A multigene circulating biomarker to predict the lack of FOLFIRINOX response after a single cycle in patients with pancreatic ductal adenocarcinoma (PDAC)

Abstract

Abstract Introduction: FOLFIRINOX chemotherapy showed promising results 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 cycle of FOLFIRINOX, 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. Methods Blood samples of 68 patients from all PDAC disease stages, who received at least four FOLFIRINOX cycles, were collected at baseline and after the first cycle. Patients were divided into “disease control” and “progressive disease” following the RECIST criteria 1.1. RNA was isolated and targeted immune-gene expression profiling was performed using the PanCancer Immune profiling panel of NanoString. The FOLFIRINOX delta Gene Expression Profiling (FFX-ΔGEP) score was calculated using the weight of eight genes following LASSO multivariate regression analysis. Results Comparing the immune gene expression profile of samples at baseline to after a single FOLFIRINOX cycle resulted in the identification of 395 differentially expressed genes (BH.P < 0.05), correlating to 30 significant alterations in relative immune cell abundancies and pathway activities (BH.P < 0.05). The patient cohort included 48 disease control and 10 progressive disease patients. The FFX-ΔGEP score, composed of eight genes (BID, FOXP3, KIR3DL1, MAF, PDGFRB, RRAD, SIGLEC1, and TGFB2), could predict the lack of FOLFIRINOX response with a leave-one-out cross-validated AUC [95% CI] of 0.87 [0.60–0.98]. Our FFX-ΔGEP score outperformed the predictiveness of absolute and proportional ΔCA19-9 values with an AUC [95% CI] of 0.70 [0.27–1.0] and 0.52 [0.24–0.80], respectively. Notably, immune-gene expression profiles of baseline samples could not predict the lack of FOLFIRINOX response. Conclusions A single FOLFIRINOX cycle, combined with G-CSF, alters the peripheral immune transcriptome indisputably. We revealed a novel multigene FFX-ΔGEP score which is, to our knowledge, the first gene expression-based early circulating biomarker that predicts the lack of FOLFIRINOX response after only a single cycle. Validation in a larger independent cohort of samples is crucial before clinical implementation.