A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study - 02/11/21

Doi : 10.1016/S1470-2045(21)00522-2

Elizabeth K Bancroft, PhD ^a,^b,^{*
Joint first authors}, Elizabeth C Page, MSc ^a,^{*
Joint first authors}, Mark N Brook, PhD ^a, Sarah Thomas, MSc ^b, Natalie Taylor, RN ^b, Jennifer Pope ^a, Jana McHugh, MBChB ^a, Ann-Britt Jones, MRCP ^a, Questa Karlsson, PhD ^a, Susan Merson, BSc ^a, Kai Ren Ong, MD ^c, Jonathan Hoffman, BMedSc ^c, Camilla Huber, MSc ^c, Lovise Maehle, MD ^d, Eli Marie Grindedal, PhD ^d, Astrid Stormorken, PhD ^d, D Gareth Evans, MD ^e, Jeanette Rothwell ^e, Fiona Lalloo, MD ^e, Angela F Brady, PhD ^f, Marion Bartlett, MSc ^f, Katie Snape, PhD ^g, Helen Hanson, MD ^g, Paul James, PhD ^h,^i,^j, Joanne McKinley, BSc ^h, Lyon Mascarenhas, MSc ^h, Sapna Syngal, MD ^k,^l, Chinedu Ukaegbu, MBBS ^k, Lucy Side, MD ^m,ⁿ, Tessy Thomas, BSc ^m,ⁿ, Julian Barwell, PhD ^o,^p, Manuel R Teixeira, PhD ^q,^r, Louise Izatt, PhD ^s, Mohnish Suri, MD ^t, Finlay A Macrae, MD ^j,^u,^v, Nicola Poplawski, MD ^w,^x, Rakefet Chen-Shtoyerman, PhD ^y,^z, Munaza Ahmed, FRCP ^aa, Hannah Musgrave, MSc ^ab, Nicola Nicolai, MD ^ac, Lynn Greenhalgh, MSc ^ad, Carole Brewer, MBBS ^ae,^af, Nicholas Pachter, MBChB ^ag,^ah, Allan D Spigelman, MD ^ai,^aj,^ak, Ashraf Azzabi, MD ^al, Brian T Helfand, MD ^am, Dorothy Halliday, PhD ^an, Saundra Buys, MD ^ao, Teresa Ramon y Cajal, MD ^ap, Alan Donaldson, MBChB ^aq, Kathleen A Cooney, MD ^ar, Marion Harris, MBBS ^as,^at, John McGrath, FRCS ^af,^au, Rosemarie Davidson, MBChB ^av, Amy Taylor, PhD ^aw, Peter Cooke, MD ^ax, Kathryn Myhill, MSc ^b, Matthew Hogben, BSc ^b, Neil K Aaronson, PhD ^ay, Audrey Ardern-Jones, MSc ^b, Chris H Bangma, MD ^az, Elena Castro, PhD ^ba, David Dearnaley, FRCP ^bb, Alexander Dias, MD ^bc, Tim Dudderidge, MD ^m, Diana M Eccles, MD ^n,^bd, Kate Green, MPhil ^e, Jorunn Eyfjord, DPhil ^be, Alison Falconer, FRCR ^bf, Christopher S Foster, MD ^bg, Henrik Gronberg, PhD ^bh, Freddie C Hamdy, FMedSci ^bi,^bj, Oskar Johannsson, MD ^bk, Vincent Khoo, MD ^b,^g,^j,^bb, Hans Lilja, MD ^bl,^bm, Geoffrey J Lindeman, PhD ^j,^u,^bn, Jan Lubinski, MD ^bo, Karol Axcrona, PhD ^bp, Christos Mikropoulos, MD ^bq, Anita V Mitra, MD ^br, Clare Moynihan, MSc ^a, Holly Ni Raghallaigh, MBChB ^a, Gad Rennert, MD ^bs, Rebecca Collier, MSc ^t,
The IMPACT Study Collaborators^{^†}
Collaborators are listed in the Supplementary Material)
Lisa Adams, Julian Adlard, Rosa Alfonso, Saira Ali, Angela Andrew, Luís Araújo, Nazya Azam, Darran Ball, Queenstone Barker, Alon Basevitch, Barbara Benton, Cheryl Berlin, Nicola Bermingham, Leah Biller, Angela Bloss, Matilda Bradford, Nicola Bradshaw, Amy Branson, Charles Brendler, Maria Brennan, Barbara Bulman, Lucy Burgess, Declan Cahill, Alice Callard, Nuria Calvo Verges, Marta Cardoso, Vanda Carter, Mario Catanzaro, Anthony Chamberlain, Cyril Chapman, Michael Chong, Caroline Clark, Virginia Clowes, Lyn Cogley, Trevor Cole, Cecilia Compton, Tom Conner, Sandra Cookson, Philip Cornford, Philandra Costello, Laura Coulier, Michaela Davies, Christopher Dechet, Bianca DeSouza, Gemma Devlin, Fiona Douglas, Emma Douglas, Darshna Dudakia, Alexis Duncan, Natalie Ellery, Sarah Everest, Sue Freemantle, Mark Frydenberg, Debbie Fuller, Camila Gabriel, Madeline Gale, Lynda Garcia, Simona Gay, Elena Genova, Angela George, Demetra Georgiou, Alexandra Gisbert, Margaret Gleeson, Wayne Glover, Vincent Gnanapragasam, Sally Goff, David Goldgar, Nuno Gonçalves, Selina Goodman, Jennifer Gorrie, Hannah Gott, Anna Grant, Catherine Gray, Julie Griffiths, Karin Gupwell, Jana Gurasashvili, Eldbjørg Hanslien, Sigurdis Haraldsdottir, Rachel Hart, Catherine Hartigan, Lara Hawkes, Tricia Heaton, Alex Henderson, Rui Henrique, Kathrine Hilario, Kathryn Hill, Peter Hulick, Clare Hunt, Melanie Hutchings, Rita Ibitoye, Thomas Inglehearn, Joanna Ireland, Farah Islam, Siti Ismail, Chris Jacobs, Denzil James, Sharon Jenkins, Irene Jobson, Anne Johnstone, Oliver Jones, Sagi Josefsberg Ben-Yehoshua, Beckie Kaemba, Karen Kaul, Zoe Kemp, Netty Kinsella, Margaret Klehm, Roger Kockelbergh, Kelly Kohut, Monika Kosicka-Slawinska, Anjana Kulkarni, Pardeep Kumar, Jimmy Lam, Mandy LeButt, Dan Leibovici, Ramona Lim, Lauren Limb, Claire Lomas, Mark Longmuir, Consol López, Tiziana Magnani, Sofia Maia, Jessica Maiden, Alison Male, Merrie Manalo, Phoebe Martin, Donna McBride, Michael McGuire, Romayne McMahon, Claire McNally, Terri McVeigh, Ehud Melzer, Mark Mencias, Catherine Mercer, Gillian Mitchell, Josefina Mora, Catherine Morton, Cathryn Moss, Morgan Murphy, Declan Murphy, Shumi Mzazi, Maria Nadolski, Anna Newlin, Pedro Nogueira, Rachael O’Keefe, Karen O’Toole, Shona O’Connell, Chris Ogden, Linda Okoth, Jorge Oliveira, Edgar Paez, Joan Palou, Linda Park, Nafisa Patel, João Paulo Souto, Allison Pearce, Ana Peixoto, Kimberley Perez, Lara Petelin, Gabriella Pichert, Charlotte Poile, Alison Potter, Nadia Preitner, Helen Purnell, Ellen Quinn, Paolo Radice, Brigette Rankin, Katie Rees, Caroline Renton, Kate Richardson, Peter Risby, Jason Rogers, Maggie Ruderman, April Ruiz, Anaar Sajoo, Natale Salvatore, Victoria Sands, Francesco Sanguedolce, Ayisha Sattar, Kathryn Saunders, Lyn Schofield, Rodney Scott, Anne Searle, Ravinder Sehra, Christina Selkirk, Kylie Shackleton, Sue Shanley, Adam Shaw, Daniel Shevrin, Hannah Shipman, Zahirah Sidat, Kas Siguake, Kate Simon, Courtney Smyth, Lesley Snadden, Nita Solanky, Joyce Solomons, Margherita Sorrentino, Barbara Stayner, Robert Stephenson, Elena Stoffel, Maggie Thomas, Alan Thompson, Lizzie Tidey, Marc Tischkowitz, Audrey Torokwa, Sharron Townshend, Katy Treherne, Karen Tricker, Quoc-Dien Trinh, Vishakha Tripathi, Clare Turnbull, Riccardo Valdagni, Nicholas Van As, Vickie Venne, Lizzie Verdon, Marco Vitellaro, Kristen Vogel, Lisa Walker, Amy Watford, Cathy Watt, Ilana Weintroub, Shelly Weiss, Scott Weissman, Michelle Weston, Jennifer Wiggins, Gillian Wise, Christopher Woodhouse, Pembe Yesildag, Alice Youngs, Matthew Yurgelun, Fabiana Zollo

