COMMON CANCERS

Breast cancer

use of exogenous hormones, obesity, lack of exercise and alcohol

consumption. Fewer than 5% of breast cancers are genetic.
Patients with proven gene mutations (BRCA-1/BRCA-2) have an
estimated lifetime risk of developing breast cancer of 40e85%.
Breast cancer clearly poses a significant economic burden on
an already struggling NHS. The cost of the NHS Breast Screening
programme alone is 75 million (37.50/woman invited and
45.50/woman screened). The cost of treating early breast cancer
is poorly documented in the literature, but a recent publication
estimated the total population cost of treating metastatic breast
cancer at 26 million/year.1 With new technologies and targeted
therapies it is inevitable that these costs will increase, putting
more pressure on the economy.

Eleri Lloyd Davies

Abstract
Breast cancer is the commonest cancer to affect women with a recent estimate of lifetime risk of 1:8. The number of women found to have breast
cancer in the UK has risen to 47,000 with the highest rise being in the
50e69 years age group. This is probably attributable to several lifestyle
factors such as diet, alcohol consumption, lack of exercise and late pregnancies. Because of earlier diagnosis and major treatment advances,
survival rates have been gradually improving; 80% of patients with early
breast cancer now survive for 5 years after diagnosis. Recent advances in
surgical management include the use of oncoplastic procedures and
sentinel node biopsy. The majority of patients will be offered adjuvant treatment, such as radiotherapy, hormones, chemotherapy and biological
agents, which aim to reduce local recurrence and improve survival. Novel
developments include the use of biological markers to predict outcome
and response to chemotherapy. This overview discusses the up-to-date
management of breast cancer and recent developments in this field.

Pathology
The majority of breast cancers (70e80%) are ductal with several
special subtypes (medullary, papillary, tubular and mucinous).
Lobular cancers account for the remaining 20%. TNM classification
looks at size, nodal status and distant metastasis. When considering
nodal status, the presence of individual tumour cells (ITC) is classed
as node-negative whereas micrometastasis (>0.2e2 mm) is classed
as node-positive (Figure 1). The American Joint Committee on
Cancer (AJCC) staging system provides a strategy for grouping
patients with respect to prognosis (Figure 2). Development of
microarray-based gene expression profiling has shown breast
cancer to be heterogeneous e it can be subclassified into five
distinct subtypes: luminal A, luminal B, HER2-overexpressing,
basal-like and normal-like. These subtypes have very different
prognoses and responses to adjuvant therapies.2

Keywords adjuvant therapy; biological markers; breast cancer; Herceptin;

oncoplastic; sentinel node biopsy

Terminology
Breast cancer is caused by the presence of malignant cells in the
breast. Cancer cells are characterized by uncontrolled division,
leading to abnormal growth (in situ carcinoma), and their ability
to invade normal tissue locally. Depending on whether the
glandular or ductal units of the breast are involved enables
pathologists to sub-classify breast cancer into types. The primary
tumour begins in the breast but, once it becomes invasive, may
progress to the regional lymph nodes (axillary/internal
mammary) or metastasize. The commonest sites of systemic
involvement are the lung, bones, liver, skin, and soft tissue. The
presence of, and the number of regional lymph nodes containing
cancer remains the single best indicator of whether or not the
cancer has metastasized.

Diagnosis
Patients present with symptoms or are detected through the NHS
breast screening programme. NICE guidance3 states that both
symptomatic and screen-detected patients should be referred to

TNM classification of breast cancer

Tumour stage

Epidemiology

Tumour <2 cm

Tumour 25 cm

Tumour 5 cm

Tumour fixed chest wall/skin or inflammatory

Nodal stage

Each year, breast cancer is diagnosed in 1.3 million women

worldwide and 465,000 deaths result from the disease. It occurs
very infrequently in men (300/year in UK). Incidence increases
with age, 80% occurring in women over the age of 50 years. It
occurs less commonly in younger women, but they tend to
display more aggressive disease (5-year survival rates 81% <45
years, 86% >65 years). Other risk factors include early
menarche, late menopause, parity, breastfeeding and prolonged

Clinical

Pathological pN

No nodes

Negative of Individual
tumour cells (ITC)

Mobile regional nodes

13 micro or
macrometastasis

Fixed regional or internal

mammary nodes

49 nodes

Supraclavicular nodes

>10 nodes, axillary and

internal mammary or
supraclavicular nodes

Distant metastasis

Eleri Lloyd Davies FRCS(Eng) is Consultant Breast Surgeon at the Cardiff

Breast Centre, University Hospital Llandough, UK. Conflicts of interest:
none declared.

MEDICINE 40:1

No distant metastasis

Distant metastasis

Figure 1

2011 Elsevier Ltd. All rights reserved.

COMMON CANCERS

Radiological staging (CT thorax, abdomen and pelvis, and

bone scan) e performed only if there is a high suspicion of
metastasis (i.e. bone pain or locally advanced disease,
lymph nodes discovered postoperatively or recurrent
disease).

