Contemporary risk assessment and risk-reducing strategies for tubo-ovarian cancer in women with BRCA pathogenic variants.

For BRCA1/2 pathogenic variant carriers, risk-reducing salpingo-oophorectomy remains the evidence-based preventive standard for tubo-ovarian cancer, but emerging data on risk-reducing salpingectomy with delayed oophorectomy in clinical trials underscore a shift toward individualized, patient-centered care. Further research is required to understand whether integrating genetic, reproductive, and lifestyle factors with evolving surgical and non-surgical strategies may optimize timing, minimize morbidity, and support shared decision-making in hereditary tubo-ovarian cancer prevention.

Consider an illustrative case: A 31-year-old woman presents to a gynecologic oncology clinic for counseling after testing positive for a pathogenic BRCA1 variant. She has a strong family history of breast cancer in her mother and sister but has no family history of tubo-ovarian cancer. The patient has no other personal medical history and has completed childbearing, expressing no desire to preserve fertility. She previously underwent a risk-reducing bilateral mastectomy and is now seeking information about options for tubo-ovarian cancer risk reduction. Her primary concerns include the onset of early menopause and long-term bone health following any risk-reducing surgical interventions. She wishes to make an informed decision. What would you tell her? ( Fig .). Tubo-ovarian cancer remains one of the most lethal gynecologic malignancies worldwide, largely owing to advanced-stage diagnoses and lack of effective screening strategies. 1 Globally, there are approximately 300,000 new cases and about 200,000 deaths from tubo-ovarian cancer annually, rendering the disease the eighth most common cancer in women but the leading cause of death among gynecologic cancers, highlighting its disproportionately high mortality relative to its incidence. 2 The insidious onset, non-specific symptoms, and absence of reliable early detection methods contribute to the fact that more than 70% of patients present with stage III or IV disease at diagnosis. 3 For women with germline BRCA1 or BRCA2 pathogenic variants, the burden is amplified by their markedly elevated lifetime risk of tubo-ovarian cancer (estimated at 34%−46% for BRCA1 and 11%−20% for BRCA2 carriers) underscoring the need for effective risk-reducing strategies. 4 , 5 In this context, tubo-ovarian cancer represents not only a substantial global health challenge but also a deeply personal and familial concern for women with hereditary cancer syndromes. Given the absence of effective screening modalities for tubo-ovarian cancer, women carrying pathogenic BRCA1 and BRCA2 variants face a markedly elevated lifetime risk of tubo-ovarian cancer juxtaposed against the failure of early detection efforts to alter outcomes. In this scenario, primary surgical prevention remains the cornerstone of risk management. 6 – 9 For this group, risk-reducing salpingo-oophorectomy, have been shown to significantly reduce cancer incidence and improve overall survival. 10 However, surgical prevention carries its own risks, including surgical and peri-operative morbidity, premature menopause, infertility, and impact on long-term cardiovascular and bone health. Ongoing research continues to explore alternative and adjunctive approaches, such as risk-reducing salpingectomy with delayed oophorectomy, chemoprevention, lifestyle interventions, and salpingo-oophorectomy age threshold modifications. 11 , 12 Meanwhile, global contemporary guidelines for these patients are not uniform. While most guidelines recommend risk-reducing salpingo-oophorectomy as the standard strategy, applied at broadly similar ages, for carriers of BRCA1/2 pathogenic variants, 13 – 16 their recommendations vary regarding trans-vaginal ultrasound and CA125 surveillance, risk-reducing salpingectomy with delayed oophorectomy, and oral contraceptive use. Unlike the other guidelines, Australian guidelines also explicitly endorse the use of individualized risk calculators to estimate future tubo-ovarian cancer risk. 16 The objective of this narrative review is to present contemporary perspectives and evidence regarding tubo-ovarian cancer risk assessment and risk-reducing strategies for patients with BRCA1/2 pathogenic variants, with a focus on individualized counseling and shared decision-making. The BRCA1 and BRCA2 genes encode large, multi-functional proteins that are essential for preserving genomic stability, primarily by the homologous recombination pathway responsible for repairing DNA double-strand breaks. The loss of BRCA1 or BRCA2 function via pathogenic variants leads to accumulation of DNA damage, chromosomal instability, and ultimately tumorigenesis, underlying a substantially increased risk of breast and tubo-ovarian cancer, among other neoplasias. 