Family History of Prostate and Breast Cancer Integrated with a Polygenic Risk Score Identifies Men at Highest Risk of Dying from Prostate Cancer before Age 75 Years

Abstract

Purpose: Family history of prostate cancer is one of the few universally accepted risk factors for prostate cancer. How much an assessment of inherited polygenic risk for prostate cancer adds to lifetime risk stratification beyond family history is unknown. Experimental Design: We followed 10,120 men in the Health Professionals Follow-up Study with existing genotype data for risk of prostate cancer and prostate cancer-specific death. We assessed to which extent family history of prostate or breast cancer combined with a validated polygenic risk score (PRS) including 269 prostate cancer risk variants identifies men at risk of prostate cancer and prostate cancer death across the age span. Results: During 20 years of follow-up, 1,915 prostate cancer and 166 fatal prostate cancer events were observed. Men in the top PRS quartile with a family history of prostate or breast cancer had the highest rate of both prostate cancer and prostate cancer-specific death. Compared with men at lowest genetic risk (bottom PRS quartile and no family history), the hazard ratio was 6.95 (95% CI 5.57-8.66) for prostate cancer and 4.84 (95% CI 2.59-9.03) for prostate cancer death. Men in the two upper PRS quartiles (50-100%) or with a family history of prostate or breast cancer (61.8% of the population) accounted for 97.5% of prostate cancer deaths by age 75 years. Conclusions: Our study shows that prostate cancer risk stratification on the basis of family history and inherited polygenic risk can identify men at highest risk of dying from prostate cancer before age 75 years.

Impact of Family History and Germline Genetic Risk Single Nucleotide Polymorphisms on Long-Term Outcomes of Favorable-Risk Prostate Cancer

“…Most recently, the combination of family history and PRS has been shown to stratify lifetime risk of developing prostate cancer among the overall HPFS cohort. 48 Our study has several limitations. Family history data were self-reported by study participants, and family history was only available for first-degree relatives.…”

“…Most recently, the combination of family history and PRS has been shown to stratify lifetime risk of developing prostate cancer among the overall HPFS cohort. 48…”

Early Prostate Cancer Deaths Among Men With Higher vs Lower Genetic Risk

“…We previously showed that men with a family history of prostate or breast cancer who were in the PRS 75% to 100% category had the highest lifetime risk, but the risk was nearly as high for men with a family history in the PRS 50% to 75% category. 7 A genetic risk-based screening program would be more powerful if we could identify the 20% of the population in which 90% of all prostate cancer deaths occurred. 32 Nevertheless, the available PRS already provides strong risk stratification for both early and late prostate cancer mortality as demonstrated in the current analysis, and may be informative for clinical practice.…”

“…Further work is required to refine the broad high genetic risk group. We previously showed that men with a family history of prostate or breast cancer who were in the PRS 75% to 100% category had the highest lifetime risk, but the risk was nearly as high for men with a family history in the PRS 50% to 75% category . A genetic risk-based screening program would be more powerful if we could identify the 20% of the population in which 90% of all prostate cancer deaths occurred …”

“…The definition of a positive family history of cancer was dependent on the data available and was defined as any cancer (MDCS) or prostate or breast cancer (HPFS) in at least 1 first-degree relative. Based on prior work, we defined a higher genetic risk as having a PRS above the median or a family history of cancer, with the remaining men categorized as being at lower genetic risk …”