Delayed Bilateral Oophorectomy; Hereditary Breast And Tubo-Ovarian Cancers; Radical Fimbriectomy; Risk-Reducing Surgery; Tubo-Ovarian Cancer Prevention; Oncology; Obstetrics and Gynecology
Abstract :
[en] [en] BACKGROUND: Bilateral salpingo-oophorectomy is the gold-standard risk-reducing surgery for women at high risk of tubo-ovarian or primary peritoneal cancer. Fimbriectomy with delayed oophorectomy has emerged as a promising alternative, potentially reducing tubo-ovarian cancer risk while minimizing the adverse effects of premature menopause. Larger cohorts and longer follow-up are required to confirm these findings.
PRIMARY OBJECTIVES: To evaluate the effectiveness of the chosen care pathway in controlling the risk of advanced-stage tubo-ovarian carcinoma, and more specifically to determine whether prophylactic fimbriectomy with delayed oophorectomy is non-inferior to standard bilateral salpingo-oophorectomy in women at high risk and with germline mutations.
STUDY HYPOTHESIS: Fimbriectomy with delayed oophorectomy is non-inferior to bilateral salpingo-oophorectomy in preventing oncological risk and reduces menopause-related health disorders.
TRIAL DESIGN: This multi-center, non-randomized, pragmatic, preference-based controlled trial allows participants to choose their preventive surgical strategy between standard bilateral salpingo-oophorectomy (according to national guidelines) and fimbriectomy (considered from the age of 35, once childbearing is completed), followed by delayed oophorectomy at age 50 or at clinical menopause. Participants will undergo annual long-term follow-up until age 70. The association between the chosen care pathway and outcomes will be estimated using an inverse probability-weighted, cause-specific Cox model, with age as the time scale.
MAJOR INCLUSION/EXCLUSION CRITERIA: This study will be proposed during oncogenetic counseling to pre-menopausal women aged 30 to 50 years with a documented pathogenic germline mutation (BRCA1, BRCA2, RAD51C, RAD51D, or PALB2). Exclusion criteria include prior bilateral oophorectomy or salpingectomy and a personal history of tubo-ovarian cancer.
PRIMARY ENDPOINT: Advanced-stage tubo-ovarian or primary peritoneal carcinoma.
SAMPLE SIZE: A total of 1100 patients is planned.
ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment will last 5 years (2026-2031). The first interim analysis is planned 6 to 8 years after study initiation (2032-2034). Final analysis is planned when all patients reach age 70 (around 2071).
TRIAL REGISTRATION NUMBER: NCT06726330.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Schoenen, Sophie ; Université de Liège - ULiège > Département des sciences cliniques
Mailliez, Audrey; Centre Oscar Lambret, Department of Medical Oncology, Lille, France
Risbourg, Séverine ; Centre Oscar Lambret, DRCI, Biostatistics and Methodology Unit, Lille, France
Decoupigny, Emilie; Centre Oscar Lambret, DRCI, Sponsorship Unit, Lille, France
Vanseymortier, Marie; Centre Oscar Lambret, DRCI, Sponsorship Unit, Lille, France
Pasquesoone, Camille; Centre Oscar Lambret, Department of Pathology, Lille, France
Le Saux, Olivia ; Centre Léon Bérard et Université de Lyon I, Department of Medical Oncology, Lyon, France
Ray-Coquard, Isabelle ; Centre Léon Bérard et Université de Lyon I, Department of Medical Oncology, Lyon, France
Navarro, Anne-Sophie; Centre Oscar Lambret, Department of Gynecologic Oncology, Lille, France
Bresson, Lucie; Centre Oscar Lambret, Department of Gynecologic Oncology, Lille, France
