Section 1: Epidemiology and aetiology
Breast cancer has been the most common cancer diagnosed in the UK since 1997 (except for Scotland where lung cancer is more common overall) and accounts for 31% of all new cancers in females.
Close to 49,000 new cases of breast cancer were diagnosed in 2009 and less than 1% of these were in males. This translates into an age-standardised (AS) incidence of 124.4 per 100,000 with almost 50% diagnosed in women aged 50-69 years.
The AS incidence has increased in the past 35 years by almost 70%, but levelled off since 2005. This was partly due to the introduction of screening, now offset by a reduction in HRT use.
As of 2010, breast cancer is the third most common cause of cancer death in the UK and the second most common cause of cancer death among women (after lung cancer), accounting for 15% of female deaths due to cancer. The AS mortality rate in 2010 for women was 24.4 per 100,000, accounting for more than 11,500 deaths in that year. Almost 90% of these deaths occurred in women aged 50 years and over.
In contrast to incidence rates, mortality has dropped by almost 40% since a peak in the mid-1980s (see graph).
Modifiable risk factors
Aetiology can be classified as hereditary (thought to account for almost 25% of risk), with the remaining 75% of risk factors being environmental, hence potentially modifiable.1
Factors potentially amenable to intervention in primary care include postmenopausal obesity, lack of exercise, high saturated fat intake, HRT and alcohol.
There is a 9% relative increase in incidence for every 10g of alcohol consumed per day. This is based on well-designed, large prospective studies and may be linked more to estrogen receptor (ER) positive cancers for both preand postmenopausal women. The current recommendation is for women to limit intake to 10g (one standard drink per day), although there is no threshold cut-off for risk.2
Family history
Strong family history is the main risk factor in about 2% of patients. Women under 50 at diagnosis with a triple negative phenotype (ER, progesterone receptor (PR) and HER2 negative) have a 20% chance of carrying a germ-line mutation in BRCA1. Assessment of family history should include the number of first-degree relatives, age of onset and bilateral breast cancer as well as ovarian cancer, male breast cancer (BRCA2) and Ashkenazy Jewish heritage.
A past history of breast cancer, no matter how distant, should always be sought. New symptoms suggesting either a primary lesion or metastatic disease should be promptly excluded.
Classification
Historically, breast cancers were classified by histological appearance. For invasive carcinoma, ductal is the most common subtype found in almost 90% of patients, the remainder being lobular.
Originally, gene expression studies were performed to group breast cancer on molecular RNA expression.3 This resulted in at least four groups based on ER, HER2 and proliferative markers. They are known as basal-like (ER, PR and HER2 negative), luminal (A: low proliferation and B: high proliferation), HER2 enriched and normal breast-like.
Section 2: Making the diagnosis
MRI showing primary invasive lobular carcinoma in right breast (Photograph: Elizabeth O'Flynn)
For women presenting with a lump, clinically important features include skin dimpling, nipple/areolar retraction, overlying skin changes such as inflammation, oedema (peau d'orange), and fixity to either skin, chest wall musculature, or both.
Early changes, for example, dimpling, may be accentuated by dynamic manouevres such as raising the arms, which also provides a more complete view of the inferior pole of the breast and should be performed during routine breast examination.
Pain and nipple discharge are rarely indicative of cancer in the absence of a lump, but a full history and examination should guide further investigation if any clinical suspicion remains.
Particular clinical findings also include Paget's disease of the nipple, which needs to be differentiated from eczema; where doubt persists, nipple biopsy may also be required.
Many women who are now diagnosed through the national screening programme are generally asymptomatic.
Mammographic features of malignancy include an asymmetric density, spiculations (stellate), architectural distortion and clustered microcalcification (pleomorphic in density, shape and size), the latter suggestive of ductal carcinoma in situ (DCIS).
A mass lesion on ultrasound is very suggestive of the presence of invasive disease in this context.
Investigations
The triple test continues to provide a safety net for the diagnosis of malignancy.
The use of mammography, ultrasound and fine needle aspiration (where expertise in cytology exists), or core biopsy by image guidance is essential. Perhaps even more important than adherence to these tests is careful correlation of each test and ensuring that any lack of concordance between tests is judiciously scrutinised before malignancy is excluded.
These are ideally conducted in the multidisciplinary setting with a breast radiologist/physician and surgeon at minimum. One negative test does not exclude malignancy.
