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

This is a self-archived version of an original article. This version may differ from the original in pagination and typographic details. Author(s): Title: Year: Version: Copyright: Rights: Rights url: Please cite the original version: CC BY 4.0 https://creativecommons.org/licenses/by/4.0/ Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants : a Prospective Lynch Syndrome Database report © 2021 The Author(s). Published by Elsevier Ltd. Published version Seppälä, Toni T.; Dominguez-Valentin, Mev; Crosbie, Emma J.; Engel, Christoph; Aretz, Stefan; Macrae, Finlay; Winship, Ingrid; Capella, Gabriel; Thomas, Huw; Hovig, Eivind; Nielsen, Maartje; Sijmons, Rolf H.; Bertario, Lucio; Bonanni, Bernardo; Tibiletti, Maria G.; Cavestro, Giulia M.; Mints, Miriam; Gluck, Nathan; Katz, Lior; Heinimann, Karl; Vaccaro, Carlos A.; Green, Kate; Lalloo, Fiona; Hill, James; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Strauß, Hans-Georg; Tecklenburg, Johanna; Holinski-Feder, Elke; Steinke-Lange, Verena; Mecklin, Jukka-Pekka; Plazzer, John-Paul; Pineda, Marta; Navarro, Matilde; Vida, Joan B.; Kariv, Revital; Rosner, Guy; Piñero, Tamara A.; Pavicic, Walter; Kalfayan, Pablo; ten Broeke, Sanne W.; Jenkins, Mark A.; Sunde, Lone; Bernstein, Inge; Burn, John; Greenblatt, Marc; de Vos tot Nederveen Cappel, Wouter H.; Della Valle, Adriana; Lopez-Koestner, Francisco; Alvarez, Karin; Büttner, Reinhard; Görgens, Heike; Morak, Monika; Holzapfel, Stefanie; Hüneburg, Robert; von Knebel Doeberitz, Magnus; Loeffler, Markus; Redler, Silke; Weitz, Jürgen; Pylvänäinen, Kirsi; Renkonen-Sinisalo, Laura; Lepistö, Anna; Hopper, John L.; Win, Aung K.; Lindor, Noralane M.; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A.; Figueiredo, Jane C.; Thibodeau, Stephen N.; Therkildsen, Christina; Wadt, Karin A.W.; Mourits, Marian J.E.; Ketabi, Zohreh; Denton, Oliver G.; Rødland, Einar A.; Vasen, Hans; Neffa, Florencia; Esperon, Patricia; Tjandra, Douglas; Möslein, Gabriela; Rokkones, Erik; Sampson, Julian R.; Evans, D.G.; Møller, Pål Seppälä, T. T., Dominguez-Valentin, M., Crosbie, E. J., Engel, C., Aretz, S., Macrae, F., Winship, I., Capella, G., Thomas, H., Hovig, E., Nielsen, M., Sijmons, R. H., Bertario, L., Bonanni, B., Tibiletti, M. G., Cavestro, G. M., Mints, M., Gluck, N., Katz, L., . . . Møller, P. (2021). Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants : a Prospective Lynch Syndrome Database report. European Journal of Cancer, 148, 124-133. https://doi.org/10.1016/j.ejca.2021.02.022 2021 Original Research Uptake of hysterectomy and bilateral salpingooophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report Toni T. Seppa ¨la ¨ a,b,bt,bu, *, Mev Dominguez-Valentin c,bt,bu , Emma J. Crosbie d,e , Christoph Engel f,bt , Stefan Aretz g,h , Finlay Macrae i,j,bt , Ingrid Winship i,j , Gabriel Capella k,bt,bu , Huw Thomas l , Eivind Hovig c,m , Maartje Nielsen n , Rolf H. Sijmons o,bt,bu , Lucio Bertario p,q , Bernardo Bonanni p , Maria G. Tibiletti r , Giulia M. Cavestro s , Miriam Mints t , Nathan Gluck u,v , Lior Katz w , Karl Heinimann x , Carlos A. Vaccaro y,z , Kate Green aa , Fiona Lalloo aa , James Hill ab , Wolff Schmiegel ac , Deepak Vangala ac , Claudia Perne g,h , Hans-Georg Strauß ad , Johanna Tecklenburg ae , Elke Holinski-Feder af,ag,bt,bu , Verena Steinke-Lange af,ag , Jukka-Pekka Mecklin ah,bt,bu , John-Paul Plazzer ai,bt , Marta Pineda aj , Matilde Navarro aj , Joan B. Vida aj , Revital Kariv v , Guy Rosner v , Tamara A. Pin˜ero z , Walter Pavicic z , Pablo Kalfayan z , Sanne W. ten Broeke o , Mark A. Jenkins ak , Lone Sunde al,am , Inge Bernstein an,ao , John Burn ap,bt,bu , Marc Greenblatt aq , Wouter H. de Vos tot Nederveen Cappel ar , Adriana Della Valle as , Francisco Lopez-Koestner at , Karin Alvarez at , Reinhard Bu ¨ttner au , Heike Go ¨rgens av , Monika Morak af,ag , Stefanie Holzapfel aw , Robert Hu ¨neburg ax , Magnus von Knebel Doeberitz ay,az , Markus Loeffler f , Silke Redler ba ,Ju ¨rgen Weitz av , Kirsi Pylva ¨na ¨inen bb , Laura