Chaoran Ma

Background: Few studies have investigated postdiagnostic pro-inflammatory, hyperinsulinemic, and insulin-resistant dietary and lifestyle patterns in relation to the risk of prostate cancer–specific mortality (PCSM). Methods: In 4,501 men diagnosed with nonmetastatic prostate cancer from the Health Professionals Follow-up Study, we investigated the empirical dietary inflammatory pattern, empirical dietary index for hyperinsulinemia, empirical lifestyle index for hyperinsulinemia, empirical dietary index for insulin resistance, and empirical lifestyle index for insulin resistance in relation to the risk of PCSM. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. Results: Over a median follow-up of 13.3 years starting at the time of prostate cancer diagnosis, we identified 281 prostate cancer–specific deaths. None of the indices were statistically significantly associated with the risk of PCSM. Conclusions: Our results do not provide evidence that postdiagnostic dietary and lifestyle patterns that promote inflammation, hyperinsulinemia, or insulin resistance are associated with the risk of PCSM. Impact: Inflammation and insulin signaling have been implicated in prostate cancer progression, but their associated dietary and lifestyle patterns did not correlate with prostate cancer survival in this study sample.

Background: Prostate cancer is the second leading cause of cancer death in US men, yet most patients die from other causes. We examined whether adherence to healthy dietary patterns after diagnosis is associated with overall and cause-specific survival. Methods: We analyzed 6085 men with prostate cancer (1986-2016) in the Health Professionals Follow-up Study. Five dietary patterns—Alternative Healthy Eating Index (AHEI), Mediterranean diet (AMED), Dietary Approaches to Stop Hypertension, anti-insulinemic, and anti-inflammatory diets—were derived from validated food frequency questionnaires every 4 years. Postdiagnosis scores were cumulatively averaged, and changes from pre- to postdiagnosis were calculated. Multivariable Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality through 2024. Results: Over 71 760 person-years, 3710 deaths occurred (592 prostate cancer, 971 cardiovascular disease, 2147 other). Greater postdiagnosis adherence to AHEI (quintile 5 vs quintile 1, HR = 0.75, 95% CI = 0.66 to 0.86) and AMED (HR = 0.80, 95% CI = 0.70 to 0.92) was associated with lower all-cause mortality. Increased adherence after diagnosis also predicted better survival, particularly for AHEI. Survival benefits were stronger among men with less aggressive disease. Increased AHEI adherence was associated with lower cardiovascular disease mortality (HR = 0.82, 95% CI = 0.66 to 1.03), but no associations were observed for prostate cancer–specific survival. Limitations include the observational design and potential residual confounding. Conclusions: Adherence to healthy dietary patterns, especially AHEI and AMED, after prostate cancer diagnosis was associated with improved survival, particularly in less aggressive disease. These findings support dietary improvement as a part of survivorship care.

Supplementary materials, Supplementary Tables 1-12, Supplementary Figures 1-2

Supplementary Table 1. Differentially expressed genes between tumor- and benign-adjacent stroma Supplementary Table 2. Differentially enriched pathways between tumor- and benign-adjacent stroma Supplementary Table 3. Differentially expressed genes between high- and low-Gleason score in tumor-adjacent stroma Supplementary Table 4. Differentially expressed genes between high- and low-Gleason score in benign-adjacent stroma Supplementary Table 5. Differentially enriched pathways between high- and low-Gleason score in tumor-adjacent stroma Supplementary Table 6. Differentially enriched pathways between high- and low-Gleason score in benign-adjacent stroma Supplementary Table 7. Differentially expressed genes between cribriform and non-cribriform patterns Supplementary Table 8. Differentially enriched pathways between cribriform and non-cribriform patterns Supplementary Table 9. Differentially expressed genes between lethal and non-lethal cases in tumor-adjacent stroma Supplementary Table 10. Differentially expressed genes between lethal and non-lethal cases in benign-adjacent stroma Supplementary Table 11. Differentially enriched pathways between lethal and non-lethal cases in tumor-adjacent stroma Supplementary Table 12. Differentially enriched pathways between lethal and non-lethal cases in benign-adjacent stroma Supplementary Figure 1. Single sample gene set enrichment signature scores by Gleason score and lethal outcome in tumor-adjacent stromal samples. Supplementary Figure 2. Correlation of log2 fold change values between the current data and the LCM data (GSE97284)

Prostate cancer has a heterogeneous prognosis. Most previous studies have focused on the identification of prognostic biomarkers in the prostate cancer tumor. However, it is increasingly recognized that the tumor microenvironment contributes to prostate cancer aggressiveness and progression. We therefore examined whole transcriptome expression of the prostate stroma and associations with aggressive and lethal prostate cancer. We performed RNA sequencing (Illumina TruSeq Exome Capture) of 272 tumor-adjacent and 120 benign-adjacent macrodissected prostate stromal samples from 293 men with prostate cancer from the Health Professionals Follow-up Study and Physicians’ Health Study. We performed differential expression analysis comparing gene expression and pathways by Gleason score and lethal outcome. We also tested a previously developed stromal gene signature of Gleason score in these datasets. Comparing high- with low-Gleason score cancers, 26 genes (P < 0.001) and 12 pathways (FDR < 0.20) were significantly differentially expressed in tumor-adjacent stroma, including pathways related to stroma composition remodeling and DNA repair, with 73 genes and 65 pathways significant in benign-adjacent stroma. Comparing lethal with nonlethal prostate cancer, 11 genes were differentially expressed in tumor-adjacent and 15 genes in benign-adjacent stroma, and pathways involved in inflammatory response were differentially enriched in both tumor and benign-adjacent stroma. In addition, our previously identified Gleason stromal gene signature was validated to be associated with Gleason score in these data.Implications: Our study uncovers stroma-specific genes and pathways that are differentially enriched with high Gleason score and lethal prostate cancer, demonstrating that the molecular investigation of the tumor microenvironment can provide additional information about prostate cancer prognosis.

Associations of previously reported prostate cancer risk variants with ERG fusion status in the Health Professionals Follow-up Study/Physicians Health Study (HPFS/PHS) and Fred Hutchinson (FH) Prostate Cancer Study.

Quantile-quantile plots of GWAS in the pooled analysis of ERG (+) vs. ERG (-) tumor (A) ERG (+) tumors vs. controls (B) and ERG (-) tumors vs. controls (C).

Associations of previously reported prostate cancer risk variants with ERG fusion status in the Health Professionals Follow-up Study/Physicians Health Study (HPFS/PHS) and Fred Hutchinson (FH) Prostate Cancer Study.

Quantile-quantile plots of GWAS in the pooled analysis of ERG (+) vs. ERG (-) tumor (A) ERG (+) tumors vs. controls (B) and ERG (-) tumors vs. controls (C).

Quantile-quantile plots of GWAS in the pooled analysis of ERG (+) vs. ERG (-) tumor (A) ERG (+) tumors vs. controls (B) and ERG (-) tumors vs. controls (C).