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

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.