Abstract 261: Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis
Authors: Pashayan Nora , Duffy Stephen W. , Neal David E. , Hamdy Freddie , Donovan Jenny , Martin Richard M. , Harrington Patricia , Benlloch Sara , Olama Ali A. Al , Shah Mitul , Kote-Jarai Zsofia , Easton Douglas F. , Eeles Rosalind , Pharoah Paul D. 
Published: May 2015

Abstract
Purpose
Personalized screening for prostate cancer with eligibility for screening based on an absolute risk that is dependent on age and polygenic risk-profile would improve the efficiency of the screening program. However, yet there is no evidence from empirical data that such personalized screening strategy would reduce harms of screening, by reducing overdiagnosis and subsequent overtreatment. This study aims at quantifying the probabilities of overdiagnosis by polygenic risk profile.
Methods
We calculated polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,729 men aged 50-69 years (9,404 men identified with prostate cancer and 8,325 with no cancer) derived from three UK-based ongoing studies: Prostate Testing for Cancer and Treatment (ProtecT), Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH), and UK Genetic Prostate Cancer Study (UKGPCS). We estimated absolute risk of developing prostate cancer dependent on age and polygenic profile for each man. For each quartile of polygenic risk score distribution among the population, we calculated the observed prevalence of screen-detected prostate cancer within ProtecT and the mean absolute risk for clinically detected cancers within SEARCH and UKGPCS. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence is a combination of underlying incidence, the duration of the preclinical detectable period (sojourn time), test sensitivity, and overdiagnosis.
Results
The polygenic risk score among the population had log-normal distribution with variance of 0.40, with polygenic risk score of -0.63, -0.20, and 0.23 at 25th, 50th and 75th percentile respectively. Quartiles 1 to 4 had 17%, 21%, 25% and 37% of the cases respectively. From the lowest to highest quartile of risk, 42%, 29%, 25% and 19% of the prevalent screen-detected cancers were likely to be overdiagnosed cancers. The proportion of overdiagnosed cases decreased with increasing polygenic risk, with 50% drop in overdiagnosis between the lowest and the highest polygenic risk quartiles.
Conclusion
Targeting screening to men at higher polygenic risk would reduce the problem of overdiagnosis in prostate cancer.
Citation Format: Nora Pashayan, Stephen W. Duffy, David E. Neal, Freddie Hamdy, Jenny Donovan, Richard M. Martin, Patricia Harrington, Sara Benlloch, Ali A. Al Olama, Mitul Shah, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind Eeles, Paul D. Pharoah. Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 261. doi:10.1158/1538-7445.AM2014-261