Abstract
BACKGROUND: The non-breast non-ovarian cancers associated with BRCA1 and BRCA2 pathogenic variants (PVs) are controversial. We aimed to examine this using a prospective cohort design. METHODS: This study included 1260 BRCA1 and 1058 BRCA2 PV carriers (91% were females) from two consortia: the Breast Cancer Family Registry (BCFR) and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer Follow-Up Study (kConFab-FUS). The carriers were free of cancer other than breast or ovarian cancer at baseline and had a median baseline age of 45.5 years. For 16 types of non-breast, non-ovarian cancers, standardized incidence ratios (SIRs) relative to population incidence, the probabilities of relative risk effect size > 2 (i.e., moderate risk) and cumulative risks to age 80 years were estimated. RESULTS: During a median follow-up time of 11.4 years, 161 non-breast, non-ovarian cancers were observed. For BRCA1 PV carriers, little evidence of increased risk was observed. The prostate, pancreatic, and all non-pancreatic cancer SIRs were 1.7 (95% CI 0.7-4.2), 1.1 (95% CI 0.3-4.6) and 0.85 (95% CI 0.68-1.06), respectively; the probabilities of relative risk > 2 were 0 and 67% for prostate and pancreatic cancers, respectively. For BRCA2 PV carriers, increased risks of pancreatic (SIR = 6.6, 95% CI 3.8-11.6), prostate (SIR = 3.6, 95% CI 1.9-6.8) and stomach (SIR = 3.1, 95% CI 1.01-9.8) cancer were observed, with a cumulative risk to age 80 years of 8.3, 82.0, and 1.6%, respectively. For all the other non-breast, non-ovarian cancers combined, the SIR was 0.85 (95% CI 0.66-1.10). CONCLUSIONS: Apart from pancreatic, prostate, and possibly stomach cancers for BRCA2 PV carriers, and possibly pancreatic cancer for BRCA1 PV carriers, there is no evidence that BRCA1 and BRCA2 PV carriers have substantially increased risks of other non-breast, non-ovarian cancers. Our prospective risk estimates are informative for cancer risk assessment for people with BRCA1 and BRCA2 PVs.