Excision Repair Cross-Complementation Group 6 Gene Polymorphism Is Associated with the Response to FOLFIRINOX Chemotherapy in Asian Patients with Pancreatic Cancer.

Young Hoon Choi,Sang Hyub Lee,Woo Hyun Paik,Younggyun Lim,Ju Han Kim,Yong-Tae Kim,Ji Kon Ryu

doi:10.3390/cancers13061196

Abstract

Simple SummaryFOLFIRINOX is a platinum-based chemotherapy regimen for patients with pancreatic cancer and is known to be more effective in the presence of the BRCA mutation, one of the DNA damage repair (DDR) gene mutations. However, BRCA mutations are less common in pancreatic cancer patients, accounting for only about 5% of cases worldwide, and are known to be even rarer in Asians. Therefore, this study aimed to uncover new genetic variants of DDR genes related to the response of FOLFIRINOX by analyzing variants of DDR genes using whole exome sequencing. Multivariable Cox regression analysis adjusted for clinical variables showed that a single nucleotide polymorphism (SNP) of the ERCC6 gene is an independent predictor for progression-free survival. If validated, the ERCC6 SNP found in this study could be used as a biomarker to predict responses to FOLFIRINOX.FOLFIRINOX is currently one of the standard chemotherapy regimens for pancreatic cancer patients, but little is known about the factors that can predict a response to it. We performed a study to discover novel DNA damage repair (DDR) gene variants associated with the response to FOLFIRINOX chemotherapy in patients with pancreatic cancer. We queried a cohort of pancreatic cancer patients who received FOLFIRINOX chemotherapy as the first treatment and who had tissue obtained through an endoscopic ultrasound-guided biopsy that was suitable for DNA sequencing. We explored variants of 148 DDR genes based on whole exome sequencing and performed multivariate Cox regression to find genetic variants associated with progression-free survival (PFS). Overall, 103 patients were included. Among 2384 variants of 141 DDR genes, 612 non-synonymous variants of 123 genes were selected for Cox regression analysis. The multivariate Cox model showed that rs2228528 in ERCC6 was significantly associated with improved PFS (hazard ratio 0.54, p = 0.001). The median PFS was significantly longer in patients with rs2228528 genotype AA vs. genotype GA and GG (23.5 vs. 16.2 and 8.6 months; log-rank p < 0.001). This study suggests that rs2228528 in ERCC6 could be a potential predictor of response to FOLFIRINOX chemotherapy in patients with pancreatic cancer.

Highlights

Pancreatic cancer is a lethal disease with a 5-year survival rate of 9% [1]
304 patients were diagnosed with pancreatic cancer through endoscopic ultrasound EUS-FNB
We demonstrated that the A alleles of rs2228528 in ERCC6 were significantly associated with longer progression-free survival (PFS) in pancreatic cancer patients who received FOLFIRINOX chemotherapy

Summary

Introduction

Pancreatic cancer is a lethal disease with a 5-year survival rate of 9% [1]. One of the reasons for this poor prognosis is that 85–90% of patients are diagnosed at an advanced stage where surgical resection is not possible [1,2]. A large number of pancreatic cancer patients receive chemotherapy as an initial treatment, and the two preferred chemotherapy regimens today are FOLFIRINOX and Gemcitabine plus albumin-bound paclitaxel [3,4,5]. Predicting which of these two chemotherapy regimens will be more effective for each patient helps determine the best first-line chemotherapy. In this study, we aimed to find novel variants of DDR genes that could predict the response to FOLFIRINOX chemotherapy based on whole exome sequencing analysis

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