Renkonen-Sinisalo bc , Anna Lepisto ¨ bc , John L. Hopper ak , Aung K. Win ak,bd,be , Noralane M. Lindor bf , Steven Gallinger bg , Loı ¨c Le Marchand bh , Polly A. Newcomb bi , Jane C. Figueiredo bi , Stephen N. Thibodeau bj , Christina Therkildsen bk , Karin A.W. Wadt bl , Marian J.E. Mourits bv , Zohreh Ketabi bm , Oliver G. Denton bn , *Corresponding author: Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland. E-mail address: [email protected] (T.T. Seppa ¨la ¨). https://doi.org/10.1016/j.ejca.2021.02.022 0959-8049/ª2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/). Available online at www.sciencedirect.com ScienceDirect journal homepage: www.ejcancer.com European Journal of Cancer 148 (2021) 124e133 Einar A. Rødland c , Hans Vasen bo , Florencia Neffa at , Patricia Esperon at , Douglas Tjandra i , Gabriela Mo ¨slein bp,bt,bu , Erik Rokkones bq , Julian R. Sampson bn,bt,bu , D.G. Evans br,bs ,Pa ˚l Møller c,bt,bu a Department of Gastrointestinal Surgery, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland b Department of Surgical Oncology, Johns Hopkins Hospital, Baltimore, MD, USA c Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo, Norway d Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester and St Mary’s Hospital, Manchester, UK e Directorate of Gynaecology, Manchester University, NHS Foundation Trust, Manchester, M13 9WL, UK f Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany g Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany h National Center for Hereditary Tumor Syndromes, University Hospital Bonn, Germany i Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia j Department of Medicine, Melbourne University, Melbourne, Australia k Hereditary Cancer Program, Institut Catal. D’Oncologia-IDIBELL Institut D’Investigacio ´Biome `dica de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain l St Mark’s Hospital, Department of Surgery and Cancer, Imperial College London, London, UK m Department of Informatics, University of Oslo, Oslo, Norway n Department of Clinical Genetics, Leids Universitair Medisch Centrum, Leiden, Netherlands o Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands p Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy q Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy r Ospedale di Circolo ASST Settelaghi, Centro di Ricerca Tumori Eredo-familiari, Universita `Dell’Insubria, Varese, Italy s Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy t Department of Women’s and Children’s Health, Division of Obstetrics and Gyneacology, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden u Tel-Aviv Sourasky Medical Center, Research Center for Digestive Disorders and Liver Diseases v Department of Gastroenterology, Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel-Aviv University, Israel w High Risk and GI Cancer Prevention Clinic, Gatro-Oncology Unit, The Department of Gastroenterology, Sheba Medical Center, Israel x Medical Genetics, Institute for Medical Genetics and Pathology, University Hospital Basel, Switzerland y Hereditary Cancer Program (PROCANHE) Hospital Italiano de Buenos Aires, Buenos Aires, Argentina z Instituto de Medicina Traslacional e Ingenieria Biomedica (IMTIB), Argentina aa Manchester Centre for Genomic Medicine, Manchester University Hospitals NHS Foundation Trust, Manchester, UK ab Department of Surgery, Manchester University Hospitals NHS Foundation Trust and University of Manchester, Manchester, UK ac Department of Medicine, Knappschaftskrankenhaus, Ruhr-University Bochum, Bochum, Germany ad Department of Gynaecology, University Clinics, Martin-Luther University, Halle-Wittenberg, Germany ae Institute of Human Genetics, Hannover Medical School, Hannover, Germany af Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universita ¨tMu ¨nchen, Munich, Germany ag MGZ- Medical Genetics Center, Munich, Germany ah Faculty of Sport and Health Sciences, University of Jyva ¨skyla ¨, Jyva ¨skyla ¨, Finland & Department of Surgery, Central Finland Health Care District, Jyva ¨skyla ¨, Finland ai The Royal Melbourne