Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers
Top Cited Papers
- 15 April 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 19 (8), 2240-2247
- https://doi.org/10.1158/1078-0432.ccr-12-2246
Abstract
Purpose: All patients with EGF receptor (EGFR)–mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been conducted. Experimental Design: Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a rebiopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2. Results: Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations [63%; 95% confidence interval (CI), 55%–70%] and four had small cell transformation (3%, 95% CI, 0%–6%). MET amplification was seen in 4 of 75 (5%; 95% CI, 1%–13%). HER2 amplification was seen in 3 of 24 (13%; 95% CI, 3%–32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS (0 of 88, 0%; 95% CI, 0%–4%). Overlap among mechanisms of acquired resistance was seen in 4%. Conclusions: This is the largest series reporting mechanisms of acquired resistance to EGFR-TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, whereas MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR-TKIs. Clin Cancer Res; 19(8); 2240–7. ©2013 AACR.Keywords
This publication has 40 references indexed in Scilit:
- Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1Proceedings of the National Academy of Sciences of the United States of America, 2012
- Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancerNature Genetics, 2012
- Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion SequencingThe New England Journal of Medicine, 2012
- Optimization of Dosing for EGFR-Mutant Non–Small Cell Lung Cancer with Evolutionary Cancer ModelingScience Translational Medicine, 2011
- Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR InhibitorsScience Translational Medicine, 2011
- Rebiopsy of Lung Cancer Patients with Acquired Resistance to EGFR Inhibitors and Enhanced Detection of the T790M Mutation Using a Locked Nucleic Acid-Based AssayClinical Cancer Research, 2011
- Gefitinib or Carboplatin–Paclitaxel in Pulmonary AdenocarcinomaThe New England Journal of Medicine, 2009
- MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinibProceedings of the National Academy of Sciences of the United States of America, 2007
- MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 SignalingScience, 2007
- EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinibProceedings of the National Academy of Sciences of the United States of America, 2004