Clinical Review: Breast cancer

Breast cancer remains the second most common cause of cancer death in women. It is the leading cause of death in women aged 40-55 years.

Coloured mammogram showing tumour in green (SPL)
Coloured mammogram showing tumour in green (SPL)

Section 1: Epidemiology and aetiology

Epidemiology
In 2013, breast cancer continued to be the most common female cancer and incidence is still rising.1

However, mortality from breast cancer is falling (see figure 1). Eighty per cent of women diagnosed are alive at five years. This may be a result of earlier diagnosis through screening,2 improved surgical and radiotherapy techniques, and more advanced adjuvant medical therapies.

Aetiology
Breast cancer has a complicated aetiology that includes genetic, biological, behavioural, environmental and social factors.

Factors known to increase a woman's chance of developing it include age (risk increases with age), family history (inherited genetic predisposition), previous radiotherapy to the chest wall, certain breast conditions (such as lobular neoplasia and multiple papillomatosis), early menarche, late menopause, later age at first full-term pregnancy and nulliparity (all related to exposure of higher levels of hormones for longer).

Risk factors include use of alcohol and tobacco,3,4 prolonged use of the oral contraceptive pill,5 HRT6 and obesity in postmenopausal women.7

Classification
Breast cancer falls broadly into three categories: histopathological, biological and molecular.8

Histopathological classification
Breast cancers can be divided histopathologically into invasive and non-invasive cancer.

Invasive cancer is further subdivided into invasive ductal carcinoma (80%) arising from the breast ducts, or invasive lobular carcinoma (10%) arising from the breast lobules. These are graded from 1 (low grade) to 3 (high grade).

Both forms of invasive carcinoma have the ability to metastasise. An uncommon form of invasive breast cancer is known as inflammatory breast cancer (incidence 1-3%). This has a poorer prognosis.

Non-invasive cancer is commonly referred to as ductal carcinoma in situ, which is early breast cancer that has not invaded through the basement membrane of the ductal cell.

Biological classification
Biological classification refers to the expression of hormone receptors, such as estrogen and progesterone receptors (the ER/PR status) and HER2 (human epidermal growth factor receptor 2) status. This is more commonly used to guide systemic adjuvant therapies.

Molecular classification
The three major molecular subtypes are luminal-type (subtype A and B), HER2 amplified, and basal-like, and these all have distinctive biological and clinical features.9,10

Molecular tests are performed to provide more information on tumour biology and improve the accuracy of prognosis.

Section 2: Making the diagnosis

Most breast cancer presents in women aged 50 and above. Less than 2% presents in those aged below 35.11,12 It may be asymptomatic and only picked up on screening.

Male breast cancer is rare. About 350 men are diagnosed each year in the UK, compared with about 50,000 women.13 Presentation in men is similar to that in women.

Symptomatic cancer can present in multiple ways. Suspicions should be raised by a lump that is new or different, a new inversion of the nipple, bloody or blood-stained nipple discharge, skin changes such as dimpling, indentation or 'orange peel' skin, a new asymmetry of the breasts or lymphadenopathy at the axilla. Breast pain is rarely a symptom.

In the UK, population-based screening by mammography for those who are asymptomatic is offered to all women aged 47-73 years by the NHS Breast Screening Programme, with an 'opt-in' system after the age of 73.2 Those who are symptomatic are referred by the GP to local specialist breast units, under the two-week rule, for rapid assessment.

The diagnosis of breast cancer by triple assessment (clinical examination, radiological investigations with mammography, ultrasound or both, and pathological assessment with core biopsy) is well established in the context of multidisciplinary managementof the condition.14

The axilla is now routinely assessed at the same time. If suspicious lymph nodes are seen, a fine needle aspirate or core biopsy of the lymph node is usually performed to check for any metastases.

One-stop clinic
Many units run one-stop clinics, where all of these investigations are done in one sitting and results given on the same day. However, if a core biopsy is performed, there is usually a turnaround time of one week.

The diagnosis is based on the histopathological findings, along with correlation from radiological imaging.

MRI is not routinely used for the diagnosis of breast cancer, but it is used in selected cases to define tumour extent, especially in invasive lobular breast cancer.

MRI is used for detecting multifocal disease before surgery and to assess the contralateral breast. It is also a screening tool for high-risk patients.

CT scan, nuclear medicine bone scan and functional imaging with PET using fluorodeoxyglucose are accepted in the staging of many cancers, but not routinely used in the diagnosis of breast cancer.

