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 (original) (raw)

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.

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Abbreviations

(ARMS):

amplification refractory mutation system

(EGFR):

epidermal growth factor receptor

(NSCLC):

non-small cell lung cancer

(OS):

overall survival

(PFS):

progression free survival

(TKI):

tyrosine kinase inhibitor

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Acknowledgements

This work was supported by the National Natural Science Foundation of China 30772531, the Foundation of Guangdong Science and Technology Department, 2007A032000002, and the Chinese Lung Cancer Research Foundation.

We thank Pasi A. Jänne (Dana-Farber Cancer Institute, Boston, MA, USA) for DNA samples of NSCLC cell lines HCC827 parental and HCC827 GR6. We thank Qiu-Xiong Lin and Dong-Lan Luo (Department of Pathology, Guangdong General Hospital) for their assistance in microdissection. We also thank the AstraZeneca Innovation Center China (ICC) in Shanghai for the excellent technical support.

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Authors and Affiliations

  1. Cancer Center, Sun Yat-Sen University, Guangzhou, China
    Hua-Jun Chen
  2. Guangdong Lung Cancer Institute, Guangdong General Hospital, 106 Zhongshan Er Road, Guangzhou, Guangdong, 510080, China
    Hua-Jun Chen, Zhi-Hong Chen, Jian Su & Yi-Long Wu
  3. Department of Clinical Oncology, Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
    Tony S. Mok
  4. Department of Biochip, Guangdong Academy of Medical Sciences, Guangzhou, China
    Ai-Lin Guo & Xu-Chao Zhang

Authors

  1. Hua-Jun Chen
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  2. Tony S. Mok
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  3. Zhi-Hong Chen
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  4. Ai-Lin Guo
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  5. Xu-Chao Zhang
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  6. Jian Su
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  7. Yi-Long Wu
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Corresponding author

Correspondence toYi-Long Wu.

Additional information

The data were presented in part at the 2008 ASCO annual meeting (Abstract-No. 8107).

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Chen, HJ., Mok, T.S., Chen, ZH. et al. 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. 15, 651–658 (2009). https://doi.org/10.1007/s12253-009-9167-8

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