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Updated: Nov 9, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs
Li Ma1, Haoyang Li1, Dongpo Wang2
1Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China.
Purpose:
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.
Methods:
From 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.
Results:
In 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.
Conclusions:
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.
Insights
Clear circulating tumor DNA (ctDNA) during third-generation EGFR tyrosine kinase inhibitor (TKI) treatment predicts better outcomes for non-small cell lung cancer (NSCLC) patients. Dynamic ctDNA analysis using next-generation sequencing (NGS) aids in identifying resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Circulating cell-free DNA (cfDNA) levels correlate with treatment efficacy in non-small cell lung cancer (NSCLC) patients receiving first-generation EGFR TKIs.
- The utility of dynamic cfDNA analysis via next-generation sequencing (NGS) with third-generation EGFR TKIs is not well-established.
Purpose of the Study:
- To investigate the role of dynamic cfDNA analysis in patients with NSCLC treated with third-generation EGFR TKIs.
- To determine the association between cfDNA and T790M mutation levels and treatment outcomes.
Main Methods:
- Enrolled 81 NSCLC patients with EGFR T790M mutations receiving third-generation EGFR TKIs (2016-2019).
- Sequenced cfDNA using NGS with a 425-gene panel.
- Analyzed associations between clinical characteristics, cfDNA dynamics, T790M levels, and patient outcomes.
Main Results:
- Undetectable cfDNA during treatment correlated with significantly longer progression-free survival (PFS) (16.97 vs. 6.10 months).
- Undetectable T790M mutation during treatment also showed significantly longer PFS (14.1 vs. 4.4 months).
- cfDNA clearance independently predicted longer PFS and overall survival (OS). EGFR C797S was the most common resistance mutation (24%), with other gene mutations/CNVs potentially indicating novel resistance mechanisms.
Conclusions:
- Patients achieving undetectable cfDNA during third-generation EGFR TKI therapy exhibit superior clinical outcomes.
- Dynamic cfDNA analysis by NGS is a valuable tool for uncovering potential mechanisms of drug resistance in NSCLC.
