Endometrial Cancer Risk in Women with Germline BRCA1 or BRCA2 Mutations: Multicenter Cohort Study.

BACKGROUND Endometrial cancer (EC) risk in BReast CAncer gene 1/2 (BRCA1/2) mutation carriers is uncertain, therefore we assessed this in a large Dutch nationwide cohort study. METHODS 5,980 BRCA1/2 (3,788 BRCA1, 2,151 gBRCA2, 41 both BRCA1/BRCA2) and 8,451 non-BRCA1/2 mutation carriers were selected from the HEBON-cohort. Follow-up started at date of nationwide PALGA coverage (January 1, 1989) or at the age of 25 years (whichever came last), and ended at date of EC diagnosis, last follow-up or death (whichever came first). EC risk in BRCA1/2 mutation carriers was compared to: 1) general population, estimating standardized incidence ratios (SIRs) based on Dutch population-based incidence rates; and 2) non-BRCA1/2 mutation carriers, using Cox-regression analyses, expressed as hazard ratio (HR). Statistical tests were two-sided. RESULTS Fifty-eight BRCA1/2 and 33 non-BRCA1/2 mutation carriers developed EC over 119,296 and 160,841 person-years, respectively (SIR = 2.83, 95% confidence interval (CI) = 2.18-3.65; and HR = 2.37, 95% CI = 1.53-3.69, respectively). gBRCA1 mutation carriers showed increased risks for EC overall (SIR = 3.51, 95% CI = 2.61-4.72; HR = 2.91, 95% CI = 1.83-4.66), serous-like EC (SIR: 12.64, 95% CI = 7.62-20.96; HR = 10.48, 95% CI = 2.95-37.20), endometrioid EC (SIR = 2.63, 95% CI = 1.80-3.83; HR = 2.01, 95% CI = 1.18-3.45) and TP53-mutated EC (HR = 15.71, 95% CI = 4.62-53.40). For BRCA2 mutation carriers, overall (SIR = 1.70, 95% CI = 1.01-2.87), and serous-like EC risks (SIR = 5.11, 95% CI = 1.92-13.63) were increased when compared to the general population. Absolute risks by 75 years remained low (overall EC = 3.0%; serous-like EC = 1.1%). CONCLUSIONS BRCA1/2 mutation carriers have a 2- to 3-fold increased risk for EC, with highest risk observed for the rare subgroups of serous-like and p53-abnormal EC in BRCA1 mutation carriers.