Hospital, Melbourne, Australia aj Hereditary Cancer Program, Institut Catala `D’Oncologia-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain ak Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia al Department of Clinical Genetics, Aalborg University Hospital, Aarhus, Denmark am Department of Biomedicine, Aarhus University, Aarhus, Denmark an Department of Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark ao Faculty of Clinical Medicine, Aalborg University, Aalborg, Denmark ap Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK aq University of Vermont, Larner College of Medicine, Burlington, VT 05405, USA ar Department of Gastroenterology and Hepatology, Isala Clinics, Zwolle, the Netherlands as Grupo Colaborativo Uruguayo, Investigacio ´n de Afecciones Oncolo ´gicas Hereditarias (GCU), Hospital Fuerzas Armadas, Montevideo, Uruguay at Lab. Oncologı ´ a y Gene ´tica Molecular, Unidad de Coloproctologı ´ a Clı ´ nica Las Condes, Santiago, Chile au Institute of Pathology, University of Cologne, Cologne, Germany av Department of Surgery, Technische Universita ¨t Dresden, Dresden, Germany aw Institute of Human Genetics, University of Bonn, Bonn, Germany ax Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany ay Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany T.T. Seppa ¨la ¨et al. / European Journal of Cancer 148 (2021) 124e133 125 az Cooperation Unit Applied Tumour Biology, German Cancer Research Center (DKFZ), Heidelberg, Germany ba Heinrich-Heine-University, Medical Faculty, Institute of Human Genetics, Du ¨sseldorf, Germany bb Department of Education and Science, Central Finland Health Care District, Jyva ¨skyla ¨, Finland bc Department of Gastrointestinal Surgery, Helsinki University Central Hospital, Applied Tumour Genomics Research Program, University of Helsinki, Helsinki, Finland bd University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, VIC, 3010, Australia be Genetic Medicine, Royal Melbourne Hospital, Parkville, VIC, 3050, Australia bf Department of Health Science Research, Mayo Clinic Arizona bg Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto bh University of Hawaii Cancer Center, Honolulu, HI 96813, USA bi Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA bj Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA bk The Danish HNPCC Register, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark bl Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Denmark bm Dept. of Obstetrics and Gynaecology, Copenhagen University Hospital, Rigshospitalet, Denmark bn Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK bo Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands bp Department of Surgery, Ev. Krankenhaus Bethesda Hospital, Duisburg, Germany bq Department of Gynaecological Oncology, Division of Cancer Medicine, The Norwegian Radium Hospital, Oslo, Norway br Division of Evolution and Genomic Medicine, University of Manchester, Manchester, UK bs Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK bt The International Society for Gastrointestinal Hereditary Tumours (InSiGHT), The Polyposis Registry, St Mark’s Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK bu European Hereditary Tumour Group (EHTG), C/o Lindsays, Caledonian Exchange, 19A Canning Street, Edinburgh, EH3 8HE, United Kingdom bv Department of Gynaecologic Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands Received 19 December 2020; received in revised form 8 February 2021; accepted 15 February 2021 KEYWORDS Lynch syndrome; Endometrial cancer; Ovarian cancer; Risk-reducing surgery; Hysterectomy; Oophorectomy; MLH1; MSH2; MSH6; PMS2 Abstract Purpose: This 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. Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30e69 years. Results: Overall, 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. Conclusion: Uptake 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. ª2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). T.T. Seppa ¨la ¨et al. / European Journal of Cancer 148 (2021) 124e133126 1. 