17 , 18 The diagnosis of hereditary breast and tubo-ovarian cancer syndrome (also referred to as King syndrome 19 , 20 ) attributable to BRCA1 or BRCA2 is established by the identification of a heterozygous germline pathogenic or likely pathogenic variant in either gene through molecular genetic testing. Although this review focuses on tubo-ovarian cancer prevention, BRCA1/2 pathogenic variants should be understood within the broader context of hereditary cancer predisposition, as they are associated with other neoplasias and have implications for cascade testing in relatives, including men. Current standard diagnostic approaches for BRCA1/2 employ next-generation sequencing-based analyses to detect single-nucleotide variants and small insertions or deletions across the full coding regions and exon–intron boundaries of BRCA1 and BRCA2 . 21 Concurrent testing of both genes is the accepted practice, given their overlapping clinical spectra and implications for management. 22 Where available, multi-gene panel testing may also be used to detect pathogenic variants in other homologous recombination repair genes (eg, PALB2, BRIP1, RAD51C, RAD51D ), which can inform risk assessment and preventive strategies. The current National Comprehensive Cancer Center (NCCN) Genetic/Familial High-Risk Assessment guidelines recommend simultaneous sequencing plus deletion/duplication testing of BRCA1/2 as the standard approach and support the use of multi-gene panels that include other homologous recombination genes when indicated. 13 Clinical surveys of testing laboratories likewise show broad adoption of next-generation sequencing plus copy number analysis approaches. 23 Substantial evidence indicates that tubo-ovarian cancer risk differs significantly between BRCA1 and BRCA2 pathogenic variant carriers. Large cohort analyses show that BRCA1 carriers face a higher lifetime risk (34%−44%) compared to BRCA2 carriers (11%−17%), with BRCA1 -associated cancers diagnosed at a younger median age of 54 years (interquartile range; 43.5–62.5) than BRCA2 at 59.5 years (53.3–64.7). 4 , 5 Emerging data show that the location and type of the pathogenic variant in the BRCA gene may determine the magnitude of cancer risk. In one multi-center observational study 24 spanning 55 centers and 31,481 women with BRCA1 and BRCA2 pathogenic variants, sequencing analyses identified localized cluster regions, and parallel analyses compared mutation classes (frameshift, nonsense, missense, splice; nonsense-mediated decay vs non–nonsense-mediated decay). In BRCA1 , one ovarian cancer cluster region showed a reduced relative hazard ratio (RHR) (0.62, 95% confidence interval [CI] 0.56 to 0.70, p = 9 × 10 − 17 ) that was consistent with increased ovarian cancer risk relative to breast cancer risk. Three breast cancer cluster regions exhibited elevated RHRs, indicating increased breast cancer risk versus ovarian cancer risk at 5′ and 3′ ends including the Really Interesting New Gene (RING) and the BRCA1 C-terminal (BRCT) domains. Several mutation classes (eg, missense in RING, founder c.5266dupC) were associated with higher breast and lower ovarian cancer HRs relative to exon 11 nonsense mutations as a reference, and some classes correlated with modest shifts in age at diagnosis. In BRCA2 , 2 ovarian cancer cluster regions were identified. Even with limitations of small sub-group counts and laboratory method heterogeneity, the pathogenic variant position and class influenced the relative distribution of breast versus ovarian cancer risk. 24 Together, these data underscore the biological and clinical importance of not only differentiating BRCA1 from BRCA2 , but also specific pathogenic variant characteristics when devising risk-reduction strategies to refine risk prediction. These findings support individualized counseling now and suggest that future management may become increasingly pathogenic variant-specific. 25 For breast cancer, risk among BRCA1/2 pathogenic variant carriers increases with the burden of affected relatives. In a prospective cohort including 9856 BRCA1/2 carriers, 4 women with ≥2 first- or second-degree relatives with breast cancer had significantly higher risk of breast cancer than those without family history: for BRCA1 , the cumulative risk was 73% (95% CI 65% to 80%) versus 53% (95% CI 39% to 69%) by age 70 years, and for BRCA2 , the cumulative risk was 65% (95% CI 56% to 74%) versus 39% (95% CI 25% to 56%) ( p <.001). These findings were supported by a study in 2025, which included 67,692 women with pathogenic variants in 7 genes (including BRCA1/2 ). For BRCA1 pathogenic variants, the cumulative risk of breast cancer by age 50 years was 23.3% (95% CI 16.9% to 31.2%) with first-degree family history versus 15.5% (95% CI 11.0% to 22.6%) with no family history, and for BRCA2 pathogenic variants, the risk was 27.3% (95% CI 20.5% to 37.7%) with first-degree family history versus 11.6% (95% CI 9.3% to 14.8%) with no family history. 