Image-guided core biopsy and the pathology report should be enough to plan definitive management. This includes the presence of invasive carcinoma (B5b), in-situ disease, subtype, grade, and ER/PR receptor status, which should always be performed on the diagnostic core.
Although stage for stage, the prognosis is similar, lobular pathology may have a more insidious presentation and the clinical extent of the primary is commonly underestimated. One indication for preoperative MRI is to provide a more accurate assessment of the extent of lobular carcinoma (see box).
| BREAST MRI INDICATIONS5 |
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Section 3: Managing the condition
Generally, for early breast cancer (absence of metastatic disease or locally advanced disease), surgery is the initial treatment.
In cases of a large primary tumour to breast volume ratio, particularly for more centrally located tumours, consideration may be given to neo-adjuvant chemotherapy (or endocrine therapy) to convert a potential mastectomy into a breast conservation procedure.
There is generally greater scope for breast conservation with the availability of a range of oncoplastic techniques as well.
Oncoplastic surgery
Oncoplastic surgery has gained traction in the UK as a means of optimising complete resection of the primary cancer while maximising aesthetic outcome, including overcompensation for anticipated radiotherapy effects, such as nipple-areolar displacement by recentralisation of this structure.
Oncoplastic techniques allow resection of tumours otherwise unresectable by conventional means, with greater margins. They also extend breast conservation to those tumours which were not conservable by standard means, potentially reducing the need for mastectomy.
Some techniques permit this by incorporating a breast reduction - therapeutic mammoplasty - in suitable patients. Sometimes the contralateral (unaffected) breast requires symmetrisation (surgical adjustment), although it is prudent to minimise complications and keep initial surgery to a minimum to prevent possible delays in adjuvant therapies.
The patient's oncological management and potential outcome should never be compromised for the sake of enhanced cosmesis. As such, delayed reconstructive surgery may be more prudent.
Breast reconstruction following mastectomy can be undertaken as an immediate or delayed procedure. The choice of silicone-based implants, autologous tissue-based flaps or a combination of the two should be offered to all patients. Decisions about method and timing are based on patient preference, comorbidity and risk, as well as oncological considerations, and are best made in a multidisciplinary team setting, involving both oncoplastic and reconstructive surgeons.
Recent enhancements to reconstruction include biological materials (acellular dermal matrices) which may enhance soft tissue coverage over implants. Techniques such as lipomodelling (fat transfer) are also finding a greater role both post-mastectomy and radiotherapy, as well as to correct deformity following breast conservation treatment.
Management of axillary nodes
A number of changes have occurred in recent years, leading to more conservative and selective surgical treatment of the axilla to minimise morbidity.
All patients with invasive carcinoma are recommended to have full axillary staging.
Preoperatively, this includes an ultrasound, followed by fine needle aspiration cytology or core biopsy of any suspicious findings.
Axillary nodal dissection is indicated for cytological or biopsy-proven malignant involvement. Otherwise, all patients should undergo sentinel lymph node biopsy as part of axillary staging.
The results of the American College of Surgeons Oncology Group (ACOSOG) Z0011 trial4 suggested, furthermore, safety in avoiding axillary nodal dissection for patients with sentinel nodes harbouring not only micrometastases (nodal deposits <2mm), but even for those in whom one or two nodes contained larger deposits in the absence of gross disease at the time of surgery.
Neo-adjuvant chemotherapy
The main aim of chemotherapy is to make a patient initially suitable only for mastectomy amenable to breast conservation. Although it has not been shown that long-term survival improvement results from neo-adjuvant versus adjuvant treatment, a patient who has a complete pathological response to the former carries, in general, a more favourable prognosis.
For all breast conservation patients, lumpectomy with clear margins (>1mm for invasive disease, >2mm for DCIS) should be followed by adjuvant radiotherapy to the breast to reduce the risk of local recurrence.
Section 4: Prognosis
Long-term outlook is still governed by tumour size and nodal status at the time of initial diagnosis. TNM staging reflects this, but there are more accurate systems based also on grade, such as the Nottingham Prognostic Index.
Prognostic tools
PREDICT is a prognostic tool for early breast cancer including HER2 positive patients. As a Cambridge-based tool based on UK data but validated on patient datasets from British Columbia, it indicates the additional benefit conferred by adjuvant treatments.
