Discovery of targetable genetic alterations in advanced non-small cell lung cancer using a next-generation sequencing-based circulating tumor DNA assay

Sci Rep. 2017 Nov 6;7(1):14605. doi: 10.1038/s41598-017-14962-0.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / genetics
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Circulating Tumor DNA*
  • Cohort Studies
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics
  • ErbB Receptors / genetics
  • Female
  • Genetic Association Studies / methods
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics*
  • Male
  • Middle Aged
  • Mutation


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • EGFR protein, human
  • ErbB Receptors