Breast Cancer

Breast cancer is the commonest malignancy affecting women in the great majority of populations worldwide. It arises predominantly from the ductal or, less commonly, lobular epithelium of the breast.

It is a biologically and clinically heterogeneous group of tumours. They are classified by histological subtype, grade and, critically, molecular receptor status (oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2), which informs both prognosis and treatment selection.

Contemporary management is delivered through structured multidisciplinary team assessment and increasingly individualised, biomarker-directed treatment. Advances in screening detection and systemic treatment have transformed prognosis for the great majority of affected women over recent decades.

Classification and risk factors

• Invasive ductal carcinoma is the commonest histological subtype. It arises from the ductal epithelium and invades through the basement membrane into surrounding breast tissue.
• Invasive lobular carcinoma is the second commonest subtype. It arises from the lobular epithelium and characteristically shows E-cadherin loss, as in lobular carcinoma in situ.
• Lobular carcinoma has a somewhat distinct growth pattern and clinical behaviour. It tends toward more subtle mammographic and clinical presentation, sometimes producing diffuse tissue thickening rather than a discrete, palpable mass.
• Molecular receptor status directly informs prognosis and treatment selection.
• Hormone receptor-positive (oestrogen and/or progesterone receptor-positive) tumours are the commonest subtype overall. They generally carry a more favourable prognosis and are eligible for endocrine therapy.
• Human epidermal growth factor receptor 2-positive tumours are a biologically distinct, historically more aggressive subtype. They are now managed with highly effective, specifically targeted therapy.
• Triple-negative tumours lack expression of all three receptors. They are biologically more aggressive, with more limited targeted options beyond standard chemotherapy. Recent advances include immunotherapy for appropriately selected patients.
• Well established risk factors are advancing age and a relevant family history. In a proportion of women there is an identifiable pathogenic genetic mutation, most notably BRCA1 and BRCA2, and several less common genes.
• Further risk factors are early menarche and late menopause (reflecting cumulative lifetime oestrogen exposure), nulliparity or later age at first pregnancy, hormone replacement therapy use, and significant alcohol consumption.
• A personal history of certain benign breast conditions also carries elevated risk, including lobular carcinoma in situ and atypical hyperplasia.

• A painless, firm, irregular breast lump is the classic, though not universal, presenting feature.
• In contemporary practice a substantial proportion of cases are identified through structured, population-based screening mammography before becoming clinically apparent. This reflects the established value of screening programmes in detecting disease at an earlier, more favourable stage.
• Skin changes include dimpling, peau d'orange appearance (from cutaneous lymphatic involvement) and, in advanced, locally invasive disease, frank ulceration.
• Nipple changes include retraction and, in Paget disease of the nipple (a distinct clinical entity), eczematous change of the nipple and areola reflecting underlying intraepithelial malignant involvement.
• Axillary lymphadenopathy may be present. Any of these features warrants prompt, full assessment.
• Inflammatory breast cancer is a rare, aggressive and clinically distinct presentation. It presents with rapid onset of breast erythema, warmth and oedema (producing the characteristic peau d'orange appearance), frequently without a discrete, palpable mass.
• Inflammatory breast cancer can be mistaken for mastitis. Keep a low threshold for biopsy in any such presentation that does not respond rapidly and completely to a trial of antibiotics.
• Metastatic disease, present at diagnosis or developing later, most commonly affects bone, lung and liver. The brain is also affected, particularly in hormone receptor-positive and human epidermal growth factor receptor 2-positive subtypes. The pattern of spread has some relevance to the molecular subtype.

• The essential diagnostic approach is full triple assessment: clinical assessment, imaging (mammography and/or ultrasound according to age and clinical context), and core needle biopsy.
• Core needle biopsy gives definitive histological diagnosis and receptor status, which direct treatment planning.
• Population-based mammographic screening programmes offer screening to women within a defined age range at regular intervals, according to national or regional protocols. They allow earlier detection and have demonstrated mortality reduction.
• This must be balanced against the risk of overdiagnosis and overtreatment inherent to any population-based screening programme.
• Staging includes axillary lymph node assessment. This is typically ultrasound with biopsy of any suspicious node or, at surgery, sentinel lymph node biopsy for clinically and radiologically node-negative disease.
• For higher-risk or more advanced disease, systemic staging assesses for distant metastatic spread. It uses computed tomography and bone scan or, increasingly, positron emission tomography combined with computed tomography. Staging directly informs treatment planning.
• Genetic counselling and testing for inherited pathogenic mutations (most notably BRCA1 and BRCA2) is offered to women meeting established risk criteria. These are based on age at diagnosis, tumour subtype including triple-negative disease, and family history.
• Results guide the individual's own treatment, including consideration of risk-reducing bilateral surgery and targeted systemic options for confirmed carriers. They also guide family cascade testing and counselling.

• Surgery is central for the great majority of early-stage disease. It is either breast-conserving surgery (wide local excision) or mastectomy, according to tumour size and location relative to breast size, with axillary surgical staging.
• Breast-conserving surgery is generally combined with adjuvant radiotherapy to the remaining breast tissue. Overall survival is equivalent to mastectomy with this approach in appropriately selected tumours.
• Adjuvant (postoperative) systemic therapy is selected by tumour receptor status, grade, stage and, increasingly, genomic risk assessment with validated molecular profiling assays. These assays support more individualised decisions on the benefit of adjuvant chemotherapy beyond standard clinicopathological factors.
• Endocrine therapy is given for hormone receptor-positive disease: tamoxifen in premenopausal women, or an aromatase inhibitor in postmenopausal women. It is typically continued for a prolonged duration, commonly five to ten years.
• Targeted human epidermal growth factor receptor 2-directed therapy (trastuzumab, with additional targeted agents for higher-risk disease) is given for human epidermal growth factor receptor 2-positive disease.
• Chemotherapy is selected according to tumour characteristics and overall risk profile.
• Neoadjuvant (preoperative) systemic therapy is increasingly used for locally advanced disease or tumours with a favourable predicted response, particularly human epidermal growth factor receptor 2-positive and triple-negative disease.
• Neoadjuvant therapy can downstage the tumour to support breast-conserving surgery, and gives direct in vivo information on treatment response.
• Radiotherapy follows breast-conserving surgery in the great majority of cases. It follows mastectomy for higher-risk disease (including larger tumours or significant nodal involvement). Regional nodal irradiation is added where indicated by the extent of nodal disease.
• Management of metastatic, incurable disease focuses on disease control, symptom palliation and quality of life, with treatment guided by receptor status.
• Hormone receptor-positive metastatic disease continues endocrine therapy, often combined with targeted agents including CDK4/6 inhibitors. Human epidermal growth factor receptor 2-directed therapy continues for that subtype. Integrated palliative care addresses symptomatic and psychosocial needs.
• Long-term multidisciplinary follow-up includes ongoing surveillance mammography and clinical assessment. It also covers management of longer-term treatment consequences, including lymphoedema following axillary surgery and the adverse effects of prolonged endocrine therapy.
• Psychological support addresses the wide-ranging impact of the diagnosis and its treatment. Breast cancer is common but now substantially more treatable and, for the great majority of affected women, curable.