vant systemic therapy: long-term results from the Danish
Breast Cancer Cooperative Group DBCG 82 B and C ran-
domized studies. J Clin Oncol 2006;24:2268–75.
156. Aebi S, Gelber S, Anderson SJ, et al. Chemotherapy for iso-
lated locoregional recurrence of breast cancer (CALOR): a
randomised trial. Lancet Oncol 2014;15:156–63.
157. Morrow M, Jagsi R, Alderman AK, et al. Surgeon recom-
mendations and receipt of mastectomy for treatment of
breast cancer. JAMA 2009;302:1551–6.
158. Opatt D, Morrow M, Hawley S, et al. Conflicts in deci-
sion-making for breast cancer surgery. Ann Surg Oncol
2007;14:2463–9.
159. Hawley ST, Lillie SE, Morris A, et al. Surgeon-level varia-
tion in patients’ appraisals of their breast cancer treatment
experiences. Ann Surg Oncol 2013;20:7–14.
160. Collins ED, Moore CP, Clay KF, et al. Can women with
early-stage breast cancer make an informed decision for
mastectomy? J Clin Oncol 2009;27:519–25.
161. Katz SJ, Hawley ST, Morrow M, et al. Coordinating cancer
care: patient and practice management processes among
surgeons who treat breast cancer. Med Care 2010;48:45–51.
162. Kaufmann M, Hortobagyi GN, Goldhirsch A, et al. Recom-
mendations from an international expert panel on the use
of neoadjuvant (primary) systemic treatment of operable
breast cancer: an update. J Clin Oncol 2006;24:1940–9.
163. Wolmark N, Wang J, Mamounas E, et al. Preoperative che-
motherapy in patients with operable breast cancer: nine-
year results from National Surgical Adjuvant Breast and
Bowel Project B-18. J Natl Cancer Inst Monogr
2001;30: 96–102.
164. Jeruss JS, Mittendorf EA, Tucker SL, et al. Combined use of
clinical and pathologic staging variables to define outcomes
for breast cancer patients treated with neoadjuvant ther-
apy. J Clin Oncol 2008;26:246–52.
165. Symmans WF, Peintinger F, Hatzis C, et al. Measurement
of residual breast cancer burden to predict survival after
neoadjuvant chemotherapy. J Clin Oncol 2007;25:4414–22.
166. Esserman LJ, DeMichele A. Accelerated approval for pertu-
zumab in the neoadjuvant setting: winds of change? Clin
Cancer Res 2014;20:3632–6.
167. Wong ZW, Ellis MJ. Neoadjuvant endocrine therapy for
breast cancer: an overlooked option? Oncology (Williston
Park) 2004;18:411–20; discussion 421, 424, 429 passim.
168. Ma CX, Ellis MJ. Neoadjuvant endocrine therapy for locally
advanced breast cancer. Semin Oncol 2006;33:650–6.
169. Bristol IJ, Woodward WA, Strom EA, et al. Locoregional
treatment outcomes after multimodality management of
inflammatory breast cancer. Int J Radiat Oncol Biol Phys
2008;72:474–84.
170. Zelnak AB, O’Regan R. Adjuvant hormonal therapy for
early-stage breast cancer. Cancer Treat Res 2008;141:63–78.
171. Jankowitz RC, Davidson NE. Adjuvant endocrine therapy
for breast cancer: how long is long enough? Oncology
(Williston Park) 2013;27:1210–6, 1224.
breast breast cancer — 37
172. Johnston SR, Yeo B. The optimal duration of adjuvant endo-
crine therapy for early stage breast cancer—with what
drugs and for how long? Curr Oncol Rep 2014;16:358.
173. Petrelli F, Coinu A, Cabiddu M, et al. Five or more years of
adjuvant endocrine therapy in breast cancer: a meta-analy-
sis of published randomised trials. Breast Cancer Res Treat
2013;140:233–40.
174. Ravdin P. Overview of randomized trials of systemic adju-
vant therapy. Cancer Treat Res 2008;141:55–62.