Judith Offman, PhD ^bt, Zsofia Kote-Jarai, PhD ^a, Rosalind A Eeles, PhD ^a,^b,⁎
^a Oncogenetics Team, Institute of Cancer Research, London, UK
^b Cancer Genetics Unit & Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK
^c Clinical Genetics Unit, Birmingham Women’s Hospital, Birmingham, UK
^d Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
^e Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, Manchester, UK
^f North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Harrow, UK
^g St George’s Hospital, Tooting, London, UK
^h Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
ⁱ The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
^j Department of Medicine, The University of Melbourne, Parkville, VIC, Australia
^k Division of Population Sciences, Dana Farber Cancer Institute, Boston, MA, USA
^l Brigham and Women’s Hospital, Boston, MA, USA
^m University Hospital Southampton, Southampton, UK
ⁿ Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK
^o Department of Genetics, University of Leicester, Leicester, UK
^p University Hospitals Leicester, Leicester, UK
^q Genetics Department and Research Center, Portuguese Oncology Institute (IPO Porto), Porto, Portugal
^r Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal
^s Clinical Genetics Service, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
^t Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK
^u Parkville Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC, Australia
^v Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, VIC, Australia
^w Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia
^x Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
^y The Genetic Institute, Kaplan Medical Center, Rehovot, Israel
^z Biology Department, Ariel University, Ariel, Israel
^aa North East Thames Regional Genetics Service, Institute of Child Health, London, UK
^ab Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK
^ac Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
^ad Clinical Genetics Service, Liverpool Women’s Hospital, Liverpool, UK
^ae Peninsular Genetics, Derriford Hospital, Plymouth, UK
^af Royal Devon and Exeter Hospital, Exeter, UK
^ag Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, WA, Australia
^ah Department of Paediatrics, University of Western Australia, Perth, WA, Australia
^ai Hunter Family Cancer Service, Waratah, NSW, Australia
^aj University of New South Wales, St Vincent’s Clinical School, NSW, Australia
^ak Cancer Genetics Clinic, The Kinghorn Cancer Centre, St Vincent’s Hospital, Sydney, NSW, Australia
^al Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
^am John and Carol Walter Center for Urological Health, Division of Urology, NorthShore University HealthSystem, Evanston, IL, USA
^an Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK
^ao Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
^ap Hospital de Sant Pau, Barcelona, Spain
^aq St Michael’s Hospital, Bristol, UK
^ar Duke Cancer Institute and Duke University School of Medicine, Durham, NC, USA
^as Monash Health, Clayton, VIC, Australia
^at Monash University, Clayton, VIC, Australia
^au University of Exeter Medical School, St Luke’s Campus, Exeter, UK
^av West of Scotland Genetic Service, Queen Elizabeth University Hospital, Glasgow, UK
^aw East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Trust, Cambridge, UK
^ax New Cross Hospital, Wolverhampton, UK
^ay Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, Netherlands
^az Department of Urology, Erasmus Cancer Institute, Erasmus University Medical Centre, Rotterdam, Netherlands
^ba Spanish National Cancer Research Center, Madrid, Spain
^bb Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, Surrey, UK
^bc Instituto Nacional de Cancer Jose de Alencar Gomes da Silva INCA, Rio de Janeiro, Brazil
^bd Faculty of Medicine, University of Southampton, Southampton, UK
^be Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
^bf Imperial College Healthcare NHS Trust, London, UK
^bg HCA Pathology Laboratories, London, UK
^bh University Hospital of Umeå, Umeå, Sweden
^bi Churchill Hospital, Headington, Oxford, UK
^bj Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
^bk Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland
^bl Department of Translational Medicine, Lund University, Malmö, Sweden
^bm Department of Laboratory Medicine, Department of Surgery, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
^bn Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
^bo International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
^bp Department of Urology, Akershus University Hospital, Lørenskog, Norway
^bq Royal Surrey County Hospital, Guildford, UK
^br University College London Hospitals NHS Foundation Trust, London, UK
^bs CHS National Cancer Control Center, Carmel Medical Center, Haifa, Israel
^bt School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, Guy’s Cancer Centre, Guy’s Hospital, London, UK