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]. The distribution of ages at which RRS takes place in path_MMR women is not well known, and there is limited information on opportunistic RRS being undertaken in association with surgery for colorectal cancer (CRC). Undertaking RRS as the first major abdominal surgery before the occurrence of CRC constitutes a truly prophylactic procedure that may be performed on healthy path_MMR carriers. By contrast, some CRC patients are identified as path_MMR carriers after tumour MMR screening and are offered RRS as a secondary operation. In known path_MMR carriers, the timing of the RRS may avoid multiple surgeries if based on a predicted sequence of events with respect to CRC and the menopause. For women who choose not to undergo RRS, an understanding of ‘red flag’ symptoms (abnormal vaginal bleeding) is important to trigger prompt referral for urgent examination, and many centres provide gynaecological surveillance [5,6]. There is limited information on the uptake of RRS in path_MMR carriers, a corresponding lack of information on the extent to which clinical guidelines have been adopted and a lack of information on the alignment of gynaecological cancer risk and mortality with RRS uptake. In this report, we describe the uptake of hysterectomy and BSO reported to the Prospective Lynch Syndrome Database (PLSD) by age and gene and consider uptake in the context of recently published gynaecological cancer risk and mortality determined through PLSD. 2. Patients and methods 2.1. PLSD design The PLSD is an international, multicentre, prospective observational study without a control group [7e10]. In brief, carriers of Class 4 or 5 pathogenic variants listed in the InSiGHT database (https://www.insight-group. org/variants/databases/), who had been recruited for prospective follow-up in each participating centre, are included. Inclusion was from the first prospectively planned and completed colonoscopy. The methods to define previous cancer, censoring of each patient, and observation time until organ removal have been previously described [7e10]. 2.2. Ethics statement All reporting centres exported deidentified data to the PLSD based on local institutional reviews, as previously described [7e10]. 2.3. Selection criteria The inclusion criteria for calculating the uptake of RRS were (1) female, (2) carrier of pathogenic or likely pathogenic (Class 4 or 5) MMR variant according to InSiGHT database classification [11], (3) aged 30e69 years at last examination, (4) no endometrial or ovarian cancer before or at inclusion age, and (5) at least 2 years of follow-up after first prospectively planned and carried-out colonoscopy (to ensure time from disclosure of carrier status to undertake RRS). The last observation was prospectively detected endometrial or ovarian cancer or last prospective examination without cancer. In premenopausal women, hysterectomy may or may not be performed during treatment for early stage ovarian cancer, and BSO may or may not be performed during treatment of early stage endometrial cancer. Therefore, in all previous PLSD reports, when endometrial or ovarian cancer was diagnosed, observation time was right censored for the other organ. Correspondingly, in the present study, removal of the second organ during or after treatment for ovarian or endometrial cancer was not classified as an RRS procedure. RRS in this report indicates surgery for prophylaxis or for benign indications, unless otherwise specified. 