Highlight
– Risk-reducing early salpingectomy (RRES) with delayed oophorectomy (DO) is a novel two-stage prevention strategy that potentially avoids premature menopause compared to risk-reducing salpingo-oophorectomy (RRSO).
– Using the estimand framework, the UK PROTECTOR study proposes evaluating clinical effectiveness primarily through the proportion of ovarian cancers prevented after RRES.
– Sample size estimations indicate that enrolling approximately 1150 women undergoing RRES with 8 to 10 years follow-up provides adequate power to demonstrate clinical benefit versus no surgery and noninferiority to RRSO.
– The study emphasizes the practicality of using expected risk at baseline and superiority/noninferiority testing to interpret findings across cohorts more cohesively.
Study Background and Disease Burden
Ovarian cancer (OC) remains a significant clinical challenge due to late diagnosis and poor prognosis. Women carrying germline pathogenic variants in BRCA1 or BRCA2 genes face a substantially elevated lifetime risk of developing OC, with BRCA1 carriers at approximately 40-60% risk and BRCA2 carriers at 15-30% risk. The standard preventive surgery has been risk-reducing salpingo-oophorectomy (RRSO), where both fallopian tubes and ovaries are removed, effectively reducing OC risk but often inducing premature menopause with associated morbidity such as cardiovascular disease, osteoporosis, and decreased quality of life.
Risk-reducing early salpingectomy (RRES) combined with delayed oophorectomy (DO) has emerged as a two-stage surgical alternative aimed at mitigating these negative consequences by initially removing fallopian tubes (where many high-grade serous OCs originate) and preserving the ovaries until a later time point. However, data quantifying the magnitude of OC risk reduction through this staged approach remain limited. Understanding the clinical effectiveness of RRES with DO is essential to guide patient counseling and clinical recommendations.
Study Design
The UK PROTECTOR study is a multicenter, prospective, observational national cohort study designed to assess surgical prevention strategies for OC among women at high genetic risk (BRCA1/BRCA2 mutation carriers). Recruitment spanned from January 1, 2019, to December 31, 2024, with a target sample size of 1250 participants. Eligible women were premenopausal and aged 30 years or older, able to choose one of three options upon study entry: RRES, RRSO, or no surgery.
Primary endpoint focused on the incidence of OC after surgery (post-RRES or post-RRSO) but before DO for those undergoing RRES and DO. The study excluded malignancy detected at the time of surgery (occult cancers) to focus on risk reduction effectiveness during the follow-up period. Histologic findings at surgery were normal to ensure baseline cancer-free status.
Key methodological innovation involved applying the estimand framework, recently endorsed to better define clinical trial objectives aligned with treatment effect interpretation amid intercurrent events (such as surgery timing variations or crossover). The primary estimand was the proportion of cancers prevented (expressed as 1 minus the observed-to-expected cancer ratio [1 – O/E]), where expected cancers were modeled assuming no preventive effect.
Key Findings
Initial data analysis included 889 women: 255 (28.7%) underwent RRSO, 405 (45.5%) chose RRES, and 229 (25.7%) opted for no surgery. The mean ages were 42 years for RRSO, 38 for RRES, and 38 for no surgery, reflecting clinical preference patterns.
The study identified that the preferred estimand outcome for clinical effectiveness is the OC incidence occurring after surgery, employing a ‘while on intervention’ strategy accounting for varying times to delayed oophorectomy and other intercurrent events.
Sample size modeling suggested requiring approximately 1150 women undergoing RRES with follow-up of 8 to 10 years would achieve 92% power to detect a prevention of at least 20% of expected ovarian cancers compared with no surgery, assessed by a 1-sample binomial test on the observed-to-expected cancer ratio at a two-sided 5% significance level.
Secondary analyses centered on demonstrating noninferiority of RRES compared to RRSO in the proportion of prevented cancers, with similar power assumptions. However, defining clinical effectiveness using incidence ratios required prohibitively large sample sizes, rendering this approach impractical.
These results underscore that the proportion-prevented estimand leveraging externally derived expected risks is more interpretable and feasible than absolute risk differences or incidence ratios, supporting cross-cohort comparability and offering clinically relevant effect measures for patient and clinician decision-making.
Expert Commentary
The PROTECTOR study’s adoption of the estimand framework represents an important methodological advancement in OC prevention research, enabling nuanced interpretation of surgical intervention effectiveness in the presence of complex treatment pathways and intercurrent events. This approach aligns with contemporary regulatory guidance on estimand specification and addresses challenges inherent in observational cohort analyses where randomized controlled trials are challenging to conduct.
Current OC risk reduction strategies indirectly infer effectiveness from surrogate endpoints or retrospective data. The prospective, detailed quantification through PROTECTOR offers a more robust evidence base to assess whether the staged RRES with DO approach meaningfully approximates the risk reduction of standard RRSO while preserving quality of life by delaying premature menopause.
Limitations include nonrandomized allocation to interventions, potential baseline risk heterogeneity, and uncertainties in external expected risk modeling, which require cautious interpretation. Nonetheless, the defined sample size and statistical strategy offer a clear pathway for validating the clinical utility of RRES.
Conclusion
The PROTECTOR cohort study effectively applies the estimand framework to define and power clinical effectiveness assessments of risk-reducing early salpingectomy with delayed oophorectomy among BRCA1/2 mutation carriers. By focusing on the proportion of ovarian cancers prevented and employing a ‘while on intervention’ perspective, the study presents a feasible and interpretable approach to evaluating a promising alternative to standard risk-reducing surgery that may enhance quality of life outcomes. Pending completion of long-term follow-up, this research will critically inform surgical decision-making and guidelines for OC risk management in high-risk populations.
References
- Sia J, Lane EF, Fierheller CT, et al; PROTECTOR team. Estimands for Clinical Effectiveness of Risk-Reducing Early Salpingectomy in Women With High Risk of Ovarian Cancer. JAMA Netw Open. 2025;8(9):e2532195. doi:10.1001/jamanetworkopen.2025.32195
- Manchanda R, Gaba F, Evans DG, et al. Risk-reducing early salpingectomy with delayed oophorectomy versus risk-reducing salpingo-oophorectomy for ovarian cancer prevention: a systematic review and meta-analysis. Gynecol Oncol. 2021;161(1):161–169.
- National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2024.