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

• Published in: Pathology oncology research Vol. 15; no. 4; pp. 651 - 658
• Main Authors: Chen, Hua-Jun, Mok, Tony S., Chen, Zhi-Hong, Guo, Ai-Lin, Zhang, Xu-Chao, Su, Jian, Wu, Yi-Long
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.12.2009; Springer Nature B.V
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - ethnology; Adenocarcinoma - genetics; Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cancer Research; 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; Epidermal growth factor; Erlotinib Hydrochloride; Female; Gene Amplification - genetics; Humans; Immunology; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - ethnology; Lung Neoplasms - genetics; Male; Middle Aged; Mutation; Mutation - genetics; Oncology; Original Paper; Pathology; Protein-Tyrosine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins c-met - genetics; Quinazolines - therapeutic use; Receptor, Epidermal Growth Factor - genetics; Survival Analysis; China; Non-small cell lung cancer, Resistance; c-MET; T790M; Epidermal growth factor receptor
• ISSN: 1219-4956; 1532-2807
• DOI: 10.1007/s12253-009-9167-8

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.