Background: Phosphodiesterase 5 (PDE5) inhibitors have been hypothesized to have chemoprotective effects in colorectal cancer. Current population-based epidemiologic evidence is, however, limited and inconsistent. Methods: Among 18,123 men in the Health Professionals Follow-up Study who had at least one lower gastrointestinal endoscopy, we evaluated the association between PDE5 inhibitor use and risk of conventional adenoma and serrated lesion between 2000 and 2010, adjusted for repeated observations and multiple risk factors. We stratified by erectile dysfunction to account for potential “confounding by indication.” Results: We documented 2,595 conventional adenomas and 1,395 serrated lesion polyps during the follow-up period. Using people without erectile dysfunction as reference group, recent PDE5 inhibitor use at baseline was not associated with lower risk of conventional adenoma [erectile dysfunction with PDE5 inhibitors: OR = 1.08; 95% confidence interval (CI) = 0.92–1.26; erectile dysfunction without PDE5 inhibitors: OR = 0.95; 95% CI, 0.85–1.06], serrated lesions (erectile dysfunction with PDE5 inhibitors: OR = 1.19; 95% CI = 0.97–1.45; erectile dysfunction without PDE5 inhibitors: OR = 1.03; 95% CI = 0.89–1.19), or advanced conventional adenomas (erectile dysfunction with PDE5 inhibitors: OR = 1.20; 95% CI = 0.94–1.53; erectile dysfunction without PDE5 inhibitors: OR = 0.95; 95% CI = 0.79–1.14). No association was found for PDE5 inhibitor use ever before as well. Conclusions: We found no evidence of an association between PDE5 inhibitor use and risk of conventional and serrated precursors of colorectal cancer. Impact: We show that PDE5 inhibitor use is not associated with precursors of colorectal cancer adjusted for medical and lifestyle risk factors among a large population of men with 10 years of follow-up.

Background: Inflammation and focal atrophy are common features adjacent to prostate tumors. Limited evidence exists on whether these features have prognostic significance.Methods: In the Health Professionals Follow-Up Study and Physicians' Health Study, we studied 1,035 men diagnosed with prostate cancer. A genitourinary pathologist centrally reviewed tumor and normal areas of hematoxylin and eosin slides from prostate cancer specimens for the presence of acute and chronic inflammation, and four subtypes of focal atrophy. Cox proportional hazards models adjusted for potential confounders were used to estimate HRs and 95% confidence intervals (CI) for the association of these features with lethal prostate cancer, defined as development of metastatic disease or death during follow-up.Results: During a median of 12 years of follow-up, 153 men developed lethal prostate cancer. A total of 84% of men had histologic evidence of chronic inflammation and 30% had acute inflammation. Both chronic and acute inflammation were inversely associated with lethal prostate cancer in age-and lifestyle-adjusted models. Chronic inflammation remained inversely associated with lethal prostate cancer after additionally adjusting for prognostic clinical features (HR ¼ 0.45; 95% CI, 0.30-0.69 for mild and HR ¼ 0.51; 95% CI, 0.33-0.80 for moderate to severe). None of the atrophic lesions were associated with lethal prostate cancer.Conclusions: Our data suggest that the presence of inflammation, particularly chronic inflammation, in prostate cancer tissue is associated with better prognosis among patients with prostate cancer.Impact: This is the largest prospective cohort study to examine the association between inflammation, focal atrophy, and lethal prostate cancer.

Purpose:Biological and experimental evidence support restoration of normal zinc levels in malignant prostate cells as a promising prostate cancer treatment, yet the influence of zinc supplementation after diagnosis on prostate cancer survival in a human population is unknown.Materials and Methods:We prospectively assessed post-diagnostic zinc supplementation in relation to prostate cancer survival among 5,788 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study (1986-2019). We used Cox regression models to estimate the multivariable hazard ratios and 95% confidence intervals of lethal prostate cancer (distant metastases or prostate cancer–specific death) and all-cause mortality according to post-diagnostic zinc supplement use and dosage.Results:During a median follow-up of 11 years, we documented 527 lethal prostate cancer events and 3,198 all-cause deaths. Fifteen percent of men reported zinc supplement use post-diagnosis. Compared to nonusers, post-diagnostic zinc supplement use was associated suggestively with a lower risk of lethal prostate cancer (HR [95% CI], 0.82 [0.60-1.13]) and significantly with all-cause mortality (0.84 [0.74-0.96]). The inverse association was mostly observed among men who used post-diagnostic zinc supplements of 1-24 mg/d (lethal prostate cancer: 0.55 [0.32-0.96]; all-cause mortality: 0.77 [0.64-0.93]), while higher dosage did not show a lower risk.Conclusions:Post-diagnostic low-dose zinc supplement use among nonmetastatic prostate cancer patients was associated with lower risk of lethal prostate cancer and all-cause mortality. A potential benefit of low-dose post-diagnostic zinc supplement for prostate cancer survival merits further study.

