Prostate cancer remains a leading cause of cancer-related deaths in men.^1,2 Despite early detection and treatment, the mortality burden of early prostate cancer by 75 years of age remains high.^1,2 A recent cohort study has estimated that among men at higher genetic risk, one-third of early prostate cancer deaths were preventable by adherence to a healthy lifestyle, suggesting that prostate cancer prevention strategies should target men with higher genetic risk.¹

Prostate cancer is the 4th most common cancer globally, leading to around 400,000 deaths worldwide every year.² Despite continuous advancement in early detection and treatment for prostate cancer, it continues to be a leading cause of cancer-related deaths in men.^1,2 About one-third of prostate cancer-induced deaths occur in those under the age of 75.¹ New strategies of prevention are necessary for lowering the burden of early prostate cancer death.¹

To investigate the differences between the risk of early prostate cancer death in men with higher vs. lower genetic risk, researchers conducted a cohort study (n=19,607) that analyzed data collected between 1991 and 2019 from two prospective cohorts from the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-up Study (HPFS).¹ The MDCS recruited a cohort of 10,270 men with a median age of 59.0, who were free of prostate cancer, had complete lifestyle data available, and were successfully genotyped between 1991 and 1996.¹ The HPFS recruited 9,337 male health professionals in the United States, with a median age of 65.1 years, who were free of prostate cancer in 1996 and had available genotype, family history, and lifestyle data from 1986.¹ Participants were categorized by their genetic risk and lifestyle score.¹

Early prostate cancer death was defined as those occurring by 75 years of age and the rest were classified as late prostate cancer deaths.¹ Genetic risk for overall prostate cancer was assessed using a multiancestry polygenic risk score (PRS) that included 400 genetic variants, with participants' PRS calculated from their genotyped data.¹ Men at higher genetic risk (n=13,186) were those with a PRS above the median or with a family history of cancer, while the remaining men were at a lower genetic risk (n=6,421).¹ A healthy lifestyle was defined by a high score on a previously published lifestyle score for lethal prostate cancer.^1,3 One point was assigned for each lifestyle factor (not smoking, healthy weight, high physical activity, high intakes of tomato-based products and fatty fish, and low intake of processed meat).^1,3 A score of 3-6 represented a healthy lifestyle while an unhealthy lifestyle was defined by a score of 0-2.¹ The healthy group also included men who were nonsmokers with a BMI <30, had high levels of physical activity, and a healthy diet (fulfilling 2 of the dietary components).¹

The key primary outcome of this study was the association between genetic risk, lifestyle factors, and death due to prostate cancer.¹ Secondary outcomes included age-specific absolute risk (cumulative incidence) of prostate cancer death and the estimated proportion of prostate cancer deaths that would have been prevented by healthy lifestyle adherence.¹ Overall, 107 early and 337 late prostate cancer deaths were observed.¹ Men at a higher genetic risk had a >3-fold higher risk of early prostate cancer death (HR=3.26; 95% CI: 1.82-5.84), and a >2-fold higher risk of late prostate cancer death.¹ 88% of early prostate cancer deaths occurred in men with higher genetic risk, of which between 22% (95% CI: 11-34) to 36% (95% CI: 12-60) were estimated to be preventable by healthy lifestyle behaviors.¹

In summary, men with a higher genetic risk of prostate cancer had a significantly higher risk of early death by age 75 years, and up to 36% of them were estimated to be preventable.¹ Based on this study, targeting men with higher genetic risk with preventative interventions, such as a healthy lifestyle, may significantly reduce early prostate cancer deaths.