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Clinical Cancer Research Vol. 10, 8195-8203, December 15, 2004
© 2004 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

High Frequency of Epidermal Growth Factor Receptor Mutations with Complex Patterns in Non–Small Cell Lung Cancers Related to Gefitinib Responsiveness in Taiwan

Shiu-Feng Huang1,2, Hui-Ping Liu3, Ling-Hui Li1, Yuan-Chieh Ku1, Yu-Ning Fu1, Hsien-Yu Tsai1, Ya-Ting Chen1, Yung-Feng Lin1, Wen-Cheng Chang4, Han-Pin Kuo5, Yi-Cheng Wu3, Yi-Rong Chen1 and Shih-Feng Tsai1,6

1 Division of Molecular and Genomic Medicine, National Health Research Institutes, Departments 2 Pathology, 3 Cardio-Thoracic Surgery, 4 Hematology and Oncology, and 5 Thoracic Medicine, Chang-Gung Memorial Hospital, and 6 Institute of Genetics and Genome Research Center, National Yang-Ming University, Taipei, Taiwan

Purpose: Epidermal growth factor receptor (EGFR) mutations related to gefitinib responsiveness in non–small cell lung cancer have been found recently. Detection of EGFR mutations has become an important issue for therapeutic decision-making in non–small cell lung cancer.

Experimental Design: Mutational analysis of the kinase domain of EGFR coding sequence was done on 101 fresh frozen tumor tissues from patients without prior gefitinib treatment and 16 paraffin-embedded tumor tissues from patients treated with gefitinib. Detection of phosphorylated EGFR by immunoblot was also done on frozen tumor tissues.

Results: The 101 non–small cell lung cancer tumor specimens include 69 adenocarcinomas, 24 squamous cell carcinomas, and 8 other types of non–small cell lung cancers. Mutation(s) in the kinase domain (exon 18 to exon 21) of the EGFR gene were identified in 39 patients. All of the mutations occurred in adenocarcinoma, except one that was in an adenosquamous carcinoma. The mutation rate in adenocarcinoma was 55% (38 of 69). For the 16 patients treated with gefitinib, 7 of the 9 responders had EGFR mutations, and only 1 of the 7 nonresponders had mutations, which included a nonsense mutation. The mutations seem to be complex in that altogether 23 different mutations were observed, and 9 tumors carried 2 mutations.

Conclusions: Data from our study would predict a higher gefitinib response rate in lung adenocarcinoma patients in Chinese and, possibly, other East Asian populations. The tight association with adenocarcinoma and the high frequency of mutations raise the possibility that EGFR mutations play an important role in the tumorigenesis of adenocarcinoma of lung, especially in East Asians.




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