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

Abstract

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.

Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location

“…Recently, in a prospective cohort study of BRCA carriers who received only RRSO, not hysterectomy, endometrial cancer developed in eight patients in a median follow-up of 5.1 years, with no apparent increased risk after RRSO, on the other hand, BRCA1 carriers had an increased risk of endometrial serous adenocarcinoma [ 92 ]. Furthermore, a large Dutch nationwide cohort study revealed that BRCA1/2 carriers have a 2- to 3-fold increased risk for endometrial cancer, with the highest risk observed for the rare subgroups of serous-like and p53-abnormal endometrial cancer in BRCA1 carriers [ 93 ].…”

Case–case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer

“…Moreover, previous reports have suggested that BRCA1 pathogenic variants elevate the risk of the aggressive serous EC subtype in particular (Ring et al, 2016; Saule et al, 2018; Shu et al, 2016), a subtype with even later age at onset than other more common EC subtypes (Setiawan et al, 2013). Interestingly, a recent publication estimating standardized incidence ratios for EC in the Dutch population identified an increased risk of serous EC associated with BRCA1 and BRCA2 pathogenic variants, with significantly increased risk also detectable for endometrioid subtype for BRCA1 but not BRCA2 pathogenic variant carriers (de Jonge et al, 2021). Unfortunately, due to a lack of relevant information, we could not investigate if pathogenic variants occurred more often in women with serous EC subtype in this study.…”

Hereditary gynecologic tumors and precision cancer medicine

“…However, cumulative risks of EC at 75 years of age remain low. 61 Riskreducing hysterectomy may be an option during RRSO, but the potential for increased complications and uterine lesions must be considered.…”