OncotypeDx is one of the many first-generation gene expression profile derived prognostic tests. The score predicts the need for chemotherapy.
Current tools based on gene expression are best integrated with clinically derived parameters to make clinical decisions about adjuvant therapy.
IHC4+C6 is a less costly, more widely applicable score based on the four immunohistochemical parameters (ER, PR, HER2 and Ki-67), as well as clinical parameters for patients with ER-positive disease.
This score accurately predicts five- and 10-year outcomes.
Its main utility when tested against the other scores discussed above was that it more accurately reclassified intermediate risk patients as low risk, allowing them to avoid chemotherapy and enhancing the concept of personalised medicine in a cost-effective manner. IHC4+C is likely to become more widely adopted throughout the UK.
Follow-up
The care of breast cancer survivors requires an understanding of relapse patterns and the unique medical and psychological needs that arise in this patient group.
The goals of surveillance are early recognition and treatment of potentially curable disease recurrences and second primaries, and screening for therapy-related complications.
Knowledge of the time course and most common sites of disease relapse can be used as a guide to focus the clinical history and physical examination during follow-up visits and to choose screening tests that are most likely to be informative.
Level 2 evidence indicates that generalists can provide equivalent care to specialists and fulfil more of the overall care needs required by such patients.
Section: 5 Case study
A 35-year-old premenopausal woman presented with two lumps and some nipple retraction of two months' duration in the left breast.
She denied nipple discharge, pain or skin changes. Her menses are irregular and she was on an oral contraceptive preparation for 10 years.
She also has migraine and depression and takes medication for both. She smokes 10 cigarettes per day. Alcohol intake is occasional.
Her mother had bilateral breast cancer, initially diagnosed at the age of 42 years.
On examination, there were two hard lumps in the six o'clock and retro-areolar positions in the left breast. There was a hard axillary lymph node measuring 2cm.
Mammography was scored as M4 on the left and M3 (equivocal) on the right. Ultrasound was U5 (malignant) for the left breast lumps and axilla. Microcalcifications in the right (contralateral) breast were biopsied using a stereotactic technique.
Although NICE guidelines would not recommend mammography as the initial investigation, in this case, owing to the malignant appearance on ultrasound, bilateral mammography was indicated to stage both breasts. The microcalcification on the right returned as intermediate grade DCIS (B5a) and the foci on the left were both grade 2 invasive ductal carcinoma (B5b). ER was 8/8, PR 6/8 and HER2, 1+ (considered negative) for both foci.
The axillary fine needle aspiration returned blood only, so ultrasound-guided core was performed and a B5 (malignant) diagnosis obtained.
Mastectomy on the right was the patient's preference. She underwent immediate reconstruction with submuscular implants and acellular dermal matrix.
Postoperative recommendations were staging with CT and bone scan, six cycles of FEC-T chemotherapy, D-CARE (a trial of denosumab treatment for high-risk patients) followed by post-mastectomy chest wall and possible supraclavicular radiotherapy on the left, then five years of tamoxifen therapy and open access follow-up.
Section 6: Evidence base
Mammogram demonstrating a central breast cancer (Photograph: Janet MacDonald)
Clinical trials
- Early Breast Cancer Trialists' Collaborative Group. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet 2012; 379: 432-44.
- Veronesi U, Cascinelli N, Mariaani L et al. Twenty-year follow up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002; 347: 1227-32.
- Fisher B, Anderson S, Bryant J et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002; 347: 1233-41.
Guidelines
Online
- Cancer Research UK Up-to-date facts and figures.
- CancerStats Key Facts breast cancer. Cancer Research UK. The latest key facts about breast cancer.
Key text
- Dixon JM. ABC of Breast Diseases (fourth edition). BMJ Books, Blackwell Publishing, 2012.
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References
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2. Boyle P, Boffetta P. Breast Cancer Res 2009; 11 (Suppl 3): S3.
3. Perou C, Sorlie T, Eisen M et al. Molecular portraits of human breast tumours. Nature 2000; 406: 747-52.
4. Giuliano AE, Hunt KK, Ballman KV et al. JAMA 2011; 305: 569-75.
5. Dall BJG, Vinnicombe S, Gilbert FJ. Clin Radiol 2011; 66(12): 1120-8.
6. Barton S, Zabaglo L, A'Hern R et al. Br J Cancer 2012; 106: 1760-5.
