Clinicopathologic Significance of the Mutations of theEpidermal Growth Factor ReceptorGene in Patients with Non–Small Cell Lung Cancer

Abstract

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.

The ERBB3 receptor in cancer and cancer gene therapy

“…[396][397][398][399] These mutations are especially prevalent in non-smokers, females, East Asians and bronchioalveolar carcinomas. [400][401][402][403][404][405] EGFR polysomy/amplification and high mRNA and protein expression were also associated with survival after treatment with these inhibitors. [406][407][408][409] In PC-13 cells, which have no endogenous EGFR expression, transfected mutant EGFR showed high constitutive phosphorylation of itself and of AKT and STAT3, and prolonged cell survival under serum-free conditions.…”

Distinct clinical features and outcomes in never‐smokers with nonsmall cell lung cancer who harbor EGFR or KRAS mutations or ALK rearrangement

“…EGFR mutations have been reported in approximately 50% of never-smoker lung cancer patients compared with 10% of smoker lung cancer patients. 2,[12][13][14] The high frequency of EGFR mutations in never-smoker patients is associated with dramatic and durable responses to EGFR tyrosine kinase inhibitors (TKIs). 2,[15][16][17][18][19][20] ALK rearrangement, which results from a small inversion within chromosome 2p, is a newly identified driver oncogene in nonsmall cell lung cancer (NSCLC).…”

Abnormalities of epidermal growth factor receptor in lung squamous‐cell carcinomas, adenosquamous carcinomas, and large‐cell carcinomas

“…[1][2][3][6][7][8][9]11 These types of mutations are widely recognized as occurring more frequently in adenocarcinomas than in tumors of other histology. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] The frequency of EGFR TKD mutations in NSCLC except for adenocarcinoma is reported to be generally low (Table 1). These results lead clinicians to refrain from using gefitinib on patients with nonadenocarcinoma NSCLC.…”