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Background: We conducted a study to assess whether testosterone therapy (TT) alters prostate cancer risk using a large U.S. commercial insurance research database. Methods: From the HealthCore Integrated Research Database (HIRD), we selected men ages 30 years or greater who were new users of TT during 2007 to 2015. We selected two comparison groups: (i) unexposed (matched 10:1) and (ii) new users of phosphodiesterase type 5 inhibitor (PDE5i). Incident prostate cancer was defined as diagnosis of prostate cancer within 4 weeks following prostate biopsy. Propensity scores and inverse probability of treatment weights were used in Poisson regression models to estimate adjusted incidence rates, incidence rate ratios (IRR), and 95% confidence intervals (CI). Subgroup analyses included stratification by prostate cancer screening, hypogonadism, and follow-up time. Results: The adjusted prostate cancer IRR was 0.77 (95% CI, 0.68–0.86) when comparing TT with the unexposed group and 0.85 (95% CI, 0.79–0.91) in comparison with the PDE5i group. Inverse associations between TT and prostate cancer were observed in a majority of subgroup analyses, although in both comparisons estimates generally attenuated with increasing time following initial exposure. Among TT users, duration of exposure was not associated with prostate cancer. Conclusions: Men who received TT did not have a higher rate of prostate cancer compared with the unexposed or PDE5i comparison groups. The inverse association between TT and prostate cancer could be the result of residual confounding, contraindication bias, or undefined biological effect. Impact: This study suggests that limited TT exposure does not increase risk of prostate cancer in the short term.

Background: Chronic inflammation has been implicated in prostate cancer etiology and progression. The pro-inflammatory cyclooxygenase (COX) pathway, where arachidonic acid is converted to bioactive prostaglandins and eicosanoids via the COX1 and COX2 enzymes, has been linked to elevated systemic inflammation. Urinary PGE-M is a stable and measurable metabolite of prostaglandin E2 (PGE2). PGE2 is a product of the inflammatory COX signaling pathway and elevated levels have been associated with risk of cancer in many sites including colorectal and gastric cancers. PGE2 synthesis can be inhibited by aspirin. We investigated the association of PGE-M with lethal prostate cancer in a case-control study of African American and European American men. Identifying PGE-M as a novel marker of aggressive disease would have importance for high risk groups like men of African descent who experience a disproportionately high burden of prostate cancer lethality. Methods: We measured urinary PGE-M using mass-spectrometry. Samples were obtained from 977 cases and 1022 controls at time of recruitment. For analysis, we assessed PGE-M as either a continuous measure or assigned PGE-M values to quartiles and median with cutoff points determined using the distribution of PGE-M values among all controls. We applied multivariable logistic and Cox regression modeling to examine associations of PGE-M with prostate cancer and participant survival. Median survival follow-up was 8.4 years with 246 deaths among cases. Self-reported aspirin use over the past five years was assessed with a questionnaire. Race/ethnicity was self-reported. Results: Urinary PGE-M levels did not differ between men with prostate cancer and population-based controls. We report a lack of robust PGE-M inhibition in both cases and controls who reported aspirin use in our study. We observed no association between PGE-M and aggressive disease as defined by the National Comprehensive Cancer Network risk score. We also observed no association between PGE-M and prostate cancer-specific survival. However, we observed a statistically significant association between higher (> median) PGE-M and all-cause mortality in African American cases who did not regularly use aspirin (HR = 2.04, 95% CI 1.23-3.37). Among cases, who reported using aspirin, there was no association. Conclusions: Our study does not support a meaningful association between urinary PGE-M and prostate cancer. Moreover, PGE-M levels were not associated with aggressive prostate cancer. However, the observed association between elevated PGE-M and all-cause mortality in AA non-aspirin users reinforces the potential benefit of aspirin to reduce mortality among African American men with prostate cancer. Citation Format: Maeve Kiely, Ginger L. Milne, Tsion Z. Minas, Tiffany H. Dorsey, Wei Tang, Cheryl J. Smith, Francine Baker, Christopher A. Loffredo, Clayton Yates, Michael B. Cook, Stefan Ambs. Association of urinary PGE-M with all-cause mortality in men with prostate cancer is influenced by aspirin use [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-168.

