Endometriosis in Carriers of a Pathogenic Variant in BRCA1 or BRCA2: A Descriptive Analysis of a Large Multicentral BRCA Carrier Cohort

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, affecting approximately 10% of reproductive-aged women globally [ 1 , 2 ]. This multifactorial condition is associated with significant morbidity, notably chronic pelvic pain, dysmenorrhea, dyspareunia, infertility, and depression [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. The pathophysiology of endometriosis is complex with potential contributions from retrograde menstruation, immune dysregulation, hormonal imbalances, and genetic predisposition [ 8 , 9 , 10 , 11 ]. Endometriosis is estrogen-dependent, with estrogen driving lesion growth and progesterone resistance limiting its suppression [ 10 , 11 ]. This condition has been associated with increased risk of ovarian cancer, particularly the clear cell and endometrioid subtypes [ 12 , 13 ], with some recent evidence also suggesting a modest link with high-grade serous subtypes [ 14 ]. Although twin studies have suggested a heritable component to endometriosis, no high-penetrance susceptibility genes have been identified [ 15 , 16 ]. Findings from genome-wide association studies suggest a role of genetic variation in WNT4 , FN1 , and GREB1 genes, all of which are implicated in estrogen signaling and inflammation [ 1 , 17 ]. BRCA1 and BRCA2 are tumor suppressor genes that play a critical role in maintaining genomic stability, among other critical functions. Pathogenic (or likely pathogenic) BRCA variants confer the highest known lifetime risks of developing ovarian and/or fallopian tube cancer [ 18 ]. Given the association between endometriosis and ovarian cancer, it is important to understand how endometriosis presents in women at high genetic risk of ovarian cancer, including BRCA carriers. While BRCA mutations are well-established in hereditary cancer syndromes, their relationship to benign gynecologic conditions such as endometriosis is not evaluated. Moreover, other burdens of endometriosis, including chronic pain, infertility, and mental health impacts, remain underexplored in this high-risk population. This study aims to evaluate the prevalence and clinical characteristics of endometriosis in a large multicenter cohort of BRCA carriers and to provide real-world insights into how endometriosis manifests in this high-risk population.

Participants were identified from a longitudinal study of women aged 18 to 70 with a confirmed pathogenic or likely pathogenic variant in the BRCA1 or BRCA2 gene (carriers hereafter) and has been previously described in detail [ 19 ]. Briefly, eligible participants had undergone genetic testing based on a personal or family history of breast and/or ovarian cancer. While various methods were used to detect mutations, all identified variants were confirmed through direct DNA sequencing. Informed written consent was obtained from all participants. The study was conducted in accordance with the ethical standards of the relevant institutional or national research committees and with the 1964 Declaration of Helsinki and its later amendments. Ethical approval was obtained from the Institutional Review Boards of all participating centers. Participants complete a research questionnaire at the time enrollment (between 1995 and 2024), which was administered either in person during a clinic visit or remotely via telephone or mail. The questionnaire gathered self-reported data on established and potential risk factors for breast and ovarian cancer, including personal and family cancer history, medical and reproductive history, medication use, and select lifestyle factors. Menopausal status was also assessed, with questions addressing natural, surgical, medication-induced, or other causes of menopause. Follow-up questionnaires were distributed every two years to collect updated information on exposures, new cancer diagnoses, treatments received, and vital status. These follow-ups were conducted by mail or telephone by a research assistant. Self-reported diagnoses of primary invasive ovarian or fallopian tube cancer, collectively referred to as ovarian cancer, were collected. The questionnaires asked specifically about a personal diagnosis of endometriosis (yes/no), including details on the data of diagnosis and treatments received. We also included cases of endometriosis identified incidentally during surgery. Date of diagnosis was based on the participant’s report where available. All BRCA1 and BRCA2 mutation carriers who completed at least one follow-up questionnaire were eligible for inclusion. Participants were excluded if they reported a history of any malignancy other than breast or ovarian cancer (n = 2301). To limit misclassification, women who had undergone bilateral salpingo-oophorectomy (BSO) or hysterectomy prior to an endometriosis diagnosis were also excluded (n = 20). For analyses involving ovarian cancer, self-reported ovarian cancer diagnoses were included only if they occurred after the reported endometriosis diagnosis and in women without a history of prophylactic BSO. Women with missing data on endometriosis status or date of diagnosis were excluded from all analyses (n = 263). After applying these criteria, 16,950 women remained eligible: 402 with self-reported endometriosis and 16,547 without. Descriptive statistics were used to summarize baseline characteristics, comparing BRCA carriers with and without endometriosis. Continuous variables were presented as means and corresponding minimum and maximum values (min–max) and compared using Student’s t -test, while categorical variables were presented as counts and percentages and compared using the χ 2 test. All statistical analyses were conducted using SAS On Demand for Academics (Cary, NC, USA), and statistical significance was set at p ≤ 0.05.

