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Clinicopathologic Significance of the Mutations of the Epidermal Growth Factor Receptor Gene in Patients with Non–Small Cell Lung Cancer

Authors' Affiliations: Departments of ¹ Medicine and Molecular Science, ² Thoracic and Visceral Organ Surgery, ³ General Surgical Science, ⁴ Medicine and Biological Science, and ⁵ Tumor Pathology, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma, Japan; ⁶ National Nishigunma Hospital, Kanai, Shibukawa, Gunma, Japan; and ⁷ Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Yoshio Tomizawa, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan. Phone: 27-220-7111 ext. 8123; Fax: 27-220-8136; E-mail: ytomizaw{at}showa.gunma-u.ac.jp.

Purpose: It has been reported that the mutations of epidermal growth factor receptor (EGFR) are detected in lung cancers. Studies of EGFR mutations in large numbers of patients' tumors with clinical data including response to EGFR tyrosine kinase directed therapy are needed to develop a robust database for clinical use. The purpose of the present study is to gain further insights into the significance of EGFR mutation in non–small cell lung cancer (NSCLC).

Experimental Design: We investigated the clinicopathologic significance of tyrosine kinase domain (exons 18-21) EGFR mutations in 120 patients with primary NSCLC and the correlation between EGFR mutation and sensitivity to gefitinib in an additional 20 NSCLC patients treated with gefitinib. In addition, onocogenic KRAS mutations and RASSF1A promoter methylation were determined in the same samples.

Results: EGFR mutation was detected in 29 of 120 (24%) tumors. All of the 29 (40%) mutations occurred in 72 adenocarcinomas. EGFR mutation was significantly more frequent in females (47%) than males (12%, P < 0.0001), in younger patients (38%) than older patients (10%, P = 0.0005), in nonsmokers (47%) than smokers (13%, P < 0.0001), and in well-differentiated tumors (39%) than moderately and poorly differentiated tumors (7%, P < 0.0001). Mutation of the EGFR gene was preferentially observed in advanced disease. Furthermore, EGFR mutations were detected in 11 of 14 (79%) responders, whereas none of six (0%) nonresponders had the mutation (P = 0.0022).

Conclusions: These results in Japanese (East Asian) patients indicated that EGFR mutation plays an important role in pathogenesis of lung adenocarcinoma.

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