Addition of a Genetic Risk Score for Identification of Men with a Low Prostate-specific Antigen Level in Midlife at Risk of Developing Lethal Prostate Cancer

Men with a low prostate-specific antigen (PSA) level (<1 ng/ml) in midlife may extend the rescreening interval (if aged 40–59 yr) or forgo future PSA screening (if aged >60 yr) owing to their low risk of aggressive prostate cancer (PCa). However, there is a subset of men who develop lethal PCa despite low baseline PSA. We investigated how a PCa polygenic risk score (PRS) in addition to baseline PSA impacts the prediction of lethal PCa among 483 men aged 40–70 yr from the Physicians’ Health Study followed over a median of 33 yr. We examined the association of the PRS with the risk of lethal PCa (lethal cases vs controls) using logistic regression adjusted for baseline PSA. The PCa PRS was associated with risk of lethal PCa (odds ratio per 1 standard deviation in PRS [OR] 1.79, 95% confidence interval [CI] 1.28–2.49). The association between the PRS and lethal PCa was stronger for those with PSA <1 ng/ml (OR 2.23, 95% CI 1.19–4.21) than for men with PSA ≥1 ng/ml (OR 1.61, 95% CI 1.07–2.42). Our PCa PRS improved the identification of men with PSA <1 ng/ml at greater risk of future lethal PCa who should consider ongoing PSA testing. PATIENT SUMMARY: A subset of men develop fatal prostate cancer despite having low prostate-specific antigen (PSA) levels in middle age. A risk score based on multiple genes can help in predicting men who may be at risk of developing lethal prostate cancer and who should be advised to have regular PSA measurements.