2.4. Reported uptake of hysterectomy or BSO In our analysis, we report total incidences of hysterectomy and BSO, and some of the interventions may not have been prophylactic surgeries per se, but organ removals for benign indications. Of note, BSO reported to the PLSD was specified as complete removal of both ovaries, which by current standards includes salpingectomy, reflecting the understanding that most high-grade serous ovarian cancers with serious prognosis may originate from the distal end of the salpinx [12]. We did not specifically ask about peritoneal cancer after BSO or endometrial cancer after hysterectomy [1]. T.T. Seppa ¨la ¨et al. / European Journal of Cancer 148 (2021) 124e133 127 2.5. Statistical methods The following information was used for analyses: age at hysterectomy, age at BSO, age at last observation, and path_MMR variant. The selected carriers were grouped in four 10-year cohorts categorised according to age at last observation. The numbers of carriers who had or did not have hysterectomy or BSO before or at last observation in each age cohort was counted, and the fractions of carriers who had these interventions in each category were calculated. The uptake of prophylactic surgery is reported as the cross-sectional frequency in each of the four different 10-year cohorts according to age at censoring. In contrast to some former reports from the PLSD, this report is a cross-sectional study reporting age at last observation rather than annual incidences by age or cumulative incidences. 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 PLSD and events after inclusion for follow-up were logged as reported by the collaborating centres. 3. Results 3.1. Inclusion of path_MMR carriers Among the carriers included in the last PLSD version [10], 2292 female path_MMR carriers from 18 countries met the inclusion criteria for the current cross-sectional study (Supplementary Table 1). Of these, 1016, 833, 271, 152, and 20 were carriers of path_MLH1,path_MSH2, path_MSH6,path_PMS2, and path_EPCAM, respectively. 3.2. Uptake of risk-reducing hysterectomy and/or BSO The mean ages at first RRS together with the mean ages at first CRC are presented by gene in Table 1. The mean age at first RRS was 45 years for path_MLH1, 44 years for path_MSH2, 48 years for path_MSH6, and 53 years for path_PMS2 carriers, whereas the mean ages for first CRC were 41, 41, 44, and 47 years, respectively. Of the 2292 path_MMR carriers aged 30e69 years, 664 (29%) had hysterectomy and 598 (26%) had BSO (Table 2). Of 1178 of 2292 carriers aged 30e49 years, 204 (17%) had hysterectomy and 188 (16%) had BSO (Table 2). At 40e49 years of age, the uptake for hysterectomy and/or BSO was 32% (102/320) and 30% (80/269) for path_MLH1 and path_MSH2, respectively, whereas for path_MSH6 carriers and path_PMS2 carriers the uptake reached 18% (13/73) and 13% (4/32), respectively (Table 3). As 144 (9.4%), 79 (3.5%), 517 (22.8%), and 1532 (67.4%) carriers underwent only risk-reducing hysterectomy, only BSO, both combined, or neither, respectively, 81% of surgical procedures included BSO (Table 3). Two-thirds (157/235, 67%) of procedures before age 50 years were combined hysterectomy and BSO. The number of path_EPCAM carriers (N Z20) was too low for meaningful statistical analyses by gene and age, and they were excluded from the analysis (Table 3 Table 1 Mean age at the end of observation, at first risk-reducing gynaecological surgery (RRS) and at first colorectal cancer (CRC) diagnosis, by gene. Mean SD 95% CI Age at last observation nZ1016 path_MLH1 48.7 10.2 0.6 nZ833 path_MSH2 48.7 10.3 0.7 nZ271 path_MSH6 49.9 10.3 1.2 nZ152 path_PMS2 54.0 10.3 1.6 nZ20 path_EPCAM 50.0 14.3 6.3 Age at first RRS nZ342 path_MLH1 45.4 7.6 0.8 nZ299 path_MSH2 44.4 7.9 0.9 nZ70 path_MSH6 47.6 8.3 1.9 nZ29 path_PMS2 48.3 9.8 3.6 nZ3path_EPCAM 53.3 11.0 12.4 Age at first CRC nZ388 path_MLH1 40.8 9.1 0.9 nZ283 path_MSH2 40.8 9.7 1.1 nZ52 path_MSH6 43.7 8.4 2.3 nZ38 path_PMS2 46.8 8.3 2.6 nZ8path_EPCAM 45.4 14.8 10.3 SD, standard deviation; CI, confidence interval (for mean point estimate); CRC, colorectal cancer. Table 2 Numbers of risk-reducing gynaecological surgery (RRS) events with respect to previous or future cancers (percentage of all who underwent RRS a ). All (30e69 years) RRS at 30e49 years All Hysterectomy 664 204 BSO 598 188 No prior or prevalent cancer Hysterectomy 400 (60%) 126 (62%) BSO 328 (55%) 107 (57%) CRC at same age as RRS Hysterectomy 50 (7.5%) 11 (5.4%) BSO 41 (6.9%) 9 (4.8%) CRC before RRS Hysterectomy 197 (30%) 58 (28%) BSO 203 (34%) 64 (34%) CRC after RRS Hysterectomy 123 (19%) 14 (6.9%) BSO 