Breast Cancer

COMMON CANCERS

Breast cancerEleri Lloyd Davies

AbstractBreast cancer is the commonest cancer to affect women with a recent esti-

mate 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 preg-

nancies. 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. Themajority of patientswill be offered adjuvant treat-

ment, 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.

Keywords adjuvant therapy; biologicalmarkers; breast cancer; Herceptin;

oncoplastic; sentinel node biopsy

Tumour stage

T Tumour <2 cm

T Tumour 2–5 cm

T Tumour 5 cm

T Tumour fixed chest wall/skin or inflammatory

Nodal stage

Pathological pNClinical

N No nodes Negative of Individual tumour cells (ITC)

N Mobile regional nodes 1–3 micro or macrometastasis

N Fixed regional or internal mammary nodes

4–9 nodes

N Supraclavicular nodes >10 nodes, axillary and internal mammary or supraclavicular nodes

TNM classification of breast cancer

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.

Epidemiology

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

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 5

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.

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%. TNMclassification

looks at size, nodal status and distantmetastasis.When considering

nodal status, the presence of individual tumour cells (ITC) is classed

as node-negativewhereasmicrometastasis (>0.2e2mm) 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

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

Distant metastasis

M No distant metastasis

M Distant metastasis

Figure 1

� 2011 Elsevier Ltd. All rights reserved.

http://dx.doi.org/10.1016/j.mpmed.2011.09.010

14%Any T, ANY N, Mlv

30%Any T N Mlllc

40%T N M or T N M

or T N M

lllb

45%T N M or T N M

or T N M

llla

65%T N M or T N Mllb

80%T N M or T N Mlla

90%T N Ml

5 year survivalTNM classificationStage

AJCC staging system for breast cancer

AJCC, American Joint Committee on Cancer.

Figure 2

COMMON CANCERS

a specialist breast clinic for triple assessment (clinical, radio-

logical 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.

Investigations

� Histological investigations e as well as confirming the

diagnosis (type, grade), provide useful information about

oestrogen (ER), progesterone (PR) and HER2 receptor

status.

MDT, multidisciplinary team; USS, ultrasound scanning.

Screening Symptomatic

Clinical and USS

Reassure Biopsy

Reassure Treatment options

Reassure Ultrasound biopsy

Lump/abnormality

NormalLump

< 35 years > 35 years

Normal

Benign Malignant

Clinical and Mammography

MDT

Triple Assessment

Algorithm of the triple assessment process

Figure 3

MEDICINE 40:1 6

� 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 pre-

operatively in breast cancer.4 The current indications are

lobular breast cancer, multifocal disease, dense breast

(where estimation of cancer size is an issue) and assess-

ment 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.

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 decision-

making. 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

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 post-

operative radiotherapy or mastectomy. With increasing interest

in oncoplastic breast procedures, a wide selection of breast-

conserving approaches (i.e. therapeutic mammoplasty) are now

being offered, which achieve better cosmetic outcomes. In

addition, in those 25e30% of patients who require a mastec-

tomy, more women are being offered immediate or delayed

reconstruction. Skin- and nipple-sparing mastectomy with

reconstruction offers an excellent final cosmetic result for suit-

able patients. Other advances include lipofilling/lipomodulation,

which involves the use of autologous fat transplantation tech-

niques to improve breast-volume defects following breast

conservation or reconstruction.8

Historically, axillary surgery involved an axillary node clear-

ance (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



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.

COMMON CANCERS

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 recur-

rence 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 dr

MEDICINE 40:1 7

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 radio-

therapy, 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 radio-

therapy 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

aining into it. (b) Measuring how hot the node is with a probe.



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 (ERþ). 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 ERþ. 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).

Chemotherapy

Adjuvant chemotherapy has been shown to reduce local recur-

rence 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, HER2-

overexpression, 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 myelosup-

pression, alopecia, nausea, diarrhoea and infertility. Anthracy-

clines are cardiotoxic.

