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 (BRCA1) or 45–50 (BRCA2) years, compared with the current standard salpingo-oophorectomy at age 35–40 (BRCA1) or 40–45 (BRCA2) 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 (BRCA1), 25 and 45 (BRCA2), or 25 and 50 (BRIP1, RAD51C, and RAD51D 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 BRCA1, 40–45 years for BRCA2, and 45–50 years for BRIP1, RAD51C, and RAD51D pathogenic variant carriers. Major Inclusion/Exclusion Criteria Premenopausal individuals with a documented class IV or V germline pathogenic variant in the BRCA1, BRCA2, BRIP1, RAD51C, or RAD51D 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 BRCA1 and 51 years for BRCA2 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 BRCA1 and 1500 BRCA2 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.

as in a smaller time period the positive effects on menopause-related outcomes are expected to be minimal and will not outweigh the potential side-effects of two surgeries within that time period.
Childbearing should be completed or not desired. In case of a previous malignancy, participants should have completed treatment (including for example tamoxifen) in order to have similar inclusion criteria to the TUBA study.

Novel treatment
Risk-reducing salpingectomy upon completion of childbearing, but within the age range of 25-40 for  Tissues have to be totally embedded for pathological examination; the fallopian tubes must be embedded in conformity with the Sectioning and Extensively Examining the FIMbriated End (SEE-FIM) protocol. 3 Tissue will be firstly assessed on regular hematoxylin & eosin staining. When the epithelium shows cytological atypia, immunohistochemistry with p53 and Ki-67 staining will be performed additionally. In case of a serous tubal intraepithelial carcinoma (STIC) in the fallopian tube of a salpingectomy specimen, oophorectomy within short notice is advised. A panel consisting of gynecologic pathologists is available for consultation in case of difficult cases.

Data collection
All data will be collected in a secure web-based electronic database including questionnaires and case report forms. At inclusion, the treating physician will complete a case report form to provide information on in-and exclusion criteria and baseline characteristics. The participants will provide their baseline characteristics by filling in a web-based electronic questionnaire with questions regarding their medical history, family history, and use of medication. Within three months after surgery, pathological and surgical outcomes will be reported by the treating physician by completing the corresponding form. Long-term follow-up will consist of annual updates including the incidence of pelvic cancer, breast cancer, and uptake and results of prophylactic breast surgery, and of oophorectomy in case of earlier salpingectomy. Three methods of follow-up are allowed, depending on the specific policy and facilities in participating countries and institutes. First, annual out-patient visit in which the results are provided in a case report form by the treating physician, transvaginal ultrasound and blood tests (i.e., CA125) can be added depending on local policy. As second method, a yearly questionnaire is sent to the participant. As third method, a nationwide pathology database is assessed yearly and used to complete a case report form. An example of this third method is used in the Netherlands, the Pathological-Anatomical National Automated Archives is used as it includes all pathological assessments of tissues in the Netherlands. 4 The third method is combined with a yearly check in the municipal personal records database to assess whether participants are still alive. In case of death, the cause of death will be determined from the central bureau of statistics.

Steenbeek MP
The primary endpoint is set on target age 46 (BRCA1) and 51 (BRCA2) as we observed an age difference at inclusion of 1.6 years in BRCA1 and 2.8 years in BRCA2 pathogenic variant carriers (due to different guideline ages for salpingo-oophorectomy) between both treatment arms in the combined data from the TUBA and WISP study. Some participants, especially BRCA2 pathogenic variant carriers, might thus be substantially younger at salpingectomy than participants at salpingooophorectomy. As the risk for tubo-ovarian cancer increases with age, use of a certain period of follow-up, e.g., 10 years since inclusion, would lead to an assumed advantage for the salpingectomy group. Tubo-ovarian cancers will be counted from inclusion onwards to deal with possible imbalance in waiting times between inclusion and first surgery, e.g., in case of limited surgery sessions, participants below the guideline age might be longer on a waiting list, and as participants choosing salpingectomy are younger, waiting time might depend on the treatment strategy. To determine the target age, we assumed that after oophorectomy the risk of tubo-ovarian cancer is similar to the risk after salpingo-oophorectomy. The preferred timepoint to evaluate non-inferiority is when the contrast between both treatment arms is assumed to be the largest; shortly after the recommended age of oophorectomy. Meaning, the contrast will be maximal at the age of 45 for BRCA1 and 50 for BRCA2 pathogenic variant carriers. However, the salpingo-oophorectomy surgery is conducted at the latest at age 40 (45 for BRCA2) whereas the oophorectomy surgery might be conducted till age 45 (50 for BRCA2). Surgery is a moment in which early-stage ovarian cancers might be detected and the salpingo-oophorectomy patient of 45 (50 for BRCA2) will not undergo surgery at that age. Therefore, we added one additional year which is considered to be sufficient to also detect peritoneal carcinomatosis based on clinical symptoms (latent at age 45 for BRCA1 or 50 for BRCA2) in the salpingo-oophorectomy group (Figure 2). We assume that after salpingo-oophorectomy and oophorectomy the differences in tubo-ovarian cancer risk across the treatment groups are similar. Steenbeek MP treatment group only is expected to be more sensitive, since direct comparison of treatment arms would require adjustment for confounding, and incidence is expected to be very low, which is thus unfeasible early in the study. If the rule is met, study enrolment will be put on hold and a meeting of the DSMB will be convened to analyse and discuss tubo-ovarian cancer cases and safety of the study.
The DSMB will provide independent advice to the principal investigators and may recommend changes in the conduct of the study or premature termination.

Ethical considerations and participating sites
The study will be conducted in accordance with the principles of the Declaration of Helsinki and the University Hospital Stockholm Sweden. All participants will provide a written informed consent. The study protocol is registered in ClinicalTrials.gov (registration number NCT04294927).