92 (15%) 6 (3.2%) BSO, bilateral salpingo-oophorectomy. a Percentages do not sum to 100%, as some individuals are included in multiple groups. T.T. Seppa ¨la ¨et al. / European Journal of Cancer 148 (2021) 124e133128 Table 3 Cumulative uptake of risk-reducing hysterectomy with or without BSO or BSO with or without hysterectomy (95% confidence interval) by gene and age.The table gives the figures corresponding to the graphical presentation in Fig. 1. Pathogenic variant 30e39 years 40e49 years 50e59 years 60e69 years 30e69 years Number with or without RRS Number with RRS Frequency RRS 95% CI Number with or without RRS Number with RRS Frequency RRS 95% CI Number with or without RRS Number with RRS Frequency RRS 95% CI Number with or without RRS Number with RRS Frequency RRS 95% CI Number with or without RRS Number with RRS Sum carriers Sum carriers with RRS Hysterectomy and oophorectomy path_MLH1 221 10 0.05 0.03 320 70 0.22 0.05 298 105 0.35 0.05 177 68 0.38 0.07 1016 263 2272 517 path_MSH2 182 10 0.05 0.03 269 53 0.20 0.05 221 74 0.33 0.06 161 63 0.39 0.08 833 214 path_MSH6 53 1 0.02 0.04 73 8 0.11 0.07 91 23 0.25 0.09 54 17 0.31 0.12 271 51 path_PMS2 18 2 0.11 0.15 32 3 0.09 0.10 49 5 0.10 0.08 53 5 0.09 0.08 152 17 Oophorectomy without hysterectomy path_MLH1 221 0 0.00 0.00 320 12 0.04 0.02 298 10 0.03 0.02 177 7 0.04 0.03 1016 29 2272 79 path_MSH2 182 2 0.01 0.02 269 13 0.05 0.03 221 14 0.06 0.03 161 11 0.07 0.04 833 40 path_MSH6 53 1 0.02 0.04 73 2 0.03 0.04 91 2 0.02 0.03 54 2 0.04 0.05 271 7 path_PMS2 18 0 0.00 0.00 32 1 0.03 0.06 49 2 0.04 0.06 53 0 0.00 0.00 152 3 Hysterectomy without oophorectomy path_MLH1 221 4 0.02 0.02 320 20 0.06 0.03 298 22 0.07 0.03 177 14 0.08 0.04 1016 60 2272 144 path_MSH2 182 4 0.02 0.02 269 14 0.05 0.03 221 20 0.09 0.04 161 21 0.13 0.05 833 59 path_MSH6 53 2 0.04 0.05 73 3 0.04 0.05 91 7 0.08 0.05 54 2 0.04 0.05 271 14 path_PMS2 18 0 0.00 0.00 32 0 0,00 0,00 49 2 0.04 0.06 53 9 0.17 0.10 152 11 Hysterectomy and/or oophorectomy path_MLH1 221 14 0.06 0.03 320 102 0.32 0.05 298 137 0.46 0.06 177 89 0.50 0.07 1016 342 2272 740 path_MSH2 182 16 0.09 0.04 269 80 0.30 0.05 221 108 0.49 0.07 161 95 0.59 0.08 833 299 path_MSH6 53 4 0.08 0.07 73 13 0.18 0.09 91 32 0.35 0.10 54 21 0.39 0.13 271 70 path_PMS2 18 2 0.11 0.15 32 4 0.13 0.11 49 9 0.18 0.11 53 14 0.26 0.12 152 29 Hysterectomy path_MLH1 221 14 0.06 0.03 320 90 0.28 0.05 298 127 0.43 0.06 177 82 0.46 0.07 1016 313 2272 661 path_MSH2 182 14 0.08 0.04 269 67 0.25 0.05 221 94 0.43 0.07 161 84 0.52 0.08 833 259 path_MSH6 53 3 0.06 0.06 73 11 0.15 0.08 91 30 0.33 0.10 54 19 0.35 0.13 271 63 path_PMS2 18 2 0.11 0.15 32 3 0.09 0.10 49 7 0.14 0.10 53 14 0.26 0.12 152 26 Oophorectomy path_MLH1 221 10 0.05 0.03 320 82 0.26 0.05 298 115 0.39 0.06 177 75 0.42 0.07 1016 282 2272 596 path_MSH2 182 12 0.07 0.04 269 66 0.25 0.05 221 88 0.40 0.06 161 74 0.46 0.08 833 240 path_MSH6 53 2 0.04 0.05 73 10 0.14 0.08 91 25 0.27 0.09 54 19 0.35 0.13 271 56 path_PMS2 18 2 0.11 0.15 32 4 0.13 0.11 49 7 0.14 0.10 53 5 0.09 0.08 152 18 RRS, risk-reducing gynaecological surgery; CI, confidence interval (for mean point estimate); BSO, bilateral salpingo-oophorectomy. T.T. Seppa ¨la ¨et al. / European Journal of Cancer 148 (2021) 124e133 129 and Fig. 1). Among the remaining 2272 path_MMR carriers, 342 path_MLH1, 299 path_MSH2, 70 path_MSH6, and 29 path_PMS2 carriers had hysterectomy and/or BSO. The frequencies in the uptake of hysterectomies and BSO were calculated separately and in combination in 10-year age cohorts between 30 and 69 years of age and are presented in Table 3. Four hundred of the 664 (60%) hysterectomies undertaken and 126 of the 204 (62%) done before 50 years of age were performed before cancer was diagnosed in any organ. Similarly, of the 598 women who had BSO, 328 (55%) had no prior or prevalent cancer at the time of the BSO, and among the 188 who had BSO before 50 years of age, 107 (57%) had no prior or prevalent cancer at the time of the BSO. Thus, the majority of the procedures were performed as first major abdominal surgery