BREAST CANCER OVERVIEW
Breast cancer is the most frequently diagnosed cancer in women in the United States, accounting for an estimated 226,870 new cases (163,570 invasive cancers and 63,300 in situ carcinomas) and 39,510 deaths in 2012. In the United States, the age-specific incidence of breast cancer increases with age, to a lifetime risk of breast cancer of 1 in 8 (to 110 years of age); by age 40 years, approximately 1 in 203 women will have been diagnosed with breast cancer annually; at 60 years of age, the figure is 1 in 28 women. Incidence rates rose 21% from 1973 to 1990, but then began to decline; mortality rates stayed relatively constant until recently, when annual decreases were seen. A sharp decline in the incidence of breast cancer in the early 2000s followed a decrease in the use of postmenopausal hormone replacement therapy. Age, family history, and both endogenous and exogenous ovarian hormone exposure have an important effect on risk and have been incorporated into models that predict individual risk of breast cancer; diet, alcohol use, and other factors play a smaller role. Inherited mutations in BRCA1, BRCA2 , PTEN, and TP53 play a role in the development of breast cancer and can be directly tested in individuals.
The expression of nuclear oestrogen and progesterone receptors plays an important role in the differentiation and growth of normal breast epithelium and the response of breast cancer cells to hormonal therapeutics. ERBB2 (human epidermal growth factor receptor 2 [HER2]) is a growth-signalling molecule on the surface of normal breast cells that is overexpressed in approximately 20% of breast cancer tumours, contributing to growth autonomy and genomic instability. Molecular analyses have defined at least four biological subtypes of breast cancer, including the basal type, two luminal types (so-called luminal-A and luminal-B ), and the HER2-positive type. BRCA1 and BRCA2 are tumour suppressor genes that play a critical role in the cellular response to DNA damage; inherited mutations in these genes are associated with an increased risk of breast cancer. Regardless of the criteria used by an individual physician and patient to define high risk, four possible actions may be taken, some of which can be used simultaneously: (a) enhanced surveillance, (b) behavioural modification, (c) chemopreventive strategies, and (d) prophylactic mastectomy or oophorectomy.
Screening guidelines currently differ between organizations. The 2009 United States Preventive Service Task Force breast cancer screening guideline recommends biennial screening mammography for women ages 50 to 74 years and an individualized (rather than standardized) approach for women ages 40 to 49 years. The American Cancer Society continues to recommend yearly mammogram starting at age 40 years. The American Cancer Society also recommends that breast magnetic resonance imaging (MRI) be used in addition to mammographic screening in women with a lifetime risk of breast cancer greater than 20%. Microcalcification and soft-tissue density are the major indications for biopsy in mammographic screening; the mammographic abnormality with the highest rate of malignancy is a mass density with associated calcification. For patients with breast symptoms or palpable abnormalities, mammography characterizes the suspicious area, evaluates the remainder of the breast for occult lesions, and assesses the contralateral breast. Malignant breast masses classically are nontender and firm, with irregular borders. Diagnostic methods include fine-needle aspiration cytology, needle-core biopsy with ultrasound or stereotactic guidance, and excisional biopsy, with or without wire or tack localization.
Lobular carcinoma in situ (LCIS) is a nonpalpable lesion that usually is discovered with another indicator for biopsy; it is more common in premenopausal women and accounts for 30% to 50% of cases of carcinoma in situ. LCIS has a propensity for multicentricity and bilaterality; it is an indicator of risk of subsequent invasive breast cancer. The rare pleomorphic variant of LCIS seems to have a more aggressive behaviour and is considered more as a precursor of invasive lobular cancer rather than a marker of breast cancer risk. Some groups advocate complete excision with free margins. Management of LCIS has shifted toward observation after biopsy rather than mastectomy; increasing evidence shows that tamoxifen should be considered as a preventive approach. The multifocal nature of LCIS makes margin clearance an unrealistic and unnecessary goal. Unlike LCIS, ductal carcinoma in situ (DCIS) is almost always first identified by mammography; the peak incidence is between 51 and 59 years of age, and it accounts for most of the increasing number of carcinoma in situ lesions diagnosed. DCIS is more likely to be localized to one area of the breast; thus, most patients are candidates for breast conservation. Tamoxifen should also be considered following lumpectomy and radiation to reduce the risk of another ipsilateral or a new contralateral event, invasive or noninvasive.
