Hereditary breast cancer: molecular biology and management update

Excerpt

For BRCA1 and BRCA2 carriers, lifetime estimates of breast cancer risk range from 49% to 88%, whereas the risk of ovarian cancer ranges from 40% to 59%, and from 18% to 35%, for BRCA1 or BRCA2 carriers, respectively [1, 2]. Approximately 5% of unselected patients with breast cancer carry a germline BRCA mutation. The identification of BRCA1 and BRCA2 mutations permits the implementation of prevention strategies, including screening by magnetic resonance imaging or risk-reducing surgeries. As tumor suppressor genes, BRCA1 and BRCA2 encode proteins involved in the repair of DNA double-strand breaks by way of a homologous recombination repair pathway. Members of the poly (ADP-ribose) polymerase (PARP) family of enzymes are central to the repair of DNA single-strand breaks. Consequently, the oral PARP inhibitor, olaparib, is approved for the treatment of patients with recurrent ovarian cancer and a BRCA mutation. Moreover, olaparib has also been shown to have significant benefits compared with standard therapy in patients with metastatic breast cancer and a germline BRCA mutation [3]. In addition, since the initial discovery that pathogenic germline alterations in BRCA1 and BRCA2 genes increase susceptibility to breast and ovarian cancers, many genes have subsequently been discovered that also increase breast cancer risk [4]. Advances in technology have resulted in the ability to test for multiple genes associated with a hereditary predisposition to breast cancer. …