on young carriers without current or previous cancer. Among the 188 who underwent BSO before 50 years, the BSO was performed after CRC as further abdominal surgery in 64 (34%), and among these procedures, nine (4.8%) BSO and 11 (5.4%) hysterectomies were undertaken at the same age as CRC was diagnosed and 6 (3.2%) and 14 (6.9%) before the age of first CRC (Table 2). Thus, the majority of premenopausal RRS in women who had CRC were performed before first CRC, although in the cohort as a whole, the mean age at diagnosis of CRC was lower than the age at RRS. 4. Discussion In this report, we provide information on the frequency and timing of risk-reducing hysterectomy and/or BSO by age and gene in female path_MMR carriers. The findings complement our previous reports on cumulative risks and mortality associated with gynaecological cancers in LS by age and gene [10,13]. We do not make management recommendations at this time, but our findings may inform future guidelines. Although current guidelines recommend that hysterectomy and BSO are offered to path_MMR carriers to reduce their gynaecological cancer risk [14], PLSD data demonstrate that the uptake of RRS is only 26e36% in path_MLH1,path_MSH2,and path_MSH6 and 19% in path_PMS2 carriers. In the oldest cohort investigated in the present study, comprising 60- to 69-years-olds, 39e59% of path_MLH1/MSH2 and path_MSH6 carriers had undergone RRS. The reasons behind decisions made for or against RRS warrant further attention. For carriers of path_PMS2, the place for prophylactic surgery is still under debate because there is no good evidence of increased risk for ovarian cancer. Yet, 9e14% of path_PMS2 carriers had undergone RRS. We have recently published the estimates of the preventive impact of RRS. Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers and death in 2%, 2%, 1%, and 0%, respectively [13]. Riskreducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. In line with the low risk for either endometrial or ovarian cancer before 40 years of age and the family planning considerations for this group, we found the uptake of hysterectomy was low before 40 years of age. Before 50 years of age, 21% of path_MLH1 and path_MSH2 carriers underwent hysterectomy compared with only 13% of path_MSH6 carriers, despite the latter having similar cumulative risk for endometrial cancer. A difference in uptake was Fig. 1. Uptake of hysterectomy and bilateral salpingo-oophorectomy (%) by age cohort and path_MMR gene. T.T. Seppa ¨la ¨et al. / European Journal of Cancer 148 (2021) 124e133130 observed at older ages as well, but not to the same extent. The uptake of BSO was slightly lower and followed the same pattern, although path_MSH6 carriers have a very low risk for ovarian cancer before 50 years of age. Notably, several path_PMS2 carriers had premenopausal oophorectomy despite there being no evidence for increased risk for ovarian cancer either before or after the menopause [9,10], which is known to cause a negative impact on sexual health and endocrine symptoms [15]. Most surgical procedures were combined hysterectomy and BSO, irrespective of age, perhaps reflecting a desire to minimise gynaecological cancer risk ‘once and for all’. Modern-day minimally invasive surgical techniques may have fewer peri- and post-operative complications so that separate postmenopausal BSO may now be a reasonable option. Hysterectomy combined with BSO after 50 years of age for path_PMS2 carriers effectively removes the gynaecological cancer risk. For younger carriers keen to mitigate their risks but also to avoid the surgical menopause, hysterectomy at the completion of childbearing followed by BSO at age 50 years would be an option for path_MLH1, path_MSH2, and particularly for path_MSH6 carriers, in whom the risk of premenopausal ovarian cancer is low. Because genetic testing has been available for only 25 years and identification of LS has been changing from phenotype/family historyebased to molecular screening based, there may be a time-trend bias in the uptake of risk-reducing