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Observational Study
. 2025 Sep 2;8(9):e2532195.
doi: 10.1001/jamanetworkopen.2025.32195.

Estimands for Clinical Effectiveness of Risk-Reducing Early Salpingectomy in Women With High Risk of Ovarian Cancer

Jacqueline Sia  1   2 , Emily F Lane  1 , Caitlin T Fierheller  1 , Samuel Oxley  1   2 , Ashwin Kalra  1   2 , Michail Sideris  1   2 , Xia Wei  1   3 , Lea Mansour  1 , Annika Idahl  1   4 , Holly Fraser  1 , Subhasheenee Ganesan  1   2 , Priyanka Deshmukh  1   2 , Raji Ganesan  5 , Helen Hanson  6   7 , Ertan Saridogan  8 , Hisham Hamed  9 , W Glenn McCluggage  10 , Rosa Legood  3 , Peter Sasieni  1 , D Gareth Evans  11 , Usha Menon  12 , Adam Brentnall  1 , Ranjit Manchanda  1   2   3 ; PROTECTOR team
Collaborators, Affiliations
Observational Study

Estimands for Clinical Effectiveness of Risk-Reducing Early Salpingectomy in Women With High Risk of Ovarian Cancer

Jacqueline Sia et al. JAMA Netw Open. .

Abstract

Importance: Risk-reducing early-salpingectomy (RRES) and delayed oophorectomy (DO) is a novel 2-stage alternative prevention strategy to risk-reducing salpingo-oophorectomy (RRSO) that avoids detrimental consequences of premature menopause. However, direct data on the clinical effectiveness for ovarian cancer (OC) risk reduction are lacking.

Objective: To explore how to define clinical effectiveness from prospective cohort studies using the estimand framework and sample size requirements.

Design, setting, and participants: In this comparative effectiveness research study, estimand and analysis options were considered to evaluate the clinical effectiveness of RRES with DO by extending the UK PROTECTOR cohort study, a multicenter, prospective, observational, national cohort study (N = 1250 recruited from January 1, 2019, to December 31, 2024) evaluating RRES and DO for OC surgical prevention. Participants were premenopausal women 30 years or older at increased OC risk due to BRCA1/BRCA2 pathogenic variants. Participants could choose RRES, RRSO, or no surgery at entry. Sample size requirements used initial data (eg, age and BRCA1/2 distribution) from PROTECTOR (analysis undertaken from January 1, 2024, to December 31, 2025).

Main outcomes and measures: Incidence of OC after (not at) RRES and before or at DO in women with normal histologic analysis findings at surgery. The proportion of cancers prevented was estimated as the completement of the observed (O) to expected (E; assuming no preventive effect of surgery) number of cancers detected (1 - O/E).

Results: Initial data were obtained from 889 women in PROTECTOR (overall mean [SD] age, 39 [5] years), with 255 (28.7%) choosing RRSO (mean [SD] age, 42 [4] years), 405 (45.5%) choosing RRES (mean [SD] age, 38 [4] years), and 229 (25.7%) choosing no surgery (mean [SD], 38 [5] years). The preferred estimand outcome was OC incidence after surgery (RRES or RRSO) with a "while on intervention" strategy to account for intercurrent events. The primary target measure was the proportion of cancers prevented for RRES vs no surgery with superiority testing. The secondary target measure was noninferiority of RRES vs RRSO. An estimated 1150 RRES participants with 8 to 10 years of follow-up would provide approximately 92% power to show that 20% or more of cancers are prevented using a 1-sample binomial test of the O:E risk (external reference) at the 5% level under a range of assumptions and at least the same power for a noninferiority margin for the proportion of cancers prevented by RRES of those prevented by RRSO. Estimands based on incidence ratios had an infeasible sample size.

Conclusions and relevance: In this comparative effectiveness study of UK BRCA carriers, the estimand differed from other ongoing clinical effectiveness studies of RRES and DO. Advantages include direct use of expected risk at baseline (unknown at design stage), easier interpretation across cohorts than absolute risk differences, and providing a feasible recruitment target for PROTECTOR to evaluate clinical effectiveness.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Fierheller reported receiving grants from Wellbeing of Women–Peaches Womb Cancer Trust Postdoctoral Research Fellowship outside the submitted work. Dr Sasieni reported receiving grants from Cancer Research UK during the conduct of the study. Dr Evans reported receiving personal fees from Antegenes during the conduct of the study and personal fees from Sprinwoorks outside the submitted work. Dr Menon reported receiving personal fees from Mercy BioAnalytics, grants from Intelligent Lab and RNA Guardian, and honorarium for membership of Tina’s Wish Scientific Advisory Board. Dr Brentnall reported receiving royalties from Cancer Research UK outside the submitted work. Dr Manchanda reported receiving grants from Yorkshire Cancer Research, GSK, National Health Service, and North East London Cancer Alliance Research, and honoraria from MSD, Astra Zeneca, and EGL outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Population, Interventions, Outcome, and Intercurrent Event Treatment in PROTECTOR-2
DO indicates delayed oophorectomy; RRES, risk-reducing early salpingectomy; RRSO, risk-reducing salpingo-oophorectomy. aOccult cancers at surgery (RRES or RRSO) are excluded from analysis.
Figure 2.
Figure 2.. Noninferiority of Risk-Reducing Early Salpingectomy (RRES) vs Risk-Reducing Salpingo-Oophorectomy (RRSO) for Ovarian Cancer Incidence After Surgery and Until and Including Delayed Oophorectomy
aOccult cancers at surgery (RRES or RRSO) are excluded from analysis.
Figure 3.
Figure 3.. Noninferiority of Risk-Reducing Early Salpingectomy (RRES) vs Risk-Reducing Salpingo-Oophorectomy (RRSO) for Ovarian Cancer Incidence at or After Surgery Until Delayed Oophorectomy (DO) (TUBA-WISP-II)
Figure 4.
Figure 4.. Noninferiority of Risk-Reducing Early Salpingectomy (RRES) vs Risk-Reducing Salpingo-Oophorectomy (RRSO) for Lifetime Ovarian Cancer Risk After Surgery (SOROCk)
DO indicates delayed oophorectomy.
See this image and copyright information in PMC

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