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Updated: Feb 4, 2026

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Cell-Free DNA Next-Generation Sequencing Prediction of Response and Resistance to Third-Generation EGFR Inhibitor

Elena Helman1, Minh Nguyen2, Chris A Karlovich3

  • 1Guardant Health Inc, Redwood City, CA.

Clinical Lung Cancer
|October 4, 2018
PubMed
Abstract

Insights

Cell-free DNA (cfDNA) testing noninvasively identifies EGFR mutations and resistance mechanisms in non-small cell lung cancer (NSCLC) patients treated with third-generation tyrosine kinase inhibitors (TKIs). This approach offers high sensitivity and reveals genomic heterogeneity at progression.

Area of Science:

  • Genomics and Molecular Biology
  • Oncology
  • Translational Medicine

Background:

  • Genomic alterations driving resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are not fully understood.
  • Tissue biopsies for resistance profiling are invasive and pose potential complications.
  • Cell-free circulating DNA (cfDNA) offers a noninvasive alternative for identifying resistance mechanisms.

Purpose of the Study:

  • To evaluate the utility of a 70-gene cfDNA next-generation sequencing (NGS) test for identifying genomic alterations in EGFR-mutated NSCLC patients.
  • To analyze cfDNA from pretreatment and progression samples of patients treated with third-generation EGFR TKIs.
  • To elucidate comprehensive genomic profiles and resistance mechanisms noninvasively.

Main Methods:

  • Utilized a 70-gene cfDNA NGS test on plasma samples from 77 EGFR-mutated NSCLC patients.
  • Samples were collected at baseline (pretreatment) and at the time of systemic progression.
  • Sequenced critical exons in 70 genes to identify mutations, amplifications, and fusions.

Main Results:

  • cfDNA analysis detected 93% of initial EGFR activating mutations and 85% of EGFR T790M resistance mutations in pretreatment samples.
  • Progression samples revealed significant genomic heterogeneity, including alterations in EGFR, MET, and RB1.
  • Novel resistance alterations, such as an NTRK1 fusion, were identified, expanding the known landscape of TKI resistance.

Conclusions:

  • cfDNA NGS is a highly sensitive method for detecting both initial EGFR mutations and secondary T790M resistance mutations in NSCLC.
  • Plasma-based cfDNA profiling demonstrated high sensitivity, comparable to tissue analysis, in predicting treatment response.
  • This noninvasive approach successfully identified diverse and novel resistance alterations, aiding in personalized treatment strategies.
Keywords:
Circulating tumor DNADrug resistanceDrug responseEGFR C797SEGFR T790MNSCLCNTRK fusionPlasmaThird-generation TKITyrosine kinase inhibitorctDNA gene panelctDNA sequencing

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