1. Froelich, Warren

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A prospective study analyzing thousands of men with the highest genetic risk for prostate cancer found that regular vigorous exercise and maintaining other hallmarks of a healthy lifestyle reduced their chances of developing lethal forms of the disease by about half.

healthy lifestyle. h... - Click to enlarge in new windowhealthy lifestyle. healthy lifestyle

"A healthy lifestyle did attenuate the genetic risk of lethal disease in men at highest genetic risk," said Anna Plym, PhD, a postdoctoral research fellow at Brigham and Women's Hospital and Harvard T.H. Chan School of Public Health.


"While further studies are needed, this suggests that modification factors can mitigate the consequences of having a genetic susceptibility to prostate cancer," Plym added during a virtual press briefing held during week 1 of the 2021 Annual Meeting of the American Association for Cancer Research (AACR) held April 10-15.

Anna Plym, PhD. Anna... - Click to enlarge in new windowAnna Plym, PhD. Anna Plym, PhD

According to the American Cancer Society, about one man in eight will be diagnosed with prostate cancer during his life and it is the second-leading cause of cancer death in American men, behind only lung cancer. That said, most prostate cancers are non-life-threatening, though a minority of patients diagnosed with aggressive disease that invades the bone and other organs die from this disease.


Mitigating factors, including lifestyle differences, have been shown to play a role in some outcomes. For example, a 2015 study led by researchers at the University of California, San Francisco-tracking tens of thousands of midlife and older men for more than 20 years-suggested that maintaining a healthy lifestyle might slash the risk of developing lethal prostate cancer by up to 68 percent.


Genetic factors account for approximately 58 percent of the variability in prostate cancer risk, Plym added, "with a 10-fold gradient in disease risk between the lowest and highest genetic risk quartiles."


However, it's been unclear if the increased genetic risk of prostate cancer, including progression to lethal disease, can be offset by adherence to a healthy lifestyle.


Study Details

To help answer this question, Plym and colleagues analyzed data from 10,443 men in the Health Professional Follow-up Study, a prospective cohort of 50,000 male health professionals who were recruited in 1986.


Using a validated polygenic risk score (PRS) for overall prostate cancer, the researchers quantified the genetic risk of prostate cancer among men in the study group whose genotype data was available.


"While individual genetic variants contribute to overall risk, combining information from multiple SNPs (single nucleotide polymorphisms) into a genetic risk score has shown promise in risk stratification," Plym said. "Most recently, a 269-SNP polygenic risk score for prostate cancer was found to be highly predictive of prostate cancer."


The team then applied a validated lifestyle score for lethal prostate cancer, assigning points for regular exercise, body mass index under 30, tobacco-free status for a minimum of 10 years, high intake of fatty fish, high intake of tomatoes, and low intake of processed meats. Lifestyle scores ranged from 1-2 for least healthy, 3-4 for moderate healthy, and 5-6 for most healthy.


With this data, the team examined the incidence of overall and lethal disease-defined as metastatic disease or prostate cancer-specific death.


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


From this population of men, the researchers identified 2,111 overall prostate cancer cases and 238 lethal prostate cancer events during a median follow-up of 18 and 22 years, respectively, for each outcome.


Men with the highest risk quartile according to their polygenic risk score were found to be 5.4 times more likely to develop prostate cancer (HR=5.39, 95% Cl=4.59-6.33) and 3.5 times more likely to develop lethal prostate cancer (HR=3.53, 95% Cl=2.34-5.32) than those in the lowest risk quartile.


Among men with the highest genetic risk quartile, those with the healthiest lifestyle had about half the risk of developing lethal prostate cancer compared to those with the least healthy lifestyle (HR=.54, 95% Cl=.31-.94).


In the group of men with the highest genetic risk, those with the healthiest lifestyle at the beginning of the study were associated with a lifetime cumulative incidence of lethal prostate cancer of 3 percent. This was lower than the men having the least healthy lifestyle of 6 percent, and similar to the study's population as a whole.


However, adhering to a healthy lifestyle was not associated with a decreased risk of overall prostate cancer (HR=1.01, 95% Cl=.84-1.22).


Plym said that further research is necessary to determine why the healthy lifestyle benefit was limited to lethal prostate cancer risk in men with the highest genetic risk. One possible explanation, she noted, is that the genetic variants that contribute to a high polygenic risk score are also the variants with the strongest interaction with lifestyle factors.


Overall, Plym said the study underscored the importance of surveillance for those with a genetic predisposition to develop prostate cancer.


"Our findings add to current evidence suggesting that men with the highest genetic risk may benefit from a targeted prostate cancer screening program, aiming to detect a potentially lethal prostate cancer while it is still curable," Plym said in a press release.


Asked to comment during the AACR press briefing, Charles Swanton, MBPHD, FRCP, FMEDSCI, FRS, FAACR, Royal Society Napier Professor with The Francis Crick Institute and Genome Instability Lab in London, England, said: "It should be stressed there was a small number of deaths overall and the reduced risk of lethal diseases was restricted to the highest genetic risk score-polygenic risk score category."


He further noted that some of the study's findings raised questions that should be answered by other studies. In particular, he pointed to the apparent conundrum that healthy lifestyle did not associate with prostate cancer risk overall, but did associate with lethal prostate cancer disease among those with the highest PRS risk.

Charles Swanton, MBP... - Click to enlarge in new windowCharles Swanton, MBPHD, FRCP, FMEDSCI, FRS, FAACR. Charles Swanton, MBPHD, FRCP, FMEDSCI, FRS, FAACR

"So, the question is, why did a healthy lifestyle only protect those in the highest PRS category?" he asked. "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."


Warren Froelich is a contributing writer.