For years, investigators have attempted to understand the clustering of breast cancer that occurs in certain families. Familial breast cancer has been characterized by an earlier average age of onset, an increased risk of bilateral disease, and an increased risk of ovarian cancer. Mutations in two genes, BRCA1 and BRCA2, have subsequently been found to confer an inherited predisposition to breast and ovarian cancer. An estimated 5% of breast cancer cases are thought to be due to such mutations, and the lifetime risk of cancer in mutation carriers is high. In women with BRCA1 mutations, cumulative risk of breast cancer is estimated to be 3.2% by age 30, 19.1% by age 40, 50.8% by age 50, 54.2% by age 60, and 85% by age 70.Furthermore, BRCA1+ women who have had breast cancer have a 64% estimated cumulative risk of a contralateral breast cancer by age 70. This risk is substantially increased from the estimated 1.0% annual risk of contralateral breast cancer for women with a history of sporadic breast cancer. In women with BRCA2 mutations, the risk of breast cancer appears to be similar to the risk among women with BRCA1 mutations. More recent population-based studies have demonstrated lower, although still substantial, breast cancer risk ranging from 55% to 85% for BRCA1 carriers and 37% to 85% for BRCA2 carriers.

To date, no significant differences have been observed in terms of response to treatment between sporadic and inherited forms of breast cancer. However, two recent studies have suggested that the presence of a BRCA1/2 mutation in women with breast cancer with a strong family history or of Ashkenazi Jewish ethnicity may portend a worse prognosis.

Further studies are necessary to confirm and extend these findings. As mutations of BRCA1 and BRCA2 have been identified, testing for these genetic mutations has become more common. This practice has led to recommendations for screening and prevention strategies for women with one of these mutations or with a high likelihood of having one. These strategies, including more frequent and earlier screening, chemoprevention, or surgical prevention (prophylactic mastectomy), may make a substantial impact on the incidence and mortality of breast cancer in these populations. Ultimately, deciphering the functions of BRCA1 and BRCA2, which are assumed to have tumor suppressor functions, will lead to a better understanding of carcinogenesis and may lead to new strategies for therapy and prevention. Although known mutations of BRCA1 and BRCA2 are thought to account for only approximately 5% of all breast cancers, and an even smaller percentage among older women, this is still an important issue to consider in an older woman with breast cancer and a strong family history.

BRCA1 and BRCA2 are the first of what may be a series of breast cancer susceptibility genes. Other known although less common genetic syndromes that confer increased breast cancer risk include Li-Fraumeni syndrome, Cowden’s disease, Peutz-Jeghers syndrome, Muir-Torre syndrome, and ataxia telangiectasia. These syndromes are associated with several other abnormalities and, in general, breast cancer appears earlier in life.