Magnetic resonance imaging (MRI) is currently used in
limited situations in breast cancer patients because a large
multicentre trial (COMICE) demonstrated an increased
incidence of overtreatment when MRI was used preoperatively in breast cancer.4 The current indications are
lobular breast cancer, multifocal disease, dense breast
(where estimation of cancer size is an issue) and assessment of implant integrity. In lobular cancers there is a high
incidence of bilateral disease and multifocality, and MRI
has proved beneficial in the surgical planning of these
patients.5 In addition, Figure 4 illustrates how MRI can be
useful for accurate sizing of the cancer in very dense
breasts.

AJCC staging system for breast cancer

Stage

TNM classification

5 year survival

T N M

90%

lla

T N M or T N M

80%

llb

T N M or T N M

65%

llla

T N M or T N M
or T N M

45%

lllb

T N M or T N M
or T N M

40%

lllc

Any T N M

30%

lv

Any T, ANY N, M

14%

AJCC, American Joint Committee on Cancer.

Figure 2

a specialist breast clinic for triple assessment (clinical, radiological and pathological). These assessments are now being
performed more frequently in one-stop clinics. Figure 3 shows an
algorithm illustrating the triple assessment process. Clinical
assessment includes a history and an examination by a specialist
breast surgeon. All patients over the age of 35 years will have
a two-view mammogram. A scoring system is used, ranging from
1 (benign) to 5 (malignant) for each component of the triple
assessment. All patients are finally discussed at multidisciplinary
team meeting to confirm a diagnosis and treatment plan.

Management
Multidisciplinary team (MDT) meeting
Therapeutic decisions are made according to tumour size, lymph
node status, oestrogen receptor (ER), progesterone receptor (PR)
and human epidermal growth receptor 2 (HER2) status, and
general health of the patient. A number of tools (e.g. Adjuvant!
online, Predict and NICE guidelines) are used to aid decisionmaking. In addition, the use of commercially-available kits (e.g.
Oncotype DX, Mammaprint), which characterize expression of
a subset of genes within the breast cancer tissue, are increasingly
being employed to estimate the likelihood of disease recurrence
and/or response to chemotherapy in certain breast cancer
subtypes.6,7

Investigations

Histological investigations e as well as confirming the
diagnosis (type, grade), provide useful information about
oestrogen (ER), progesterone (PR) and HER2 receptor
status.

Surgery
Traditionally, the aim of surgery was to remove the primary
breast lesion and axillary lymph nodes completely. Most patients
were offered wide local excision (WLE) followed by postoperative radiotherapy or mastectomy. With increasing interest
in oncoplastic breast procedures, a wide selection of breastconserving approaches (i.e. therapeutic mammoplasty) are now
being offered, which achieve better cosmetic outcomes. In
addition, in those 25e30% of patients who require a mastectomy, more women are being offered immediate or delayed
reconstruction. Skin- and nipple-sparing mastectomy with
reconstruction offers an excellent final cosmetic result for suitable patients. Other advances include lipofilling/lipomodulation,
which involves the use of autologous fat transplantation techniques to improve breast-volume defects following breast
conservation or reconstruction.8
Historically, axillary surgery involved an axillary node clearance (ANC). With only 25e30% of patients being node-positive,
the remaining node-negative patients were subjected to the risk
of lymphoedema, shoulder stiffness and paraesthesia without
benefit. Sentinel node biopsy (SNB) allows accurate staging of
the axilla using a minimally invasive surgical procedure with
reduced morbidity. The sentinel lymph node (SLN) is identified
by using a combination of radioactive colloid suspension and
blue dye (Figure 5). If the SLN is negative on histological

Algorithm of the triple assessment process

Screening

Symptomatic

Triple Assessment
< 35 years

> 35 years

Clinical and USS

Normal

Lump

Reassure

Biopsy

Clinical and Mammography

Normal
Reassure

Lump/
abnormality
Ultrasound biopsy

MDT
Benign
Reassure

Malignant
Treatment options

MDT, multidisciplinary team; USS, ultrasound scanning.

Figure 3

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COMMON CANCERS

Figure 4 (a) Right mammogram showing very dense breast tissue. (b) MRI scan in same patient demonstrating a 4.1 cm lobular cancer not visible on
initial mammograms.

