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Updated: Feb 19, 2026
Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Discovery of targetable genetic alterations in advanced non-small cell lung cancer using a next-generation
Helei Hou1, Xiaonan Yang2, Jinping Zhang3
1Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiangsu Road, Qingdao, 266005, China.
Abstract:
Next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) assays have provided a new method of identifying tumor-driving genes in patients with advanced non-small cell lung carcinoma (NSCLC), especially in those whose cancer tissues are unavailable or in those that have acquired treatment resistance. Here, we describe a total of 119 patients with advanced EGFR-TKI-naive NSCLC and 15 EGFR-TKI-resistant patients to identify somatic SNVs, small indels, CNVs and gene fusions in 508 tumor-related genes. Somatic ctDNA mutations were detected in 82.8% (111/134) of patients in the total cohort. Of the 119 patients with advanced NSCLC, 27.7% (33/119) were suitable for treatment with National Comprehensive Cancer Network (NCCN) guideline-approved targeted drugs. Actionable genetic alterations included 25 EGFR mutations, 5 BRAF mutations, and 1 MET mutation, as well as 1 EML4-ALK gene fusion and 1 KIF5B-RET gene fusion. In 19.3% (23/119) of the patients, we also identified genomic alterations with that could be targeted by agents that are in clinical trials, such as mTOR inhibitors, PARP inhibitors, and CDK4/6 inhibitors. Additionally, the EGFR T790M mutation was found in 46.7% (7/15) of the patients with EGFR-TKI-resistant NSCLC, suggesting that the NGS-based ctDNA assay might be an optional method to monitor EGFR-TKI resistance and to discover mechanisms of drug resistance.
Insights
Next-generation sequencing of circulating tumor DNA (ctDNA) effectively identifies actionable mutations in advanced non-small cell lung cancer (NSCLC). This blood test aids in guiding targeted therapies and monitoring treatment resistance in NSCLC patients.
Area of Science:
- Oncology
- Genetics
- Molecular Diagnostics
Background:
- Circulating tumor DNA (ctDNA) analysis via next-generation sequencing (NGS) offers a minimally invasive approach for molecular profiling.
- Identifying actionable genetic alterations is crucial for personalized treatment in advanced non-small cell lung carcinoma (NSCLC).
- Challenges in obtaining tumor tissue and understanding treatment resistance necessitate advanced diagnostic tools.
Purpose of the Study:
- To evaluate the utility of NGS-based ctDNA assays in identifying somatic mutations, copy number variations (CNVs), and gene fusions in advanced NSCLC.
- To determine the proportion of patients with actionable alterations and those eligible for targeted therapies or clinical trials.
- To assess the potential of ctDNA assays in monitoring resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).
Main Methods:
- Somatic mutations, small indels, CNVs, and gene fusions were analyzed in 508 tumor-related genes using NGS on ctDNA samples.
- The study cohort comprised 119 treatment-naive advanced NSCLC patients and 15 EGFR-TKI-resistant NSCLC patients.
- Detected alterations were correlated with National Comprehensive Cancer Network (NCCN) guidelines and ongoing clinical trials.
Main Results:
- Somatic ctDNA mutations were detected in 82.8% of the total cohort (111/134).
- Actionable genetic alterations, including EGFR, BRAF, MET mutations, and EML4-ALK, KIF5B-RET fusions, were identified in 27.7% (33/119) of treatment-naive patients.
- Genomic alterations targetable by agents in clinical trials were found in 19.3% (23/119) of patients, and the EGFR T790M mutation was detected in 46.7% (7/15) of resistant cases.
Conclusions:
- NGS-based ctDNA assays are effective in detecting a wide range of genomic alterations in advanced NSCLC.
- ctDNA analysis can identify patients eligible for guideline-approved targeted therapies and those who may benefit from investigational agents.
- ctDNA assays show promise for monitoring EGFR-TKI resistance and uncovering resistance mechanisms in NSCLC.