25 In contrast, evidence for modification of ovarian cancer risk by family history is mixed. In the prospective cohort described above including 9856 carriers, 4 a family history of ovarian cancer did not significantly increase the risk of this cancer for BRCA1 (HR 1.37, 95% CI 0.89 to 2.11; p = .16) or for BRCA2 carriers (HR 1.09, 95% CI 0.37 to 3.25; p = .87) compared with no family history. Similar findings were reported in a nationwide prospective cohort from the Netherlands, 26 which included 3310 female carriers of BRCA1/2 pathogenic variants. After adjustment for pathogenic variant position, ovarian cancer risk in this population was not significantly associated with a family history of breast cancer in BRCA1 (HR 0.85, 95% CI 0.55 to 1.30) or BRCA2 carriers (HR 0.64, 95% CI 0.34 to 1.21) or with a family history of ovarian cancer in BRCA1 carriers (HR 1.46, 95% CI 0.80 to 2.68) or BRCA2 carriers (HR 1.49, 95% CI 0.44 to 4.02). In contrast, in an earlier multi-center cohort study 27 including 3011 BRCA1/2 carriers, each additional first- or second-degree relative with ovarian cancer was associated with higher ovarian cancer risk among BRCA1 carriers (HR 1.61, 95% CI 1.21 to 2.14, p = .001). Together, these findings suggest that, unlike in breast cancer, the modifying effect of family history on ovarian cancer risk is not consistent and may depend on study population, analytic approach, or other factors. Several reproductive and hormonal factors, especially parity, breastfeeding, and use of oral contraceptives, could modify tubo-ovarian cancer risk among BRCA1/2 pathogenic variant carriers and should be considered during individualized counseling, as they provide context for personalized risk estimates. In an observational study including 1018 BRCA carriers 28 ( BRCA1 : n = 515, BRCA2 : n = 503), ever having a live birth was associated with lower ovarian cancer risk among BRCA1 carriers (HR 0.41, 95% CI 0.18 to 0.94, p =.03), and each additional live birth was associated with a reduction in overall cancer risk (per birth HR 0.87, 95% CI 0.77 to 0.98, p =.02), with this inverse association most evident at age ≥40 years. Evidence for the effect of parity on ovarian cancer risk in BRCA2 carriers was inconclusive due to limited events. This inverse association was also observed in a case–control analysis 29 (1329 cases and 5267 controls) that modeled lifetime ovulatory cycles and reported an inverse trend with parity in BRCA1 carriers (per birth odds ratio [OR] 0.87, 95% CI 0.79 to 0.96, p =.005), but not in BRCA2 carriers (OR 0.98, 95% CI 0.81 to 1.19, p =.85). Additionally, later age at menopause was associated with higher ovarian cancer risk in BRCA1 carriers (per category OR 1.18, 95% CI 1.03 to 1.35, p =.02), consistent with an ovulation-related mechanism. Breastfeeding has also been associated with reduced ovarian cancer risk in BRCA1/2 pathogenic variant carriers, likely related to periods of suppressed ovulation. In a matched case–control study 30 of 1650 cases and 2702 controls with BRCA1/2 pathogenic variants, ever breastfeeding was associated with a 23% lower ovarian cancer risk (OR 0.77, 95% CI 0.66 to 0.90, p =.001). Joint exposure to breastfeeding plus oral contraceptive use yielded a stronger association (OR 0.47, 95% CI 0.37 to 0.58). Finally, oral contraceptives also influence tubo-ovarian cancer risk in BRCA1/2 pathogenic variant carriers. A meta-analysis 31 of 18 studies including 2855 breast and 1503 ovarian cancer cases among BRCA1/2 carriers found that ever oral contraceptive use was associated with a statistically significant reduction in ovarian cancer risk (relative risk [RR] 0.50, 95% CI 0.33 to 0.75). Risk declined further with longer duration (an additional 36% reduction per 10 years of use [RR 0.64, 95% CI 0.53 to 0.78, p <.01]). Breast cancer risk was not significantly associated with oral contraceptive use overall (RR 1.13, 95% CI 0.88 to 1.45), as a significant increase in risk was limited to pre-1975 formulations (RR 1.47, 95% CI 1.06 to 2.04) and no significant association was seen for more recent formulations (RR 1.17, 95% CI 0.74 to 1.86). A subsequent systematic review and meta-analysis 32 of high-risk women (with BRCA1/2 pathogenic variants or a strong family history) similarly reported an inverse association between oral contraceptive use and ovarian cancer (OR 0.58, 95% CI 0.46 to 0.73) and no statistically significant increase in breast cancer (OR 1.21, 95% CI 0.93 