A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study
Por:
Bancroft, EK, Page, EC, Brook, MN, Thomas, S, Taylor, N, Pope, J, McHugh, J, Jones, AB, Karlsson, Q, Merson, S, Ong, KR, Hoffman, J, Huber, C, Maehle, L, Grindedal, EM, Stormorken, A, Evans, DG, Rothwell, J, Lalloo, F, Brady, AF, Bartlett, M, Snape, K, Hanson, H, James, P, McKinley, J, Mascarenhas, L, Syngal, S, Ukaegbu, C, Side, L, Thomas, T, Barwell, J, Teixeira, MR, Izatt, L, Suri, M, Macrae, FA, Poplawski, N, Chen-Shtoyerman, R, Ahmed, M, Musgrave, H, Nicolai, N, Greenhalgh, L, Brewer, C, Pachter, N, Spigelman, AD, Azzabi, A, Helfand, BT, Halliday, D, Buys, S, Cajal, TRY, Donaldson, A, Cooney, KA, Harris, M, McGrath, J, Davidson, R, Taylor, A, Cooke, P, Myhill, K, Hogben, M, Aaronson, NK, Ardern-Jones, A, Bangma, CH, Castro, E, Dearnaley, D, Dias, A, Dudderidge, T, Eccles, DM, Green, K, Eyfjord, J, Falconer, A, Foster, CS, Gronberg, H, Hamdy, FC, Johannsson, O, Khoo, V, Lilja, H, Lindeman, GJ, Lubinski, J, Axcrona, K, Mikropoulos, C, Mitra, AV, Moynihan, C, Raghallaigh, HN, Rennert, G, Collier, R, Offman, J, Kote-Jarai, Z, Eeles, RA
Publicada:
1 nov 2021
Ahead of Print:
1 nov 2021
Resumen:
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. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
Filiaciones:
Bancroft, EK:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Page, EC:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Brook, MN:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Thomas, S:
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Taylor, N:
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Pope, J:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
McHugh, J:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Jones, AB:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Karlsson, Q:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Merson, S:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Ong, KR:
Birmingham Womens Hosp, Clin Genet Unit, Birmingham, W Midlands, England
Hoffman, J:
Birmingham Womens Hosp, Clin Genet Unit, Birmingham, W Midlands, England
Huber, C:
Birmingham Womens Hosp, Clin Genet Unit, Birmingham, W Midlands, England
Maehle, L:
Oslo Univ Hosp, Dept Med Genet, Oslo, Norway
Grindedal, EM:
Oslo Univ Hosp, Dept Med Genet, Oslo, Norway
Stormorken, A:
Oslo Univ Hosp, Dept Med Genet, Oslo, Norway
Evans, DG:
Univ Manchester, Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Div Evolut & Genom Sci,Genom Med, Manchester, Lancs, England
Rothwell, J:
Univ Manchester, Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Div Evolut & Genom Sci,Genom Med, Manchester, Lancs, England
Lalloo, F:
Univ Manchester, Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Div Evolut & Genom Sci,Genom Med, Manchester, Lancs, England
Brady, AF:
London North West Univ Healthcare NHS Trust, North West Thames Reg Genet Serv, Harrow, Middx, England
Bartlett, M:
London North West Univ Healthcare NHS Trust, North West Thames Reg Genet Serv, Harrow, Middx, England
Snape, K:
St George Hosp, London, England
Hanson, H:
St George Hosp, London, England
James, P:
Peter MacCallum Canc Ctr, Parkville Familial Canc Ctr, Melbourne, Vic, Australia
Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic, Australia