Purpose: Family history of prostate cancer is one of the few universally accepted risk factors for prostate cancer. How much an assessment of inherited polygenic risk for prostate cancer adds to lifetime risk stratification beyond family history is unknown. Experimental Design: We followed 10,120 men in the Health Professionals Follow-up Study with existing genotype data for risk of prostate cancer and prostate cancer-specific death. We assessed to which extent family history of prostate or breast cancer combined with a validated polygenic risk score (PRS) including 269 prostate cancer risk variants identifies men at risk of prostate cancer and prostate cancer death across the age span. Results: During 20 years of follow-up, 1,915 prostate cancer and 166 fatal prostate cancer events were observed. Men in the top PRS quartile with a family history of prostate or breast cancer had the highest rate of both prostate cancer and prostate cancer-specific death. Compared with men at lowest genetic risk (bottom PRS quartile and no family history), the hazard ratio was 6.95 (95% CI 5.57-8.66) for prostate cancer and 4.84 (95% CI 2.59-9.03) for prostate cancer death. Men in the two upper PRS quartiles (50-100%) or with a family history of prostate or breast cancer (61.8% of the population) accounted for 97.5% of prostate cancer deaths by age 75 years. Conclusions: Our study shows that prostate cancer risk stratification on the basis of family history and inherited polygenic risk can identify men at highest risk of dying from prostate cancer before age 75 years.

Purpose:Multivitamin supplement is commonly used among older adults in the United States. Evidence on multivitamin use and prostate cancer risk is limited, and some suggested potential risk for clinically important subtypes of cancer.Materials and Methods:A total of 48,137 men from the Health Professionals Follow-up Study were followed from 1986 to 2017. Multivitamin use and frequency were self-reported at baseline and updated biennially. Clinical features of prostate cancer included advanced, lethal and high-grade outcomes. Cox proportional hazards models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) of multivitamin use and incidence of prostate cancer.Results:The median followup for men without prostate cancer diagnosis or death was 30.7 years. We documented 7,108 incident prostate cancer cases including 564 advanced and 1,065 lethal. Overall, we observed a null association between multivitamin use and risk of prostate cancer. Compared to never-users, men who used multivitamin 10 or more tablets per week had similar risk of advanced (HR: 1.14, 95% CI: 0.77–1.70, Ptrend=0.46) or lethal (HR: 1.07, 95% CI: 0.80–1.44, Ptrend=0.59) prostate cancer, and multivitamin use of 15 years or more was not associated with risk of advanced (HR: 1.10, 95% CI: 0.80–1.50, Ptrend=0.46) or lethal (HR: 1.04, 95% CI: 0.83–1.31, Ptrend=0.13) prostate cancer.Conclusions:Regular or long-duration multivitamin use among older, generally well-nourished men was not associated with either increased or lower risk of overall or aggressive prostate cancer.

Supplementary Data from Family History of Prostate and Breast Cancer Integrated with a Polygenic Risk Score Identifies Men at Highest Risk of Dying from Prostate Cancer before Age 75 Years

<div>AbstractPurpose:<p>Family history of prostate cancer is one of the few universally accepted risk factors for prostate cancer. How much an assessment of inherited polygenic risk for prostate cancer adds to lifetime risk stratification beyond family history is unknown.</p>Experimental Design:<p>We followed 10,120 men in the Health Professionals Follow-up Study with existing genotype data for risk of prostate cancer and prostate cancer–specific death. We assessed to what extent family history of prostate or breast cancer, combined with a validated polygenic risk score (PRS) including 269 prostate cancer risk variants, identifies men at risk of prostate cancer and prostate cancer death across the age span.</p>Results:<p>During 20 years of follow-up, 1,915 prostate cancer and 166 fatal prostate cancer events were observed. Men in the top PRS quartile with a family history of prostate or breast cancer had the highest rate of both prostate cancer and prostate cancer–specific death. Compared with men at lowest genetic risk (bottom PRS quartile and no family history), the HR was 6.95 [95% confidence interval (CI), 5.57–8.66] for prostate cancer and 4.84 (95% CI, 2.59–9.03) for prostate cancer death. Men in the two upper PRS quartiles (50%–100%) or with a family history of prostate or breast cancer (61.8% of the population) accounted for 97.5% of prostate cancer deaths by age 75 years.</p>Conclusions:<p>Our study shows that prostate cancer risk stratification on the basis of family history and inherited polygenic risk can identify men at highest risk of dying from prostate cancer before age 75 years.</p></div>

Background and Aims: We examined multiple dietary patterns in relation to total digestive system cancer (DSC) incidence and death. Method: A total of 213,038 health professionals from the Health Professionals Follow-up Study (1986-2016) and the Nurses’ Health Study (NHS) (1986-2018) and the NHS II (1991-2017) with no cancer diagnosis at baseline were analyzed. DSC incidence and death were estimated using time varying Cox proportional hazards regression models. Results: During up to 32 years of follow-up, 5724 DSC cases accrued. Adherence to eight healthy diet patterns were associated with a 7-13% lower risk of DSC, particularly for digestive tract cancers. An inverse association with gastrointestinal tract cancer was also shown for all pattern scores except alternative Mediterranean diet (AMED) and healthy Plant Dietary Index, with hazard ratios (HRs) between 0.84 and 0.89. Inverse associations were shown for the rEDIH (HR for 90th versus 10th percentile 0.64, 95% confidence interval (CI) 0.47 to 0.87) and the empirical dietary index associated with lower inflammation (rEDIP) (0.53, 95% CI 0.39 to 0.72) for stomach cancer, and for the rEDIP (0.58, 95% CI 0.37 to 0.92) for small intestine cancer. Among accessory cancers, the Alternate Healthy Eating Index-2010 (AHEI-2010), AMED, and diabetes risk reduction diet were associated with a 43-51% lower risk of liver cancer. The rEDIH, rEDIP, and the AHEI-2010 were inversely associated with risk of digestive system fatal cancer. Conclusions: Adherence to healthy diets was associated with a lower risk of incident and fatal DSC, although the magnitude of the association varied slightly among the patterns.