Section 3: Managing the condition

The mainstay of treating breast cancer is multimodal. Surgery to the breast and axilla aims to excise the tumour to achieve clear margins of more than 1mm and to clinically stage the disease.

Mastectomy confers no survival benefit over breast-conserving surgery (BCS) with adjuvant radiotherapy.15 BCS should be the surgery of choice if complete tumour excision can be achieved with adequate margins and an acceptable cosmetic outcome.16

Neoadjuvant therapies are gaining in popularity, with the aim of reducing the tumour size to enable breast conservation.

Mastectomy may be recommended when BCS is impossible owing to tumour size, multifocal disease, or aesthetically unfavourable ratio of breast size to tumour volume, or at the patient's request.

Clinical staging of the axilla is performed at the time of the diagnosis of breast cancer. In clinically negative axillae, a sentinel lymph node biopsy performed at the time of breast surgery is the gold standard to pathologically stage the axilla.17

This will help to guide further adjuvant therapies. In those with a confirmed clinically positive axilla, an axillary lymph node dissection will be performed at the time of breast surgery.

Postsurgical therapy in breast cancer is dictated by the pathology of the tumour and the lymph node status. It will often involve a combination of endocrine therapy, radiotherapy and/or chemotherapy, and is a multidisciplinary decision.

Those with hormone receptor-positive cancers will be offered adjuvant endocrine therapy. Tamoxifen is the drug of choice for premenopausal women or those who are intolerant to other forms of endocrine treatment. Postmenopausal women will receive an aromatase inhibitor, anastrazole.

Those who have undergone BCS will receive radiotherapy to the breast. Radiotherapy to the chest wall in those who have undergone a mastectomy or to the nodal basins will be a multidisciplinary decision and depends on the tumour biology and the lymph node status.

Chemotherapy is often offered to patients who are hormone- insensitive ('triple negative' cancers), and those with large tumours or a heavy nodal burden.

New developments

The axilla
Controversies have arisen regarding patients with a positive sentinel lymph node biopsy and whether further axillary surgery is appropriate,18,19 because arm morbidity with lymphoedema is very debilitating.

Subtyping, HER2 status, new therapies
The molecular subtyping of breast cancer has led to further fine-tuning of adjuvant therapies. The HER2-positive breast cancer characterised by overexpression of HER2 with amplification of the HER2 gene has led to the use of the targeted monoclonal antibody trastuzumab, together with chemotherapy.

The newer monoclonal antibody pertuzumab may be combined with trastuzumab and chemotherapy and is often used to treat metastatic breast cancer.

The tyrosine kinase inhibitor lapatinib blocks the effects of HER2 and other proteins inside the tumour cells. It may be used in HER2-positive breast cancer that has progressed after treatment with trastuzumab.

Extended adjuvant endocrine therapy
Five years of adjuvant tamoxifen in those with estrogen-receptor positive breast cancers reduces the RR of relapse by 41% and death by 31%.20 The aTTom and ATLAS trials have confirmed that 10 years of adjuvant tamoxifen reduces death from breast cancer by one third in the first 10 years of follow-up.21,22

Section 4: Prognosis

Traditionally, most units follow up patients for five years with annual mammograms and clinical reviews. However, there is little benefit from routine clinical examination and most units now see patients up to one year postoperatively, then discharge them to annual mammographic surveillance for a further four years.23

Survival from breast cancer has improved dramatically in the past 20 years24 and 10-year survival is now 77%.25

Prognosis can be estimated using online web-based tools, such as Adjuvant! Online or PREDICT, which take into account various pathological factors and how likely adjuvant therapies are to be of benefit.

NICE recommends Oncotype DX, a 21-gene assay prognostic test, to guide chemotherapy treatment decisions for intermediate-risk patients who have early invasive breast cancer.26

This provides information concerning 10-year risk of recurrence and the likelihood of benefit from chemotherapy.

Section 5: Case study

Sarah is a 35-year-old woman who presents with a new area of nodularity in her upper right breast. There are no risk factors for breast cancer and she has no family history.

Examination confirms a firm mass about 3cm in size. Imaging and core biopsy identify an invasive ductal carcinoma.

Traditionally, Sarah would have gone straight to surgery to remove a portion of breast tissue about 5cm in diameter to achieve disease clearance. At her age, with a tumour of this size, she would then have adjuvant chemotherapy and radiotherapy.

