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

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

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.643199

DOI=10.3389/fonc.2021.643199

ISSN=2234-943X

ABSTRACT=<sec><title>Purpose</title><p>Circulating 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.</p></sec><sec><title>Methods</title><p>From 2016 to 2019, 81 NSCLC patients with <italic>EGFR</italic> 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.</p></sec><sec><title>Results</title><p>In univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 <italic>vs</italic>. 6.10 months; HR 0.2109; <italic>P</italic> &lt; 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 <italic>vs</italic>. 4.4 months; HR 0.2192; <italic>P</italic> &lt; 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; <italic>P</italic> &lt; 0.001) and longer OS (HR 0.499; <italic>P</italic> = 0.034). The most common resistant mutations of the third-generation TKIs were <italic>EGFR</italic> C797S (24%). <italic>CDK6</italic> CNV, <italic>GRIN2A</italic>, <italic>BRCA2, EGFR</italic> D761N, <italic>EGFR</italic> Q791H, <italic>EGFR</italic> V843I, and <italic>ERBB4</italic> mutation genes may possibly be new resistant mechanisms.</p></sec><sec><title>Conclusions</title><p>Patients 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.</p></sec>