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.
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.
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).
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.
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.
The Lancet. Oncology. 2021 Oct 19 [Epub ahead of print]
Elizabeth K Bancroft, Elizabeth C Page, Mark N Brook, Sarah Thomas, Natalie Taylor, Jennifer Pope, Jana McHugh, Ann-Britt Jones, Questa Karlsson, Susan Merson, Kai Ren Ong, Jonathan Hoffman, Camilla Huber, Lovise Maehle, Eli Marie Grindedal, Astrid Stormorken, D Gareth Evans, Jeanette Rothwell, Fiona Lalloo, Angela F Brady, Marion Bartlett, Katie Snape, Helen Hanson, Paul James, Joanne McKinley, Lyon Mascarenhas, Sapna Syngal, Chinedu Ukaegbu, Lucy Side, Tessy Thomas, Julian Barwell, Manuel R Teixeira, Louise Izatt, Mohnish Suri, Finlay A Macrae, Nicola Poplawski, Rakefet Chen-Shtoyerman, Munaza Ahmed, Hannah Musgrave, Nicola Nicolai, Lynn Greenhalgh, Carole Brewer, Nicholas Pachter, Allan D Spigelman, Ashraf Azzabi, Brian T Helfand, Dorothy Halliday, Saundra Buys, Teresa Ramon Y Cajal, Alan Donaldson, Kathleen A Cooney, Marion Harris, John McGrath, Rosemarie Davidson, Amy Taylor, Peter Cooke, Kathryn Myhill, Matthew Hogben, Neil K Aaronson, Audrey Ardern-Jones, Chris H Bangma, Elena Castro, David Dearnaley, Alexander Dias, Tim Dudderidge, Diana M Eccles, Kate Green, Jorunn Eyfjord, Alison Falconer, Christopher S Foster, Henrik Gronberg, Freddie C Hamdy, Oskar Johannsson, Vincent Khoo, Hans Lilja, Geoffrey J Lindeman, Jan Lubinski, Karol Axcrona, Christos Mikropoulos, Anita V Mitra, Clare Moynihan, Holly Ni Raghallaigh, Gad Rennert, Rebecca Collier, IMPACT Study Collaborators , Judith Offman, Zsofia Kote-Jarai, Rosalind A Eeles
Oncogenetics Team, Institute of Cancer Research, London, UK; Cancer Genetics Unit & Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK., Oncogenetics Team, Institute of Cancer Research, London, UK., Cancer Genetics Unit & Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK., Clinical Genetics Unit, Birmingham Women's Hospital, Birmingham, UK., Department of Medical Genetics, Oslo University Hospital, Oslo, Norway., Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, Manchester, UK., North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Harrow, UK., St George's Hospital, Tooting, London, UK., Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC, Australia., Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., Division of Population Sciences, Dana Farber Cancer Institute, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA., Division of Population Sciences, Dana Farber Cancer Institute, Boston, MA, USA., University Hospital Southampton, Southampton, UK; Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK., Department of Genetics, University of Leicester, Leicester, UK; University Hospitals Leicester, Leicester, UK., Genetics Department and Research Center, Portuguese Oncology Institute (IPO Porto), Porto, Portugal; Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal., Clinical Genetics Service, Guy's and St Thomas' NHS Foundation Trust, London, UK., Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK., Department of Medicine, The University of Melbourne, Parkville, VIC, Australia; Parkville Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC, Australia; Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, VIC, Australia., Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, Australia; Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia., The Genetic Institute, Kaplan Medical Center, Rehovot, Israel; Biology Department, Ariel University, Ariel, Israel., North East Thames Regional Genetics Service, Institute of Child Health, London, UK., Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Leeds, UK., Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Clinical Genetics Service, Liverpool Women's Hospital, Liverpool, UK., Peninsular Genetics, Derriford Hospital, Plymouth, UK; Royal Devon and Exeter Hospital, Exeter, UK., Genetic Services of Western Australia, King Edward Memorial Hospital, Subiaco, WA, Australia; Department of Paediatrics, University of Western Australia, Perth, WA, Australia., Hunter Family Cancer Service, Waratah, NSW, Australia; University of New South Wales, St Vincent's Clinical School, NSW, Australia; Cancer Genetics Clinic, The Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia., Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK., John and Carol Walter Center for Urological Health, Division of Urology, NorthShore University HealthSystem, Evanston, IL, USA., Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK., Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Hospital de Sant Pau, Barcelona, Spain., St Michael's Hospital, Bristol, UK., Duke Cancer Institute and Duke University School of Medicine, Durham, NC, USA., Monash Health, Clayton, VIC, Australia; Monash University, Clayton, VIC, Australia., Royal Devon and Exeter Hospital, Exeter, UK; University of Exeter Medical School, St Luke's Campus, Exeter, UK., West of Scotland Genetic Service, Queen Elizabeth University Hospital, Glasgow, UK., East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Trust, Cambridge, UK., New Cross Hospital, Wolverhampton, UK., Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, Netherlands., Department of Urology, Erasmus Cancer Institute, Erasmus University Medical Centre, Rotterdam, Netherlands., Spanish National Cancer Research Center, Madrid, Spain., Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, Surrey, UK., Instituto Nacional de Cancer Jose de Alencar Gomes da Silva INCA, Rio de Janeiro, Brazil., University Hospital Southampton, Southampton, UK., Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK; Faculty of Medicine, University of Southampton, Southampton, UK., Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Imperial College Healthcare NHS Trust, London, UK., HCA Pathology Laboratories, London, UK., University Hospital of Umeå, Umeå, Sweden., Churchill Hospital, Headington, Oxford, UK; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK., Landspitali - the National University Hospital of Iceland, Reykjavik, Iceland., Cancer Genetics Unit & Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK; St George's Hospital, Tooting, London, UK; Department of Medicine, The University of Melbourne, Parkville, VIC, Australia; Division of Radiotherapy and Imaging, The Institute of Cancer Research, Sutton, Surrey, UK., Department of Translational Medicine, Lund University, Malmö, Sweden; Department of Laboratory Medicine, Department of Surgery, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA., Department of Medicine, The University of Melbourne, Parkville, VIC, Australia; Parkville Familial Cancer Centre, The Royal Melbourne Hospital, Parkville, VIC, Australia; Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia., International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland., Department of Urology, Akershus University Hospital, Lørenskog, Norway., Royal Surrey County Hospital, Guildford, UK., University College London Hospitals NHS Foundation Trust, London, UK., CHS National Cancer Control Center, Carmel Medical Center, Haifa, Israel., 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., Oncogenetics Team, Institute of Cancer Research, London, UK; Cancer Genetics Unit & Academic Urology Unit, Royal Marsden NHS Foundation Trust, London, UK. 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