Background: Etiologic studies of prostate cancer have shown inconsistent associations with coffee consumption. We have previously shown increased risk with number of cups/day, with the strongest association for men consuming 4+ cups/day. The association was evident in the first 10 years of cohort follow-up, however, suggesting possible reverse causality. We conducted a serum metabolomic profiling study to biochemically re-evaluate our coffee findings and determine whether caffeine metabolites are similarly associated with prostate cancer risk.

Methods: A prospective, nested case-control analysis within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort was conducted using 200 cases and 200 controls matched on age and date of baseline fasting serum collection. Sera were analyzed using ultrahigh performance liquid chromatography/mass spectroscopy (LC-MS) and gas chromatography/mass spectroscopy (GS-MS) (Metabolon, Inc.) which identified 626 known compounds, including 13 caffeine-related metabolites. Each metabolite was assessed using conditional logistic regression that estimated odds ratios (OR) and 95% confidence intervals (CI) of prostate cancer associated with a one standard deviation (1-S.D.) increment in metabolite signal strength. The analysis was also stratified by median time from baseline blood draw to prostate cancer diagnosis (<10 years vs. ≥10 years).

Results: Overall, caffeine metabolite associations with prostate cancer risk showed null results (e.g., caffeine OR 1.02, 95% CI 0.84-1.24, p = 0.82; paraxanthine OR 0.99, 95% CI 0.83-1.20, p = 0.96). Similar to our findings for coffee consumption, caffeine metabolites were positively associated with prostate cancer risk for men diagnosed within 10 years of blood collection. Theobromine and 1,7-dimethylurate showed the strongest signals (respectively, OR 1.69, 95% CI 1.13-2.54, p = 0.01; OR 1.63, 95% CI 1.14-2.32, p = 0.01). By contrast, in men diagnosed at least 10 years from baseline, caffeine metabolites were non-significantly inversely related to risk; e.g., 5-acetylamino-6-formylamino-3-methyluracil (AFMU), OR 0.77, 95% CI 0.56-1.06, p = 0.10). Caffeine metabolites were positively correlated with both caffeine and coffee (median correlation coefficients, 0.78 and 0.20, respectively). Including coffee in the metabolite risk models led to little or no attenuation of the associations in either the early or later 10 year observation periods.

Conclusions: In this prospective analysis, serum caffeine metabolites were positively associated with risk of prostate cancer in men diagnosed within 10 years of blood collection. The findings provide biochemical corroboration of our previous findings for a positive coffee-prostate cancer risk association, and appear to support the possibility of reverse causality; i.e., men with subclinical tumors may increase their coffee consumption as a result of their underlying disease

Citation Format: Shakira M. Nelson, Alison M. Mondul, Stephanie J. Weinstein, Demetrius Albanes. Serum caffeine metabolites and prostate cancer risk in the ATBC Study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 13.