Risk of Serous Endometrial Carcinoma in Women With Pathogenic BRCA1/2 Variant After Risk-Reducing Salpingo-Oophorectomy

Abstract

It has recently been shown that the risk of a rare subtype of endometrial carcinoma (serous type) in women carrying a germline BRCA1/2 pathogenic variant is increased. We assessed the incidence of serous endometrial carcinoma in an independent prospective cohort study of 369 BRCA1/2 women (1779 woman-years of follow-up) who underwent risk-reducing salpingo-oophorectomy by laparoscopy. This occurrence in two BRCA1 carriers led us to estimate that BRCA1/2 carriers present a higher risk than the control population (standardized incidence ratio = 32.2, 95% confidence interval = 11.5 to 116.4, P < .001, two-sided chi-square test, 1 degree of freedom). In addition, in both tumors, the wild-type BRCA1 allele was lost, indicating the inactivation of the BRCA1 gene and arguing for a link with endometrial carcinogenesis. Prophylactic hysterectomy could be discussed with informed women through a shared decision-making process although the estimated 3% life-long risk is moderate. Additional studies are required to establish future prophylactic surgery guidelines.

Uterine cancer in Jewish Israeli BRCA1/2 mutation carriers

“…Similar results were reported for Australian BRCA1/2 carriers restricted to those who used tamoxifen . Saule et al, in a study of 369 French BRCA1/2 mutation carriers, reported a 3% risk for developing serous endometrial cancer by age 70 years but no increased risk for all endometrial cancer subtypes combined in BRCA1/2 mutation carriers. Recently, an Italian group that analyzed the rate of uterine carcinosarcomas in 1854 high‐risk families reported that 11 families had a case of gynecological carcinosarcoma, including 4 families with a BRCA1 mutation, 4 families with a BRCA2 mutation, and 3 high‐risk families without mutations in either BRCA gene …”

“…Ninety‐five percent confidence intervals (CIs) for the observed‐to‐expected ratio (O:E) for uterine SIRs were calculated assuming a Poisson distribution. To calculate SIRS for serous papillary endometrial cancer, we assumed that the national rates for this cancer type were 10% of the total reported rates for uterine cancer in all age groups, as previously assumed …”

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).…”

“…Other cancer types reported to be increased in patients with germline BRCA2 mutations (gBRCA) are pancreatic and prostate cancer (3,4). 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).…”

“…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).…”