to 1.58). Due to insufficient data, a meta-analysis of the duration or timing of use among carriers could not be performed. Altogether, these findings suggest that, in BRCA pathogenic variant carriers, oral contraceptives may confer meaningful tubo-ovarian cancer risk reduction, with no increase in breast cancer risk for modern formulations. Emerging clinical tools operationalize individualized tubo-ovarian cancer estimates by combining genotype, pedigree, and epidemiologic factors. The CanRisk platform, which implements the BOADICEA 33 risk prediction model, provides personalized estimates of an individual’s future ovarian and breast cancer risk by considering multiple factors, including genetics, family history, and lifestyle. It combines (1) pathogenic variants ( BRCA1/2 and additional susceptibility genes), (2) detailed pedigree structure and ages, (3) tumor pathology where relevant, (4) epidemiologic/lifestyle modifiers, and (5) optional polygenic risk scores. Recent BOADICEA updates incorporated refined penetrance for RAD51C/RAD51D and BARD1 , enabling more accurate, gene-specific risk estimates alongside BRCA1/2 and updated incidence inputs. For ovarian risk specifically, the BOADICEA/CanRisk 34 ovarian model integrates multiple validated epidemiological factors (parity, oral contraceptive and menopausal hormone use, endometriosis, tubal ligation, body mass index, and height) together with high-risk variants and a common-variant polygenic risk scores, allowing recalibration of lifetime risk around a carrier’s baseline penetrance. While this model may support moving beyond a “one-size-fits-all” penetrance estimate and toward the development of individualized risk projections, no prospective evidence supports the use of BOADICEA-based risk estimates to de-escalate surgery or to safely modify the recommended timing of risk-reducing salpingo-oophorectomy in BRCA1/2 pathogenic variant carriers. Although this strategy has been integrated into Australian guidelines, 16 it has not been recognized or recommended in other guideline frameworks ( Table 1 ). Thus, although multi-factorial risk models are promising and align with a more individualized prevention framework, they should not yet be viewed as a substitute for evidence-based standard recommendations. Prior to March 2023, the NCCN recommended trans-vaginal ultrasonography and serum CA125 screening for high-risk women who elected not to undergo risk-reducing salpingo-oophorectomy at the recommended age. Per the NCCN, trans-vaginal ultrasonography and CA125 could be obtained every 6 to 12 months at the physician’s discretion, with abnormal results triggering further investigation. However, emerging studies have challenged the paradigm of ultrasonography and CA125 in this population. In the United Kingdom Collaborative Trial of Ovarian Cancer Screening and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, 7 2 screening strategies were assessed: (1) multi-modal screening using a longitudinal CA125 algorithm with repeat CA125 testing and trans-vaginal ultrasonography as a second-line test and (2) ultrasound screening using trans-vaginal ultrasonography alone with repeat scanning to confirm any abnormality. Neither strategy conferred significant benefits in terms of mortality reduction, although early-stage detection was higher in the multi-modal screening group. However, in the multi-modal screening group, for each screen-detected ovarian or tubal cancer, an additional 2.3 women had unnecessary surgery, defined by the identification of benign adnexal pathology or normal adnexa (ie, 489 false positives and 212 cancers). Although these findings based on studies conducted in the general population are not directly generalizable to BRCA1/2 pathogenic variant carriers or to all health care settings globally, studies conducted specifically in BRCA1/2 carriers have likewise failed to demonstrate a meaningful benefit in stage shift or clinical outcomes. In a multi-center observational study, 9 883 women with BRCA1/2 pathogenic variants (683 BRCA1 and 200 BRCA2 ) underwent annual trans-vaginal ultrasonography and CA125 screening across 6 centers. Ten incident cancers were identified, and of these, 5 were diagnosed in women who had a normal screening result within 3 to 10 months before diagnosis. There was no difference in stage distribution between incident screen-detected and interval tumors, with 8 of the 10 (80%) incident cancers diagnosed at stage III or IV. In another study, 4348 women with estimated lifetime ovarian cancer risk >10% underwent screening using the risk of ovarian cancer algorithm every 4 months. In total, 19 invasive ovarian cancer cases were diagnosed within 1 year of screening, with 13 screen-detected and 6 occult cancers found by risk-reducing salpingo-oophorectomy. However, only 5 (38.5%) of the 13 screen-detected cancers were stage I or II. The overall positive predictive value of the risk of ovarian cancer algorithm was low, at 10.8% (95% CI 6.5% to 16.5%), raising questions about the utility of this screening model in this population. 