OBJECTIVE: Differentiating men who have lethal forms of prostate cancer from those with a more slow-growing disease remains a major challenge in clinical oncology. Risk stratification strategies are particularly needed for men of African descent who disproportionately bear the prostate cancer burden. Methods: Using a high throughput proximal extension assay, we simultaneously measured 82 immune-oncological proteins in the blood of 819 prostate cancer patients at diagnosis of whom 394 were African American (AA) and 425 were European American (EA). These patients were followed up for a median of 8.6 years since their diagnosis during which 57 died of prostate cancer while 202 died of all causes. To identify an immune-oncology protein signature predictive of lethal prostate cancer, we applied a cross-validated, regularized Cox regression model. Included in this model were the 82 immune-oncology proteins and 6 covariates of clinical significance (age, education, BMI, smoking history, aspirin use, and diabetes). Results: We did not identify a robust predictive signature of lethal prostate cancer for EA patients. However, for AA patients a signature primarily driven by tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and pleiotrophin (PTN) (both positively associated with the risk of lethal disease) and regular aspirin use (negatively associated with risk) were the top predictors (P < 0.05) based on two selection criteria: the feature frequency and the weight of the features' contribution to the prediction. These features combined predicted prostate cancer-specific mortality with an accuracy of 83.7% (SE=3.8%). The two proteins alone, TNFRSF9 and PTN, predicted prostate cancer-specific mortality with an accuracy of 78.2% (SE=4.2%). AA prostate cancer patients with high levels (> median) of both TNFRSF9 and PTN in their blood at diagnosis had the worst prostate cancer-specific survival. By 10 years, 33% of cases with high levels of both TNFRSF9 and PTN died of prostate cancer compared to only 5% of cases with low levels of both or either of these proteins. Conclusions: Our study describes novel blood markers of lethal prostate cancer that can be used for risk stratification of AA patients at the time of diagnosis. AA patients with high levels of both TNFRSF9 and PTN in their sera had the highest risk of dying from prostate cancer. These markers may also be applicable to African prostate cancer patients since the blood-based immunome of Ghanaian and AA men are similar, as shown by our data. Citation Format: Tsion Zewdu Minas, Julián Candia, Tiffany H. Dorsey, Francine Baker, Wei Tang, Maeve Kiely, Cheryl J. Smith, Symone V. Jordan, Obadi M. Obadi, Anuoluwapo Ajao, Christopher A. Loffredo, Clayton Yates, Michael B. Cook, Stefan Ambs. Blood levels of TNFRSF9 and PTN predict lethal prostate cancer among African American men [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PR-11.

Men of African descent, including African American (AA) men and Ghanaian (AFR) men, have a disproportionately higher burden of lethal prostate cancer (PCa) when compared to European American (EA) men. This increased mortality burden could be partially attributed to lifestyle factors including the intake of dietary fatty acids and their metabolism, but may also relate to differences in inflammation and immune function. Although the extent to which fatty acids are PCa risk factors remains controversial, the relationship between fatty acids, inflammation and immune function, and PCa in men of African descent remains largely unexplored. Therefore, the goal of our study was to characterize the relationship between circulating fatty acids, immune-oncological mediators, and PCa in the ethnically diverse NCI-Maryland and NCI-Ghana Prostate Cancer Case-Control studies, with an over-representation of men of African descent. A CLIA-certified, mass spectrometry-based assay was applied to measure 24 fatty acids in sera from 1,562 cases and 1,693 controls. Logistic regression analyses were performed on seven types of fatty acids including total, saturated, trans, cis-monounsaturated, omega-6, omega-3 fatty acids, and the omega 6:3 fatty acid ratio to explore disease associations by population group. Additionally, we measured 82 immune-oncological proteins in the same sera and explored their role as potential mediators of the relationship between fatty acids and PCa. Using this approach, we observed a significant association between trans fatty acid levels and the odds of developing PCa in all three racial/ethnic groups. Although AFR men were found to have the lowest level of trans fatty acids compared to AA and EA men, they still experienced significantly increased odds of developing PCa with increasing trans fatty acid levels. Exploratory mediation analyses found a relationship between Palmitelaidic trans fatty acid levels and two circulating proteins, CD27 and CXCL1, with protein levels being higher in men with elevated levels of circulating Palmitelaidic trans fatty acids and an increased risk of PCa. Our findings point to a previously unexplored oncogenic role of fatty acids and immune-oncological mediators in men of African descent with PCa. Citation Format: Brittany D. Lord, Tsion Minas, Tiffany H. Dorsey, Francine Baker, Wei Tang, Edward D. Yeboah, Yao Tettey, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, James E. Mensah, Robert N. Hoover, Ann W. Hsing, Michael B. Cook, Stefan Ambs. Determining the association between circulating fatty acids, immune oncological markers, and prostate cancer risk in a diverse cohort [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-199.

