Please use this identifier to cite or link to this item: https://ninho.inca.gov.br/jspui/handle/123456789/12856
Title: A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study
Authors: Bancroft, Elizabeth
Page, Elizabeth C
Brook, Mark
Thomas, Sarah
Taylor, Natalie
Pope, Jennifer
McHugh, Jana
Jones, Ann-Britt
Karlsson, Questa
Merson, Susan
Ong, Kai Ren
Hoffman, Jonathan
Huber, Camilla
Maehle, Lovise Olaug
Grindedal, Eli Marie
Stormorken, Astrid
Evans, Dafydd Gareth Richard
Rothwell, Jeanette
Lalloo, Fiona
Brady, Angela
Bartlett, Marion
Snape, Katie
Hanson, Helen
James, Paul
McKinley, Joanne
Mascarenhas, Lyon
Syngal, Sapna
Ukaegbu, Chinedu
Side, Lucy
Thomas, Tessy
Barwell, Julian
Teixeira, Manuel António Rodrigues
Izatt, Louise
Suri, Mohnish
Macrae, Finlay
Poplawski, Nicola
Chen-Shtoyerman, Rakefet
Ahmed, Munaza
Musgrave, Hannah
Nicolai, Nicola
Greenhalgh, Lynn
Brewer, Carole
Pachter, Nicholas
Spigelman, Allan
Azzabi, Ashraf
Helfand, Brian
Halliday, Dorothy
Buys, Saundra
Cajal, Teresa Ramon y
Donaldson, Alan
Cooney, Kathleen
Harris, Marion
McGrath, John
Davidson, Rosemarie
Taylor, Amy
Cooke, Peter
Myhill, Kathryn
Hogben, Matthew
Aaronson, Neil K.
Ardern-Jones, Audrey
Bangma, Chris H.
Castro, Elena
Dearnaley, David
Dias, Alexander Edwin Teixeira
Dudderidge, Tim
Eccles, Diana M.
Green, Kate
Eyfjord, Jorunn
Falconer, Alison
Foster, Christopher S.
Gronberg, Henrik
Hamdy, Freddie C.
Johannsson, Oskar
Khoo, Vincent
Lilja, Hans
Lindeman, Geoffrey J
Lubinski, Jan
Axcrona, Karol
Mikropoulos, Christos
Mitra, Anita
Moynihan, Clare
Raghallaigh, Holly Ni
Rennert, Gad
Collier, Rebecca
Offman, Judith
Kote-Jarai, Zsofia
Eeles, Rosalind
Keywords: Neoplasias da Próstata
Prostatic Neoplasms
Neoplasias de la Próstata
Antígeno Prostático Específico
Prostate-Specific Antigen
Issue Date: 2021
Publisher: The Lancet Oncology
Citation: BANCROFT, Elizabeth et al. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. The Lancet Oncology, [s. l.], v. 22, n. 11, p. 1618-1631, nov. 2021. DOI: doi.org/10.1016/ S1470-2045(21)00522-2.
Series/Report no.: v. 22;n. 11
Abstract: 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 earlyonset 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 noncarriers 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.
Description: v. 22, n. 11, p. 1618-1631, nov. 2021
URI: https://ninho.inca.gov.br/jspui/handle/123456789/12856
ISSN: 1470-2045
Appears in Collections:Artigos de Periódicos da Pesquisa Experimental e Translacional



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