Clinicopathologic and Molecular Features of Epidermal Growth Factor Receptor T790M Mutation and c-MET Amplification in Tyrosine Kinase Inhibitor-Resistant Chinese Non-Small Cell Lung Cancer

Pathol Oncol Res. 2009 Dec;15(4):651-8. doi: 10.1007/s12253-009-9167-8. Epub 2009 Apr 21.

Abstract

To investigate the clinicopathologic and molecular features of the T790M mutation and c-MET amplification in a cohort of Chinese non-small cell lung cancer (NSCLC) patients resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). EGFR TKI-resistant NSCLC patients (n = 29) and corresponding tumor specimens, and 53 samples of postoperative TKI-naïve NSCLC patients were collected. EGFR exon 19, 20, and 21 mutations were analyzed. And c-MET gene copy number was determined. The EGFR T790M mutation in exon 20 was not detected in the population of 53 TKI-naïve patients, but found in 48.3% (14/29) of the enrolled TKI-resistant patients. c-MET was amplified in 3.8% (2/53) of the TKI-naïve NSCLC patients and highly amplified in 17.2% (5/29) of the cohort. Most of T790M mutations were frequently associated with non-smoker, adenocarcinoma and EGFR activating mutations. Three male patients with T790M mutation occurred with wild-type EGFR, and were resistant to the treatments following TKI resistance. Features of c-MET amplification in TKI-naïve patients were indistinguishable from TKI-resistant patients. In the group of wild-type EGFR, patients with T790M mutation had median progression free survival (PFS) and overall survival (OS) as 9.6 months and 12.6 months, respectively; whereas the median PFS and OS of c-MET amplified patients was 4.1 months and 8.0 months, respectively. These results suggest that EGFR T790M mutation and c-MET amplification can occur in TKI-resistant NSCLC with wild-type EGFR, and these genetic defects might be related to different survival outcome. c-MET amplification in TKI-naïve or -resistant patients might share similarities in clinicopathologic features.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / ethnology
  • Adenocarcinoma / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Large Cell / drug therapy
  • Carcinoma, Large Cell / ethnology
  • Carcinoma, Large Cell / genetics
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Squamous Cell / drug therapy
  • Carcinoma, Squamous Cell / ethnology
  • Carcinoma, Squamous Cell / genetics
  • Case-Control Studies
  • China
  • Drug Resistance, Neoplasm / genetics*
  • ErbB Receptors / genetics*
  • Erlotinib Hydrochloride
  • Female
  • Gefitinib
  • Gene Amplification / genetics*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / ethnology
  • Lung Neoplasms / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / genetics*
  • Quinazolines / therapeutic use
  • Survival Analysis

Substances

  • Antineoplastic Agents
  • Quinazolines
  • Erlotinib Hydrochloride
  • ErbB Receptors
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-met
  • Gefitinib