35 A possible explanation when comparing with general population randomized trial, is the more aggressive biology and shorter preclinical phase of BRCA -associated high-grade serous cancers, together with the limited sensitivity of trans-vaginal ultrasonography and CA125 and the occurrence of interval cancers. Alternative screening strategies may include liquid biopsy, which aims to detect tumor cells, DNA, and/or extracellular vesicles in peripheral circulation. 36 This method is minimally-invasive and allows repeated sampling that could be used for both early detection and long-term monitoring of ovarian cancer. However, early-stage tumors shed little DNA, and background circulating free DNA/clonal hematopoiesis introduces false positives, demanding ultra-sensitive, well-controlled assays. 37 – 39 Implementation of these strategies is limited by assay standardization, the need for extremely high specificity to avoid harm from false positives, cost-effectiveness, and a lack of prospective mortality data; thus, routine use of this screening remains unjustified. Bilateral salpingo-oophorectomy is the current standard for surgical risk reduction in BRCA1/2 pathogenic variant carriers. In a systematic review and meta-analysis 10 of observational cohorts in BRCA1/2 carriers, risk-reducing salpingo-oophorectomy was associated with improved overall survival (HR 0.32, 95% CI 0.19 to 0.54, p <.001), high-grade serous cancer-related mortality (HR 0.06, 95% CI 0.02 to 0.17, p <.0001), and breast cancer mortality (HR 0.58, 95% CI 0.39 to 0.88; p =.009) compared with no surgery. Overall survival benefit was evident for both BRCA1 carriers (HR 0.30, 95% CI 0.17 to 0.52; p <.001) and BRCA2 carriers (HR 0.44, 95% CI 0.23 to 0.85; p =.01). Of note, none of the studies included in the systematic review reported adverse events as an outcome. A more recent cohort study reaffirmed these results, including 4332 BRCA1/2 pathogenic variant carriers without prior cancer who were followed for a mean of 9 years. Overall, risk-reducing surgery (undertaken by 67.8% of women at a mean age of 45.4 years) was associated with a 68% reduction in all-cause mortality (HR 0.32, 95% CI 0.24 to 0.42), and these benefits were similar between BRCA1 carriers (HR 0.28, 95% CI 0.20–0.38) and BRCA2 carriers (HR 0.43, 95% CI 0.22 to 0.90). The surgery was also associated with significant reductions in deaths from ovarian, fallopian tube, or peritoneal cancer (HR 0.19, 95% CI 0.12 to 0.33) and from breast cancer (HR 0.44, 95% CI 0.25 to 0.78). 40 In a systematic review including 10 observational studies, only 1 study reported quality of life after risk-reducing salpingo-oopho-rectomy. 10 That study, assessed the overall quality of life using the single quality of life item of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, and showed that women with risk-reducing salpingo-oophorectomy had worse general health perception than those without it (mean difference [MD] [standard deviation]: 70.9 [20.5] vs 82.0 [13.3], p <.0001) but there were no differences in global health status (76.0 [20.6] vs 79.8 [17.9], p = 0.26) or mental health quality of life (70.2 [16.6] vs 73.1 [14.5], p =.28). Risk-reducing surgery was associated with better cancer risk-perception quality of life for ovarian cancer (MD 15.40, 95% CI 8.76 to 22.04, p <.0001) and breast cancer (MD 8.20, 95% CI 0.85 to 15.55, p =.03). In contrast, surgery can increase vasomotor symptoms. In a prospective cohort study including premenopausal women who underwent risk-reducing bilateral salpingo-oophorectomy and 102 age-matched premenopausal controls, in the surgery group the prevalence of vasomotor symptoms increased from 6% to 59% and night sweats from 21% to 39% from baseline to 24 months. 41 Compared with controls, the surgery group had a 1.14-point higher vasomotor domain score on the Menopause-Specific Quality of Life questionnaire from baseline to 24 months (95% CI 0.71 to 1.57, p <.001), indicating a statistically significant worsening; the point estimate also exceeded the study-defined threshold for clinical relevance. This difference is notable given that 61% of the surgery group started hormonal replacement therapy after surgery, most (79%) within 3 months. Similarly, overall menopause-related quality of life worsened between baseline and 3 months in the risk-reducing surgery group but remained stable in the comparison group up to 24 months. Sexual function is a key quality-of-life outcome after surgical menopause, reflecting both physiological and psychosocial factors. In a prospective cohort there was no difference between risk-reducing salpingo-oophorectomy and no-surgery groups in 12-month change in Female Sexual Function Index desire and satisfaction scores. 