Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs.

Li Ma,Jialin Lv,Yuhua Wu,Haoyang Li,Xi Li,Mengjun Yu,Xinjie Yang,Quan Zhang,Ruoying Yu,Na Qin,Shucai Zhang,Ying Hu,Jinghui Wang,Hui Zhang,Dongpo Wang,Xinyong Zhang

doi:10.3389/fonc.2021.643199

Li Ma, Jialin Lv + Show 14 more

Open Access

https://doi.org/10.3389/fonc.2021.643199

Copy DOI

Abstract

PurposeCirculating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.MethodsFrom 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.ResultsIn univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms.ConclusionsPatients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

Highlights

EGFR gene mutations account for the most frequency of oncogenic mutations in advanced non-small cell lung cancer (NSCLC)
The results showed that undetectable cell-free DNA (cfDNA) level during treatment was an independent predictor for longer Progression-free survival (PFS) of the thirdgeneration TKIs (HR 0.3085, 95%CI 0.1617–0.5885; P = 0.000359), while undetectable T790M was not (HR 0.57, 95% CI 0.2874–1.1303; P = 0.1075)
This study evaluated the role of dynamic cfDNA level based on a large-panel NGS with 425 genes in predicting outcomes and identifying possible resistant mutations in EGFR T790M-positive NSCLC patients who received the third-generation EGFR TKIs

Summary

Introduction

EGFR gene mutations account for the most frequency of oncogenic mutations in advanced non-small cell lung cancer (NSCLC). About 50–60% resistant mechanism of the first generation EGFR TKIs was EGFR T790M gene mutation. As a viable alternative for tissue biopsy, liquid biopsy with circulating cell-free DNA (cfDNA) analysis has been used in identifying molecular target, predicting response and prognosis, and monitoring resistance during targeted treatment for lung cancer [3]. CfDNA clearance during anticancer therapies has been an emerging topic in lung cancer, especially in EGFRmutated NSCLCs. Previous studies have reported a promising role of cfDNA longitudinal monitoring using different liquid biopsy methodologies [4,5,6,7]. The longitudinal cfDNA monitoring has been proposed as a follow-up tool in the identification of acquired mechanisms of resistance that can impact sequential treatment management [5, 8]. Several studies have reported cfDNA clearance as a potential predictive biomarker for NSCLC patients during immunotherapy [9]

Methods

Results

Conclusion