Background: Guidelines for PSA screening in subgroups with increased risk of prostate cancer diagnosis due to race or genotype are underdeveloped. Our goal was to investigate types of increased prostate cancer risk and implications for targeted screening. Methods: We investigated computer simulation of subgroups with average and hypothetical increased risk(s) of onset of latent disease, progression, and/or cancer-specific death. For each subgroup, we predicted lifetime probabilities of overdiagnosis and life saved under more and less intensive PSA screening strategies. An application estimated risks of onset among BRCA1/2 mutation carriers in the Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls (IMPACT) study using maximum likelihood. Results: Our simulations implied PSA screening can save more lives among subgroups with increased risk than with average risk, but more intensive screening did not always improve harm-benefit trade-offs. IMPACT data were consistent with increased risks of onset among BRCA1 and BRCA2 mutation carriers [HR = 1.05; 95% confidence interval (CI), 0.63-1.59 and HR = 1.81; 95% CI, 1.14-2.78, respectively]. Our analysis suggests screening BRCA2 mutation carriers earlier and more frequently than the average-risk population, but a lower PSA threshold for biopsy is unlikely to improve outcomes. Conclusions: Effective screening in men with increased prostate cancer risk depends on the manner in which the risk is increased. More intensive screening is not always optimal. Impact: Guidelines for screening men at increased prostate cancer risk should consider the mechanism inducing the increased risk. Although the benefit of screening may be greater in men with increased risks, more intensive screening is not always appropriate.
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