TUBectomy with delayed oophorectomy as an alternative to risk-reducing salpingo-oophorectomy in high-risk women to assess the safety of prevention: the TUBA-WISP II study protocol.

Background: Risk-reducing salpingectomy with delayed oophorectomy has gained interest for individuals at high risk for tubo-ovarian cancer as there is compelling evidence that especially high-grade serous carcinoma originates in the fallopian tubes. Two studies have demonstrated a positive effect of salpingectomy on menopause-related quality of life and sexual health compared with standard risk-reducing salpingo-oophorectomy.

Primary Objective: To investigate whether salpingectomy with delayed oophorectomy is non-inferior to the current standard salpingo-oophorectomy for the prevention of tubo-ovarian cancer among individuals at high inherited risk.

Study Hypothesis: We hypothesize that postponement of oophorectomy after salpingectomy, to the age of 40-45 () or 45-50 () years, compared with the current standard salpingo-oophorectomy at age 35-40 () or 40-45 () years, is non-inferior in regard to tubo-ovarian cancer risk.

Trial Design: In this international prospective preference trial, participants will choose between the novel salpingectomy with delayed oophorectomy and the current standard salpingo-oophorectomy. Salpingectomy can be performed after the completion of childbearing and between the age of 25 and 40 (), 25 and 45 (), or 25 and 50 ( and pathogenic variant carriers) years. Subsequent oophorectomy is recommended at a maximum delay of 5 years beyond the upper limit of the current guideline age for salpingo-oophorectomy. The current National Comprehensive Cancer Network (NCCN) guideline age, which is also the recommended age for salpingo-oophorectomy within the study, is 35-40 years for , 40-45 years for and 45-50 years for , , and pathogenic variant carriers.

Major Inclusion/exclusion Criteria: Premenopausal individuals with a documented class IV or V germline pathogenic variant in the or gene who have completed childbearing are eligible for participation. Participants may have a personal history of a non-ovarian malignancy.

Primary Endpoint: The primary outcome is the cumulative tubo-ovarian cancer incidence at the target age: 46 years for and 51 years for pathogenic variant carriers.

Sample Size: The sample size to ensure sufficient power to test non-inferiority of salpingectomy with delayed oophorectomy compared with salpingo-oophorectomy requires 1500 and 1500 pathogenic variant carriers.

Estimated Dates For Completing Accrual And Presenting Results: Participant recruitment is expected to be completed at the end of 2026 (total recruitment period of 5 years). The primary outcome is expected to be available in 2036 (minimal follow-up period of 10 years).

Trial Registration Number: NCT04294927.