Identifying Patients at Risk of Early Lethal Prostate Cancer by Integrating Family History, Polygenic Risk Score, Rare Variants in DNA Repair Genes, and Lifestyle Factors

In men with prostate cancer, one-third of deaths occur before the age of 75 yr. There remains a need to characterize heritable and environmental risk factors for these early deaths. This study aims to improve risk stratification for early lethal outcomes among prostate cancer patients with genetic factors beyond family history and with modifiable factors. This study included 966 prostate cancer patients, enriched for high-risk localized disease and with germline genetic data, in two prospective cohorts. Three genetic factors (family history of prostate cancer, polygenic risk score [PRS] in the top 20%, and rare variants in DNA repair genes) and a lifestyle score were examined for their association with early lethal (metastases/prostate cancer death before the age of 75 yr) compared with nonlethal cases using logistic regression and by calculating 10-yr lethal disease risks. In total, 289 lethal, including 77 early lethal, cases were observed (median age at the end follow-up: 84.3 yr). Early lethal cases had higher percentages of men with a family history (23% vs 15%), a high PRS (47% vs 36%), and rare variants (14% vs 7.8%). Having two or more genetic factors was strongly associated with increased odds of early lethal disease (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.8-7.0) and linked to higher 10-yr lethal disease risks in high-risk localized patients diagnosed before the age of 75 yr. Healthy men with none of the genetic factors had the lowest odds of early lethal disease (OR, 0.3: 95% CI, 0.1-0.7), compared with unhealthy men with any genetic factor. The pattterns were similar for early fatal disease. The study had limited data for more detailed analyses. The combination of family history with rare variants, a PRS, and lifestyle factors may improve the identification of prostate cancer patients at risk of early lethal and fatal disease.