Background: Sex hormones have been implicated in prostate carcinogenesis, yet epidemiologic studies have not provided substantiating evidence. We tested the hypothesis that circulating concentrations of sex steroid hormones reflect intraprostatic concentrations using serum and adjacent microscopically verified benign prostate tissue from prostate cancer cases. Methods: Incident localized prostate cancer cases scheduled for surgery were invited to participate. Consented participants completed surveys, and provided resected tissues and blood. Histologic assessment of the ends of fresh frozen tissue confirmed adjacent microscopically verified benign pathology. Sex steroid hormones in sera and tissues were extracted, chromatographically separated, and then quantitated by radioimmunoassays. Linear regression was used to account for variations in intraprostatic hormone concentrations by age, body mass index, race, and study site, and subsequently to assess relationships with serum hormone concentrations. Gleason score (from adjacent tumor tissue), race, and age were assessed as potential effect modifiers. Results: Circulating sex steroid hormone concentrations had low-to-moderate correlations with, and explained small proportions of variations in, intraprostatic sex steroid hormone concentrations. Androstane-3α,17β-diol glucuronide (3α-diol G) explained the highest variance of tissue concentrations of 3α-diol G (linear regression r2 = 0.21), followed by serum testosterone and tissue dihydrotestosterone (r2 = 0.10), and then serum estrone and tissue estrone (r2 = 0.09). There was no effect modification by Gleason score, race, or age. Conclusions: Circulating concentrations of sex steroid hormones are poor surrogate measures of the intraprostatic hormonal milieu. Impact: The high exposure misclassification provided by circulating sex steroid hormone concentrations for intraprostatic levels may partly explain the lack of any consistent association of circulating hormones with prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 26(11); 1660–6. ©2017 AACR.

PURPOSE: This study sought to describe the physical activity-endometrial cancer association and potential mediation of this relationship by obesity in midlife. METHODS: Participants were 67,705 women (aged 50–71 years) enrolled in the NIH-AARP cohort who reported their historical leisure-time physical activity patterns starting at age 15–18 years. We identified five long-term physical activity patterns between adolescence and cohort entry (i.e., inactive, maintained-low, maintained-high, increasers, decreasers). We used Cox regression (Hazard ratio - HR [95% CI]) to assess the relationship between these patterns and midlife obesity and endometrial cancer, adjusting for covariates. Mediation analysis was used to decompose the physical activity patterns-endometrial cancer association to estimate the proportion of the physical activity-endometrial cancer association mediated by midlife obesity. RESULTS: During an average 12.3 years of follow-up 1,468 endometrial cancers occurred. Long-term physical activity patterns were inactive, maintained-low, maintained-high, increasers, and decreasers. Compared to long- term inactive women, women who maintained-high or increased activity levels had a 19–26% lower risk for endometrial cancer (maintained-high: HR = 0.81 [0.67, 0.98]; increasers: HR = 0.74 [0.61, 0.91]). They also had a 45–77% lower risk for obesity in midlife (e.g., maintained-high, BMI 30–39.9: HR = 0.50 [0.46, 0.55]; maintained- high, BMI 40+: HR = 0.32 [0.26, 0.39]). Obesity was a significant mediator and appeared to account for 55–63% of the physical activity-endometrial cancer associations observed. CONCLUSIONS: Both initiating and maintaining physical activity throughout adulthood can play a role in preventing obesity and in turn, lowering the risk for endometrial cancer.

