The Combination of Neutrophil–Lymphocyte Ratio and Platelet–Lymphocyte Ratio with Liquid Biopsy Biomarkers Improves Prognosis Prediction in Metastatic Pancreatic Cancer

SIMPLE SUMMARY: Liquid biopsy is a noninvasive approach that provides tumor molecular profiling. On the other hand, the vast majority of pancreatic tumors are pancreatic ductal adenocarcinomas (PDAC), which are characterized by pronounced inflammation. Therefore, we hypothesized that the combination of biomarkers of systemic inflammation, such as the neutrophil-to-lymphocyte-ratio (NLR) and platelet-to-lymphocyte ratio (PLR), with liquid biopsy-based biomarkers may increase their clinical usefulness. Our study shows that combining NLR, PLR, and the standard PDAC marker CA19-9 with circulating cell-free DNA and circulating RAS-mutated DNA outperforms traditional clinical tools for the clinical management of metastatic PDAC patients. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a highly inflammatory microenvironment and liquid biopsy has emerged as a promising tool for the noninvasive analysis of this tumor. In this study, plasma was obtained from 58 metastatic PDAC patients, and neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), circulating cell-free DNA (cfDNA) concentration, and circulating RAS mutation were determined. We found that NLR was significantly associated with both overall survival (OS) and progression-free survival. Remarkably, NLR was an independent risk factor for poor OS. Moreover, NLR and PLR positively correlated, and combination of both inflammatory markers significantly improved the prognostic stratification of metastatic PDAC patients. NLR also showed a positive correlation with cfDNA levels and RAS mutant allelic fraction (MAF). Besides, we found that neutrophil activation contributed to cfDNA content in the plasma of metastatic PDAC patients. Finally, a multi-parameter prognosis model was designed by combining NLR, PLR, cfDNA levels, RAS mutation, RAS MAF, and CA19-9, which performs as a promising tool to predict the prognosis of metastatic PDAC patients. In conclusion, our study supports the idea that the use of systemic inflammatory markers along with circulating tumor-specific markers may constitute a valuable tool for the clinical management of metastatic PDAC patients.