Breast cancer - symptoms and treatment

Symptoms of breast cancer vary widely but include a lump that can be felt, change in the breast size or shape, altered skin texture and drawing in of the nipple. Breast lumps are, however, common, especially in younger women, and the majority are not cancerous. About 30% of women diagnosed with breast cancer have no symptoms and are detected by breast screening.

Breast cancer is diagnosed by taking a biopsy, or sample of breast tissue, and examining it under the microscope. Subsequent treatment decisions are based on the extent of the disease (Table 6.1) and characteristics of the cancer, menopausal status and general health of the patient. Treatment is usually multimodality, requiring careful co-ordination and planning among surgeons, medical/clinical oncologists, pathologists, radiologists and other staff.1-4

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Ductal carcinoma in situ (DCIS)

Breast screening has led to an increase in the detection of DCIS, where cancerous cells are found in the lining of the breast ducts. DCIS is “non-invasive” meaning that it cannot spread, but can progress and become invasive. It is treated, usually by breast conserving surgery +/- radiotherapy, or by mastectomy.

Lobular carcinoma in situ (LCIS)

Here abnormal cells are found in the breast lobes.5 LCIS is often an incidental finding in biopsies taken for other reasons or it may be diagnosed through screening. Although not itself pre-cancerous, the presence of LCIS is associated with slightly increased risk of developing invasive cancer in the future; as such, patients are kept under surveillance. Occasionally an area of LCIS may be surgically removed if it has high grade features.

Surgery

Initial treatment is usually to remove the cancer surgically, either by breast conservation followed by radiotherapy, or mastectomy, which may be followed by immediate or delayed reconstruction. The choice of operation depends on the characteristics of the cancer and the patient’s preference. Prior to surgery if there is no evidence that the cancer has spread to the axillary lymph nodes, patients may be offered sentinel lymph node biopsy in which only one or two critical lymph nodes are removed; this reduces complications such as lymphoedema. If the sentinel node(s) contains cancer, or if cancer cells have already been detected in ultrasound-guided fine needle aspiration cytology/core biopsy, it is necessary to surgically remove all the lymph nodes by an axillary dissection.3

Adjuvant treatment

Adjuvant therapy is given to reduce the risk of cancer recurrence or death from microscopic spread of the cancer that is suspected, but cannot be detected, at the time of diagnosis. Increasing size of the primary cancer, higher histological grade and the presence of tumour in the axillary nodes all increase the risk of subsequent recurrence and death.

• Radiotherapy to the breast is routine after breast conserving surgery; together they are as effective at treating the primary cancer as mastectomy in reducing the risk of local recurrence.[6] After mastectomy, radiotherapy to the chest wall and regional lymph nodes is given to patients considered at higher risk of loco-regional recurrence, for example, those with large cancers or involvement of several axillary lymph nodes.
• Endocrine therapy is offered only to the two-thirds of women whose cancer is oestrogen receptor (ER) positive. In such women, adjuvant endocrine therapy reduces the risk of breast cancer recurrence and death by 40% and 30%, respectively.7 Oral tamoxifen given for 5 years is well established and effective in both pre- and post-menopausal women. In pre-menopausal women removing the ovaries has a similar effect. In post-menopausal women only, the aromatase inhibitors (anastrozole, letrozole and exemestane) given orally, block oestrogen production and are more effective than tamoxifen.8 They may be given in place of tamoxifen, after 5 years of tamoxifen use9, or women may switch to an aromatase inhibitor after 2 or 3 years of tamoxifen.10,11
• Adjuvant chemotherapy reduces the risk of breast cancer recurrence and death by about 30% and 20%, respectively.7 Because of its side-effects, adjuvant chemotherapy is usually given to women at significant risk of recurrence, or if their cancers are ER negative. The benefits of adjuvant chemotherapy in women over 70 are not well established as this age group of patients are under-represented in clinical trials. Anthracycline-based regimens are the current standard. The addition of a taxane (Paclitaxel or docetaxel) may benefit sub-groups of women with higher risk disease.12
• Biological therapies. The HER2 receptor is over-expressed in around 15- 20% of invasive breast cancers and biological therapies may be used.1, 13 The monoclonal antibody trastuzumab is given intravenously which targets the HER2 receptor in women with HER2 positive cancers. Preliminary analysis shows that the addition of trastuzumab to adjuvant chemotherapy reduces the risk of relapse and death by about 50% and 30% respectively for this subgroup of patients but with some increased risk of cardiotoxicity.14-16 As yet, the optimal duration of adjuvant trastuzumab is unclear.

