Plasma metabolomic signatures for predicting pancreatic ductal adenocarcinoma survival: The clinical application of targeted mass spectrometry lipidomics.

e16409 Background: Pancreatic ductal adenocarcinoma (PDAC) is one the most lethal human cancers with an overall 5-year survival of 12%. Diagnostic and prognostic biomarkers have the potential to improve early detection and the hope for better outcomes yet efforts to apply genomic risk-stratification to enhance PDAC screening have not proven cost effective (Peters et al., JCO, 2023). We previously reported the application of mass spectrometry to identify PDAC in plasma (D’Amora et al., Metabolites, 2024). We now show that plasma lipidomics provide risk stratification for PDAC survival. Methods: Plasma from 29 PDAC patients were analyzed by targeted MS/MS using the Absolute IDQ p180 on a Sciex 6500 triple quad platform. Metabolic ratios incorporating phosphatidylcholines (PCs) and sphingomyelins (SMs) were correlated with survival. Statistical significance used Wilcoxon rank-sum tests with false discovery rate (FDR) correction. Results: Four lipid ratios significantly correlated with survival up to 15 years of follow up. These include (PC aa C40:5/PC ae C36:0) (p = 1.13e-5, FDR = 0.001), (PC aa C40:5/SM C18:1) (p = 4.74e-5, FDR = 0.003), (PC aa C36:5/PC ae C36:0) (p = 2.87e-4, FDR = 0.007), and (PC aa C40:5/SM C16:1) (p = 3.177e-4, FDR = 0.007). In PDAC higher concentrations of unsaturated PCs & SMs correlated with longer survival. The equation (Lysophophatidylcholine a 26:1/ Phosphatidylcholine aa C34:4) separated survivors from non-survivors with a Receiver Operator Curve (ROC) AUC = 0.968 (p = 4.01e-4). To interrogate micro-environmental conditions, we applied MS/MS to the media of PDAC explants derived from surgical specimens. Following 72 hour incubation (37°, 5% CO2) unsaturated PC concentrations were found significantly lower in the media isolated from PDAC explants compared with controls (p < 0.007). Conclusions: Higher concentrations of unsaturated lipids and higher ratios of unsaturated to saturated lipids in the plasma of PDAC patients correlate with improved survival. As malignant transformation is associated with increased dependence upon exogenous sources of unsaturated lipids, we confirmed lower concentrations of unsaturated lipids in the media from PDAC explant cultures highly consistent with enhanced tumor avidity for these lipid species. We have previously found that plasma unsaturated lipid concentrations differ by tumor type (unpublished). Here we show higher unsaturated lipid concentrations and ratios in the plasma of PDAC patients appear to reflect a systemic protective effect. We demonstrate that plasma lipidomic signatures can stratify PDAC-patient survival, offering a novel prognostic biomarker. Lipid alterations reflective of metabolic reprogramming may offer a new method for risk stratification. Further validation is warranted to confirm the observed correlations between plasma lipidomics and PDAC survival.