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A genetic hazard score to personalize prostate cancer screening, applied to population data

Background Genetic risk stratification may inform decisions of whether—and when—a man should undergo prostate cancer (PCa) screening. We previously validated a polygenic hazard score (PHS), a weighted sum of 54 single-nucleotide polymorphism genotypes, for accurate prediction of age of onset of aggressive PCa and improved screening performance. We now assess the potential impact of PHS-informed screening. Methods United Kingdom population data were fit to a continuous model of age-specific PCa incidence. Using hazard ratios estimated from ProtecT trial data, age-specific incidence rates were calculated for percentiles of genetic risk. Incidence of higher-grade PCa (Gleason≥7) was estimated from age-specific data from the linked CAP trial. PHS and incidence data were combined to give a risk-equivalent age, when a man with a given PHS percentile will have risk of higher-grade PCa equivalent to that of a typical man at age 50 (50-years standard). Positive predictive value (PPV) of PSA testing was calculated using PHS-adjusted (PCa-risk-equivalent age) groups identified from ProtecT. Results Expected age of onset of higher-grade PCa is modulated by 19 years between the 1st and 99th PHS percentiles. A man with PHS in the 99th percentile reaches 50-years-standard risk at age 41; conversely, a man in the 1st percentile reaches this risk at age 60. PPV of PSA was higher for men with higher PHS-adjusted age. Conclusions PHS informs PCa screening strategies with individualized estimates of risk-equivalent age for higher-grade PCa. Screening initiation could be adjusted according to a man’s genetic hazard score, improving PPV of PSA screening.