Background: The tissue specificity and robustness of miRNAs may aid risk prediction in individuals diagnosed with Barrett's esophagus. As an initial step, we assessed whether miRNAs can positively distinguish esophageal adenocarcinoma from the precursor metaplasia Barrett's esophagus. Methods: In a case–control study of 150 esophageal adenocarcinomas frequency matched to 148 Barrett's esophagus cases, we quantitated expression of 800 human miRNAs in formalin-fixed paraffin-embedded tissue RNA using NanoString miRNA v2. We tested differences in detection by case group using the χ2 test and differences in expression using the Wilcoxon rank-sum test. Bonferroni-corrected statistical significance threshold was set at P < 6.25E−05. Sensitivity and specificity were assessed for the most significant miRNAs using 5-fold cross-validation. Results: We observed 46 distinct miRNAs significantly increased in esophageal adenocarcinoma compared with Barrett's esophagus, 35 of which remained when restricted to T1b and T2 malignancies. Three miRNAs (miR-663b, miR-421, and miR-502-5p) were detected in >80% esophageal adenocarcinoma, but 5-fold increases. Using 5-fold cross-validation, we repeated feature (miR) selection and case–control prediction and computed performance criteria. Each of the five folds selected the same top 10 miRNAs, which, together, provided 98% sensitivity and 95% specificity. Conclusion: This study provides evidence that tissue miRNA profiles can discriminate esophageal adenocarcinoma from Barrett's esophagus. This large analysis has identified miRNAs that merit further investigation in relation to pathogenesis and diagnosis of esophageal adenocarcinoma. Impact: These candidate miRNAs may provide a means for improved risk stratification and more cost-effective surveillance. Cancer Epidemiol Biomarkers Prev; 25(3); 429–37. ©2015 AACR.

Background: Esophageal and gastric cancers differ in their epidemiology but have several risk factors in common. The aim of this study was to assess age and sex differences in the burden of esophageal and gastric cancers in the context of the global obesity epidemic. Methods: Data from 50 countries were obtained from Cancer Incidence in Five Continents Volume X and GLOBOCAN 2012. Age-specific and age-standardized incidence rates of esophageal adenocarcinoma and squamous cell carcinoma (ESCC), as well as cardia (CGC) and noncardia (NCGC) gastric cancer, were estimated. Countries were grouped and analyzed according to their obesity prevalence. Results: A gradient across quartiles of obesity prevalence was found for esophageal adenocarcinoma, with the highest incidence rates in high prevalence countries (ASR 3.0 vs. 0.8 per 100,000 in highest vs. lowest obesity quartiles, males). In contrast, for ESCC as well as for CGC and NCGC the reverse was true, with the highest rates observed in countries with the lowest obesity prevalence (ESCC, 2.2 vs. 11.5; CGC, 2.8 vs. 7.8; NCGC, 3.9 vs. 17.4 in highest vs. lowest obesity quartiles, males). Although for esophageal adenocarcinoma, sex and age differences in incidence were most pronounced in countries with a high prevalence of obesity, these differences were much smaller for the other cancer sites assessed. Conclusions: Variation in obesity prevalence may partly explain age and sex differences in the incidence of esophageal adenocarcinomas. Impact: Ecologic studies can help assess relationships between risk factors and cancer, and generate new hypotheses that may be pursued through more directed research. Cancer Epidemiol Biomarkers Prev; 25(1); 90–97. ©2015 AACR.

The association between leisure-time physical activity (LTPA) and male breast cancer risk is unclear. In the Male Breast Cancer Pooling Project, with 449 cases and 13,855 matched controls, we used logistic regression with study stratification to generate adjusted ORs and 95% confidence intervals (CI) for LTPA tertiles and male breast cancer risk. Compared with low LTPA, medium and high LTPA were not associated with male breast cancer risk (OR, 1.01; 95% CI, 0.79–1.29; 0.90, 0.69–1.18, respectively). In joint-effects analyses, compared with the referent of high body mass index (BMI; ≥25 kg/m2)/low LTPA, neither medium nor high PA was associated with risk among high BMI men, but normal BMI men (