Patients should undergo a complete history and physical examination. Hemogram and renal and hepatic function tests as well as serum alkaline phosphatase evaluation should be performed in all patients. Bilateral mammography is indicated for all patients, and other breast imaging (ultrasound and MRI) should be used as needed for each individual patient; other imaging studies are recommended only to evaluate specific signs or symptoms or in patients with locally advanced disease. Prognostic factors include pathological tumour size, hormone receptors, axillary nodal status, histologic subtype, tumour grade, and perhaps age. HER2 is a strong predictive marker and accurate determination of HER2 status identifies patients with T1cN0 tumours and above who should be considered candidates for adjuvant therapy with a trastuzumab-based regimen. Expression of oestrogen receptor and/or progesterone receptor is accepted as a predictive marker for response to endocrine therapy. Multiple gene expression profiling assays have been developed as prognostic tests and two of them are undergoing further prospective testing as a predictive marker for therapy selection. The current American Joint Committee on Cancer TNM staging system takes into account the increasing use of advanced imaging and pathology techniques, such as sentinel node biopsy and immunochemistry; it also considers the number of involved nodes as a strong prognostic factor. Sentinel lymph node mapping is now the standard of care for many women with early breast cancer as it is more accurate and less morbid than axillary dissection. For patients with stages I and II disease, breast conservation and modified radical mastectomy are the major therapeutic options; for most patients, breast conservation is the preferred approach. Factors that affect local control in breast conservation include pathological margin involvement, extensive intraductal component, age, and the presence of multiple tumours. Adjuvant therapy with cytotoxic drugs or endocrine treatment, or both, is recommended for patients with node-positive disease; anti-HER2–targeted therapy should also be considered for HER2-overexpressing tumours. Pathological tumour size, hormone-receptor and HER2 status, histologic subtype, and nuclear grade are used to select patients with node-negative disease for adjuvant therapy. The results of the serial meta-analyses performed by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) show that the survival benefits of adjuvant chemotherapy and endocrine therapy persist after 15 years of follow-up. Challenges that require resolution include identification of biological parameters that more precisely predict the natural history of disease and the response to systemic therapy; more effective treatments are clearly needed.
Patients with locally advanced disease are a heterogeneous group, including those with T3N1, T0-3N2-3, and T4N0-3 disease. Multimodality therapy is recommended for virtually all patients with locally advanced disease; the sequence of systemic therapy, surgery, and radiation depends largely on the operability of the primary disease. For women with inoperable or inflammatory breast cancer (or both), preoperative chemotherapy is recommended, followed by surgery, radiation, and endocrine therapy, if appropriate. Patients with HER2-positive disease may benefit from addition of anti-HER2–targeted therapy. Preoperative endocrine therapy for patients with receptor-positive disease is also a reasonable option.
Local recurrence is an indicator of systemic relapse in most cases; an exception may be local relapse in a breast that has undergone conservation therapy. Selection of the treatment modality depends largely on the extent of local and regional failure and the presence of distant metastases. Surgical removal alone may be sufficient in some cases, but it often is combined with locoregional radiation and/or systemic therapy.
Although a small percentage of patients with metastatic breast cancer achieve long-term disease-free survival, this stage of disease is generally not curable, and therapy is largely palliative. A wide range of systemic, local, and supportive therapies are available for the palliation of metastatic breast cancer. Primary breast surgery may be indicated in selected patients who are seen with stage IV disease. The selection of endocrine, cytotoxic, or biological therapy usually is based on disease-free interval, receptor status, HER2 status, site of metastasis, performance status, age, and previous exposure to systemic therapy. Anti-HER2 agents, such as trastuzumab, lapatinib, and pertuzumab, have changed the natural history of patients with HER2-positive metastatic breast cancer. Treatment with bisphosphonates or denosumab is indicated to minimize bone complications in patients with bone metastases.