Abstract 282: Pre-diagnostic circulating metabolites and risk of overall, intermediate-risk, high-risk and lethal prostate cancer: a systematic review andmeta-analysis of untargeted metabolomic studies
Authors: Harriett Fuller, Orietta P. Agasaro, Burcu F. Darst
Journal: Cancer Research (2025)

Prostate cancer (PCa) is the 2nd most common cancer in men. Metabolomic dysregulation is expected to contribute to PCa pathogenesis; however, pre-diagnostic evidence of metabolite-PCa associations has not been quantitatively aggregated. This study aimed to quantitatively assess metabolite-PCa associations, compare these associations between distinct PCa outcomes, and evaluate sources of bias in PCa metabolomic epidemiology studies. We conducted a systematic review (October 17th, 2024) and meta-analysis to identify pre-diagnostic untargeted serum metabolomic studies of PCa risk. Restricted maximum likelihood (REML) was used to conduct meta-analyses to quantify associations between metabolites and risk of overall PCa, low- to intermediate-risk PCa, high- to very high-risk PCa and lethal PCa, as defined by the NCCN. Statistical significance was defined as FDR-adjusted P&amp;lt; 0.05. Enrichment analyses were conducted to identify biologically relevant pathways. The DrugBank Pharmaco-metabolomics database was used to determine whether identified metabolites are drug modifiable. Thirteen predominantly European ancestry studies were identified (10,467 cases/10,833 controls) and 602 metabolite biomarker associations were meta-analyzed. Three, three, eleven and nineteen metabolites were significantly associated with risk of overall, low- to intermediate-risk, high- to very high-risk and lethal PCa, respectively. No metabolite was significantly associated with &amp;gt;1 PCa outcome; however, 12 metabolites were nominally associated (P&amp;lt;0.05) with &amp;gt;1 outcome. Effect sizes between metabolites associations with overall and high- to very high-risk PCa were significantly correlated when considering all 144 metabolites (r=0.19, P=0.023) and 10 metabolites nominally associated with both outcomes (r=0.87, P=0.001). Metabolite effects associated with lethal PCa risk were largely distinct from other outcomes. Metabolites significantly associated with risk of high- to very high-risk PCa were significantly enriched for lipids (P=0.03). Using DrugBank, we found that levels of 11 significant metabolites are drug modifiable. Key sources of bias identified included the selective reporting of results, inconsistent metabolite naming, limited adjustment for fasting status and limited diversity, which could impact the generalizability of findings. In conclusion, pre-diagnostic levels of 36 circulating metabolites were associated with PCa risk, 30 of which were associated with high- to very high-risk or lethal PCa. The metabolomic profile of lethal PCa risk was largely distinct from other PCa outcomes. Future work is needed to further investigate how pre-diagnostic metabolite profiles differ by PCa aggressiveness and to evaluate the role of identified metabolites as PCa biomarkers across populations. Citation Format: Harriett Fuller, Orietta P. Agasaro, Burcu F. Darst. Pre-diagnostic circulating metabolites and risk of overall, intermediate-risk, high-risk and lethal prostate cancer: a systematic review andmeta-analysis of untargeted metabolomic studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 282.