Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Toni T Seppälä,Wouter H De Vos Tot Nederveen Cappel,Noralane M Lindor,Maartje Nielsen,Gabriela Möslein,Lucio Bertario,Matilde Navarro,Christoph Engel,Marta Pineda,Magnus Von Knebel Doeberitz,Oliver G Denton,Stefan Aretz,Julian R Sampson,Monika Morak,Inge Bernstein,Lone Sunde,Erik Rokkones,Revital Kariv,Claudia Perne,Joan B Vida,Anna Lepistö,John L Hopper,Florencia Neffa,Sanne W Ten Broeke,Francisco Lopez-Koestner,Deepak Vangala,Wolff Schmiegel,Heike Görgens,Guy Rosner,Mark A Jenkins,Adriana Della Valle,Rolf H Sijmons,Reinhard Büttner,Nathan Gluck,Jane C Figueiredo,Silke Redler,Ingrid Winship,Johanna Tecklenburg,Fiona Lalloo,John Burn,Markus Loeffler,Miriam Mints,Finlay Macrae,Pål Møller,Kirsi Pylvänäinen,Huw Thomas,Pablo Kalfayan,Christina Therkildsen,Zohreh Ketabi,Robert Hüneburg,Kate Green,Polly A Newcomb,Karl Heinimann,Stefanie Holzapfel,Jürgen Weitz,Stephen N Thibodeau,Bernardo Bonanni,Douglas Tjandra,Marian J.E Mourits,Eivind Hovig,Steven Gallinger,Lior H Katz ,John Paul Plazzer ,Gabriel Capellá ,Loı̈c Le Marchand ,Carlos Vaccaro ,D Gareth Evans ,Karin Álvarez ,Aung Ko Win ,Einar Andreas Rødland ,Walter Hernán Pavicic ,Laura Renkonen–Sinisalo ,James A Hill ,Patricia Esperón ,Mev Dominguez‐Valentin ,Hans F A Vasen ,Maria Grazia Tibiletti ,Jukka–Pekka Mecklin∥ ,Hans Strauß ,Marc S Greenblatt ,Elke Holinski‐Feder ,Tamara Alejandra Piñero ,Giulia Martina Cavestro ,Emma Crosbie ,Karin Wadt ,Verena Steinke‐Lange

doi:10.1016/j.ejca.2021.02.022

Abstract

PurposeThis study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants. MethodsThe Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30–69 years. ResultsOverall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery. ConclusionUptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.

Highlights

Lynch syndrome (LS) is a dominantly inherited cancer syndrome caused by germline pathogenic variants of mismatch repair (MMR) genes
The observation period was from birth to last observation because events that occurred before inclusion to prospective follow-up and reported by carriers were logged in Prospective Lynch Syndrome Database (PLSD) and events after inclusion for follow-up were logged as reported by the collaborating centres
We provide information on the frequency and timing of risk-reducing hysterectomy and/or bilateral salpingo-oophorectomy (BSO) by age and gene in female path_MMR carriers

Summary

Introduction

Lynch syndrome (LS) is a dominantly inherited cancer syndrome caused by germline pathogenic variants of mismatch repair (MMR) genes (path_MMR variants). In women with LS, gynaecological cancers are as common as gastrointestinal cancers. No screening programme is considered to be effective for gynaecological cancers. Risk-reducing surgery (RRS), including total hysterectomy and bilateral salpingo-oophorectomy (BSO), prevents gynaecological cancer in women with LS and is the only preventive approach that is recognised to be effective [1,2]. The Manchester International Consensus Group strongly recommended that risk-reducing hysterectomy and BSO is offered but no earlier than 35e40 years of age, following completion of childbearing in path_MLH1, path_MSH2, and path_MSH6 carriers. There was insufficient evidence to strongly recommend RRS for path_PMS2 carriers [3,4]

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