Among the 16,950 BRCA carriers included in the study, 403 (2.4%) had a self-reported diagnosis of endometriosis ( Table 1 ). The mean age at diagnosis of endometriosis was 35.2 years (min–max: 13–72). The mean follow-up time for the cohort was 5.5 years (min–max: 2–26), with a longer average follow-up among women with endometriosis (8.1 years; min–max: 2–24) compared with those without endometriosis (5.5 years; min–max: 2–26). A greater proportion of participants with endometriosis had post-secondary education compared with those without endometriosis (75% vs. 67%). Women with endometriosis reported an earlier age at menarche (mean: 12.7 vs. 13.0 years) and were more likely to be postmenopausal at the time of data collection (85% vs. 72%). Among postmenopausal women, those with endometriosis experienced menopause at a younger age (41.5 vs. 44.3 years), with surgical menopause being more common (69% vs. 55%). Parity also differed significantly, with a higher proportion of women with endometriosis never having given birth (29% vs. 20%). Women with endometriosis were more likely to have a history of oral contraceptive (75% vs. 64%) and HRT use (31% vs. 20%). Rates of hysterectomy and BSO were also higher in women with endometriosis (53% vs. 32% and 68% vs. 45%, respectively). Participants with endometriosis were more likely to carry a BRCA2 mutation compared with those without endometriosis (34% vs. 28%, p = 0.012) ( Table 2 ). The prevalence of ovarian cancer was lower in women with endometriosis (10% vs. 15%, p < 0.01).

In this report of endometriosis in a large cohort of BRCA carriers, we observed a lower prevalence of endometriosis (2.4%) compared to that estimated from women in the general population (~10%) [ 1 , 2 ]. In addition, the prevalence of ovarian cancer was significantly lower in BRCA carriers with endometriosis compared to those without (10% vs. 15%). Although limited by small number of endometriosis cases and self-reported diagnosis, these findings suggest that BRCA carriers with endometriosis are not at an increased risk of ovarian cancer. Despite the large number of BRCA carriers in our study, a very small proportion ever reported a history of endometriosis. Table 3 summarizes the small but growing body of literature that has investigated the prevalence of endometriosis among BRCA mutation carriers, with sample sizes ranging from 37 to 4926 participants [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Reported prevalence among BRCA carriers ranged from 1.6% to 34.2%, with some studies focusing solely on BRCA mutation carriers and others comparing carriers to non-carriers or women with other genetic mutations. Among studies that only analyzed BRCA mutation carriers, endometriosis prevalence was generally low, with rates under 5% in all cohorts [ 24 , 26 ]. While one study reported higher rates of endometriosis in BRCA carriers than in mutation-negative women [ 22 ], others found lower rates among carriers relative to non-carriers [ 20 , 23 ]. Among the case-only studies, which focused on cancer patients, prevalence rates were closer to the documented prevalence of endometriosis in the general population [ 1 ]. Rates ranged from approximately 8% to 10% across studies, with no significant differences between BRCA carriers and non-carriers [ 21 , 25 , 26 ]. Lower prevalence of endometriosis in this population may be explained by the high rates of prophylactic surgeries (BSO, Hysterectomy) among BRCA carriers [ 27 , 28 , 29 , 30 ], which remove the primary sites of endometriotic lesions and reduce the likelihood of a formal endometriosis diagnosis. Another potential factor is diagnostic bias due to cancer-focused medical surveillance [ 27 ], where clinical attention in BRCA carriers is directed toward malignancy risk rather than benign gynecologic conditions. As a result, endometriosis may be underdiagnosed or underreported in this population. Despite this lower prevalence, several well-established risk factors for endometriosis, including earlier menarche [ 31 , 32 , 33 ], lower early adulthood body mass [ 34 , 35 ], and nulliparity [ 33 , 36 ], were observed in our BRCA carrier cohort. These findings suggest that BRCA mutation status does not necessarily alter traditional risk profiles for endometriosis, reinforcing that hormonal and metabolic influences continue to play a role in disease development even within this high-risk genetic population. A particularly notable finding of our study was the lower prevalence of ovarian cancer among BRCA carriers with endometriosis compared to those without (10% vs. 15%, p ≤ 0.001), a contrast to the general population, where endometriosis is associated with an increased risk of ovarian cancer [ 12 , 13 , 14 ]. Our findings are aligned with previous reports on the association