Inheritance of a mutation in the BRCA1 or BRCA2 (BRCA1/2) genes is associated with an increased risk of developing breast and ovarian cancer. However, there is also substantial variability in the penetrance of ovarian cancer in BRCA1/2 mutation carriers. These observations imply that germline mutations in BRCA1/2 may be necessary to explain the Mendelian pattern of ovarian cancer in some families, but may not be sufficient to completely describe the inter-individual variability in the age-specific risk of ovarian cancer. There is substantial evidence that BRCA1/2-associated ovarian carcinogenesis involves the recognition and repair of DNA damage to maintain genomic integrity, and a number of other genes have been recently identified that are associated with hormone- and reproductive-related cancers such as breast cancer. Specific BRCA1/2 mutations may also influence cancer risks. Thus, the field is beginning to identify genotypes and exposures involved in modification of cancer risk in women with BRCA1/2 mutations.
The availability of genetic testing for inherited mutations in BRCA1/2 also provides potentially valuable information to women who may be at high risk of breast or ovarian cancer. Unfortunately, these women have relatively few clinical options to reduce their cancer risk. These options include increased surveillance (e.g., mammography), and clinical or self-examination. Chemopreventive agents such as tamoxifen hold promise, but none have been definitively shown to reduce cancer risk in BRCA1 or BRCA2 mutation carriers. Many high-risk women also consider risk-reducing mastectomy (RRM) or risk-reducing Salpingo-oophorectomy (RRSO), with the intent of removing healthy breast or ovarian tissue to reduce their risk of developing invasive malignancy. It is clear that RRM and RRSO cannot completely prevent the subsequent development of breast or ovarian cancers. However, a number of studies have now provided evidence that can help guide women who carry a BRCA1/2 mutation and their clinicians in the use of these surgeries for breast or ovarian cancer risk reduction. The existence of genetic testing for BRCA1 or BRCA2 mutations, and the subsequent use of cancer risk reducing strategies, provides a paradigm for genetically-based disease risk reducing strategies.