Background: Systemic low-grade inflammation is a candidate risk factor for prostate cancer (PC) in African American (AA) men, potentially contributing to lethal PC development. We previously reported that regular aspirin use is associated with a decreased risk of advanced stage disease and disease recurrence in AA patients with PC. The cancer-preventive benefits of aspirin have been attributed to inhibition of the cyclooxygenase (COX) pathway. Thromboxane A2 (TXA2) is an eicosanoid produced by the COX1 enzyme in platelets. Aspirin can inhibit metastasis by inhibiting COX1 activity and TXA2 synthesis. Hence, we assessed the role of TXA2 in the development of lethal PC. Because TXA2 is unstable, we measured its corresponding primary metabolite, urinary thromboxane B2 (TXB2), to examine the relationship of TXA2 with PC.
Method: TXB2 was measured in cases (977) and controls (1022) from the NCI-MD PC Case-Control study using a mass-spectrometry-based assay. TXB2 levels were modeled into low (≤median) and high (>median) levels. We calculated risk factor-adjusted odds ratios (ORs) and 95% confidence intervals (CI) using unconditional logistic regression, adjusted hazard ratios (HR) using Cox regression and sub hazard ratios (SHR) using the Fine-Gray model.
Results: We observed increased TXB2 levels in cases and an inverse relationship between levels of TXB2 and aspirin use in both cases and controls. For cases who used aspirin, the odds of having high TXB2 were reduced when compared to non-users (OR 0.46 95%CI, 0.34-0.61). This observation remained significant when stratified by race/ethnicity (AA: OR 0.36 95%CI, 0.23-0.54; EA: OR 0.58 95%CI, 0.38-0.88), indicating significant inhibition of TXB2 formation by aspirin, most notably in AA men. Further analysis showed that high TXB2 is associated with a PC case status in AA men (OR 1.44 95%CI, 1.08-1.93) but not EA men (OR 1.07 95%CI, 0.83-1.93), indicating increased TXA2 synthesis in AA men with PC compared to AA men without the disease. Also, men with high TXB2 were more likely to be diagnosed with metastasis compared to men with low TXB2 (OR 4.27 95%CI, 1.48-12.29), indicating more aggressive disease for cases with high TXB2. Furthermore, high TXB2 was associated with all-cause mortality (HR 1.56 95%CI, 1.05-2.33) and PC mortality (HR 4.02 95%CI, 1.46-11.07; SHR 2.89 95%CI, 1.03-8.11) in AA men only. Our findings indicate a distinct association between TXA2 and PC outcomes in AA men.
Conclusion: Aspirin use inversely associates with high TXB2. This is of clinical interest as we report that increased TXB2 associates with PC in AA men, with aggressive PC, and with PC death which disproportionally affects AA men. This is consistent with our previous findings that aspirin may reduce lethal PC in AA men and highlights the potential benefit of aspirin for prevention of lethal PC in this high-risk group of men through inhibition of TXA2 synthesis.
Citation Format: Maeve Bailey-Whyte, 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 lethal prostate cancer in African American men and inversely correlates with aspirin use [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 34.