Thiebaut, Anne ; CESP, INSERM, Université Paris-Saclay, Villejuif, France
Antoni, Guillemette; CESP, INSERM, Université Paris-Saclay, Villejuif, France
Bertrand, Nicolas; Centre Eugène Marquis, Department of Medical Oncology, Rennes, France
Leblanc, Eric; Centre Oscar Lambret, Department of Gynecologic Oncology, Lille, France
Narducci, Fabrice; Centre Oscar Lambret, Department of Gynecologic Oncology, Lille, France
Le Deley, Marie-Cécile ; Centre Oscar Lambret, DRCI, Biostatistics and Methodology Unit, Lille, France, Centre Oscar Lambret, DRCI, Sponsorship Unit, Lille, France, Centre Oscar Lambret, Department of Pathology, Lille, France, Centre Léon Bérard et Université de Lyon I, Department of Medical Oncology, Lyon, France, CESP, INSERM, Université Paris-Saclay, Villejuif, France
Martinez Gomez, Carlos; Centre Oscar Lambret, Department of Gynecologic Oncology, Lille, France. Electronic address: c-martinezgomez@o-lambret.fr
This project is supported by a grant (PHRC-K-24-013) from the French National Cancer Institute (INCA).We would like to thank INCa for its invaluable support of this clinical oncology project, which aims to improve patient outcomes in the context of prophylactic surgery. We are grateful to Dr Eric Leblanc and Dr Philippe Vennin for their pioneering contribution and for the initial work that laid the groundwork for this study. We also thank IMAGYN, the patient advocacy group, for its continuous support, as well as the GINECO Group and the Genetic and Cancer Group (GGC) for their collaboration, and Fabrice Mulot from the DRCI unit of the Oscar Lambret Cancer Center for his role in promoting the study. Dr Schoenen gratefully acknowledges grant support from the University of Li\u00E8ge .
Herrington CS, WHO Classification of Tumours Editorial Board. WHO classification of tumours female Genital tumours. International Agency for Research on Cancer. Accessed March 31, 2026. https://www.research.ed.ac.uk/en/publications/who-classification-of-tumours-female-genital-tumours/
Hodgson A, Turashvili G. Pathology of hereditary breast and ovarian cancer. Front Oncol. 2020;10:531790. doi:10.3389/fonc.2020.531790
Antoniou A, Pharoah PDP, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130. doi:10.1086/375033
Hermsen BBJ, Olivier RI, Verheijen RHM, et al. No efficacy of annual gynaecological screening in BRCA1/2 mutation carriers; an observational follow-up study. Br J Cancer. 2007;96(9):1335-1342. doi:10.1038/sj.bjc.6603725
Sessa C, Balmana J, Bober SL, et al. Risk reduction and screening of cancer in hereditary breast-ovarian cancer syndromes: ESMO Clinical Practice Guideline. Ann Oncol. 2023;34(1):33-47. doi:10.1016/j.annonc.2022.10.004
Trivedi MS, Armstrong KA. Increasing the uptake of cancer risk management strategies for women with BRCA1/2 sequence variations. JAMA Oncol. 2024;10(4):435-436. doi:10.1001/jamaoncol.2023.5186
Marchetti C, De Felice F, Palaia I, et al. Risk-reducing salpingo-oophorectomy: a meta-analysis on impact on ovarian cancer risk and all cause mortality in BRCA 1 and BRCA 2 mutation carriers. BMC Womens Health. 2014;14:150. doi:10.1186/s12905-014-0150-5
Steenbeek MP, Harmsen MG, Hoogerbrugge N, et al. Association of salpingectomy with delayed oophorectomy versus salpingo-oophorectomy with quality of life in BRCA1/2 pathogenic variant carriers: a nonrandomized controlled trial. JAMA Oncol. 2021;7(8):1203-1212. doi:10.1001/jamaoncol.2021.1590
Rivera CM, Grossardt BR, Rhodes DJ, et al. Increased cardiovascular mortality after early bilateral oophorectomy. Menopause. 2009;16(1):15-23. doi:10.1097/gme.0b013e31818888f7
