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

Introduction: 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (FOLFIRINOX) is promising in treating patients with pancreatic ductal adenocarcinoma. 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, on the blood immune transcriptome of patients with pancreatic ductal adenocarcinoma. We aimed to iden-ify an early circulating biomarker to predict the lack of FOLFIRINOX response. 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 Response Evaluation Criteria in Solid Tumours criteria 1.1. Targeted immune-gene expression profiling (GEP) was performed using Nano-String technologies. To predict the lack of FOLFIRINOX response, we developed a FOLFIRINOX delta GEP (FFX-Delta GEP) score. 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-Delta GEP score predicted the lack of FOLFIRINOX response with a leave-one-out cross-validated area under the curve (95% confidence interval) of 0.87 (0.60-0.98), thereby outperforming the predictiveness of absolute and proportional Delta carbohydrate antigen19-9 values. Conclusions: A single FOLFIRINOX cycle, combined with granulocyte colony-stimulating factor, alters the peripheral immune transcriptome indisputably. Our novel FFX-Delta GEP 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. (c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

This study investigated the impact of a single cycle of FOLFIRINOX in combination with a granulocyte colony-stimulating factor on the blood immune transcriptome of patients with pancreatic ductal adenocarcinoma. A novel eight-gene FFX-Delta GEP score was developed to predict the lack of FOLFIRINOX response after one cycle. The findings highlight the potential of using the peripheral immune transcriptome as an early circulating biomarker for predicting treatment outcomes.