Univ Melbourne, Dept Med, Parkville, Vic, Australia
McKinley, J:
Peter MacCallum Canc Ctr, Parkville Familial Canc Ctr, Melbourne, Vic, Australia
Mascarenhas, L:
Peter MacCallum Canc Ctr, Parkville Familial Canc Ctr, Melbourne, Vic, Australia
Syngal, S:
Brigham & Womens Hosp, Dana Farber Canc Inst, Div Populat Sci, 75 Francis St, Boston, MA 02115 USA
Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA
Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA
Ukaegbu, C:
Brigham & Womens Hosp, Dana Farber Canc Inst, Div Populat Sci, 75 Francis St, Boston, MA 02115 USA
Dana Farber Canc Inst, Div Populat Sci, Boston, MA 02115 USA
Side, L:
Univ Hosp Southampton, Southampton, Hants, England
Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England
Thomas, T:
Univ Hosp Southampton, Southampton, Hants, England
Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England
Barwell, J:
Univ Leicester, Dept Genet, Leicester, Leics, England
Univ Hosp Leicester, Leicester, Leics, England
Teixeira, MR:
Portuguese Oncol Inst IPO Porto, Genet Dept, Porto, Portugal
Portuguese Oncol Inst IPO Porto, Res Ctr, Porto, Portugal
Univ Porto, Biomed Sci Inst ICBAS, Porto, Portugal
Izatt, L:
Guys & St Thomas NHS Fdn Trust, Clin Genet Serv, London, England
Suri, M:
Nottingham Univ Hosp NHS Trust, Clin Genet Serv, Nottingham, England
Macrae, FA:
Univ Melbourne, Dept Med, Parkville, Vic, Australia
Royal Melbourne Hosp, Parkville Familial Canc Ctr, Parkville, Vic, Australia
Royal Melbourne Hosp, Colorectal Med & Genet, Parkville, Vic, Australia
Poplawski, N:
Royal Adelaide Hosp, Adult Genet Unit, Adelaide, SA, Australia
Univ Adelaide, Adelaide Med Sch, Adelaide, SA, Australia
Chen-Shtoyerman, R:
Kaplan Med Ctr, Genet Inst, Rehovot, Israel
Ariel Univ, Biol Dept, Ariel, Israel
Ahmed, M:
Inst Child Hlth, North East Thames Reg Genet Serv, London, England
Musgrave, H:
Leeds Teaching Hosp NHS Trust, Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England
Nicolai, N:
Fdn IRCCS Ist Nazl Tumori, Milan, Italy
Greenhalgh, L:
Liverpool Womens Hosp, Clin Genet Serv, Liverpool, Merseyside, England
Brewer, C:
Derriford Hosp, Peninsular Genet, Plymouth, Devon, England
Royal Devon & Exeter Hosp, Exeter, Devon, England
Pachter, N:
King Edward Mem Hosp, Genet Serv Western Australia, Subiaco, WA, Australia
Univ Western Australia, Dept Paediat, Perth, WA, Australia
Spigelman, AD:
Hunter Family Canc Serv, Waratah, NSW, Australia
Univ New South Wales, St Vincents Clin Sch, Sydney, NSW, Australia
St Vincents Hosp, Kinghorn Canc Ctr, Canc Genet Clin, Sydney, NSW, Australia
Azzabi, A:
Newcastle Upon Tyne Hosp NHS Fdn Trust, Northern Genet Serv, Newcastle Upon Tyne, Tyne & Wear, England
Helfand, BT:
NorthShore Univ HealthSyst, John & Carol Walter Ctr Urol Hlth, Div Urol, Evanston, IL USA
Halliday, D:
Oxford Univ Hosp NHS Trust, Oxford Ctr Genom Med, Oxford, England
Buys, S:
Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA
Cajal, TRY:
Hosp Santa Creu & Sant Pau, Barcelona, Spain
Donaldson, A:
St Michaels Hosp, Bristol, Avon, England
Cooney, KA:
Duke Canc Inst, Durham, NC USA
Duke Univ, Sch Med, Durham, NC USA
Harris, M:
Monash Hlth, Clayton, Vic, Australia
McGrath, J:
Royal Devon & Exeter Hosp, Exeter, Devon, England
Univ Exeter, Med Sch, St Lukes Campus, Exeter, Devon, England
Davidson, R:
Queen Elizabeth Univ Hosp, West Scotland Genet Serv, Glasgow, Lanark, Scotland
Taylor, A:
Cambridge Univ Hosp NHS Trust, East Anglian Med Genet Serv, Cambridge, England
Cooke, P:
New Cross Hosp, Wolverhampton, England
Myhill, K:
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Hogben, M:
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Aaronson, NK:
Netherlands Canc Inst, Div Psychosocial Res & Epidemiol, Amsterdam, Netherlands
Ardern-Jones, A:
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Bangma, CH:
Erasmus Univ, Erasmus Canc Inst, Dept Urol, Med Ctr, Rotterdam, Netherlands
Castro, E:
Spanish Natl Canc Res Ctr, Madrid, Spain
Dearnaley, D:
Inst Canc Res, Div Radiotherapy & Imaging, Sutton, Surrey, England
Dias, A:
Inst Nacl Canc Jose de Alencar Gomes da Silva INC, Rio De Janeiro, Brazil
Dudderidge, T:
Univ Hosp Southampton, Southampton, Hants, England
Eccles, DM:
Princess Anne Hosp, Wessex Clin Genet Serv, Southampton, Hants, England
Univ Southampton, Fac Med, Southampton, Hants, England
Green, K:
Univ Manchester, Manchester Univ NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Div Evolut & Genom Sci,Genom Med, Manchester, Lancs, England
Eyfjord, J:
Univ Iceland, Fac Med, Sch Hlth Sci, Reykjavik, Iceland
Falconer, A:
Imperial Coll Healthcare NHS Trust, London, England
Foster, CS:
HCA Pathol Labs, London, England
Gronberg, H:
Univ Hosp Umea, Umea, Sweden
Hamdy, FC:
Churchill Hosp, Oxford, England
Univ Oxford, Nuffield Dept Surg Sci, Oxford, England
Johannsson, O:
Natl Univ Hosp Iceland, Landspitali, Reykjavik, Iceland
Khoo, V:
St George Hosp, London, England
Inst Canc Res, Div Radiotherapy & Imaging, Sutton, Surrey, England
Lilja, H:
Lund Univ, Dept Translat Med, Malmo, Sweden
Mem Sloan Kettering Canc Ctr, Dept Lab Med, 1275 York Ave, New York, NY 10021 USA
Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA
Lindeman, GJ:
Univ Melbourne, Dept Med, Parkville, Vic, Australia
Royal Melbourne Hosp, Parkville Familial Canc Ctr, Parkville, Vic, Australia
Walter & Eliza Hall Inst Med Res, Canc Biol & Stem Cells Div, Parkville, Vic, Australia
Lubinski, J:
Pomeranian Med Univ, Int Hereditary Canc Ctr, Dept Genet & Pathol, Szczecin, Poland
Axcrona, K:
Akershus Univ Hosp, Dept Urol, Lorenskog, Norway
Mikropoulos, C:
Royal Surrey Cty Hosp, Guildford, Surrey, England
Mitra, AV:
Univ Coll London Hosp NHS Fdn Trust, London, England
Moynihan, C:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Raghallaigh, HN:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Rennert, G:
Carmel Hosp, CHS Natl Canc Control Ctr, Haifa, Israel
Collier, R:
Nottingham Univ Hosp NHS Trust, Clin Genet Serv, Nottingham, England
Offman, J:
Guys Hosp, Kings Coll London, Fac Life Sci & Med, Guys Canc Ctr,Sch Canc & Pharmaceut Sci, London, England
Kote-Jarai, Z:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Eeles, RA:
Inst Canc Res, Oncogenet Team, London, England
Royal Marsden NHS Fdn Trust, Canc Genet Unit, London, England
Royal Marsden NHS Fdn Trust London, Acad Urol Unit, London, England
Green Published, hybrid
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