between endometriosis and ovarian cancer risk among BRCA mutation carriers. Although limited by sample size, Gersekowski et al. reported a weaker association between endometriosis and ovarian cancer in BRCA mutation carriers compared to non-carriers (IRR = 0.75, 95% CI: 0.54–1.01) [ 25 ]. Similarly, none of the endometriosis patients with a BRCA mutation were found to have cancer in a study conducted by Loizzi et al. [ 26 ], while 81.8% of cancers associated with endometriosis in another study were associated with endometrioid carcinoma over other gynecological malignancies [ 21 ]. These findings may reflect differences in tumor histology [ 12 , 14 , 37 ]. Endometriosis has been most strongly linked to clear cell ovarian cancer [ 12 ], with emerging evidence suggesting a modest association with high-grade serous carcinomas (HGSC) [ 14 ]. In contrast, BRCA -driven ovarian cancers are predominantly HGSC [ 37 ]. Since endometriosis is not strongly linked to HGSC development, its impact on cancer risk may be less pronounced in BRCA carriers. It is also possible that, in BRCA -associated ovarian cancer, endometriosis may represent an incidental rather than causative finding, consistent with emerging histologic distinctions between endometriosis-correlated and endometriosis-incidental ovarian cancer [ 38 ]. Additionally, the low prevalence of ovarian cancer among BRCA carriers with endometriosis could be influenced by early risk-reducing surgeries [ 27 , 28 , 29 , 30 ], including bilateral oophorectomy which would dramatically reduce ovarian cancer risk. Socioeconomic and healthcare access factors may have also influenced the findings. Women with endometriosis in our BRCA cohort were more likely to have post-secondary education, a factor associated with improved access to specialist care and greater engagement in preventive health services [ 39 , 40 , 41 ]. This may have contributed to earlier diagnosis, timely surgical management, and lower observed rates of ovarian cancer in this group. This descriptive analysis offers a real-world perspective on the relationship between germline BRCA mutations and endometriosis, leveraging a large, multicenter, longitudinal cohort. In contrast to previous studies, which were limited by small sample sizes, single-center recruitment, and short follow-up durations, the scale and design of this dataset allowed for a more robust evaluation of endometriosis prevalence and associated risk factors in BRCA carriers. Our study included both BRCA1 and BRCA2 mutation carriers, allowing for mutation-specific comparisons that remain underexplored in the existing literature. To our knowledge, this is the first study to systematically characterize reproductive, hormonal, and surgical factors associated with endometriosis within a large cohort of BRCA mutation carriers, enhancing the generalizability and clinical relevance of our finding. This study had several limitations, notably that self-reported diagnoses may have led to underreporting or misclassification of endometriosis. Women with undiagnosed or asymptomatic disease may have been included in the comparison group, potentially underestimating differences in ovarian cancer prevalence. Although we did not report on the specific histology of the ovarian cancers, it has been well documented that BRCA mutations are associated with the development of serous and endometrioid subtypes [ 37 ]. In addition, ethnicity information was not available for this cohort, which is important to acknowledge as endometriosis prevalence varies by race and ethnicity [ 40 ]. Given the relatively small number of endometriosis cases and ovarian cancer events, the study was not powered to perform multivariable or time-to-event analyses. A descriptive approach was therefore adopted to characterize patterns and generate hypotheses. Future studies with larger samples, clinically confirmed diagnoses, and tumor histology data are needed to better understand the relationship between endometriosis and cancer risk in BRCA mutation carriers. Overall, our findings suggest that BRCA mutations are likely not strongly associated with endometriosis and that endometriosis is unlikely to be a significant risk factor for BRCA -ovarian cancer. While traditional risk factors for endometriosis were still present, the influence of early surgical interventions and surveillance practices may help explain these patterns. To our knowledge, this is the first study to describe endometriosis prevalence and associated risk factors within a large cohort of BRCA mutation carriers. Future studies should prioritize prospective research to clarify these interactions and their clinical implications, particularly how endometriosis may affect ovarian cancer surveillance and reproductive health in women with a BRCA mutation.