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Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis.



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Pashayan, Nora 
Duffy, Stephen W 
Hamdy, Freddie C 
Donovan, Jenny L 


PURPOSE: This study aimed to quantify the probability of overdiagnosis of prostate cancer by polygenic risk. METHODS: We calculated the polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,012 men aged 50-69 years (9,404 men identified with prostate cancer and 7,608 with no cancer) derived from three UK-based ongoing studies. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence of screen-detected prostate cancer is a combination of underlying incidence, mean sojourn time (MST), test sensitivity, and overdiagnosis. RESULTS: Polygenic risk quartiles 1 to 4 comprised 9, 18, 25, and 48% of the cases, respectively. For a prostate-specific antigen test sensitivity of 80% and MST of 9 years, 43, 30, 25, and 19% of the prevalent screen-detected cancers in quartiles 1 to 4, respectively, were likely to be overdiagnosed cancers. Overdiagnosis decreased with increasing polygenic risk, with 56% decrease between the lowest and the highest polygenic risk quartiles. CONCLUSION: Targeting screening to men at higher polygenic risk could reduce the problem of overdiagnosis and lead to a better benefit-to-harm balance in screening for prostate cancer.



Aged, Algorithms, Biomarkers, Tumor, Early Detection of Cancer, Genetic Loci, Genetic Testing, Humans, Male, Medical Overuse, Middle Aged, Models, Genetic, Models, Statistical, Neoplasm Grading, Neoplasm Staging, Prostatic Neoplasms, Risk, Sensitivity and Specificity, United Kingdom

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Genet Med

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Elsevier BV
National Institute for Health Research (NIHR) (via University of Oxford) (HTA no. 96/20/99)
European Commission (223175)
N.P. is a Cancer Research UK Clinician Scientist Fellow. The COGS project was funded through a European Commission’s Seventh Framework Programme grant (agreement number: 223175- HEALTH-F2-2009–223175), Cancer Research UK (C490/A10124), the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge. The ProtecT study is supported by the UK National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme, HTA 96/20/99; ISRCTN20141297. The Comparative Arm of ProtecT (CAP) trial is funded by Cancer Research UK and the UK Department of Health (C11043/A4286, C18281/A8145, C18281/A11326, and C18281/A15064). UKGPCS is funded by Cancer Research UK and the National Cancer Research Network. The Biomedical Research Centre at the Institute of Cancer Research and Royal Marsden NHS Foundation Trust receive funding support from NIHR. SEARCH is funded by Cancer Research UK. We thank all the participants in these studies: members of the ProtecT study research group (Anne George, Michael Davis, and Athene Lane), Don Conroy, Craig Luccarini, Caroline Baynes, the SEARCH team, the Eastern Cancer Registration and Information Centre, and the general practitioners who assisted with recruitment. This work was supported by funding from the Cancer Research UK Clinician Scientist Fellowship.