Abstract 822: Can the genetic risk of prostate cancer be attenuated by a healthy lifestyle
Authors: Plym Anna , Zhang Yiwen , Stopsack Konrad , Delcoigne Bénédicte , Kibel Adam S. , Giovannucci Edward , Penney Kathryn L. , Mucci Lorelei A. 
Published: July 2021

Abstract
Introduction: Inherited genetic factors contribute significantly to prostate cancer risk and explains 58% of the variability in prostate cancer incidence. It is unclear if the increased genetic risk of prostate cancer, including progression to lethal disease, can be offset by adherence to a healthy lifestyle.
Methods: Using a validated polygenic risk score (PRS) for overall prostate cancer, we quantified the genetic risk of prostate cancer in 10,443 men in the Health Professionals Follow-up Study for whom genotype data was available. We applied a validated lifestyle score for lethal prostate cancer (including healthy weight, vigorous physical activity, not smoking, and high consumption of tomatoes, fatty fish, and reduced intake of processed meat) and examined the incidence of overall and lethal (metastatic disease or prostate cancer-specific death) prostate cancer from the date of blood (1993-1999) or cheek collection (2005-2006) through 2014 (2016 for lethal disease). Multivariable Cox proportional hazards models were used to estimate the risk of overall and lethal prostate cancer by joint categories of genetic risk (PRS quartiles) and a time-varying lifestyle score (1-2: least healthy, 3: moderate healthy, and 4-6: most healthy). Both unweighted and inverse probability weighted (IPW) models (to account for possible bias arising from the genotype sampling design) were applied. Lifetime cumulative incidence was estimated using regression standardization.
Results: We observed 2,111 prostate cancer and 238 lethal prostate cancer events during a median follow-up of 18 and 22 years, respectively. The PRS enabled risk stratification for both overall and lethal prostate cancer, with men in the highest genetic risk quartile having a 5.4-fold increased risk of overall prostate cancer (HRipw = 5.39, 95% CI = 4.59-6.33) and a 3.5-fold increased risk of lethal prostate cancer (HRipw = 3.53, 95% CI = 2.34-5.32) compared with men in the lowest genetic risk quartile. Among men in the highest genetic risk quartile, adhering to a healthy lifestyle was significantly associated with a decreased risk of lethal prostate cancer (HRipw = 0.54, 95% CI = 0.31-0.94) compared with the least healthy lifestyle. Adhering to healthy lifestyle was not associated with a decreased risk of overall prostate cancer (HRipw = 1.01, 95% CI = 0.84-1.22). In the group of men with highest genetic risk, having a healthy lifestyle at study entry was associated with a lifetime cumulative incidence of lethal prostate cancer of 3%, lower than for men having the least healthy lifestyle (6%) and similar to the population average (3%).
Conclusion: In this large prospective cohort of US men, inherited genetic factors increased the risk of both overall and lethal prostate cancer. The associated decreased risk of aggressive disease in those with a favorable lifestyle may suggest that the excess genetic risk of lethal prostate cancer could be offset by adhering to a healthy lifestyle.
Citation Format: Anna Plym, Yiwen Zhang, Konrad Stopsack, Bénédicte Delcoigne, Adam S. Kibel, Edward Giovannucci, Kathryn L. Penney, Lorelei A. Mucci. Can the genetic risk of prostate cancer be attenuated by a healthy lifestyle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 822.