Abstract B021: Prediagnostic serum metabolomic profiling of prostate cancer survival
Authors: Huang Jiaqi , Mondul Alison , Weinstein Stephanie , Derkach Andriy , Hua Xing , Moore Steve , Sampson Joshua , Albanes Demetrius 
Published: February 2019

Prostate cancer is the most common noncutaneous malignancy among men in the United States, accounting for nearly 1 in 5 new diagnoses and ranking fourth in cancer mortality. Impaired metabolism may play a role in the development and lethality of this malignancy, yet a comprehensive analysis of circulating metabolites and prostate cancer-specific mortality appears lacking. We measured 625 known metabolites using ultrahigh performance LC/MS-GC/MS assays of prospectively collected serum of 197 prostate cancer cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median age at diagnosis and time since blood collection were 69 years and 10 years (respectively), and the case stage distribution was 52% localized, 21% locally advanced, and 28% metastatic, with 92 patients dying from their disease (median survival times for the stages were 7.0, 5.4, and 1.9 years, respectively). Cox proportional hazards models estimated the associations between serum metabolites and prostate cancer mortality (log-metabolite scale), adjusted for age, year of diagnosis, and disease stage. Metabolite chemical classes were examined through pathway analysis, and the sterol/steroid association through a principal component analysis (PCA) factor score. Bonferroni-corrected statistical threshold p-values for the main metabolite, chemical class pathway, and PCA analyses were 0.00008 (0.05/625), 0.0063 (0.05/8), and 0.0014 (0.05/45), respectively. Serum N-oleoyl taurine was statistically significantly associated with increased prostate cancer mortality (HR=1.72 per 1-standard deviation (1-SD), 95% CI: 1.34, 2.20, P=1.7×10-5), with cases in the second and third (versus lowest tertile) having mortality HRs of 2.1 and 3.6, respectively (Ptrend&lt;0.001). Higher circulating levels of 4-androsten-3beta,17beta-diol disulfate were also related to increased prostate cancer mortality (second and third tertile HRs of 1.6 and 2.7, respectively; Ptrend&lt;0.001). Pathway analyses revealed a statistically significant prostate cancer mortality association with lipids (P=0.0013), and sterol/steroid metabolites showed the strongest chemical sub-class association (P=0.0014), contributed to by monohydroxy, branched-chain amino acid (BCAA) metabolism, acyl glycine, and dicarboxylate metabolites (0.01&lt;P&lt;0.003). In the PCA analyses, a 1-SD increase in sterol/steroid metabolite score was associated with 46% higher prostate cancer mortality (95% CI: 1.16, 1.83, P=0.0012), and the strongest association was seen among cases diagnosed 7+ years after blood collection (7-13 years and &gt;13 years, 1-SD HRs of 2.1 and 2.0, respectively). Neither the N-oleoyl taurine nor the sterol/steroid-survival association differed materially by BMI or stage at diagnosis. This analysis of serum metabolites indicates that elevated prediagnostic N-oleoyl taurine and sex steroid hormones are associated with substantially decreased prostate cancer survival. Additional prospective studies should reexamine these associations, their underlying biologic mechanisms, and their potential utility as novel prognostic markers for clinical risk stratification.

Citation Format: Jiaqi Huang, Alison Mondul, Stephanie Weinstein, Andriy Derkach, Xing Hua, Steve Moore, Joshua Sampson, Demetrius Albanes. Prediagnostic serum metabolomic profiling of prostate cancer survival [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B021.