In a two-decade study published in JAMA Network Open, Researchers analyzed the risk of early death from prostate cancer in men with higher versus lower genetic risk, using data from two prospective cohort studies in Sweden and the United States of America (US).
They found that men with higher genetic risk had significantly increased rates of early and late prostate cancer mortality, with one-third of these early deaths predicted to be preventable through healthy lifestyle behaviors.
Study: Early prostate cancer deaths in men at higher versus lower genetic risk. Image credit: NTshutterth/Shutterstock.com
Record
Despite advances in early diagnosis and treatment, prostate cancer is still the leading cause of cancer death in men, with approximately 400,000 deaths per year worldwide. Specifically, one-third of these deaths occur before the age of 75, highlighting the need for new prevention approaches.
Targeting high-risk populations, including men with a high polygenic risk score (PRS), offers a promising approach. PRSs effectively stratify prostate cancer risk and mortality. Combining PRS with family history or measurements of rare variants can improve risk estimation.
While established risk factors are not modifiable, lifestyle behaviors such as maintaining a healthy weight, smoking, and regular physical activity may reduce the risk of prostate cancer progression and death, particularly in high-risk individuals.
However, the extent to which targeted prevention strategies can reduce premature deaths from prostate cancer remains unclear.
Therefore, the researchers in the present study analyzed data from two prospective cohort studies to assess the effect of genetic risk on early mortality and the effect of a healthy lifestyle on prostate cancer prevention.
About the study
Data from the Malmö Diet and Cancer Study (MDCS) and the Health Professional Follow-up Study (HPFS) were analyzed.
The MDCS and HPFS included 10,270 and 9,337 genotyped men from Sweden and the USA, respectively, without prostate cancer and with lifestyle data. The median age at start of follow-up was 59 years in the MDCS and 65.1 years in the HPFS.
Healthy lifestyle was defined using a score based on not smoking, maintaining high physical activity, a healthy weight and a diet rich in tomato products and fatty fish and low in processed meat.
This score categorized lifestyles as healthy (3-6 points) or unhealthy (0-2 points), with an additional detailed 4-group categorization and a sensitivity analysis incorporating various dietary recommendations.
Genetic risk was classified as high or low based on a polyancestral PRS of 400 variants for prostate cancer relative to the median value and family history of cancer.
Prostate cancer-related deaths were tracked through the Swedish Cause of Death Registry (MDCS) and the National Death Index, supplemented by relatives’ reports.
Early deaths were defined as those before age 75, late deaths as those after age 75, and lifetime risk included deaths by age 85. Statistical analysis included Cox regression, weighted inverse probability models and regression, pooled from fixed-effects meta-analysis.
Results and discussion
According to the study, 67% of men were classified as having a higher genetic risk based on PRS and family history, with about 30% having a lifestyle score indicating unhealthy behaviors.
During a median follow-up of 24 years in the MDCS and 23 years in the HPFS, 444 prostate cancer deaths were recorded before (107) and after age 75 (337). Higher genetic risk was associated with a threefold increased rate of early and twofold increased rate of late death from prostate cancer.
Unhealthy lifestyles significantly increased risk only in men at higher genetic risk, particularly with smoking and BMI ≥30. Cohort-specific results were found to be consistent.
Men with lower genetic risk were found to have low lifetime risks of dying from prostate cancer ranging from 0.6% to 1.3%, with no clear lifestyle pattern. However, the higher genetic risk groups showed significantly higher lifetime risks for the combined higher genetic risk men (2.3% to 3.1%).
For those in the 50–75% PRS category (1.8% to 2.9%), increasing further for men in the 75–100% PRS category (3.1% to 4.9%) in both studies. The majority of prostate cancer deaths occurred in men with a higher genetic risk, accounting for 88% of deaths by age 75.
Lifestyle changes could prevent 22% to 36% of these deaths before age 75 among men at higher genetic risk. Alternative dietary factors suggested prevention estimates of up to 39%.
The study is strengthened by the inclusion of two large, independent cohorts with 20 years of follow-up, showing consistent results in different populations. However, the analysis is limited by potential differences in prostate cancer screening and treatment, consideration of factors only at study entry, and inclusion of men of European descent only.
conclusion
In conclusion, this study suggests that prostate cancer prevention strategies should focus on men at high genetic risk.
About a third of early prostate cancer deaths in men at genetic risk can be prevented through healthy lifestyle choices or by ensuring equal access to early diagnosis and optimal treatment.
Targeted interventions for high-risk men could significantly reduce the number of premature deaths from prostate cancer.