Current management would be to advocate a switch in the order of treatment and to deliver the chemotherapy first. The advantages of neoadjuvant chemotherapy are that it is likely to shrink the tumour mass, allowing a smaller breast volume to be removed after chemotherapy, and it allows time to test for the main breast cancer genes, BRCA1 and BRCA2, if the family history justifies this.

If Sarah is positive for one of these genes, the surgical discussion would centre on the benefits of bilateral mastectomy surgery, with or without immediate reconstruction.

If she tests negative for breast cancer genes (which is more likely), breast-conserving surgery is made much easier by a reduction in the volume of breast tissue removed.

Breast surgeons can adopt a number of oncoplastic techniques to move residual breast tissue to fill in defects and great attention is paid to minimising the long-term cosmetic impact on the breast.

Radiotherapy will be required after chemotherapy and surgery, usually for a period of three weeks to the breast itself, although intraoperative radiotherapy as a single dose is being used in some centres.

Following this, assuming the tumour is estrogen-receptor positive, adjuvant tamoxifen will be recommended at a dose of 20mg per day. This is generally well tolerated, although common side-effects include hot flushes, which are difficult to control.

Follow-up would be clinical at one year, with an examination and review of key issues, psychological support provided throughout by specialist breast and oncology cancer nursing teams and annual mammography.

Tamoxifen would be recommended for 10 years and annual mammograms continued until the age of 50.

Section 6: Evidence base

Guideline

  • NICE. Early and locally advanced breast cancer: diagnosis and treatment. CG80. London, NICE, February 2009.

Online resource

Click here to reflect on this article and add notes to your CPD organiser on MIMS Learning

  • Contributed by Miss Vivien V Ng, specialist registrar in breast surgery, and Mr Andrew McLaren, consultant breast surgeon, Wycombe General Hospital, Buckinghamshire Healthcare NHS Trust
CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Organise an audit of patients in your practice who have breast cancer and review their access to one-stop specialist breast units.
  • Review your knowledge of breast cancer management in view of recent developments.
  • Arrange a meeting with the consultant breast surgeon to discuss patient review and follow-up.

References

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3. Hamajima N, Hirose K, Tajima K et al. Br J Cancer 2002; 87: 1234-45.
4. Allen NE, Beral V, Casabonne D et al. J Natl Cancer Inst 2009; 101: 296-305.
5. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1996; 347: 1713-27.
6. Chlebowski RT, Kuller LH, Prentice RL et al. NEJM 2009; 360: 573-87.
7. Kuhl H. Maturitas 2005; 51: 83-97.
8. Viale G. Ann Oncol 2012; 23 Suppl 10: x207-10.
9. Perou CM, Sorlie T, Eisen MB et al. Nature 2000; 406: 747-52.
10. Sorlie T, Tibshirani R, Parker J et al. Proc Natl Acad Sci USA 2003; 100: 8418-23.
11. Birks DM, Crawford GM, Ellison LG et al. Surg Gynecol Obstet 1973; 137: 21-5.
12. Jmor S, Al-Sayer H, Heys SD et al. J R Coll Surg Edinb 2002; 47: 693-9.
13. Cancer Research UK.
14. Yeo B, Turner NC, Jones A. BMJ 2014; 348: g3608.
15. Fisher B, Anderson S, Bryant J et al. N Engl J Med 2002; 347: 1233-41.
16. Moran MS, Schnitt SJ, Giuliano AE et al. J Clin Oncol 2014; 32: 1507-15.
17. Fleissig A, Fallowfield LJ, Langridge CI et al. Breast Cancer Res Treat 2006; 95: 279-93.
18. Giuliano AE, McCall L, Beitsch P et al. Ann Surg 2010; 252: 426-32.
19. Donker M, Straver ME, van Tienhoven G et al. Eur J Cancer 2013; 49: 2093-100.
20. Early Breast Cancer Trialists' Collaborative Group. Lancet 2005; 365: 1687-717.
21. Gray RG, Rea D, Handley K et al. J Clin Oncol 2013; 31 Suppl: abstr 5.
22. Davies C, Pan H, Godwin J et al. Lancet 2013; 381: 805-16.
23. Taggart F, Donnelly P, Dunn J. BMC Cancer 2012; 12: 238.
24. Coleman MP, Quaresma M, Berrino F et al. Lancet Oncol 2008; 9: 730-56.
25. Cancer Research UK.
26. NICE. DG10. London, NICE, September 2013.

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