A Polygenic Risk Score Predicts Incident Prostate Cancer Risk in Older Men but Does Not Select for Clinically Significant Disease

Simple Summary: Prostate cancer is a common disease in older men, yet current risk prediction models for prostate cancer do not discriminate between men at higher risk of aggressive, clinically significant disease compared to those with benign disease. If risk prediction models can be improved to identify the risk of clinically significant disease with more precision, it could help to reduce over-diagnosis, over-screening, and unnecessary invasive procedures, especially in older men. We examined whether the use of a genomic risk score improves the precision and discriminative ability of prostate cancer risk prediction in men aged 70 years and older. In a population of 5701 healthy older men, we found that the genomic risk score was strongly associated with future prostate cancer risk. However, we observed no association between the genomic risk score and more aggressive, clinically significant prostate cancer-thereby limiting the clinical utility of the genomic risk score. Despite the high prevalence of prostate cancer in older men, the predictive value of a polygenic risk score (PRS) remains uncertain in men aged >= 70 years. We used a 6.6 million-variant PRS to predict the risk of incident prostate cancer in a prospective study of 5701 men of European descent aged >= 70 years (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) clinical trial. The study endpoint was prostate cancer, including metastatic or non-metastatic disease, confirmed by an expert panel. After excluding participants with a history of prostate cancer at enrolment, we used a multivariable Cox proportional hazards model to assess the association between the PRS and incident prostate cancer risk, adjusting for covariates. Additionally, we examined the distribution of Gleason grade groups by PRS group to determine if a higher PRS was associated with higher grade disease. We tested for interaction between the PRS and aspirin treatment. Logistic regression was used to independently assess the association of the PRS with prevalent (pre-trial) prostate cancer, reported in medical histories. During a median follow-up time of 4.6 years, 218 of the 5701 participants (3.8%) were diagnosed with prostate cancer. The PRS predicted incident risk with a hazard ratio (HR) of 1.52 per standard deviation (SD) (95% confidence interval (CI) 1.33-1.74, p < 0.001). Men in the top quintile of the PRS distribution had an almost three times higher risk of prostate cancer than men in the lowest quintile (HR = 2.99 (95% CI 1.90-4.27), p < 0.001). However, a higher PRS was not associated with a higher Gleason grade groups. We found no interaction between aspirin treatment and the PRS for prostate cancer risk. The PRS was also associated with prevalent prostate cancer (odds ratio = 1.80 per SD (95% CI 1.65-1.96), p < 0.001).While a PRS for prostate cancer is strongly associated with incident risk in men aged >= 70 years, the clinical utility of the PRS as a biomarker is currently limited by its inability to select for clinically significant disease.