41 However, women undergoing risk-reducing salpingo-oophorectomy who did not use hormone replacement therapy ( n = 32) showed significant worsening in Female Sexual Function Index arousal (−2.53, 95% CI −4.86 to −0.19), lubrication (−3.40, 95% CI −5.85 to −0.96), orgasm (−1.64, 95% CI −3.23 to −0.06), and pain (−2.70, 95% CI −4.59 to −0.82) compared with the no-surgery group. Likewise, a cross-sectional study 42 of 846 high-risk women (44% who had prophylactic bilateral salpingo-oophorectomy, 56% who underwent screening only) found no difference in generic quality of life, but those who had bilateral oophorectomy reported fewer cancer worries ( p <.001), a more favorable risk perception ( p <.05), more endocrine symptoms ( p <.001) and worse sexual functioning ( p <.05); 47% were using hormone replacement therapy. Overall, these data underscore the need to balance mortality gains from cancer risk reduction against potential long-term endocrine and sexual adverse effects. A separate prospective cohort study evaluated depressive and anxiety symptoms following premenopausal risk-reducing salpingo-oophorectomy. At baseline, the prevalence of women with depression symptoms (Center for Epidemiologic Studies Depression scale score ≥16) was 10% in the salpingo-oophorectomy group (6/59) versus 12% in the comparison group (11/91), and anxiety symptoms (Generalized Anxiety Disorder-7 scale score ≥10) were 5% for the salpingo-oophorectomy group (3/59) versus 10% in the comparison group (9/91). After surgery, the proportion of women with clinically significant depressive symptoms more than doubled to 24% but did not notably change in the comparison group (14%). However, by 24 months, depressive symptoms in the surgery group had largely resolved to previous levels (15%) and were similar to those the comparison group (14%). 43 These reports are limited by the selection of the comparison group, which included women without pathogenic variants and without a similar surgical intervention, which could bias the assessments. These outcomes highlight the divergent quality-of-life outcomes regarding cancer-related worry and risk perception versus worsened vasomotor, sexual, and mood outcomes. Premenopausal women who consider or undergo risk-reducing salpingo-oophorectomy need balanced counseling and routine consideration of hormone replacement therapy if not contraindicated. In a cross-sectional study, 493 women at high risk of ovarian cancer who underwent premenopausal risk-reducing salpingo-oophorectomy (≤45 years) were compared with 228 women who underwent post-menopausal risk-reducing salpingo-oophorectomy (≥54 years). 44 Bone mineral density was assessed by dual-energy x-ray absorptiometry of the lumbar spine and femoral neck. Age differences between pre- and post-menopausal groups were accounted for using Z-scores. In multi-variable regression analyses, the bone mineral density Z-scores of the lumbar spine and femoral neck were significantly lower for the premenopausal compared with the post-menopausal group (β regression coefficient −0.88, 95% CI −1.10 to −0.66 for lumbar spine; β −0.51, 95% CI −0.71 to −0.31 for femoral neck), and the relative risks of having a Z-score ≤ −1.0 were also higher in the premenopausal compared with the post-menopausal group (RR 2.35, 95% CI 1.26 to 4.40 and RR 1.84, 95% CI 1.08 to 3.13, respectively). This study highlights that risk-reducing salpingo-oophorectomy at a premenopausal age is associated with significantly lower bone mineral density, emphasizing the importance of bone health monitoring and preventive strategies in women undergoing early oophorectomy. Emerging research has explored the possibility of bilateral risk-reducing salpingectomy with delayed oophorectomy as a potentially effective strategy for tubo-ovarian cancer risk reduction with an improved treatment-related morbidity profile. The fallopian tube origin hypothesis provides a scientific rationale for this approach. In the early 2000s, pathologic specimens from BRCA1 pathogenic variant carriers undergoing salpingo-oophorectomy showed serous tubal intra-epithelial carcinoma lesions in the fimbriated edges. 45 These lesions, which were characterized by significant cellular atypia, architectural alterations, and abnormal staining patterns of p53, share many pathologic and genomic features with high-grade serous ovarian cancers and may be precursors to malignancy. 46 BRCA1/2 carriers have higher than expected fallopian tube specimens with serous tubal intra-epithelial carcinoma lesions following risk-reducing salpingo-oophorectomy. 47 Subsequent longitudinal studies demonstrated that women who underwent bilateral salpingectomy had a reduction in tubo-ovarian cancer risk compared with those who had no surgery. In a population-based study, women with previous sterilization or salpingectomy had a statistically significant reduction of ovarian cancer risk (HR 0.72, 95% CI 0.64 to 0.81 for sterilization; HR 0.65, 95% CI 0.52 to 0.81 for salpingectomy). 48 Consequently, in 2013 the Society of Gynecologic Oncology recognized that for women at population risk (average) for ovarian cancer, salpingectomy should be considered (after completion of childbearing) at the time of hysterectomy, instead of tubal ligation, and also at the time of other pelvic surgery 49 ; a few years later, the American College of Obstetricians and Gynecologists followed suit. 50 The use of salpingectomy with delayed oophorectomy may improve uptake of risk-reducing surgery. Multiple studies have linked concerns about menopause with delays in surgical risk reduction via bilateral salpingo-oophorectomy for BRCA1/2 pathogenic variant carriers. In one study of 6223 women with BRCA1/2 pathogenic variants from 10 countries over 2 10-year time periods (before and after 2009), there was little increase between time periods in the rates of risk-reducing salpingo-oophorectomy, despite a significant increase in the uptake of bilateral prophylactic mastectomy. 51 Other studies have corroborated these data, pointing to concerns among women, especially those in their 30s, about the physical and psychological effects of menopause. 52 However, more recently, patient interest in risk-reducing salpingectomy with delayed oophorectomy is growing; a systematic review in 2023 showed acceptance rates ranging from 34% to 71%. 53 While risk-reducing salpingectomy with delayed oophorectomy is an appealing strategy, research has yet to prospectively compare its survival outcomes with the standard, bilateral risk-reducing salpingo-oophorectomy. There are many potential concerns, including its primary outcome of effect on tubo-ovarian cancer incidence, the morbidity of 2 different surgeries, the potential for poor compliance with subsequent delayed oophorectomy, and unknown effects on quality of life, menopausal symptoms, and cancer-related distress. Currently, the option to pursue risk-reducing salpingectomy in patients with BRCA1/2 pathogenic variants with delayed oophorectomy should be offered only in a clinical trial setting whenever possible. Ongoing clinical trials for this option and available data are presented in Table 2 . Each trial varies in design, eligibility criteria, and outcome. Some are designed to assess the non-inferiority of risk-reducing salpingectomy with delayed oophorectomy compared with the standard of care in reducing the incidence of tubo-ovarian cancer as a primary outcome (SOROCk and TUBA-WISP 54 ). Others are designed to assess menopausal symptoms and quality of life (PROTECTOR, 55 TUBA, 54 WISP 56 ). All trials began in the last 5 to 10 years, and most are continuing to accrue patients. The TUBA trial assessed menopause-related symptoms using the Greene Climacteric Scale 54 in 394 patients who underwent risk-reducing salpingectomy and 154 who underwent salpingo-oophorectomy, with and without hormone replacement therapy. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the scale was 6.7 points (95% CI 5.0 to 8.4, p <.001) for salpingo-oophorectomy compared with salpingectomy during the first year after surgery. With hormone replacement therapy, the increase on the scale with oophorectomy was 3.6 points (95% CI 2.3 to 4.8, p <.001). The WISP trial compared these surgical approaches with a focus on sexual function and other quality-of-life measures. Preliminary results from the WISP trial showed that women in both arms had a significant decrease in distress at 6 months post-surgery, and the women who underwent salpingo-oophorectomy experienced a greater decrease compared with the salpingectomy arm ( p <.0006). Compared with the women who had salpingectomy with delayed oophorectomy, those who underwent salpingo-oophorectomy had significant worsening of menopausal symptoms, including hot flashes, night sweats, vaginal dryness, and weight gain after surgery. However, decision regret was higher in women who underwent salpingo-oophorectomy compared with salpingectomy with delayed oophorectomy, regardless of use of hormone replacement therapy. 56 Hormone replacement therapy in those undergoing oophorectomy reduced changes in sexual function but did not provide complete relief, with patients still experiencing more burdensome symptoms in the oophorectomy group (at 12-month follow-up, 34% vs 20% reported sexual function decline; RR 1.7, 95% CI 1.0 to 2.7, p =.0062). 