Second Primary Cancer Risks After Breast Cancer in BRCA1 and BRCA2 Pathogenic Variant Carriers

PURPOSE Second primary cancer (SPC) risks after breast cancer (BC) in BRCA1/BRCA2 pathogenic variant (PV) carriers are uncertain. We estimated relative and absolute risks using a novel linkage of genetic testing data to population-scale National Disease Registration Service and Hospital Episode Statistics electronic health records. METHODS We followed 25,811 females and 480 males diagnosed with BC and tested for germline BRCA1/BRCA2 PVs in NHS Clinical Genetics centers in England between 1995 and 2019 until SPC diagnosis, death, migration, contralateral breast/ovarian surgery plus 1 year, or the 31st of December 2020. We estimated standardized incidence ratios (SIRs) using English population incidences, hazard ratios (HRs) comparing carriers to noncarriers using Cox regression, and Kaplan-Meier 10-year cumulative risks. RESULTS There were 1,840 BRCA1 and 1,750 BRCA2 female PV carriers. Compared with population incidences, BRCA1 carriers had elevated contralateral BC (CBC; SIR, 15.6 95% CI, 11.8 to 20.2), ovarian (SIR, 44.0 95% CI, 31.4 to 59.9), combined nonbreast/ovarian (SIR, 2.18 95% CI, 1.59 to 2.92), colorectal (SIR, 4.80 95% CI, 2.62 to 8.05), and endometrial (SIR, 2.92 95% CI, 1.07 to 6.35) SPC risks. BRCA2 carriers had elevated CBC (SIR, 7.70 95% CI, 5.45 to 10.6), ovarian (SIR, 16.8 95% CI, 10.3 to 26.0), pancreatic (SIR, 5.42 95% CI, 2.09 to 12.5), and combined nonbreast/ovarian (SIR, 1.68 95% CI, 1.24 to 2.23) SPC risks. Compared with females without BRCA1/BRCA2 PVs on testing, BRCA1 carriers had elevated CBC (HR, 3.60 95% CI, 2.65 to 4.90), ovarian (HR, 33.0 95% CI, 19.1 to 57.1), combined nonbreast/ovarian (HR, 1.45 95% CI, 1.05 to 2.01), and colorectal (HR, 2.93 95% CI, 1.53 to 5.62) SPC risks. BRCA2 carriers had elevated CBC (HR, 2.40 95% CI, 1.70 to 3.40), ovarian (HR, 12.0 95% CI, 6.70 to 21.5), and pancreatic (HR, 3.56 95% CI, 1.34 to 9.48) SPC risks. Ten-year cumulative CBC, ovarian, and combined nonbreast/ovarian cancer risks were 16%/6.3%/7.8% ( BRCA1 carriers), 12%/3.0%/6.2% ( BRCA2 carriers), and 3.6%/0.4%/4.9% (noncarriers). Male BRCA2 carriers had higher CBC (HR, 13.1 95% CI, 1.19 to 146) and prostate (HR, 5.61 95% CI, 1.96 to 16.0) SPC risks than noncarriers. CONCLUSION Survivors of BC carrying BRCA1 and BRCA2 PVs are at high SPC risk. They may benefit from enhanced surveillance and risk-reduction measures.