Radiotherapy
Radiotherapy after WLE reduces the 5-year local recurrence rates
from 26% to 7% and has been shown to be equivalent to
mastectomy. Recent evidence suggests an overall survival rate of
about 5% absolute for postoperative adjuvant radiotherapy.10
The majority of mastectomy patients do not require radiotherapy, but those at increased risk of recurrence (T3/T4
tumours, lymphovascular invasion, four or more positive lymph
nodes) will benefit from chest wall and supraclavicular fossa
irradiation. Recent evidence has supported the use of radiotherapy in intermediate and high-grade ductal carcinoma in situ
(DCIS). Trials of the use of axillary radiotherapy in SLN-positive
patients (AMAROS trial) and of intra-operative partial breast
irradiation are in progress.11

examination, the patient is classed as node-negative. However,

the disadvantage of SNB is that women with positive nodes
usually require a second operation to complete axillary surgery.
This has triggered an interest in intra-operative assessment of the
SLN, followed by immediate axillary surgery if the node is
positive. Several techniques have been introduced, including
frozen section, touch-imprint cytology and reverse transcription
polymerase chain reaction (RT-PCR).9

Adjuvant therapy
The aim is to reduce the risk of loco-regional and distant recurrence by targeting microscopic tumour foci in residual breast
tissue, regional lymph nodes or bloodstream.

Figure 5 (a) Illustrates a sentinel node which is blue with a blue lymphatic draining into it. (b) Measuring how hot the node is with a probe.

MEDICINE 40:1

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COMMON CANCERS

Endocrine
Oestrogens play a crucial role in breast cancer; by binding to
target receptors they promote proliferation of breast cancer cells.
The majority of breast cancers (w70%) are oestrogen receptor
positive (ER). In premenopausal women, circulating oestrogens
are produced primarily by the ovaries. Inhibition of oestrogen
action is achieved through suppression of ovarian function,
either by surgical means, using ovarian ablation, or by the use of
luteinizing hormone-releasing hormone (LHRH) agonists such as
goserelin. Alternatively, the use the selective oestrogen receptor
modulators (SERM), such as tamoxifen, has been shown to
reduce recurrence by 47% and death by 26%.12
However, most breast cancers occur in postmenopausal
women and approximately 80% of these will be ER. In these
women, the ovaries no longer produce oestrogen; instead, small
quantities of oestrogens are synthesized in non-ovarian tissues
such as the liver, adrenal glands and, importantly, the breast
tissue itself. Traditionally, the oestrogenic stimulation of breast
cancer was suppressed through the use of tamoxifen. Aromatase
inhibitors (AIs) target oestrogen production by blocking the
conversion of androgens to oestrogen through inhibition of the
aromatase enzyme. Clinical data demonstrate that AIs are
superior to tamoxifen13 and have replaced it as a first-line
therapy in postmenopausal women with breast cancer. The
optimal duration of treatment is still uncertain but it is currently
given for at least 5 years. Many patients experience adverse
effects that include hot flushes, venous thrombo-embolism and
endometrial cancer (tamoxifen), arthralgia and osteoporosis
(AIs).

Follow-up
There is current controversy over the most appropriate follow-up
procedure. NICE guidelines (2009) suggest annual mammograms
for 5 years and clinical follow-up until adjuvant therapies are
complete.3 Follow-up procedures are usually agreed at a local
level, and many are run by nurses with extended roles. Issues to
consider are management of the adverse effects of adjuvant
hormones and, in particular, bone health.
Metastatic disease
Metastatic breast cancer will be covered only briefly in this
paper. Treatment focuses on palliating symptoms to maintain
quality of life and to extend life where possible. The treatments
offered are as follows:

endocrine therapy e in ER-positive patients as first line

chemotherapy e reserved for patients who are ER-negative
or hormone resistant

trastuzumab e for HER2-positive patients, even if they
were given it at initial treatment

radiotherapy e in those with bony metastasis (to improve
pain control), cord compression and, in addition, superior
vena caval obstruction, fungating chest wall disease and
brain metastasis

bisphosphonates e to reduce risk of pathological fractures
and improve pain control.

Conclusions
Breast cancer imposes a significant clinical and economic burden
on the NHS. With earlier diagnosis and improvement in the
treatments offered, patients are surviving for longer. Oncoplastic
surgery is striving to improve cosmetic outcomes. It is essential
to maintain balance between adequate oncological treatment and
the desire to achieve cosmetic perfection. Further research into
biological markers is required to develop novel agents that will
lead to further improvements in survival from this cancer. A

Chemotherapy
Adjuvant chemotherapy has been shown to reduce local recurrence by 30% and death by 20%.12 Chemotherapy is usually
used in combination regimens to reduce toxicity and resistance,
and increase efficacy. Anthracycline regimens are considered the
gold standard. Patients are offered chemotherapy only if they
have high-risk disease (premenopausal, ER/PR-negative, HER2overexpression, large tumours and node-positive disease) to
avoid toxicity and the use of expensive drugs in those who will
not benefit. Adverse effects of treatment include myelosuppression, alopecia, nausea, diarrhoea and infertility. Anthracyclines are cardiotoxic.

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COMMON CANCERS

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2011 Elsevier Ltd. All rights reserved.