Identification of BRCA1/BRCA2 carriers by screening in the healthy population and its implications.

Abstract

1513 Background:Inherited BRCA1/BRCA2 mutations are associated with increased breast /ovarian cancer risks, and acceptable prevention measures (e.g. risk reducing salpingo-oophorectomy) reduce morbidity and mortality. In Ashkenazi Jews (AJ), three variants account for ~95% of deleterious mutations (BRCA1-185delAG, 5382insC; BRCA2-6174delT), with a combined BRCA1/BRCA2 carrier rate of 2.5%. General BRCA1/BRCA2 testing in AJ could therefore fulfill WHO screening criteria if carriers ascertained on the population level were shown to be at high cancer risk. Current risk estimates are based on female carriers ascertained through personal or family history of cancer and thus may suffer from biases. Aim: To determine cancer risk in carriers in the general AJ population, by identifying BRCA1/BRCA2 families through healthy males. Methods: 175 BRCA1/BRCA2 carriers, including 3 double BRCA1/BRCA2 heterozygotes, were identified by testing 8,196 AJ males with no cancer history (2.2% carrier rate). Relatives of carriers were tested and cancer risk was assessed based on testing and family history within these families. Results: Breast and ovarian cancer risks in female carriers ascertained through healthy males were comparable to current risk estimates (> 80% by age 70 for breast and ovarian cancer combined). Although family history was more suggestive of inherited predisposition in carriers vs. non carriers (p<0.001), family history was either not suggestive or minimal in 45% and 18% of BRCA1/BRCA2 families respectively. Thus, 63% of families would not be identified using current referral criteria. Lack of family history was related to low incidence as a result of paternal inheritance, small family size, male preponderance and few females inheriting the familial mutation. Cancer history was more suggestive of inherited predisposition in BRCA1 compared to BRCA2 families (p=0.015) Conclusions: Cancer risk in female BRCA1/BRCA2 carriers is high in the general population, suggesting general screening is justified. This is currently feasible, and likely cost-effective, in any population with common mutations, but could be universally applicable with advances in molecular testing.