Background: How 5-alpha reductase inhibitor (5-ARI) use influences prostate cancer mortality is unclear. The objective of this study was to determine whether men taking 5-ARIs with regular healthcare access have increased prostate cancer mortality. Methods: We undertook two analyses in the Health Professionals Follow-up Study examining 5-ARI use, determined by biennial questionnaires, and prostate cancer. A cohort analysis followed 38,037 cancer-free men for prostate cancer incidence from 1996 through January 2017 and mortality through January 2019. A case-only analysis followed 4,383 men with localized/locally advanced prostate cancer for mortality over a similar period. Hazard ratios (HR) and 95% confidence intervals were calculated for prostate cancer incidence and mortality. Results: Men using 5-ARIs underwent more PSA testing, prostate exams and biopsies. Over 20 years of follow-up, 509 men developed lethal disease (metastases or prostate cancer death). Among men initially free from prostate cancer, 5-ARI use was not associated with developing lethal disease (HR 1.02, 0.71-1.46), but was associated with reduced rates of overall and localized disease (HR 0.71, 0.60-0.83). Among men diagnosed with prostate cancer, there was no association between 5-ARI use and cancer-specific (HR 0.78, 0.48-1.27) or overall survival (HR 0.88, 0.72-1.07). Conclusions: Men using 5-ARIs were less likely to be diagnosed with low-risk prostate cancer, without increasing long-term risk of lethal prostate cancer or cancer-specific death after diagnosis. Impact: Our results provide evidence that 5-ARI use is safe with respect to prostate cancer mortality in the context of regular healthcare access.

Tissue microarrays (TMAs) have been used in thousands of cancer biomarker studies. To what extent batch effects, measurement error in biomarker levels between slides, affects TMA-based studies has not been assessed systematically. We evaluated 20 protein biomarkers on 14 TMAs with prospectively collected tumor tissue from 1,448 primary prostate cancers. In half of the biomarkers, more than 10% of biomarker variance was attributable to between-TMA differences (range, 1–48%). We implemented different methods to mitigate batch effects (R package batchtma), tested in plasmode simulation. Biomarker levels were more similar between mitigation approaches compared to uncorrected values. For some biomarkers, associations with clinical features changed substantially after addressing batch effects. Batch effects and resulting bias are not an error of an individual study but an inherent feature of TMA-based protein biomarker studies. They always need to be considered during study design and addressed analytically in studies using more than one TMA.

Background: Racial disparities in prostate cancer incidence and mortality rates are considerable. We previously found in the Health Professionals Follow-up Study (HPFS) that African-American men had an 80% higher prostate cancer risk than White men. With 21 additional years of follow-up and four-fold increase in cases, we undertook a contemporary analysis of racial differences in prostate cancer incidence and mortality in HPFS. Methods: For 47,679 men, we estimated HRs and 95% confidence intervals (CI) for the association between race and risk of prostate cancer through 2016 using Cox proportional hazards regression. Multivariable models (mHR) were adjusted for lifestyle, diet, family history, and PSA screening collected on biennial questionnaires. Results: 6,909 prostate cancer cases were diagnosed in White, 89 in African-American, and 90 in Asian-American men. African-Americans had higher prostate cancer incidence (mHR = 1.31; 95% CI, 1.06–1.62) and mortality (mHR = 1.67; 95% CI, 1.00–2.78), and lower PSA screening prevalence than White men. The excess risk was greater in the pre-PSA screening era (HR = 1.68; 95% CI, 1.14–2.48) than the PSA screening era (HR = 1.20; 95% CI, 0.93–1.56). Asian-Americans had lower prostate cancer risk (mHR = 0.74; 95% CI, 0.60–0.92), but similar risk of fatal disease compared with white men. Conclusions: Racial differences in prostate cancer incidence and mortality in HPFS are not fully explained by differences in lifestyle, diet, family history, or PSA screening. Impact: Additional research is necessary to address the disproportionately higher rates of prostate cancer in African-American men.

Tissue microarrays (TMAs) have been used in thousands of cancer biomarker studies. To what extent batch effects, measurement error in biomarker levels between slides, affects TMA-based studies has not been assessed systematically. We evaluated 20 protein biomarkers on 14 TMAs with prospectively collected tumor tissue from 1,448 primary prostate cancers. In half of the biomarkers, more than 10% of biomarker variance was attributable to between-TMA differences (range, 1-48%). We implemented different methods to mitigate batch effects (R package batchtma), tested in plasmode simulation. Biomarker levels were more similar between mitigation approaches compared to uncorrected values. For some biomarkers, associations with clinical features changed substantially after addressing batch effects. Batch effects and resulting bias are not an error of an individual study but an inherent feature of TMA-based protein biomarker studies. They always need to be considered during study design and addressed analytically in studies using more than one TMA.

Background: The circadian hormone melatonin has anticancer properties, and prior studies suggest a positive association between low melatonin and prostate cancer risk. The purpose of this study was to examine urinary melatonin levels and prostate cancer in a racially/ethnically diverse cohort. Methods: We conducted a nested case–control study, including 1,263 prostate cancer cases and 2,346 controls, sampled from participants in the Multiethnic Cohort Study with prediagnostic urine samples assayed for 6-sulfatoxymelatonin, the primary melatonin metabolite. Conditional logistic regression was used to examine the association between melatonin levels and the development of prostate cancer outcomes (all incident cases, advanced, lethal, high-grade, and aggressive), overall and by race/ethnicity. Results: Among 1,263 cases, 135 were advanced stage, 101 were lethal cases, and 282 were high-grade disease. Median melatonin levels were similar in controls [17.12 ng/mL; interquartile range (IQR), 19.78] and cases (17.93 ng/mL; IQR, 19.76), and we found no significant association between urinary melatonin levels and prostate cancer risk overall or in any clinical or racial subgroup. Conclusions: In this diverse cohort, there was no significant association between melatonin and any prostate cancer outcome, nor were there any differences by racial/ethnic group. Impact: These results do not support a strong association between melatonin levels and risk of prostate cancer.