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. 2024 Jul 1;7(7):e2420034.
doi: 10.1001/jamanetworkopen.2024.20034.

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

Anna Plym  1   2   3 , Yiwen Zhang  2 , Konrad H Stopsack  2   4 , Emilio Ugalde-Morales  1 , Tyler M Seibert  5 , David V Conti  6 , Christopher A Haiman  6 , Aris Baras  7 , Tanja Stocks  8 , Isabel Drake  9   10 , Kathryn L Penney  2   11 , Edward Giovannucci  2   12 , Adam S Kibel  3 , Fredrik Wiklund  1 , Lorelei A Mucci  2 ; Regeneron Genetics Center
Affiliations

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

Anna Plym et al. JAMA Netw Open. .

Abstract

Importance: Prostate cancer, a leading cause of cancer death among men, urgently requires new prevention strategies, which may involve targeting men with an underlying genetic susceptibility.

Objective: To explore differences in risk of early prostate cancer death among men with higher vs lower genetic risk to inform prevention efforts.

Design, setting, and participants: This cohort study used a combined analysis of genotyped men without prostate cancer at inclusion and with lifestyle data in 2 prospective cohort studies in Sweden and the US, the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS), followed up from 1991 to 2019. Data were analyzed between April 2023 and April 2024.

Exposures: Men were categorized according to modifiable lifestyle behaviors and genetic risk. A polygenic risk score above the median or a family history of cancer defined men at higher genetic risk (67% of the study population); the remaining men were categorized as being at lower genetic risk.

Main outcomes and measures: Prostate cancer death analyzed using time-to-event analysis estimating hazard ratios (HR), absolute risks, and preventable deaths by age.

Results: Among the 19 607 men included for analysis, the median (IQR) age at inclusion was 59.0 (53.0-64.7) years (MDCS) and 65.1 (58.0-71.8) years (HPFS). During follow-up, 107 early (by age 75 years) and 337 late (after age 75 years) prostate cancer deaths were observed. Compared with men at lower genetic risk, men at higher genetic risk had increased rates of both early (HR, 3.26; 95% CI, 1.82-5.84) and late (HR, 2.26; 95% CI, 1.70-3.01) prostate cancer death, and higher lifetime risks of prostate cancer death (3.1% vs 1.3% [MDCS] and 2.3% vs 0.6% [HPFS]). Men at higher genetic risk accounted for 94 of 107 early prostate cancer deaths (88%), of which 36% (95% CI, 12%-60%) were estimated to be preventable through adherence to behaviors associated with a healthy lifestyle (not smoking, healthy weight, high physical activity, and a healthy diet).

Conclusions and relevance: In this 20-year follow-up study, men with a genetic predisposition accounted for the vast majority of early prostate cancer deaths, of which one-third were estimated to be preventable. This suggests that men at increased genetic risk should be targeted in prostate cancer prevention strategies.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Seibert reported receiving grants from GE Healthcare; personal fees from Janssen, Varian Medical Systems, and WebMD; and stock options and personal fees from CorTechs Labs outside the submitted work. Dr Kibel reported receiving personal fees from Janssen, Pfizer, Bristol Myers Squibb, Cellvax, Merck, and Roche; and serving as a consultant for Bristol Myers Squibb and Candel outside the submitted work. Dr Mucci reported receiving grants from Bayer, Astra Zeneca, and Janssen outside the submitted work; serving on the Scientific Advisory Board and holding equity in Convergent Therapeutics; and providing expert testimony for Bayer outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Absolute Risk (Cumulative Incidence) of Prostate Cancer Death Across the Age Span According to Different Genetic Risk Categories and the Lifestyle Score in the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-Up Study (HPFS)
The 3 higher genetic risk categories may be potentially overlapping. Percentages are presented in a tabular format in eTable 5 in Supplement 1. FH indicates family history of cancer; PRS, polygenic risk score.
See this image and copyright information in PMC

References

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