hysterectomy and BSO. Older women may not have had the option of early RRS that has been advocated and available in recent years (and they may not have known they were at risk when they were younger). The uptake we observed among older women may not be representative of the choices made by younger carriers today. Because of the inherent timetrend bias, from which no statistical procedures can escape, we considered it inappropriate to investigate the reported uptake of interventions using more sophisticated statistical methods than those selected for this study. In addition to time trends, this study has other limitations. We have not recorded the exact indication for gynaecological organ removal, that is, whether this was risk reducing or conducted for benign medical indications, such as to manage menstrual dysfunction, fibroids, or benign ovarian masses. On some occasions, benign indications may favour earlier RRS than otherwise indicated. Some limitations are associated with the structure of PLSD that does not take into account whether the path_MMR variant in an individual had already been identified at the time of prospective observation, although it is now usually a prerequisite for recommending RRS. One may argue, however, that the increased incidence of endometrial and ovarian cancer in LS has been known throughout the observation period. In addition, the numbers of path_PMS2 and path_EPCAM recorded in PLSD are still low, reflecting the insensitivity of the Amsterdam and Bethesda criteria so that they are infrequently offered genetic testing [16] and causing wide confidence intervals, particularly for younger cohorts. This report and others from the PLSD, including reports on the guidelines that contributing centres have been following historically [7], their current guidelines [17], the reduction in morbidity and mortality achieved via hysterectomy or BSO by age [13], and now the uptake of hysterectomy or BSO by age and gene provide information that should help stakeholders, including patients, to address questions surrounding management options. Some patients may prefer to minimise the number of surgical procedures, some may wish to avoid the surgically induced menopause, and some may wish to maximise the cancer prevention effect of prophylactic organ removal [18]. Our results show that premenopausal women who had CRC most often had RRS performed as subsequent abdominal surgery, which increases risks for intraoperative complications and longterm complications such as hernias [19]. Although a staged approach will retain ovarian function for additional time, hormone replacement therapy is generally not contraindicated for women with LS, and adding simultaneous RRS to surgery for CRC in known path_MMR has been shown to be cost-effective and improve cancer outcomes in a Markov decision-tree model [20]. In summary, we found that uptake of RRS in LS aligned poorly with gynaecological cancer risk and mortality, both before and after menopause, with the timing of other abdominal surgery and with respect to clinical guidelines. Timing of RRS would benefit from earlier identification of LS, and there appears to be an unmet need for better multidisciplinary planning of prophylactic procedures to avoid repeated surgery. Today, the healthy young relatives of path_MMR carriers are increasingly being identified through genetic testing, and there is a need for timely presentation of options to these patients based on high-quality evidence. Authors’ contributions PM designed the study and calculated the results. TTS, MDV, EC, PM, JRS and DGE wrote the manuscript. All others contributed to acquisition of data, commenting, and revising the article. Conflict of interest statement TTS is the CEO and co-owner of Healthfund Finland Oy and reports an interview honoraria from Boehringer Ingelheim Finland. ER is a consultant for Vaccibody AS and a member of the data monitoring committee for Oncoinvent AS. DV reports speaker’s honoraria from T.T. Seppa ¨la ¨et al. / European Journal of Cancer 148 (2021) 124e133 131