Breast cancer

COMMON CANCERS

Breast cancer

Key points

Sharat Chopra

C

Eleri Lloyd Davies C

Newer treatment modalities, such as the combination of the multiple biological/immunotherapeutic agents trastuzumab and pertuzumab, have improved survival rates

C

The role of multimodality support for family and carers, including familial genetics clinics, has also improved care and outlook

Abstract Breast cancer is the most common cancer affecting women, with a recent estimate of lifetime risk of 1 in 8. In 2016 the number of women with breast cancer in the UK had risen to 54,600, accounting for 15% of new cancer cases; the highest rise was in 50e90-year-olds, with a peak in >90-year-olds. This is probably attributable to lifestyle factors such as diet, alcohol consumption, lack of exercise and late pregnancies. Because of advances in earlier diagnosis and major treatment, survival rates have gradually improved over the last 20 years, 80% of patients with early breast cancer now surviving 10 years after diagnosis. Recent advances in surgical management include oncoplastic techniques for breast conservation and advances in breast reconstruction after mastectomy. The management of the disease-positive axilla is another hot topic in management. Most patients with breast cancer are offered either neoadjuvant or adjuvant treatment in the form of radiotherapy, hormones, chemotherapy and biological agents, aiming to reduce recurrence and improve overall survival. Novel developments include the use of biological markers to predict outcome and response to chemotherapy, and newer combination immunotherapy agents, which can improve survival in the metastatic setting. This overview discusses the up-to-date management of breast cancer and recent developments.

containing cancer remains the single best indicator of whether the cancer has metastasized.

Epidemiology In 2018, breast cancer is diagnosed in 2 million women worldwide and 627,000 deaths result from the disease. It occurs very infrequently in men (350 pr year in the UK) compared with women.1 The incidence increases with age, 80% of cancers occurring in women >50 years old. It is less common in younger women but disease tends to be more aggressive (5-year survival rates 81% <45 years, 86% >65 years). Other risk factors include early menarche, late menopause, nulliparity, breastfeeding, prolonged use of exogenous hormones, obesity, lack of exercise and alcohol consumption. Fewer than 5% of breast cancers are genetic. Patients with proven gene mutations (BRCA1/BRCA2) have an estimated lifetime risk of developing breast cancer of 40 e85% (see The Royal Marsden’s NHS Hospital: a beginners guide to BRCA1 and BRCA2). Breast cancer clearly poses a significant economic burden on an already struggling NHS in the UK. The cost of the NHS breast screening programme alone in England is approximately £96 million (£37.50 per woman invited, £45.50 per 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 per year.2 These costs will inevitably increase with new technologies and targeted therapies, increasing economic pressure.

Keywords Adjuvant therapy; biological markers; breast cancer; MRCP; neoadjuvant treatment; oncoplastic; pertuzumab; sentinel node biopsy; trastuzumab

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 the ability to invade normal tissue locally (invasive cancer). Identifying whether the glandular or ductal units of the breast are involved enables pathologists to subclassify breast cancer. The primary tumour begins in the breast but, once it becomes invasive, can progress to the regional (axillary/internal mammary) lymph nodes; it then has the ability to metastasize. The most common sites of systemic involvement are the lung, bones, liver, skin and soft tissue. The presence of and number of regional lymph nodes

Pathology Most breast cancers (70e80%) are ductal, with several special subtypes (medullary, papillary, tubular, mucinous). Lobular cancers account for the remainder. The tumour, node, metastasis (TNM) classification looks at size, nodal status and distant metastasis. A simplified version is shown in Table 1. When considering nodal status, the presence of individual tumour cells and micro-metastases (>0.2e2 mm) is classed as node-negative, whereas macro-metastasis is classed as node-positive. The American Joint Committee on Cancer (AJCC) staging system groups patients with respect to prognosis (Table 2). Other variables that affect survival are oestrogen receptor (ER) and human epidermal growth receptor-2 (HER2) receptor status. DNA

Sharat Chopra MB BS MRCS(Ed) FEBS(Breast Surgery) is a Specialty Breast Surgeon at The Breast Centre, University Hospital Llandough, Cardiff, UK. Competing interests: none declared. Eleri Lloyd Davies MB BCh FRCS(Eng) is an Oncoplastic Breast Surgeon Working at The Breast Centre, University Hospital Llandough, Cardiff, UK. Competing interests: none declared.

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Early-stage breast cancer accounts for >80% of breast cancers and carries a favourable prognosis

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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.