^*Correspondence to: Prof Rosalind Eeles, Oncogenetics Team, The Institute of Cancer Research, Sutton, SM2 5NG, UKOncogenetics TeamThe Institute of Cancer ResearchSuttonSM2 5NGUK

Summary

Background

Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants.

Methods

The IMPACT study is an international, prospective study. Men aged 40–69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years’ annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher’s exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.

Findings

Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1–2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3–7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0–2·6), MSH6 carriers was 3·0% (four of 135; 0·8–7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0–68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3–46·0).

Interpretation

After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.

Funding

Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Le texte complet de cet article est disponible en PDF.

Plan

Introduction

Methods

Study design and participants

Procedures

Outcomes

Statistical analysis

Role of the funding source

Results

Discussion

Data sharing

Export

Vol 22 - N° 11

P. 1618-1631 - novembre 2021 Retour au numéro

Article précédent

Camrelizumab plus apatinib in patients with high-risk chemorefractory or relapsed gestational trophoblastic neoplasia (CAP 01): a single-arm, open-label, phase 2 trial
Hongyan Cheng, Liju Zong, Yujia Kong, Xiaoyu Wang, Yu Gu, Wei Cang, Jun Zhao, Xirun Wan, Junjun Yang, Yang Xiang

| Article suivant

National health system characteristics, breast cancer stage at diagnosis, and breast cancer mortality: a population-based analysis
Catherine Duggan, Dario Trapani, André M Ilbawi, Elena Fidarova, Mathieu Laversanne, Giuseppe Curigliano, Freddie Bray, Benjamin O Anderson

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

connectez-vous ou créez un compte

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study - 02/11/21

Summary

Background

Methods

Findings

Interpretation

Funding

Plan

Export citations

Fichier

Contenu

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL