Abstract 3338: Targeted serum metabolomics for noninvasive detection of colorectal neoplasia

Abstract

Abstract Background: Using a shotgun metabolomics approach, we have previously reported distinct features in the circulating metabolome of patients with colorectal cancer (CRC) and adenoma. A clinically useful metabolomic assay requires a targeted approach that detects CRC with high sensitivity, and which also detects pre-malignant precursor lesions. Our objective was to identify a metabolomic signature for CRC, adenomatous polyps (AP), and sessile serrated adenomas (SSA), using a targeted approach. Methods: Serum from patients with all stages of CRC (N=86), AP (N=48), SSA (N=46), as well as age- and sex-matched disease-free controls (DFC; N=120) were analyzed using a targeted metabolomic assay (Biocrates MxP® Quant 500). The assay was performed on liquid chromatography-tandem mass spectrometry (LC-MS/MS), quantifying 630 metabolites across 26 biochemical classes. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to identify metabolite patterns distinguishing each neoplastic condition relative to DFCs. A small validation cohort (N=78) was additionally analyzed to test our meta-biomarkers. Results: In comparisons with DFCs, statistically significant OPLS-DA models were constructed for all three neoplastic conditions. The OPLS-DA models for CRC, AP, and SSA consisted of 39, 14, and 22 metabolites, respectively, with the most frequently represented biochemical classes being triglycerides, phosphatidylcholines, bile acids, and acylcarnitines. Based on 7-fold internal cross validation, receiver operating characteristic (ROC) analysis demonstrated an area under the curve (AUC) of 0.85, 0.89, and 0.82 for CRC, AP, and SSA, respectively. When applied to the independent validation cohort, the sensitivity and specificity of each model were: 87.0% and 87.0% for CRC; 53.3% and 93.3% for AP; and 78.6% and 57.1% for SSA. Conclusion: Metabolomic meta-biomarkers for CRC and its precursors demonstrated excellent performance based on internal validation. Importantly, these lesions were each detected with superior sensitivity compared to readily available stool-tests. A large external validation study in progress will be used to confirm these findings. Citation Format: Liam W. Fitzgerald, Dennis J. Orton, Karen A. Kopciuk, Hans J. Vogel, Robert J. Hilsden, Oliver F. Bathe. Targeted serum metabolomics for noninvasive detection of colorectal neoplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3338.