AJCC staging system for breast cancer

Diagnosis Patients present with symptoms or are detected through the NHS breast screening programme. National Institute for Health and Care Excellence (NICE) guidance3 states that both symptomatic and screen-detected patients should be referred to a specialist breast clinic for triple assessment: clinical, radiological and pathological. These assessments are now performed more frequently in one-stop clinics (Figure 1). Clinical assessment includes a history and an examination by a specialist breast surgeon or a trained clinician/physician. All patients >35 years of age undergo a two-view mammogram with or without tomosynthesis (a three-dimensional (3D) mammogram that helps to define lesions more clearly). Areas of clinical or mammographic concern are then examined by ultrasound scanning. If there is a discrete lesion to biopsy, a core biopsy is performed. 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 a multidisciplinary team (MDT) meeting to confirm a diagnosis and treatment plan.

Stage

TNM classification

I IIa IIb IIIa IIIb IIIc IV

T1 N0 M0 T1 N1 M0 or T2 N0 T2 N1 M0 or T3 N0 T2 N2 M0 or T3 N1 T4 N0 M0 or T4 N1 Any T, N3 M0 Any T, Any N, M1

5-year survival (%)

M0 M0 M0 or T3 N2 M0 M0 or T4 N2 M0

90 80 65 45 40 30 14

Table 2

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 because the large multicentre Comparative Effectiveness of MR Imaging in Breast Cancer (COMICE) trial demonstrated an increased incidence of overtreatment when MRI was used preoperatively in breast cancer, because of its high sensitivity and low specificity rate. The current indications are lobular breast cancer, multifocal disease, dense breast (where estimation of cancer size is an issue) (Figure 2), assessment of implant integrity, neoadjuvant settings to assess response to chemotherapy and follow-up of breast cancer patients when mammographic occult. In lobular cancers there is a high incidence of bilateral disease and multifocality, and MRI has proved beneficial in surgical planning.4  Positron emission tomography-CT is used to make a new diagnosis of metastases where imaging leads to a suspicion of metastatic disease but does not prove diagnostic.

Investigations  Histological investigations e as well as confirming the diagnosis (type, grade), these provide useful information about ER, progesterone receptor (PR) and HER2 status.  Radiological staging e computed tomography (CT) of the thorax, abdomen and pelvis, and bone scanning are

Simplified TNM classification of breast cancer

Management

Tumour stage

Multidisciplinary team meeting Therapeutic decisions are made according to tumour size, lymph node status, ER, PR and HER2 status, the patient’s general health and their wishes. Several tools (e.g. Adjuvant! Online, Predict, NICE guidelines) are used to aid decisionmaking. In addition, commercially available kits (e.g. Oncotype DXÒ, MammaPrintÔ), which characterize the 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 subtypes5 (see Cytotoxic chemotherapy: clinical aspects on pages xxexx of this issue).

<2 cm 2e5 cm 5 cm fixed to chest wall/skin or inflammatory

T1 T2 T3 T4

Tumour Tumour Tumour Tumour

Nodal stage N0

Clinical pN

Pathological pN

No nodes

N1

Mobile regional nodes

N2

Fixed regional or internal mammary nodes Supraclavicular nodes

Negative of individual tumour cells 1e3 micro- or macrometastases 4e9 nodes

N3

Surgery The aim of surgery has traditionally been to completely remove the primary breast lesion and axillary lymph nodes. Most patients are offered mastectomy or wide local excision followed by postoperative radiotherapy. With increasing interest in oncoplastic breast surgery, a wide selection of breast-conserving approaches e therapeutic mammoplasty, circumareolar incisions with dermoglandular flaps and several mini-flaps e are now offered, which achieve better cosmetic outcomes. In addition, of

>10 nodes, axillary and internal mammary or supraclavicular nodes

Distant metastasis M0 M1

No distant metastasis Distant metastasis

Table 1

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Historically, axillary surgery involved axillary node clearance. As only 25e30% of patients are node-positive, the remaining node-negative patients were subjected to a 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 3) (see The use of imaging and interventional radiology in modern oncology on pages XXXeXX of this issue). If the SLN is diseasenegative on histological examination, the patient is classed as node-negative. However, the disadvantage of SNB is that women with positive nodes have traditionally required a second operation to complete the axillary clearance. This has triggered an interest in intraoperative assessment of the SLN, followed by immediate axillary surgery if it is positive. Several techniques have been introduced, including frozen section, touch imprint cytology and reverse transcription polymerase chain reaction. (See Chen JJ et al. in Further reading). Publication of the Z11 clinical trial comparing axillary dissection with no axillary treatment in women with invasive breast cancer and positive SNB has caused much controversy regarding the correct treatment of the axilla in this group of patients. In the UK there is no consensus of opinion. The Positive Sentinel Node: Adjuvant Therapy Alone Versus Adjuvant Therapy Plus Clearance or Axillary Radiotherapy (POSNOC) trial has been launched to try to answer this.

