20th June 2023

Breast Cancer

Overview of Breast Cancer

Breast cancer is the most common cancer in the UK, accounting for 15% of all new cancer cases. 1 in 7 UK females will be diagnosed with breast cancer in their lifetime. It is the 4th most common cause of cancer death in the UK, accounting for 7% of all cancer deaths. In the UK, breast screening is offered routinely to all women from the age of 50 to 70, every 3 years. Male breast cancer accounts for 1% of all breast cancers and 0.1% of male cancer deaths.

Risk Factors

Genetic, hormonal, and environmental factors play a role in the pathogenesis of breast cancer. ~5-10% of breast cancers are due to mutation in BRCA1, BRCA2, AT or TP53 genes. BRCA1 and BRCA2 genes are located in chromosomes 17q and 13q respectively, and both genes function as tumour suppressor genes. Human epidermal growth factor receptor 2 (HER2) is a membrane tyrosine kinase and proto-oncogene that is overexpressed in about 25-30% of breast cancers. It is located in the long arm of chromosome 17 (17q12). Hormonal factors, particularly oestrogen exposure, are also one of the significant risk factors for breast cancer. Reported risk factors include nulliparity, first pregnancy >30 years old, early menarche, late menopause, long term use of HRT in postmenopausal women. Short-term use of HRT may not be associated with a high risk of breast cancer. Alcohol intake, physical inactivity and obesity are also related to an increased risk of breast cancer. Prior radiotherapy to the breast or chest wall also increases the risk.

Precursor lesions and Malignant lesions

Breast cancer arises from the epithelial cells lining the terminal duct lobular unit. The development of invasive breast cancer is thought to be due to a multistep process. Lobular carcinoma in situ, atypical ductal hyperplasia, ductal carcinoma in situ (DCIS) and microinvasive carcinoma are described as precursor lesions by the modified WHO classification of breast cancer. DCIS accounts for 3-5% of palpable breast cancer and is seen as widespread or unifocal microcalcification on mammography. DCIS has variable potential for development into an invasive disease and is defined as the proliferation of malignant-appearing mammary ductal epithelial cells without evidence of invasion beyond the basement membrane. Broadly, there are five subtypes of DCIS: comedo, solid, cribriform, micropapillary and papillary. Treatment of DCIS is aimed at preventing local recurrence, particularly of invasive cancer. Treatment options include surgery alone, or surgery followed by radiotherapy and hormonal therapy. With mammographic follow-up, breast-cancer disease-free survival in DCIS approaches 100%.

Invasive ductal carcinoma accounts for 70-80% of all invasive carcinoma whereas invasive lobular carcinoma represents 10-15%. Medullary cancers tend to affect younger patients while colloid/mucoid tend to affect the elderly. 60-70% of breast cancers are oestrogen receptor positive conveying better prognosis. Overexpression of HER2 (growth factor receptor gene) is associated with aggressive disease and poor prognosis. 15% of breast cancers lack the expression of oestrogen, progesterone and HER2 receptors (often referred to as triple-negative breast cancer) and are associated with a high rate of local and systemic recurrence.

Diagnosis and Prognosis

Usual presentations are a painless breast lump, distortion of breast, or nipple discharge. All breast lumps should undergo triple assessment which consists of clinical examination in combination with imaging and histological assessment. Breast examination may reveal a non-tender, well- or ill-defined lump with or without fixity to the skin or chest wall and changes in overlying skin. Lymph nodes in the axilla and supraclavicular fossa may be involved. Clinical examination may contribute to tumour and nodal staging. Ultrasound is more accurate in detecting invasive breast cancer, though mammography remains most accurate at detecting ductal carcinoma in situ (DCIS). MRI is used in the assessment of multifocal/bilateral disease and patients with cosmetic implants who are identified as high risk. Pathological diagnosis can be obtained by FNA or core biopsy or open surgical biopsy. TNM staging is used for staging the disease and planning for management. Immunohistochemistry (IHC) evaluation is mandatory nowadays for treatment decision making.
Less than 10% of patients initially present with metastatic disease. The most common sites of distant disease include bones (70%), lungs (60%), liver (55%), pleura (40%), adrenals (35%), skin (30%) and brain (10-20%). Staging investigations should include CXR, bone scan, liver USS, CT/MRI or PET-CT, LFT and calcium.
Overall prognosis depends on tumour size, grade, lymph node status, oestrogen (ER) and progesterone receptors (PR) status, and presence, or absence of vascular invasion.

Treatment

Surgical management of breast cancer includes breast conservative surgery which is the removal of the tumour by wide local excision (WLE). Patients who are not suitable for conservative surgery undergo mastectomy with or without reconstruction. Breast cancer during pregnancy, prior radiotherapy to the breast or chest wall, tumour >5 cm, women <35 years or pre-menopausal with BRCA 1, BRCA 2 mutation, inflammatory breast disease, and multifocal disease are contraindications to breast conservation surgery.
Sentinel node biopsy is widely used in clinically node-negative breast cancer. However, patients with clinically positive nodes will undergo axillary dissection during primary breast surgery.
Radiotherapy is recommended for all patients with invasive cancer who received breast conservative surgery. Axillary radiotherapy is used if lymph node positive on sampling and surgical clearance is not performed.
Adjuvant systemic treatments such as chemotherapy, hormonal therapy and trastuzumab provide survival benefit in suitable patients. Anthracycline based chemotherapies (e.g., AC regime – Doxorubicin and Cyclophosphamide) were some of the widely used regimes for adjuvant therapy. However, cardiac-related toxicity can be a limitation to using anthracyclines, particularly in patients with underlying heart disease. The addition of taxanes (paclitaxel and docetaxel) has provided additional benefits to adjuvant treatment regimes. Taxanes act by inhibiting microtubular depolymerisation causing cancer cells to stop dividing and slowing the growth of cancer or killing the cells.
Patients with hormone receptor positive tumours should be considered for adjuvant hormonal therapy to block the oestrogen stimulus. In pre-menopausal women, tamoxifen (with or without ovarian suppression) is the standard choice. Tamoxifen is a selective oestrogen receptor modulator (SERM) and inhibits breast cancer cells by acting as a competitive antagonist at the oestrogen receptor. Side effects include an increased risk of uterine cancer and thromboembolic events. Aromatase inhibitors which block the conversion of androgens to oestrogen are used in post-menopausal women. The adjuvant use of trastuzumab, a monoclonal antibody targeted towards HER2 receptor, in selected HER2 positive breast cancer patients showed a reduction in recurrence and mortality. However, cardiac toxicity is the most concerning side effect associated with this medication.
Patients with metastatic breast cancer can present to A&E with acute oncology problems. Patients with bone metastasis can present with malignant hypercalcaemia which needs urgent medical treatment. Some patients with spinal metastasis can present with metastatic cord compression which needs urgent referral to acute oncology team and MRI whole spine. The treatment approach for metastatic breast cancer is generally considered non-curative in nature and is aimed at palliation, improving quality of life and prolonging survival. Bisphosphonate therapy together with adequate calcium and vitamin D supplementation is helpful in reducing skeletal related events in patients with bony metastasis.