Future possibilities in the prevention of breast cancer: Intervention strategies in BRCA1 and BRCA2 mutation carriers

About 5-10% of breast and ovarian cancers occur as a result of highly penetrant germline mutations in cancer predisposing genes [1,2]. Half of these are due to mutations in BRCA1 or BRCA2 [3]. BRCA1 on chromosome 17q encodes a protein of 1863 amino acids [4*] and BRCA2 on 13q is about twice the size of BRCA1 [5*]. Although deleterious mutations in both genes predispose to earlier onset and an increased risk for female breast cancer, the risk of cancers at other sites and the risk profile differs for the two genes.Collaborative studies by the Breast Cancer Linkage Consortium (BCLC) have combined data from numerous families with germline mutations in BRCA1 and BRCA2 worldwide to determine penetrance estimates and risks for other cancers in BRCA1 and BRCA2 mutation carriers. These have shown that both genes confer an increased risk for female breast cancer of 80-85% by the age of 80 years [6,7**], although the penetrance curve for BRCA1 starts to rise slightly earlier than that for BRCA2 (Figs 1 and 2). Both genes confer an increased risk for ovarian cancer, but the lifetime risks are higher for BRCA1 (60% by age 80 years) than for BRCA2 (27% by age 80 years; the population risk is just under 1%), and the penetrance curve also starts to rise earlier (late 30s) for BRCA1 than for BRCA2 (mid 40s; Figs 1 and 2) [7**].It is now clear that both genes confer an increased risk for prostate cancer, which is threefold for BRCA1 mutations [8*] and threefold to sevenfold for BRCA2 mutations [9,10], equating to an absolute risk of 6-14% by age 74 years; the population risk by this age is 2%. Mutations in BRCA1 are also thought to increase the risk of colon cancer to about 6% by age 70 years [8*], but carriers of mutations in BRCA2 do not appear to be predisposed to colon cancer.A recent analysis of the risk of other cancers in BRCA2 carriers [10] reported a significantly increased risk for cancer of the prostate, stomach, pancreas, male breast, head and neck, ocular melanoma, cuta