Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast cancer, ovarian cancer, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design and setting: Prospective cohort study of BRCA1 and BRCA2 female carriers recruited from 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the UK (EMBRACE), the Netherlands (HEBON) and France (GENEPSO). The follow-up ended December 2013. Participants: 6,036 BRCA1 and 3,820 BRCA2 mutation carriers at baseline (5,046 unaffected, 4,810 with breast or ovarian cancer or both at baseline; median follow-up: 5 years). Exposures: BRCA1/2 mutations, family cancer history, mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian and contralateral breast cancer. Results: Among 3,886 women (median age 38, IQR 30-46) eligible for the breast cancer analysis, 5,066 women (median age 38, IQR 31-47) eligible for the ovarian cancer analysis, and 2,213 women (median age 47, IQR 40-55) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer, respectively, during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95%CI:65-79%) for BRCA1 and 69% (95%CI:61-77%) for BRCA2 carriers. The breast cancer incidences increased rapidly in early adulthood, 177 until ages 30-40 for BRCA1 and until ages 40-50 for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1,000 person-years) until age 80. The cumulative ovarian cancer risk to age 80 years was 44% (95%CI:36-53%) for BRCA1 and 17% (95%CI:11-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95%CI:35-45%) for BRCA1 and 26% (95%CI:20-33%) for BRCA2 carriers (Hazard Ratio (HR) for comparing BRCA2 vs BRCA1 0.62, 95%CI:0.47-0.82, P diff=0.001). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed with breast cancer for both BRCA1 (P-trend<0.001, HR for ≥2 vs no affected relatives 1.99(95%CI:1.41-2.82)) and BRCA2 carriers (P-trend=0.02, HR=1.91 (95%CI:1.08-3.37)). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR=1.46 (95%CI:1.11- 1.93), p=0.007) and c.2831-c.6401 in BRCA2 (HR=1.93 (95%CI:1.36-2.74), p<0.001). Conclusions and Relevance: These findings provide patterns of cancer risk based on BRCA status using prospective data collection, and demonstrate the potential importance of family history and mutation location in risk assessment.