175. McArthur HL, Hudis CA. Advances in adjuvant chemo-
therapy of early stage breast cancer. Cancer Treat Res
2008;141:37–53.
176. Bao T, Davidson NE. Gene expression profiling of breast
cancer. Adv Surg 2008;42:249–60.
177. Marchionni L, Wilson RF, Wolff AC, et al. Systematic
review: gene expression profiling assays in early-stage
breast cancer. Ann Intern Med 2008;148:358–69.
178. Sparano JA, Gray RJ, Makower DF, et al. Prospective vali-
dation of a 21-gene expression assay in breast cancer.
N Engl J Med 2015;373:2005–14.
179. Drukker CA, van Tinteren H, Schmidt MK, et al. Long-term
impact of the 70-gene signature on breast cancer outcome.
Breast Cancer Res Treat 2014;143:587–92.
180. Nielsen T, Wallden B, Schaper C, et al. Analytical validation
of the PAM50-based Prosigna Breast Cancer Prognostic
Gene Signature Assay and nCounter Analysis System using
formalin-fixed paraffin-embedded breast tumor specimens.
BMC Cancer 2014;14:177.
181. Hudis CA. Trastuzumab—mechanism of action and use in
clinical practice. N Engl J Med 2007;357:39–51.
182. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus
adjuvant chemotherapy for human epidermal growth factor
receptor 2-positive breast cancer: planned joint analysis of
overall survival from NSABP B-31 and NCCTG N9831.
J Clin Oncol 2014;32:3744–52.
183. Kumler I, Tuxen MK, Nielsen DL. A systematic review of
dual targeting in HER2-positive breast cancer. Cancer Treat
Rev 2014;40:259–70.
184. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastu-
zumab, and docetaxel in Her2-positive metastatic breast
cancer. N Engl J Med 2015;372:724–34.
185. Effects of chemotherapy and hormonal therapy for early
breast cancer on recurrence and 15-year survival: an over-
view of the randomised trials. Lancet 2005;365:1687–717.
186. Olivotto IA, Bajdik CD, Ravdin PM, et al. Population-based
validation of the prognostic model ADJUVANT! for early
breast cancer. J Clin Oncol 2005;23:2716–25.
187. Mook S, Schmidt MK, Rutgers EJ, et al. Calibration and dis-
criminatory accuracy of prognosis calculation for breast
cancer with the online Adjuvant! program: a hospital-based
retrospective cohort study. Lancet Oncol 2009;10:1070–6.
188. Chen LL, Nolan ME, Silverstein MJ, et al. The impact of pri-
mary tumor size, lymph node status, and other prognostic
factors on the risk of cancer death. Cancer 2009;115:5071–83.
189. Khan SA, Stewart AK, Morrow M. Does aggressive local
therapy improve survival in metastatic breast cancer? Sur-
gery 2002;132:620–6; discussion 626–7.
190. Rapiti E, Verkooijen HM, Vlastos G, et al. Complete exci-
sion of primary breast tumor improves survival of patients
with metastatic breast cancer at diagnosis. J Clin Oncol
2006;24:2743–9.
191. Hazard HW, Gorla SR, Scholtens D, et al. Surgical resection of
the primary tumor, chest wall control, and survival in women
with metastatic breast cancer. Cancer 2008;113:2011–9.
192. Ruiterkamp J, Voogd AC, Bosscha K, et al. Impact of breast
surgery on survival in patients with distant metastases at
initial presentation: a systematic review of the literature.
Breast Cancer Res Treat 2010;120:9–16.
193. de Bresser J, de Vos B, van der Ent F, et al. Breast MRI in
clinically and mammographically occult breast cancer pre-
senting with an axillary metastasis: a systematic review. Eur
J Surg Oncol 2010;36:114–9.
194. Varadarajan R, Edge SB, Yu J, et al. Prognosis of occult
breast carcinoma presenting as isolated axillary nodal
metastasis. Oncology 2006;71:456–9.
195. Yang TJ, Yang Q, Haffty BG, et al. Prognosis for mam-
mographically occult, early-stage breast cancer patients
treated with breast-conservation therapy. Int J Radiat Oncol
Biol Phys 2010;76:79–84.
196. Molckovsky A, Madarnas Y. Breast cancer in pregnancy: a
literature review. Breast Cancer Res Treat 2008;108:333–8.
197. Amant F, Loibl S, Neven P, et al. Breast cancer in preg-
nancy. Lancet 2012;379:570–9.
198. Krishna I, Lindsay M. Breast cancer in pregnancy. Obstet
Gynecol Clin North Am 2013;40:559–71.
199. Spanheimer PM, Graham MM, Sugg SL, et al. Measurement
of uterine radiation exposure from lymphoscintigraphy
indicates safety of sentinel lymph node biopsy during preg-
nancy. Ann Surg Oncol 2009;16:1143–7.
200. Litton JK. Breast cancer and fertility. Curr Treat Options
Oncol 2012;13:137–45.
201. Valentini A, Lubinski J, Byrski T, et al. The impact of preg-
nancy on breast cancer survival in women who carry a
BRCA1 or BRCA2 mutation. Breast Cancer Res Treat
2013;142:177–85.
202. Ruddy KJ, Gelber SI, Tamimi RM, et al. Prospective study
of fertility concerns and preservation strategies in young
women with breast cancer. J Clin Oncol 2014;32:1151–6.
203. Tomasi-Cont N, Lambertini M, Hulsbosch S, et al. Strategies
for fertility preservation in young early breast cancer
patients. Breast 2014;23:503–10.
204. Rodriguez-Wallberg KA, Oktay K. Fertility preservation
and pregnancy in women with and without BRCA muta-
tion-positive breast cancer. Oncologist 2012;17:1409–17.
205. Giordano SH. A review of the diagnosis and management
of male breast cancer. Oncologist 2005;10:471–9.
206. Pant K, Dutta U. Understanding and management of male
breast cancer: a critical review. Med Oncol 2008;25:294–8.
207. Cloyd JM, Hernandez-Boussard T, Wapnir IL. Outcomes of
partial mastectomy in male breast cancer patients: analysis
of SEER, 1983-2009. Ann Surg Oncol 2013;20:1545–50.
208. Khatcheressian JL, Hurley P, Bantug E, et al. Breast cancer
follow-up and management after primary treatment: Amer-
ican Society of Clinical Oncology clinical practice guideline
update. J Clin Oncol 2013;31:961–5.
209. Jochelson M, Hayes DF, Ganz PA. Surveillance and moni-
toring in breast cancer survivors: maximizing benefit and
Scientific American Surgery
03/16
breast breast cancer — 38
minimizing harm. Am Soc Clin Oncol Educ Book 2013.
DOI: 10.1200/EdBook_AM.2013.33.e13.
210. Ganz PA. Breast cancer, menopause, and long-term survi-
vorship: critical issues for the 21st century. Am J Med
2005;118 12B:136–41.
211. Ganz PA, Hahn EE. Implementing a survivorship care plan
for patients with breast cancer. J Clin Oncol 2008;26:759–67.
212. Cowens-Alvarado R, Sharpe K, Pratt-Chapman M, et al.
Advancing survivorship care through the National Cancer
Survivorship Resource Center: developing American
Cancer Society guidelines for primary care providers. CA
Cancer J Clin 2013;63:147–50.
213. Denlinger CS, Carlson RW, Are M, et al. Survivorship:
introduction and definition. Clinical practice guidelines in
oncology. J Natl Compr Canc Netw 2014;12:34–45.
Scientific American Surgery
03/16
214. Kvale E, Urba SG. NCCN guidelines for survivorship
expanded to address two common conditions. J Natl Compr
Canc Netw 2014;12:825–7.
215. Ligibel JA, Denlinger CS. New NCCN guidelines for survi-
vorship care. J Natl Compr Canc Netw 2013;11:640–4.
216. Skolarus TA, Wolf AM, Erb NL, et al. American Cancer
Society prostate cancer survivorship care guidelines. CA
Cancer J Clin 2014;64:225–49.
Acknowledgments
Figures 2, 3, and 4 Christine Kenney
Figure 9 Alice Y. Chen