Algorithm of the triple assessment process Screening

Symptomatic

Triple assessment < 35 years

> 35 years Clinical and mammography

Clinical and USS Normal

Lump

Reassure

Biopsy

Normal

Lump/ abnormality

Reassure

Ultrasound biopsy

MDT

Benign Reassure

Malignant Treatment options

MDT, multidisciplinary team; USS, ultrasound scanning

Figure 1

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

the 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. There is an increased interest in the use of various tissue matrices (StratticeÔ, BraxonÒ, AlloDermÒ), as well as an increasing use of microvascular surgery to improve cosmetic results. Other advances include lipofilling/lipomodulation, which involves the use of autologous fat transplantation techniques to improve breast-volume defects after breast conservation or reconstruction.

Radiotherapy: radiotherapy after wide local excision reduces the 5-year local recurrence rate from 26% to 7% and has been shown to be equivalent to mastectomy. Recent evidence suggests an overall absolute survival benefit of about 5% for postoperative adjuvant radiotherapy. (See Clarke M et al. in Further reading).

Figure 2 (a) Right mammogram showing very dense breast tissue. (b) MRI in the same patient, demonstrating a 4.1 cm lobular cancer not visible on the initial mammograms.

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Figure 3 (a) A sentinel node, which has been dyed blue, with a blue lymphatic draining into it. (b) Measuring the signal from the 99mtechnetium in a lymph node using a probe.

Most mastectomy patients do not require radiotherapy, but those at increased risk of recurrence (T3/T4 tumours, lymphovascular invasion, four or more positive lymph nodes) benefit from chest wall and supraclavicular fossa nodal irradiation. Recent evidence has supported the use of radiotherapy in intermediate and highgrade ductal carcinoma-in-situ. A trial of the use of axillary radiotherapy in SLN-positive patients (EORTC 10981e22023 AMAROS Trial) has demonstrated that axillary node clearance and axillary radiotherapy after a positive SNB provide excellent and comparable regional control. Radiotherapy had a lower risk of short-term and long-term lymphoedema compared with surgery. Clinical trials are currently assessing the role of intraoperative partial breast irradiation.

such as the liver, adrenal glands and, importantly, breast tissue itself. Traditionally, the oestrogenic stimulation of breast cancer was suppressed using tamoxifen. Aromatase inhibitors target oestrogen production by blocking the conversion of androgens to oestrogen through inhibition of the aromatase enzyme. Clinical data demonstrate that aromatase inhibitors are superior to tamoxifen, (see Cuzick J et al. in Further reading) and they have replaced it as a first-line therapy in postmenopausal women with breast cancer. The optimal duration of treatment is still uncertain but they are currently given for at least 5 years. Many patients experience adverse effects including hot flushes, venous thromboembolism and endometrial cancer (tamoxifen), arthralgia and osteoporosis.

Endocrine therapy: oestrogens play a crucial role in breast cancer; by binding to target receptors, they promote proliferation of breast cancer cells. Most breast cancers (around 70%) are ERpositive. In premenopausal women, circulating oestrogens are produced primarily by the ovaries. Inhibition of oestrogen action is achieved through suppression of ovarian function, by surgical means using ovarian ablation or by using luteinizing hormonereleasing hormone agonists (e.g. goserelin). Alternatively, selective ER modulators, such as tamoxifen, have been shown to reduce recurrence by 47% and death by 26% (see Early Breast Cancer Trials’ Collaborative Group (EBCTG) in Further reading). (see also Hormonal therapy for cancer on pages XXeXX of this issue). However, most breast cancers occur in postmenopausal women and approximately 80% of these are ER-positive. In these women the ovaries no longer produce oestrogen; instead, small quantities of oestrogens are synthesized in non-ovarian tissues

Chemotherapy: adjuvant chemotherapy has been shown to reduce local recurrence by 30% and death by 20%. (see Early Breast Cancer Trials’ Collaborative Group (EBCTG) in Further reading). 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); this avoids unnecessary 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. There is increasing interest in and use of neoadjuvant chemotherapy (NACT) in a subgroup of patients. The benefits of NACT are multifold and include downstaging the disease to make it operable, for example for advanced or inflammatory cancers.

