­­­A Multigene Circulating Biomarker to Predict the Lack of FOLFIRINOX Response after a Single Cycle in Patients with Pancreatic Ductal Adenocarcinoma (PDAC)

Introduction: FOLFIRINOX is promising in treating patients with pancreatic ductal adenocarcinoma (PDAC). However, many patients and physicians are reluctant to start FOLFIRINOX due to its high toxicity and limited clinical response rates. In this study, we investigated the effect of a single FOLFIRINOX cycle, in combination with a granulocyte colony-stimulating factor (G-CSF), on the blood immune transcriptome of PDAC patients. We aimed to identify an early circulating biomarker to predict the lack of FOLFIRINOX response.<br><br>Methods: Blood samples of 68 patients from all disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. The response to treatment was radiologically evaluated following the RECIST criteria 1.1. Targeted immune-gene expression profiling was performed using NanoString technologies. To predict the lack of FOLFIRINOX response, we developed a FOLFIRINOX delta Gene Expression Profiling (FFX-ΔGEP) score.<br><br>Results: A single FOLFIRINOX cycle significantly altered 395 genes, correlating to 30 significant alterations in relative immune cell abundances and pathway activities. The eight-gene (BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1, and TGFB2) FFX-ΔGEP score predicted the lack of FOLFIRINOX response with a leave-one-out cross-validated AUC [95% CI] of 0.87 [0.60 – 0.98], thereby outperforming the predictiveness of absolute and proportional ΔCA19-9 values.<br><br>Conclusions: A single FOLFIRINOX cycle, combined with G-CSF, alters the peripheral immune transcriptome indisputably. Our novel FFX-ΔGEP is, to our knowledge, the first multigene early circulating biomarker that predicts the lack of FOLFIRINOX response after one cycle. Validation in a larger independent patient cohort is crucial before clinical implementation.