Prostate cancer risks for male BRCA1 and BRCA2 mutation carriers: a prospective cohort study

Background BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates has been reported, based on retrospective studies. ObjectiveTo estimate relative and absolute PCa risks associated with BRCA1/2 mutations, and to assess risk-modification by age, family history and mutation location.Design, Setting, and ParticipantsProspective cohort study of male BRCA1 (n=376) and BRCA2 carriers (n=447) identified through clinical genetics centres in the UK and Republic of Ireland (median follow-up: 5.9 and 5.3 yr, respectively). Outcome Measurements and Statistical Analysis Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks and hazard ratios (HRs), estimated using cohort and survival analysis methods. Results and Limitations Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had a SIR of 4.45 (95% confidence interval [CI] 2.99-6.61), and absolute PCa risk of 27% (95% CI 17%-41%) and 60% (95% CI 43%-78%) by ages 75 and 85, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at ages<65 was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risks for BRCA2 carriers increased with family history (HR per affected relative=1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831–c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to a lower PCa risk (HR=0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score≥7 (SIR=5.07, 95% CI 3.20-8.02) than Gleason score≤6 PCa (SIR=3.03, 95% CI 1.24-7.44), and increased risk of death from PCa (SMR=3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses.ConclusionsThe results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers.