Acceptability of prophylactic salpingectomy with delayed oophorectomy as risk-reducing surgery among BRCA mutation carriers

Melatonin alleviates mitochondrial damage by regulating SIRT3-mediated mitochondrial dynamics in granulosa cells under PCOS-like conditions

Xie C et al., 2026 · Molecular Medicine Reports · Free full text on PubMed Central

The present study investigated the role of melatonin (MT) in regulating mitochondrial function via sirtuin 3 (SIRT3) in granulosa cells (GCs) from patients with polycystic ovary syndrome (PCOS), with a focus on mitochondrial protection. Notably, GCs isolated from patients with PCOS exhibited mitochondrial dysfunction. Using an in vitro PCOS model established by treating KGN cells with dihydrotestosterone (DHT), decreased SIRT3 expression, dysregulated mitochondrial dynamics and hyperactivation of mitophagy were observed. Both SIRT3 overexpression and MT treatment restored the mitochondrial membrane potential, rebalanced mitochondrial dynamics and suppressed excessive autophagy in DHT-treated cells. Additionally, MT levels were shown to be reduced in the follicular fluid of patients with PCOS. Notably, the protective effects of MT on proteins associated with both mitochondrial dynamics and autophagy were abolished upon SIRT3 inhibition. In conclusion, mitochondrial dysfunction and aberrant mitophagy in GCs may serve a role in the pathogenesis of PCOS. MT appears to ameliorate these defects by modulating mitochondrial dynamics and function in a SIRT3-dependent manner. Moreover, the current study identified SIRT3 as a key molecular target of MT in PCOS.

Lipid metabolism drives dietary effects on T cell ferroptosis and immunity

Wang N et al., 2026 · Nature

Contraceptives and cancer risks in BRCA1/2 pathogenic variant carriers: a systematic review and meta-analysis

van Bommel MHD et al., 2022 · Hum Reprod Update · Free full text on PubMed Central

Increasing numbers of BReast CAncer (BRCA) 1 or 2 pathogenic variant (PV) carriers, who have an inherited predisposition to breast and ovarian cancer, are being identified. Among these women, data regarding the effects of contraception on cancer risks are unclear and various guidelines provide various recommendations. We aim to optimize counselling regarding contraception for BRCA1/2-PV carriers. Therefore, we performed a systematic review and meta-analysis. We investigated the risk ratio for developing breast cancer or ovarian cancer in BRCA1/2-PV carriers who have used any form of contraception versus non-users. Second, we analysed breast and ovarian cancer risk among BRCA1/2-PV carriers as influenced by the duration of contraceptive use and by the time since last use. In addition, we provide an overview of all relevant international guidelines regarding contraceptive use for BRCA1/2-PV carriers. A systematic search in the Medline database and Cochrane library identified studies describing breast and/or ovarian cancer risk in BRCA1/2-PV carriers as modified by contraception until June 2021. The search included medical subject headings, keywords and synonyms related to BRCA and contraceptives (any kind). PRISMA guidance was followed. Risk Of Bias In Non-randomized Studies of Interventions and Grading of Recommendations, Assessment, Development and Evaluations assessments were performed. Random-effects meta-analyses were used to estimate pooled effects for breast and ovarian cancer risk separately. Subgroup analyses were conducted for BRCA1 versus BRCA2 and for the various contraceptive methods. Outcomes: Results of the breast cancer risk with oral contraceptive pill (OCP) analysis depended on the outcome measure. Meta-analyses of seven studies with 7525 women revealed a hazard ratio (HR) of 1.55 (95% CI: 1.36-1.76) and of four studies including 9106 women resulted in an odds ratio (OR) of 1.06 (95% CI: 0.90-1.25), heterogeneity (I2) 0% and 52%, respectively. Breast cancer risk was still increased in ever-users compared with never-users >10 years after last OCP use. In contrast, ovarian cancer risk was decreased among OCP users: HR 0.62 (95% CI: 0.52-0.74) based on two studies including 10 981 women (I2: 0%), and OR 0.49 (95% CI: 0.38-0.63) based on eight studies including 10 390 women (I2: 64%). The protective effect vanished after cessation of use. Tubal ligation also protects against ovarian cancer: one study including 3319 women (I2: 0%): HR: 0.44 (95% CI: 0.26-0.74) and three studies with 7691 women (I2: 44%): OR: 0.74 (95% CI: 0.53-1.03). Data regarding other contraceptives were unavailable. No differences were observed between BRCA1 and BRCA2-PV carriers. The quality of evidence was either low or very low. The OCP potentially increases breast cancer risk, while ovarian cancer risk decreases with either the OCP and tubal ligation in BRCA1/2-PV carriers. Counselling of BRCA1/2-PV carriers should be personalized; the genetic and non-genetic factors (like prior risk-reducing surgeries, prior breast cancer and age) and patients' preferences (reversibility, ease of use, reliability and effect on menstrual cycle) should be balanced. To further optimize counselling for high-risk women, future research should focus on other (commonly used) contraceptive methods and cancer risks in this specific population, and on the potential impact of changing formulations over time.

Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers

Kuchenbaecker KB et al., 2017 · JAMA

The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. DESIGN, SETTING, Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. BRCA1/2 mutations, family cancer history, and mutation location. Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

Oral contraceptives and risk of ovarian cancer and breast cancer among high-risk women: a systematic review and meta-analysis

Moorman PG et al., 2013 · J Clin Oncol

To estimate the risks of ovarian cancer and breast cancer associated with oral contraceptive (OC) use among women at elevated risk owing to mutations in BRCA1/2 or a strong family history. We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published 2000 to 2012 that evaluated associations between OC use and breast or ovarian cancer among women who are carriers of a BRCA1/2 mutation or have a family history of breast or ovarian cancer. From 6,476 unique citations, we identified six studies examining ovarian cancer risk in BRCA1/2 mutation carriers and eight studies examining breast cancer risk in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers combined, meta-analysis showed an inverse association between OC use and ovarian cancer (odds ratio [OR], 0.58; 95% CI, 0.46 to 0.73) and a nonstatistically significant association with breast cancer (OR, 1.21; 95% CI, 0.93 to 1.58). Findings were similar when examining BRCA1 and BRCA2 mutation carriers separately. Data were inadequate to perform meta-analyses examining duration or timing of use. For women with a family history of ovarian or breast cancer, we identified four studies examining risk for ovarian cancer and three for breast cancer, but differences between studies precluded combining the data for meta-analyses, and no overall pattern could be discerned. Our analyses suggest that associations between ever use of OCs and ovarian and breast cancer among women who are BRCA1 or BRCA2 mutation carriers are similar to those reported for the general population.

Uptake and Predictors of Opportunistic Salpingectomy for Ovarian Cancer Risk Reduction in the United States

Karia PS et al., 2021 · Cancer prevention research (Philadelphia, Pa.) · Free full text on PubMed Central

Evidence suggesting that high-grade serous ovarian cancers originate in the fallopian tubes has led to the emergence of opportunistic salpingectomy (OS) as an approach to reduce ovarian-cancer risk. In the U.S., some national societies now recommend OS in place of tubal ligation for sterilization or during a benign hysterectomy in average-risk women. However, limited data exist on the dissemination of OS in clinical practice. We examined the uptake and predictors of OS in a nationwide sample of inpatient and outpatient claims (N = 48,231,235) from 2010 to 2017. Incidence rates of OS were calculated, and an interrupted time-series analysis was used to quantify changes in rates before (2010-2013) and after (2015-2017) national guideline release. Predictors of OS use were examined using Poisson regression. From 2010 to 2017, the age-adjusted incidence rate of OS for sterilization and OS during hysterectomy increased 17.8-fold [95% confidence interval (CI), 16.2-19.5] and 7.6-fold (95% CI, 5.5-10.4), respectively. The rapid increase (age-adjusted increase in quarterly rates of between 109% and 250%) coincided with the time of national guideline release. In multivariable-adjusted analyses, OS use was more common in young women and varied significantly by geographic region, rurality, family history/genetic susceptibility, surgical indication, inpatient/outpatient setting, and underlying comorbidities. Similar differences in OS uptake were noted in analyses limited to women with a family history/genetic susceptibility to breast/ovarian cancer. Our results highlight significant differences in OS uptake in both high- and average-risk women. Defining subsets of women who would benefit most from OS and identifying barriers to equitable OS uptake is needed. Opportunistic salpingectomy for ovarian-cancer risk reduction has been rapidly adopted in the U.S., with significant variation in uptake by demographic and clinical factors. Studies examining barriers to opportunistic salpingectomy access and the long-term effectiveness and potential adverse effects of opportunistic salpingectomy are needed.