Prostate cancer (PCa) is a highly heritable disease with large disparities in incidence rates across racial and ethnic populations. The inadequate representation of diverse populations in current genome-wide association studies (GWAS) limits the translational potential of findings to the world’s populations and could result in biased risk prediction, further exacerbating health disparities. To improve our understanding of genetic risk of PCa, we conducted a multiethnic meta-analysis of PCa GWAS using 107,247 cases and 127,006 controls from the Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome (PRACTICAL) consortium, including 85,554 cases and 91,972 controls of European ancestry, 10,368 cases and 10,986 controls of African ancestry, 8,611 cases and 18,809 controls of Asian ancestry, and 2,714 cases and 5,239 controls of Hispanic ancestry. We identified 269 genetic risk variants independently associated with PCa risk, 86 of which were novel. To understand the aggregate effect of the 269 variants, we constructed a genetic risk score (GRS) using the multiethnic weights of the risk variants. Compared to men in the average 40-60% GRS category, the estimated OR for men in the top GRS decile (90-100%) was 5.06 [95% CI 4.84-5.29] for men of European ancestry, 3.74 [95% CI 3.36-4.17] for men of African ancestry, 4.47 [95% CI 3.52-5.68] for men of Asian ancestry, and 4.15 [95% CI 3.33-5.17] for men of Hispanic ancestry. Men of African ancestry were estimated to have a 2.18-times higher mean GRS [95% CI 2.14-2.22], and men of Asian ancestry 0.73-times lower [95% CI 0.71- 0.76], than men of European ancestry. Age significantly modified the GRS association with PCa risk, such that in men of European ancestry, the top decile GRS category was associated with an OR of 6.71 [95 % CI 5.99-7.52] for men ages 55 years or younger and 4.39 [95% CI 4.19-4.60] for men older than 55 years. Similarly, in men of African ancestry, the top decile GRS category was associated with an OR of 4.70 [95% CI 3.65-6.07] for men ages 55 years or younger and 3.37 [95% CI 2.99-3.80] for men older than 55 years. We found that 51% of aggressive cases of European ancestry and 45% of aggressive cases of African ancestry were within the top 20% of the GRS. The lifetime absolute risk of PCa for men in the top decile of the GRS reached 38% for both African Americans [95% CI 36-41%] and Whites [95% CI 37-39%], 31% [95% CI 27-36%] for Hispanics and 26% [95% CI 22-30%] for Asians. For comparison, we constructed a genome-wide GRS, including the 269 variants and variants associated with PCa with P Citation Format: David V. Conti, Burcu F. Darst, Lilit Moss, Edward J. Saunders, Xin Sheng, Alisha Chou, Tokhir Dadaev, Sonja I. Berndt, Stephen K. Van Den Eeden, Stephen J. Chanock, Michael B. Cook, Hidewaki Nakagawa, John S. Witte, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman. Multiethnic GWAS meta-analysis identifies novel variants and informs genetic risk prediction for prostate cancer across populations [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-146.

Background: Systemic low-grade inflammation is a candidate risk factor for prostate cancer (PC) in African-American (AA) men potentially contributing to aggressive disease and mortality. Regular use of the anti-inflammatory drug aspirin is associated with decreased risk of advanced stage PC and increased disease-free survival in AA men. The chemopreventive benefits of aspirin have been attributed to inhibition of the cyclooxygenase (COX) pathway. Thromboxane A2 is an eicosanoid produced by the COX 1 enzyme in platelets. Aspirin inhibits cancer metastasis by inhibiting COX1 activity and thromboxane A2 synthesis. Hence, we assessed the role of thromboxane A2 in the development of lethal PC. Because thromboxane A2 is highly unstable, we measured its corresponding primary metabolite, urinary thromboxane b2 (TXB2), to examine the relationship of thromboxane A2 levels with PC. Method: TXB2 was measured in cases (977) and controls (1023) from the NCI-MD PC Case Control study using a mass-spectrometry-based assay. We estimated odds ratios (ORs) and 95% confidence intervals (CI) using unconditional logistic regression, with TXB2 levels modeled by quartiles. Multivariable models were adjusted for PC risk factors. Results: We observed an inverse relationship between aspirin use and levels of TXB2 in both cases and controls. For cases who used aspirin, the odds of having TXB2 urinary levels in the highest quartile (Q4) were significantly reduced when compared to non-users (adjusted OR = 0.29 95%CI 0.19-0.4) and this observation remained significant when stratified by race/ethnicity (AA men: OR 0.21 95%CI 0.11-0.38) (EA men: OR 0.34 95%CI 0.19-0.61), indicating significant inhibition of TXB2 formation by aspirin. The adjusted OR for PC was 1.42 (95%CI 1.09-1.85) for men in Q4 compared to Q1 (P trend 0.002). There was an association between TXB2 and PC in AA men (Q4 adjusted OR 1.95 95%CI 1.31-2.91, P trend Citation Format: Maeve Kiely, Ginger Milne, Tsion Z. Minas, Tiffany H. Dorsey, Wei Tang, Cheryl J. Smith, Michael B. Cook, Clayton Yates, Stefan Ambs. High urinary thromboxane B2 associates with aggressive prostate cancer and inversely correlates with aspirin use [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-157.

