Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers.

Yu HA, Arcila ME, Rekhtman N, Sima CS, Zakowski MF, Pao W, Kris MG, Miller VA, Ladanyi M, Riely GJ
Clin Cancer Res. 2013 19 (8): 2240-7

PMID: 23470965 · PMCID: PMC3630270 · DOI:10.1158/1078-0432.CCR-12-2246

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.

MeSH Terms (26)

Adenocarcinoma Adult Aged Aged, 80 and over Biopsy CD56 Antigen DNA Mutational Analysis Drug Resistance, Neoplasm ErbB Receptors Erlotinib Hydrochloride Female Gefitinib Humans Immunohistochemistry In Situ Hybridization, Fluorescence Kaplan-Meier Estimate Ki-67 Antigen Lung Lung Neoplasms Male Middle Aged Mutation Protein Kinase Inhibitors Proto-Oncogene Proteins c-met Quinazolines Receptor, ErbB-2

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