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in nearly 5e10% of patients. A family history of breast, ovarian or other unusual cancer in first- or second-degree relatives increases the likelihood of an underlying genetic predisposition, especially in those <50 years of age. Other risk factors are breast and ovarian cancer on the same side of family, Ashkenazi Jewish heritage, male breast cancer and bilateral breast cancer. The most commonly involved genes are BRCA1 and BRCA2. Other rare gene mutations associated with breast cancer occur in TP53, STK11, PALB2 and PTEN. Patients with a worrying family history should be referred to specialist genetic clinics who can stratify their risk using various assessment tools, such as MyriadÔ 1/2, Manchester or BRCAPRO. Individuals shown to have a high risk of being a gene carrier can be referred to specialized clinics for genetic testing. If they are proved to harbour a germline mutation, they can be considered for risk-reducing strategies such as enhanced MRI screening or risk-reducing surgery for breast and/or ovarian cancer. A

There is also a role for NACT in operable cancer to allow downstaging of disease to enable breast conservation and also on occasions to downstage nodal disease to avoid axillary node clearance. Biological therapy and novel agents: trastuzumab, a monoclonal antibody used in the treatment of HER2-positive patients, is used either alone or in combination with pertuzumab (an HER dimerization inhibitor); it reduces recurrence by 50% and prolongs survival by 30% when used in combination with chemotherapy. (see Piccart-Gebhart MJ, in Further reading). 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 antiangiogenic drug bevacizumab. Both have demonstrated efficacy after trastuzumab failure and are licensed for use, but are only available by application on a named-patient basis because of their cost. Early clinical trials have shown that poly (ADP-ribose) polymerase (PARP) inhibitors, controlling DNA repair and apoptosis, are particularly beneficial with BRCA mutations and in patients with basal-like and triple-negative (ER/ PR/HER2) disease.

KEY REFERENCES 1 Office for National Statistics. Cancer Statistics Regulations, England (Series MB1). http://www.ons.gov.uk/ons/rel/vsob1/ cancerstatistics-registrationseenglandeseries-mb1-/index.html. 2 Ramak E, Brazil L. Cost of managing women presenting with stage 1V breast cancer in the United Kingdom. Br J Canc 2004; 91: 77e83. 3 National Institute for Health and Care Excellence. Guidance on breast cancer (early and locally advanced): diagnosis and treatment. 2018. London: NICE. Also available at: http://guidance.nice. org/NG101. 4 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. 5 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.

Follow-up There is currently controversy over the most appropriate followup procedure. NICE guidelines (2009) suggest annual mammograms for 5 years and clinical follow-up until adjuvant therapies have been completed.3 The ideal interval for mammographic follow-up is also controversial, and the Mammo-50 trial is assessing this. Follow-up procedures are usually agreed at a local level, and many are run by nurses with extended roles. Management of the adverse effects of adjuvant hormones, in particular bone health, must be considered. Metastatic disease Metastatic breast cancer is covered only briefly here. Treatment focuses on palliating the symptoms to maintain quality of life and, where possible, extend life. The treatments offered are:  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 metastases (to improve pain control), cord compression and, in addition, superior vena caval obstruction, fungating chest wall disease or brain metastases  bisphosphonates e to reduce risk of pathological fractures and improve pain control  palliative care e involvement of the palliative care team is crucial to support patients, manage symptoms and address social and psychological concerns. All patients with metastatic disease should be offered an introduction to the team.

FURTHER READING Cen 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. Clarke M, Collins R, Darby S, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences 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. 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. 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. Piccart-Gebhart MJ, Procter M, Leyland-Jones B. Trastuzumab after adjuvant chemotherapy in Her2 positive patients. N Engl J Med 2005; 353: 1659e72.

Genetics and family history A positive family history of breast or ovarian cancer is a wellrecognized risk factor in the breast cancer history. It is present

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TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. Question 1 A 56-year-old woman presented with an irregular hard fixed lump in the right upper outer quadrant of the breast associated with skin dimpling and breast asymmetry. There was no history of trauma. She had lost weight in the previous 3 months. On clinical examination, her temperature was 37.0 C, and the findings in the breast were confirmed.

What is the most important genetic mutation for which she should be tested? A. BRCA1/2 mutation B. PALB mutation C. CHEK2 mutation D. KRAS mutation E. STK11 mutation

Investigation  Mammography showed a spiculated breast lesion

Question 3 A 45-year-old patient presents with a hard, irregular lump in the breast, which she has had for 4 weeks. She attends breast clinic and undergoes triple assessment. What does Triple assessment in breast involve? A. Mammography, ultrasound and clinical examination B. Mammography, ultrasound and genetic testing C. Mammography, genetic testing and biopsy D. Mammography/ultrasound, clinical examination and biopsy E. Open breast biopsy, ultrasound and genetic testing

What is the most likely diagnosis? A. Breast abscesses B. Fibroadenoma C. Breast cancer D. Fat necrosis E. Breast cyst Question 2 A 56-year-old woman presented with a lump in the right breast. Her aunt had had a similar problem at about the same age. Investigations confirmed an adenocarcinoma.

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