Background. In this study, we compared prostate cancer incidence and survival between rural and urban settings in the US, using a recently released census-tract rurality-urbanicity metric that serves as a proxy for geographical access to care. We also examined the associations between rurality and receipt of definitive treatment and further examined whether rural-urban status serves as an explanatory factor for observed race differences in prostate cancer incidence, treatment, and survival. Methods. Using data from the Surveillance, Epidemiology, and End Results program we identified prostate cancer patients newly diagnosed between 2000 and 2015, aged 45 years and older. Patients were classified as residing in a ‘rural’ or ‘urban’ setting based on the US Department of Agriculture’s 2-level Rural Urban Commuting Area (RUCA) measure. We defined ‘definitive treatment’ as receipt of radical prostatectomy (RP) among patients diagnosed with locoregional disease. To compare rural and urban settings we estimated relative measures for prostate cancer incidence, odds of treatment receipt, and prostate cancer survival using Poisson, logistic, and Cox regression models, respectively. We adjusted regression models for age, race, stage, or treatment, where applicable. Results. Between 2000 and 2015, men in the rural US were slightly less likely to be diagnosed with prostate cancer when compared with urban US men (incidence rate ratio (IRR) = 0.89; 95% CI: 0.88, 0.90), but were at higher risk of prostate cancer death (hazard ratio (HR) = 1.16; 95% CI: 1.13, 1.19). Patients diagnosed with locoregional disease in rural settings were also less likely to receive RP compared with their urban counterparts (odds ratio (OR) = 0.91; 95% CI: 0.89, 0.92) and were more likely to receive non-radical surgical interventions (OR = 1.31; 95% CI: 1.28, 1.35). In general, race differences were not evident by rural-urban status. Black men, however, were more likely to receive a prostate cancer diagnosis irrespective of geographical setting when compared with white men (rural IRR = 1.50; 95% CI: 1.46, 1.54 and urban IRR = 1.69; 95% CI: 1.64, 1.73). Black men were also substantially less likely to receive RP (OR = 0.49; 95% CI: 0.48, 0.49). With respect to survival, Asian or Pacific Islander men were at lower risk of prostate cancer death compared with white men (HR = 0.78; 95% CI: 0.75, 0.81). By contrast, American Indian/Alaskan Native and black men had the highest risks of death (HR = 1.26; 95% CI: 1.11, 1.43 and HR = 1.25; 95% CI: 1.22, 1.28, respectively). Conclusions. Observed differences in prostate cancer incidence, treatment, and survival may reflect spatial differences in access to cancer prevention and cancer care. Rural-urban status does not appear to modify racial/ethnic differences in prostate cancer incidence and survival. Citation Format: Eboneé N Butler, Michael B Cook. The interplay between rurality-urbanicity and race in prostate cancer risk, treatment, and survival in the United States [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D115.

