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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.

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.