Back to Search
Start Over
Cell-Free DNA Next-Generation Sequencing Prediction of Response and Resistance to Third-Generation EGFR Inhibitor.
- Source :
-
Clinical lung cancer [Clin Lung Cancer] 2018 Nov; Vol. 19 (6), pp. 518-530.e7. Date of Electronic Publication: 2018 Aug 07. - Publication Year :
- 2018
-
Abstract
- Introduction: The genomic alterations driving resistance to third-generation EGFR tyrosine kinase inhibitors (TKIs) are not well established, and collecting tissue biopsy samples poses potential complications from invasive procedures. Cell-free circulating DNA (cfDNA) testing provides a noninvasive approach to identify potentially targetable mechanisms of resistance. Here we utilized a 70-gene cfDNA next-generation sequencing test to interrogate pretreatment and progression samples from 77 EGFR-mutated non-small cell lung cancer (NSCLC) patients treated with a third-generation EGFR TKI.<br />Patients and Methods: Rociletinib was evaluated in advanced or metastatic (second line or higher) disease with EGFR T790M-positive NSCLC in the TIGER-X (NCT01526928) and TIGER-2 (NCT02147990) studies. Plasma samples were collected at baseline and at the time of systemic progression while receiving rociletinib. The critical exons in 70 genes were sequenced in cfDNA isolated from plasma samples to elucidate a comprehensive genomic profile of alterations for each patient.<br />Results: Plasma-based cfDNA analysis identified 93% of the initial EGFR activating and 85% of the EGFR T790M resistance mutations in pretreatment samples with detectable tumor DNA. Profiling of progression samples revealed significant heterogeneity, with different variant types (eg, mutations, amplifications, and fusions) detected in multiple genes (EGFR, MET, RB1) that may be driving resistance in patients. Novel alterations not previously described in association with resistance to third-generation TKIs were also detected, such as an NTRK1 fusion.<br />Conclusion: cfDNA next-generation sequencing identified initial EGFR activating and secondary T790M resistance mutations in NSCLC patients with high sensitivity, predicted treatment response equivalent to tissue analysis, and identified multiple novel and established resistance alterations.<br /> (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung genetics
Drug Resistance, Neoplasm genetics
ErbB Receptors antagonists & inhibitors
ErbB Receptors genetics
Female
High-Throughput Nucleotide Sequencing
Humans
Lung Neoplasms drug therapy
Lung Neoplasms genetics
Male
Middle Aged
Mutation genetics
Neoplasm Metastasis
Neoplasm Staging
Prognosis
Treatment Outcome
Acrylamides therapeutic use
Antinematodal Agents therapeutic use
Carcinoma, Non-Small-Cell Lung diagnosis
Cell-Free Nucleic Acids analysis
Lung Neoplasms diagnosis
Pyrimidines therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1938-0690
- Volume :
- 19
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Clinical lung cancer
- Publication Type :
- Academic Journal
- Accession number :
- 30279111
- Full Text :
- https://doi.org/10.1016/j.cllc.2018.07.008