Biological therapy and novel agents

Trastuzumab, a monoclonal antibody used in the treatment of

HER2-positive patients, reduces recurrence by 50% and

prolongs survival by 30% when used in combination with

chemotherapy.14 It is now included in NICE guidelines. Its

main toxicity is cardiac failure, and use in combination with

anthracyclines should be avoided. Other novel drugs include

the oral tyrosine kinase inhibitor, lapatinib, and the anti-

angiogenic drug, bevacizumab. Both have demonstrated effi-

cacy following trastuzumab failure and are licenced for use,

but are available through application on a named-patient basis

only because of their cost. Early clinical trials of the nuclear

enzyme poly ADP ribose polymerase (PARP) inhibitors,

controlling DNA repair and apoptosis is of particular benefit in

BRCA mutations, basal-like and triple-negative (ER/PR/HER2)

patients.

MEDICINE 40:1 8

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

REFERENCES

1 Ramak E, Brazil L. Cost of managing women presenting with stage 1V

breast cancer in the United Kingdom. Br J Cancer 2004; 91: 77e83.

2 Dowsett M, Dunbler AK. Emerging biomarkers and new under-

standing of traditional markers in personalized therapy for breast

cancer. Clin Cancer Res 2008; 14: 8019e26.

3 National Institute for Health and Clinical Excellence. Guidance on

breast cancer (early and locally advanced): diagnosis and treatment.

London: NICE; 2009. Also available at: http://guidance.nice.org/CG80.

4 Turnbull L, Brown S, Harvey I, et al. Comparative effectiveness of MRI

in breast cancer (COMICE) trial: a randomised control trial. Lancet

2010; 355: 563e71.

5 Boetes C, Veltman J, van Die L, Bult P, Wobber T, Barentsz JO. The role

of MRI in invasive lobular carcinoma. Breast Cancer Res Treat 2004;

86: 31e7.

6 Kaufman M, Puztai L, Biedenkopf Expert Panel Members, et al. Use of

standard markers and incorporation of molecular markers in breast

cancer therapy: consensus recommendation from an international

expert panel. Cancer 2011; 117: 1575e82.

7 Menta R, Jain RK, Badve S. Personalized medicine: the road ahead.

Clin Breast Cancer 2011; 11: 20e6.


http://guidance.nice.org/CG80


COMMON CANCERS

8 Elfadl D, Gavimella V, Mahapatra TK, McManus PL, Drew PJ.

Lipomodelling of the breast: a review. Breast 2010; 19: 202e9.

9 Chen JJ, Yang BC, Zhang JX. A prospective comparison of molecular

assay and touch imprint cytology for intraoperative evaluation of

sentinel lymph nodes. Clin Med J (Engl) 2011; 124: 491e7.

10 Clarke M, Collins R, Darby S, et al. Early Breast Cancer Trialists’

Collaborative Group (EBCTCG). Effects of radiotherapy and of differ-

ences in the extent of surgery for early breast cancer on local recurrence

and 15 year survival: an overview of the randomised trials. Lancet

2005; 366: 2087e106.

11 Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intra-operative

radiotherapy versus breast radiotherapy for breast cancer (TARGIT-A

MEDICINE 40:1 9

trial): an international, prospective, randomised, non-inferiority

phase 3 trial. Lancet 2010; 376: 91e102.

12 Early Breast Cancer Trials’ Collaborative Group (EBCTG). Effects of

chemotherapy and hormonal therapy for early breast cancer on

recurrence and 15 year survival: an overview of randomised control

trials. Lancet 2005; 365: 1687e717.

13 Cuzick J, Sestak I, Baum M, et al. Effect of anastrazole and tamoxifen

as adjuvant treatment for early stage breast cancer: 10 year analysis

of ATAC trial. Lancet Oncol 2010; 11: 1135e41.

14 Piccart-Gebhart MJ, Procter M, Leyland-Jones B. Trastuzumab after

adjuvant chemotherapy in Her2 positive patients. N Engl J Med 2005;

353: 1659e72.



Documents

Breast Cancer