57 Finally, in a 2-arm prospective study, 12 quality of life after surgery was compared between salpingectomy with delayed oophorectomy versus salpingo-oophorectomy in premenopausal BRCA1/2 carriers. Treatment allocation was based on patients’ preference for either risk-reducing salpingectomy from the age of 25 years with delayed oophorectomy at the maximum age of 45 years ( BRCA1 ) or 50 years ( BRCA2 ), or risk-reducing salpingo-oophorectomy at age 35 to 40 years ( BRCA1 ) or 40 to 45 ( BRCA2 ). After oophorectomy, hormone replacement therapy was recommended if not contraindicated. In total, 410 participants underwent salpingectomy and 160 underwent salpingo-oophorectomy. The BRCA1/BRCA2 proportions were 51.4%/48.6%. The mean age at surgery was 37.9 years (standard deviation 3.5). Three years after surgery, patients who underwent salpingo-oophorectomy without hormone replacement therapy had a 4.3-point (95% CI 2.1 to 6.5, p <.001) higher increase in Greene Climacteric Scale score from baseline compared with the salpingectomy group, while the difference was 7.9 points (95% CI 5.9 to 9.8) and 8.5 points (95% CI 6.5 to 10.5) at 3 and 12 months, respectively. However, participants who received hormone replacement therapy after salpingo-oophorectomy had a 2.4-point (95% CI 0.8 to 3.9, p =.002) higher increase on the scale at 3 years from baseline compared with the salpingectomy group. Given the nature of genetic risk in this population, oncologic outcomes are not yet available and will take years to emerge. Moreover, as no randomized designs are feasible due to patient preferences, residual biases remain across all studies. The risk of endometrial cancer in women with germline BRCA1/2 pathogenic variants remain uncertain, and the value of concurrent hysterectomy at salpingo-oophorectomy is debated, and international guideline recommendations are not uniform, reflecting this uncertainty. In a multi-center cohort 58 of 1083 BRCA1/2 carriers (627 BRCA1 , 453 BRCA2 , and 3 both) who underwent risk-reducing salpingo-oophorectomy without hysterectomy (median age 45.6 years, interquartile range; 40.9–52.5), the overall endometrial cancer risk was not increased compared with Surveillance, Epidemiology, and End Results data (observed to expected ratio, OR 1.9, 95% CI 0.8 to 3.7, p =.09). However, within that cohort, serous/serous-like endometrial carcinoma was elevated among BRCA1 carriers (observed to expected ratio, 22.2, 95% CI 6.1 to 56.9, p <.001), suggesting a sub-type-specific difference. Four of 5 serous/serous-like carcinomas occurred in women with prior breast cancer, of whom 3 used tamoxifen, an additional risk factor for endometrial cancer. In BRCA1/2 carriers without prior breast cancer, menopausal hormone therapy is often considered after risk-reducing salpingo-oophorectomy and (based on observational data) does not appear to negate the breast cancer risk reduction conferred by surgery. 59 For women with an intact uterus, estrogen must be paired with a progestogen to prevent endometrial hyperplasia/cancer because unopposed estrogen increases endometrial cancer risk; in contrast, after hysterectomy, estrogen-only therapy is possible 60 and, as an advantage, would not impact breast cancer risk. 61 Therefore, the decision to perform hysterectomy at the time of risk-reducing salpingo-oophorectomy should be individualized according to the patient’s mutation status, prior tamoxifen exposure, menopausal hormone therapy considerations, and personal preferences within a shared decision-making process. Returning to the clinical case, this 31-year-old woman with a pathogenic BRCA1 variant should be counseled that risk-reducing salpingo-oophorectomy remains the standard preventive strategy and is generally recommended between ages 35 and 40 years, after completion of childbearing. Because her principal concerns are early menopause and bone health, counseling should address the expected menopausal symptoms, and the sexual and bone health consequences of premenopausal oophorectomy, and the role of menopausal hormone therapy when not contraindicated. In this context, the potential role of concurrent hysterectomy should also be discussed, as it may allow the use of estrogen-only menopausal hormone therapy. She should also be informed that current screening strategies have not been shown to reduce mortality and that, if she strongly wishes to avoid early menopause, risk-reducing salpingectomy with delayed oophorectomy may be discussed as an investigational option, preferably only within a clinical trial. In accordance with the journal’s guidelines, we will provide our data for independent analysis by a selected team by the Editorial Team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.