Background: Differential uptake of prostate-specific antigen (PSA) testing in the US and UK has been linked to between-country differences in prostate cancer incidence. In the US, men of African ancestry have been shown to have a higher incidence of prostate cancer that is ultimately fatal compared with men of European ancestry, thus prompting calls for precision prevention approaches to screening. To assess whether temporal and racial differences are evident in the UK, we assessed the incidence of fatal prostate cancer in the US and England during a period of evolving screening recommendations and practices in both countries. Methods: Using data from the Surveillance, Epidemiology, and End Results program and Public Health England's National Cancer Registration and Analysis Service, we identified prostate cancer patients newly diagnosed between 1995 and 2005, aged 45-84 years old. We defined fatal prostate cancer as death attributed to the disease within 10 years of diagnosis. To evaluate incidence trends across the 11-year study period, we used age-period-cohort modeling to calculate estimated annual percentage change (EAPC) and joinpoint regression analysis to identify periods of significant change. Results: In the US, 9% (n=38,409) of the 429,541 prostate cancer cases were fatal, compared with 17% (n=39,249) of the 228,615 cases in England. The age-adjusted incidence of fatal prostate cancer declined in the US by -4.2% per year (95%CI: -4.6%, -3.8%) and increased in England by 7.7% per year (95%CI:7.2%, 8.3%). From 2002-2005, the US experienced a more rapid decline in the incidence of fatal disease (EAPC = -6.4%; 95%CI: -8.3%, -4.5%) while rates in England continued to increase, albeit to a lesser degree (EAPC = 4.3%; 95%CI: -0.1%, 8.9%). Temporal trends for each country did not differ by race. However, a black-to-white difference persisted across the study period, with black men in both the US and England experiencing 2-to-3-fold higher incidence rates of fatal prostate cancer compared with white men. Conclusions: During a period of increased PSA testing in the US and relatively low, but growing, use in England, we observed opposing trends for the incidence of fatal prostate cancer between the two countries. Our ecological study suggests that country-specific screening practices may influence temporal trends for the incidence of fatal prostate cancer similarly for black and white men, though a disparity persists in the absolute rate of disease occurrence between the two groups. Citation Format: Eboneé N. Butler, Scott P. Kelly, Victoria H. Coupland, Philip R. Rosenberg, Michael B. Cook. Racial differences in the incidence of fatal prostate cancer in two countries: An ecological comparison of the United States and England [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C016.

Prostate cancer (PCa) is a major cause of cancer death in U.S. men. Age-adjusted mortality rates for men of African ancestry (40.8 per 100,000) are more than twice that of men of European ancestry (18.2 per 100,000). Men of African ancestry are more likely to have advanced stage cancer at diagnosis and lower prostate cancer survival rates relative to men of European ancestry of similar age and stage at diagnosis. Risk factors that may explain this survival disparity remain poorly understood. Obesity, a major risk factor for cancer development, aggressiveness and progression, disproportionately affects US men of African ancestry. Age-adjusted prevalence of obesity are higher among men of African ancestry (38.0%) compared to men of European ancestry (34.7%). While it has been previously suggested that obesity may worsen disease-related outcomes among prostate cancer patients, the relationship of obesity and prostate cancer mortality remains unclear, with studies showing mixed or null results in men of African ancestry. Less is known about the underlying biological mechanisms that may contribute to the racial differences observed in the link between obesity and prostate cancer. We previously reported an obesity paradox among African-American men in the NCI-Maryland Prostate Cancer-Case Control Study, with overweight and obese men having a lower risk of being diagnosed with the disease. Here, using Cox proportional hazard regression modeling, we estimated the risk of a PCa mortality for the 976 cases in the study. Our primary analysis suggests an obesity paradox, where obesity may protect against disease mortality among the African-American men. In subsequent analyses, we will examine the role of immune and inflammation markers in mediating or moderating the observed relationship of obesity with PCa in these men. Citation Format: Margaret S Pichardo, Tsion Minas, Wei Tang, Tiffany Dorsey, Michael Cook, Stefan Ambs. Effect of obesity and inflammation on prostate cancer disease risk and mortality among African and European American men [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C076.