Although generally well tolerated, trastuzumab can cause cardiac damage. It should not be given at the same time with anthracycline chemotherapy or to patients with pre-existing heart failure. All patients must have their cardiac function assessed before and during treatment with trastuzumab. Clinical trials of lapatinib are underway in the adjuvant setting. Lapatinib also targets HER2 but is given orally and in addition acts on another receptor. Bevacizumab, which targets the formation of new blood vessels in tumours, is also being evaluated as adjuvant intravenous therapy.

Neo-adjuvant therapies

Patients may be offered neo-adjuvant chemotherapy (or less often endocrine therapy) before definitive breast surgery. Neo-adjuvant chemotherapy may allow breast conservation surgery where otherwise mastectomy was the only choice. It also has the potential advantage of allowing the response of the primary tumour to be monitored and alternative chemotherapy be offered if initial chemotherapy is not working. Neo-adjuvant treatment is standard in patients with locally advanced breast cancer (see below).

Women with LABC have substantially worse outlook than those with early breast cancer. LABC encompasses a wide range of clinical presentations including primary tumours involving the skin or chest wall (T4) and fixed axillary nodes or involvement of the internal mammary nodes (N2/3). Inflammatory breast cancer is a specific, aggressive form usually seen in younger women and characterised by inflammatory skin changes often with a diffuse underlying tumour.

Initial treatment with anthracycline-based chemotherapy is standard and may be followed by a taxane. For patients who respond, definitive local therapy may be total mastectomy and axillary nodal clearance, followed by radiotherapy to the chest wall and to the regional lymph nodes. Breast conserving surgery may be considered in those who achieve good, partial or complete response to the primary chemotherapy. Subsequent systemic therapy may include further chemotherapy, trastuzumab (if HER2 positive) and endocrine therapy (if ER positive).

Occasionally patients have visible spread of cancer, known as metastatic disease when they first present, but usually metastatic disease is a sign of disease recurrence. Treatment for patients with metastatic (stage IV) breast cancer is “palliative” in nature; the prognosis is better for women with soft tissue (e.g. bone) rather than those with visceral (e.g. liver) metastases. The aim is to control (rather than cure) the disease, prolong life, improve symptoms and maintain quality of life.

Endocrine therapy

Blocking hormones is the first option for patients with ER positive disease; the exception may be those with spread to vital organs in whom chemotherapy may be preferred. If there is a good response to first-line endocrine therapy, second and further lines of endocrine therapy may also be effective.17,18

The choice of therapy depends on the menopausal status of the patient, previous adjuvant endocrine treatment, and exposure and response to prior endocrine therapy for metastatic disease. In post-menopausal women, the aromatase inhibitors are used first-line but tamoxifen remains a useful option for pre-menopausal women. Other options include ovarian ablation for pre-menopausal women and fulvestrant19, which is given intra-muscularly, for post-menopausal women.

Cytotoxic chemotherapy

Chemotherapy is offered to patients whose disease is no longer sensitive to endocrine therapy and those with ER negative disease. Many chemotherapy drugs are active in breast cancer, including the anthracyclines (epirubicin, doxorubicin), taxanes (docetaxel, paclitaxel), capecitabine, vinca alkaloids (vinorelbine) cyclophosphamide, platinum agents (carboplatin, cisplatin) and ixebepilone. With the exception of capecitabine, they are given intravenously: vinorelbine can be given either intravenously or orally. They all have significant toxicities. Prior adjuvant therapies, the rate of disease progression, general health of the patient and clinician/patient preference all influence the choice of treatment. Single agents given in sequence are often preferred to combination chemotherapy.

Biological therapies

Single agent trastuzumab can work in women whose cancers are HER2 positive, but more often it is combined with chemotherapy, improving response rates and overall survival in these patients.20 There is increasing evidence of benefit from continuing trastuzumab beyond disease progression when a further line of chemotherapy is initiated 21,22; lapatinib also can work in this setting.23 Because trastuzumab does not cross the blood brain barrier, it is ineffective in treating brain metastases.

Other treatment modalities

Radiotherapy has an important palliative role in treating painful bone metastases, inoperable brain metastases, spinal cord compression, lung obstruction and fungating or painful breast or chest wall disease. Bisphosphonates are given to treat pain and to reduce skeletal complications in patients with bone metastases; they can be given either orally or intravenously. Surgery may be used in some patients, for example, orthopaedic interventions for fractures or weakening of bones caused by spread of the cancer, spinal surgery for spinal cord compression and pleurodesis for malignant pleural effusion.