Simple SummaryPancreatic cancer is a clinically heterogeneous disease, and treatment leads to different outcomes for people with similar diagnoses. Identifying patients who may respond to chemotherapy and thereby benefit from improved survival has important implications for treatment protocols. In this study, plasma metabolite profiling was performed to identify potential biomarker candidates that can predict the response of patients to different neoadjuvant chemotherapy regimens for pancreatic cancer. The concentrations of several metabolites from LC–MS were significantly different when comparing the response to chemotherapy. Several metabolites demonstrated a predictive performance for the response to chemotherapy. These results show promise for larger studies that would validate the findings, which could contribute to the development of more personalized treatment protocols for pancreatic cancer patients.AbstractPancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, we analyzed plasma metabolites using high-performance liquid chromatography–mass spectrometry from 31 cachectic, advanced-PC subjects enrolled into the PANCAX-1 (NCT02400398) prospective trial to receive a jejunal tube peptide-based diet for 12 weeks and who were planned for palliative chemotherapy. Overall, there were statistically significant differences in the levels of intermediates of multiple metabolic pathways in pts with a partial response (PR)/stable disease (SD) vs. progressive disease (PD) to chemotherapy. When stratified by the chemotherapy regimen, PD after 5-fluorouracil-based chemotherapy (e.g., FOLFIRINOX) was associated with decreased levels of amino acids (AAs). For gemcitabine-based chemotherapy (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis, the TCA cycle, nucleoside synthesis, and bile acid metabolism. These results demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced-PC patients for assessing the effect of enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of a patient’s response and warrant further study.