Background: Adult height has been positively associated with prostate cancer risk. However, the exposure window of importance is currently unknown and assessments of height during earlier growth periods are scarce. In addition, the association between birth weight and prostate cancer remains undetermined. We assessed these relationships in a cohort of the Copenhagen School Health Records Register (CSHRR). Methods: The CSHRR comprises 372,636 school children. For boys born between the 1930s and 1969, birth weight and annual childhood heights—measured between ages 7 and 13 years—were analyzed in relation to prostate cancer risk. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Results: There were 125,211 males for analysis, 2,987 of who were subsequently diagnosed with prostate cancer during 2.57 million person-years of follow-up. Height z-score was significantly associated with prostate cancer risk at all ages (HRs, 1.13 to 1.14). Height at age 13 years was more important than height change (P = 0.024) and height at age 7 years (P = 0.024), when estimates from mutually adjusted models were compared. Adjustment of birth weight did not alter the estimates. Birth weight was not associated with prostate cancer risk. Conclusions: The association between childhood height and prostate cancer risk was driven by height at age 13 years. Impact: Our findings implicate late childhood, adolescence, and adulthood growth periods as containing the exposure window(s) of interest that underlies the association between height and prostate cancer. The causal factor may not be singular given the complexity of both human growth and carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(12); 2232–40. ©2013 AACR.

Background: Helicobacter pylori can induce gastric atrophy in humans, which in turn increases gastric cancer risk. Whether H. pylori and gastric atrophy also affect the risk of esophageal squamous cell carcinoma (ESCC), however, remains unresolved. Methods: We performed a nested case-control study within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study to assess these relationships. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study is composed of 29,133 Finnish male smokers, ages 50 to 69 years, who were recruited during 1985-1988. Using baseline sera, we assessed H. pylori status (via immunoglobulin G antibodies against whole-cell and CagA antigens) and gastric atrophy status [via the biomarkers pepsinogen I (PGI) and pepsinogen II (PGII)] in 79 ESCC cases and 94 controls. Logistic regression with adjustment for age, date of blood draw, education, cigarette smoking, alcohol, body mass index, and fruit and vegetable intake was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI). Results: Gastric atrophy (PGI/PGII Conclusions: These results could be explained by misclassification of H. pylori status due to serologic amnesia, ESCC risk being dependent on the functional consequences or interactions of H. pylori rather than the infection per se, gastric atrophy having a different histogenesis in ESCC without being primarily dependent on H. pylori acquisition, or a lack of statistical power to detect an effect. Impact: Validation of these results may warrant mechanistic studies to determine the route of association between gastric atrophy and ESCC. Cancer Epidemiol Biomarkers Prev; 19(8); 1966–75. ©2010 AACR.

Background: Prostate cancer is the second leading cause of cancer death in American men, but few modifiable risk factors have been established for prostate cancer progression and survival. Experimental studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may improve prostate cancer survival through anti-thrombotic and anti-inflammation mechanisms. However, previous observational studies have shown mixed results. No study has examined over-the-counter non-aspirin NSAIDs in relation to prostate cancer survival. Few studies have assessed aspirin use before prostate cancer diagnosis in relation to prostate cancer survival, and whether any etiologically relevant time window of exposure exists remains unclear. Methods: We assessed two cohorts of prostate cancer cases from two large prospective studies in the United States NIH-AARP Diet and Health Study and Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to investigate associations of aspirin and other nonselective non-aspirin NSAID use before and after prostate cancer diagnosis with prostate cancer-specific and all-cause mortality. Cox proportional hazards models with age as the time metric were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results across the two studies were meta-analyzed in a fixed effects model if consistent associations were observed. Results: We did not find statistically significant associations of pre- or post-diagnostic NSAID use with prostate cancer-specific mortality. However, aspirin users versus nonusers five years or more before prostate cancer diagnosis had a 14% (95%CI=0.74 to 1.00) and a 16% (95%CI=0.78 to 0.89) reduced prostate cancer-specific and all-cause mortality when combining the two studies. Post-diagnostic occasional (less than once per day) and daily aspirin use were associated with 17% (95%CI=0.72 to 0.95) and 25% (95%CI=0.66 to 0.86) reductions in all-cause mortality independent of pre-diagnostic use, comparing with no use. Conclusions: This analysis suggests a modest delayed survival benefit of aspirin use before prostate cancer diagnosis and highlights the importance of comorbidity prevention among prostate cancer survivors. Citation Format: Cindy Ke Zhou, Sarah E. Daugherty, Amanda Black, Linda M. Liao, Neal D. Freedman, Christian C. Abnet, Ruth Pfeiffer, Michael B. Cook. Pre- and post-diagnostic use of nonsteroidal anti-inflammatory drugs and prostate cancer mortality among men diagnosed with prostate cancer in the NIH-AARP and PLCO cohorts. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B26.