Georgakis MK, Beskou-Kontou T, Theodoridis I, Skalkidou A, Petridou ET. Surgical menopause in association with cognitive function and risk of dementia: a systematic review and meta-analysis. Psychoneuroendocrinology. 2019;106:9-19. doi:10.1016/j.psyneuen.2019.03.013
Chan LN, Chen LM, Goldman M, et al. Changes in bone density in carriers of BRCA1 and BRCA2 pathogenic variants after salpingo-oophorectomy. Obstet Gynecol. 2023;142(1):160-169. doi:10.1097/AOG.0000000000005236
Seidman JD, Yemelyanova A, Zaino RJ, Kurman RJ. The fallopian tube-peritoneal junction: a potential site of carcinogenesis. Int J Gynecol Pathol. 2011;30(1):4-11. doi:10.1097/PGP.0b013e3181f29d2a
Labidi-Galy SI, Papp E, Hallberg D, et al. High grade serous ovarian carcinomas originate in the fallopian tube. Nat Commun. 2017;8(1):1093. doi:10.1038/s41467-017-00962-1
Lu KH, Nebgen DR, Norquist B, et al. WISP: a prospective, multi-center trial of salpingectomy with delayed oophorectomy versus risk reducing salpingo-oophorectomy in women at increased risk for hereditary ovarian cancer. Gynecol Oncol. 2019;154(suppl 1):22. doi:10.1016/j.ygyno.2019.04.055
Leblanc E, Narducci F, Ferron G, et al. Prophylactic radical fimbriectomy with delayed oophorectomy in women with a high risk of developing an ovarian carcinoma: results of a prospective national pilot study. Cancers (Basel). 2023;15(4):1141. doi:10.3390/cancers15041141
Schoenen S, Martinez Gomez C, Pasquesoone C, et al. Evaluation of risk-reducing radical fimbriectomy followed by delayed oophorectomy in high-risk women: a single-center retrospective study. Eur J Surg Oncol. 2025;51(12):110469. doi:10.1016/j.ejso.2025.110469
Society of gynecologic oncologists clinical practice committee statement on prophylactic salpingo-oophorectomy. Gynecol Oncol. 2005;98(2):179-181. doi:10.1016/j.ygyno.2005.05.002
Leblanc E, Narducci F, Farre I, et al. Radical fimbriectomy: a reasonable temporary risk-reducing surgery for selected women with a germ line mutation of BRCA 1 or 2 genes? Rationale and preliminary development. Gynecol Oncol. 2011;121(3):472-476. doi:10.1016/j.ygyno.2011.02.012
Medeiros F, Muto MG, Lee Y, et al. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006;30(2):230-236. doi:10.1097/01.pas.0000180854.28831.77
Steenbeek MP, van Bommel MHD, Bulten J, et al. Risk of peritoneal carcinomatosis after risk-reducing salpingo-oophorectomy: a systematic review and individual patient data meta-analysis. J Clin Oncol. 2022;40(17):1879-1891. doi:10.1200/JCO.21.02016
Steenbeek MP, van Bommel MHD, intHout J, et al. 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. Int J Gynecol Cancer. 2023;33(6):982-987. doi:10.1136/ijgc-2023-004377
Commenges D, Letenneur L, Joly P, Alioum A, Dartigues JF. Modelling age-specific risk: application to dementia. Stat Med. 1998;17(17):1973-1988. doi:10.1002/(sici)1097-0258(19980915)17:17<1973::aid-sim892>3.0.co;2-5
DeMets DL, Lan KK. Interim analysis: the alpha spending function approach. Stat Med. 1994;13(13-14):1341-1356. doi:10.1002/sim.4780131308
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549-556. doi:10.2307/2530245
Gaba F, Robbani S, Singh N, et al. Preventing Ovarian Cancer through early excision of Tubes and late Ovarian Removal (PROTECTOR): protocol for a prospective non-randomised multi-center trial. Int J Gynecol Cancer. 2021;31(2):286-291. doi:10.1136/ijgc-2020-001541
Sia J, Lane EF, Fierheller CT, et al. 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
