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, Judith Offman, Zsofia Kote-Jarai, Rosalind A Eeles, 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, Urology, Brook, Mark N [0000-0002-8969-2378], and Apollo - University of Cambridge Repository
Funder: Victorian Cancer Agency, Funder: NIHR Manchester Biomedical Research Centre, Funder: Cancer Research UK, Funder: Cancer Council Tasmania, Funder: Instituto de Salud Carlos III, Funder: Cancer Australia, Funder: NIHR Oxford Biomedical Research Centre, Funder: Fundación Científica de la Asociación Española Contra el Cáncer, Funder: Cancer Council South Australia, Funder: Swedish Cancer Society, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Institut Català de la Salut, Funder: Cancer Council Victoria, Funder: Prostate Cancer Foundation of Australia, Funder: National Institutes of Health, 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.