Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers

Abstract

for the Israeli Consortium of Hereditary Breast Cancer BACKGROUND: BRCA1/2 mutation carriers have an increased risk of developing ovarian cancer, leading to the recommendation of risk-reducing salpingo-oophorectomy (RRSO) at 35-40 years of age. The role, if any, that BRCA mutations play in conferring uterine cancer risk, is unresolved. METHOD: Jewish Israeli women, carriers of one of the predominant Jewish mutations in BRCA1/2 from 1998 to 2016, were recruited. Cancer diagnoses were determined through the Israeli National Cancer Registry. Uterine cancer risk was assessed by computing the standardized incidence ratio of observed-to-expected number of cases, using the exact 2-sided P value of Poisson count. RESULTS: Overall, 2627 eligible mutation carriers were recruited from 1998 to 2016, 2312 (88%) of whom were Ashkenazi Jews (1463 BRCA1, 1154 BRCA2 mutation carriers, 10 double mutation carriers). Among these participants, 1310 underwent RRSO without hysterectomy at a mean (± standard deviation) age of 43.6 years (± 4.4 years). During 32,774 women-years of follow up, 14 women developed uterine cancer, and the observed-to-expected rate of all histological subtypes was 3.98 (95% confidence interval [CI], 2.17-6.67; P < .001). For serous papillary (n = 5), the observed-to-expected ratio was 14.29 (95% CI, 4.64-33.34; P < .001), and for sarcoma (n = 4) it was 37.74 (95% CI, 10.28-96.62). These rates were also higher than those detected in a group of 1844 age-and ethnicity-matched women (53% with breast cancer). CONCLUSION: Israeli BRCA1 or BRCA2 mutation carriers are at an increased risk for developing uterine cancer, especially serous papillary and sarcoma. These elevated risks of uterine cancer should be discussed with BRCA carriers. Cancer 2019;125:698-703.

Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity

“…A distinct phenotype of tumors in a cancer syndrome is considered to be in support of a causal relationship. Although previous studies show contradictory results about excess risk of EC (all histotypes) for gBRCA carriers (6)(7)(8)(9)(10)(11)38), most recent studies did find increased risks to develop serous-like ECs, with reported standardized incidence ratios (SIR) ranging from 14.29 to 32.2 (6,7,10). These SIRs are comparable with the reported relative risk increase for prostate cancer (up to 20-fold) and pancreatic cancer (up to 10fold) for gBRCA2 carriers (1).…”

“…Whether endometrial carcinoma (EC) should be considered part of gBRCA-associated HBOC syndrome is still under debate due to conflicting data (5)(6)(7)(8)(9). A number of studies have shown an increased risk to develop EC especially for gBRCA1 carriers, with highest risks observed for an aggressive subtype of EC-the serous-like ECs (5)(6)(7)(9)(10)(11). However, others did not observe this increased risk or attributed it to previous tamoxifen treatment rather than to the gBRCA mutation (8,9,11).…”

Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology

“…113 In a retrospective case control study including 2,627 Jewish Israeli women (88% Ashkenazi Jewish) who were carriers of a pathogenic BRCA1/2 variant, risk of developing uterine cancer was increased, with an observed-to-expected ratio of 3.98 (95% CI, 2.17-6.67; P,.001). 116 This association persisted regardless of uterine cancer histology. Despite some evidence of increased risk of uterine cancer in carriers of a pathogenic BRCA1/2 variant, the absolute risk is low.…”

“…Some studies have suggested an increased risk specifically of serous uterine cancer in carriers of a pathogenic BRCA1/2 variant. [113][114][115][116] Analyses from a multicenter prospective cohort study including 1,083 women carrying a pathogenic BRCA1 variant who underwent RRSO without hysterectomy showed an increased risk for serous and/or serouslike endometrial cancer. 117 However, it has been suggested that the increased risk for endometrial cancer observed in some carriers of BRCA1/2 pathogenic or likely pathogenic variants may be due to the use of tamoxifen therapy by these women rather than the presence of a gene mutation.…”

BRCA Mutations and Breast Cancer Prevention

“…Segev et al have previously reported an increased risk of endometrial cancer with tamoxifen exposure among BRCA mutation carriers (OR = 3.50; 95% CI 1.51–8.10) [100]. More recently, Laitman et al have very recently published a significantly higher observed-to-expected ratio of uterine cancer among 1310 Israeli BRCA mutation carries compared to non-carriers (3.98; 95% CI 2.17–6.67) [101]. Together, the data suggest that hysterectomy at the time of oophorectomy may be warranted for this high-risk population.…”