Men With High Genetic Risk of Lethal Prostate Cancer May Lower Their Risk With a Healthier Lifestyle

According to new research presented during the virtual AACR Annual Meeting 2021, the likelihood of developing metastatic disease or dying of prostate cancer among men with high genetic risk was lowered in men who maintained a healthy lifestyle.¹

The research also showed, however, that maintaining a healthy lifestyle was not associated with a lower risk of overall prostate cancer among patients in any of the 4 genetic risk categories defined by the study.

“In our study, a healthy lifestyle did not attenuate genetic risk of overall prostate cancer. However, a healthy lifestyle did attenuate the genetic risk of lethal disease in men at highest genetic risk,” one of the study’s lead authors, Anna Plym, PhD, a postdoctoral research fellow at Brigham and Women's Hospital and Harvard T. H. Chan School of Public Health, said when presenting the results during the AACR meeting.

“While further studies are needed, this suggests that modifiable factors can mitigate the consequences of having a genetic susceptibility to prostate cancer,” added Plym.

The study included 10,443 men with available genotype data from the Health Professionals Follow-up Study, a prospective cohort study that accrues data from participating healthcare professionals. The investigators quantified the genetic risk of prostate cancer in these men using a validated polygenic risk score (PRS) for overall prostate cancer. The researchers then applied a validated lifestyle score for lethal prostate cancer. Elements factored into the score included healthy weight, vigorous physical activity, not smoking, reduced intake of processed meat, and high consumption of tomatoes and fatty fish.

The investigators assessed the incidence of overall prostate cancer and lethal prostate cancer (metastatic disease or prostate cancer-specific death). Men were followed from the date of DNA collection (1993-1994 or 2005-2006) until prostate cancer event or death.

“To account for the genotype sampling strategy within the Health Professionals Follow-up Study, in which not all recruited men were genotyped, we applied an inverse probability weighted Cox regression model, adjusting for [several] factors, including [age, year of inclusion, genetic ancestry, PSA screening, other cancers, diabetes, medication use, and total energy intake,” said Plym.

Using multivariable Cox proportional hazards models, the investigators estimated the overall and lethal prostate cancer risk by joint categories of a time-varying lifestyle score and genetic risk (PRS quartiles). The investigators used both inverse probability weighted (IPW) and unweighted models for their analysis, and estimated lifetime cumulative incidence using regression standardization.

At a median follow-up of 18 years, there were 2111 prostate cancer events; at a median follow-up of 22 years there were 238 lethal prostate cancer events.

The risk of overall prostate cancer was 5.4 times higher in men whose PRS score placed them in the highest genetic risk quartile versus those in the lowest genetic risk quartile (HRipw, 5.39; 95% CI, 4.59-6.33). The risk of lethal prostate cancer was 3.5 times higher in the highest versus the lowest genetic risk quartile (HRipw, 3.53, 95% CI, 2.34-5.32) compared with men in the lowest genetic risk quartile.

Maintaining a healthy lifestyle was significantly associated with a reduced risk of developing lethal prostate cancer compared with men living the least healthy lifestyle (HRipw, 0.54; 95% CI, 0.31- 0.94). In contrast, there was no link between maintaining a healthy lifestyle and a reduced risk of overall prostate cancer (HRipw, 1.01; 95% CI, 0.84-1.22).

Also of note, among men maintaining a healthy lifestyle at study entry who had the highest genetic risk, there was a 3% lifetime cumulative occurrence of lethal prostate cancer. This was half of the 6% lifetime cumulative incidence for men with the least healthy lifestyle. It is also comparable to the 3% population average.

In a statement included in a press release made available during the AACR meeting, Plym stated, “Our findings add to current evidence suggesting that men with a high genetic risk may benefit from a targeted prostate cancer screening program, aiming at detecting a potentially lethal prostate cancer while it is still curable.”²

Commenting on the results during the AACR meeting, moderator Charles Swanton MBPhD, FRCP, FMedSci, FRS, FAACR, Royal Society Napier Professor, The Francis Crick Institute and UCL Cancer Institute, Cancer Evolution and Genome Instability Lab, London, England, said, “Healthy lifestyle did not associate with prostate cancer risk overall, but was associated with lethal prostate disease in those with the highest PRS risk. So, the question is, why did a healthy lifestyle only protect those in the highest PRS category? And so I think we need future validation in larger cohorts using similar thresholds and a biological mechanism that might explain an interaction between the healthy lifestyle and a highest genetic risk and the risk of lethal prostate cancer.”

_References

_{1. Plym A, Zhang Y, Stopsack K, et al. Can the genetic risk of prostate cancer be attenuated by a healthy lifestyle? Presented at: 2021 AACR Virtual Annual Meeting Week 1; April 10-15, 2021. Abstract 822.}

_{2. Healthy Lifestyle May Offset Risk of Lethal Prostate Cancer in Men With High Genetic Risk. Published online April 10, 2021. Accessed April 10, 2021.}