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

Abstract

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.

Non-responsiveness to gefitinib in a patient with lung adenocarcinoma having rare EGFR mutations S768I and V769L

“…This case suggests that in vitro sensitivity to gefitinib correlates with distinct clinical responsiveness to gefitinib in various types of EGFR mutations. [4][5][6][7][8][9][10] however, in in-vitro studies, some of these mutations (including S768I) conferred less sensitivity to gefitinib than the two major types of mutations, and even its wild-type counterpart. 11 Because of lower frequency of these novel mutations, clinical information of their relationships with drug responsiveness is very limited so far.…”

“…[1][2][3][4][5][6][7][8][9][10]13 Although multiple studies have shown striking correlation between these factors, [1][2][3]5,[8][9][10] a correlative study in a large clinical phase III trial, BR21, showed no significant association of EGFR mutations with responsiveness to erlotinib or with survival after this agent was administered. 13 One possible reason for such a discrepancy could be that different mutations have different effects on response to EGFR-TKIs.…”

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

“…These phenotypic features had already been marked as clinical predictors of response to TKIs before the discovery of the mutations (Fukuoka et al, 2003;Kris et al, 2003). The prevalence of EGFR mutations varies by ethnicity with ranges from 20-40% in Asian populations (Huang et al, 2004;Kosaka et al, 2004;Han et al, 2005;Shigematsu et al, 2005;Tokumo et al, 2005) to 5-20% among Caucasians (Cappuzzo et al, 2005;Marchetti et al, 2005).…”

“…The overall response rates were as high as 80% in patients harboring mutations compared with p10% in patients with wildtype EGFR (Huang et al, 2004;Lynch et al, 2004;Mu et al, 2004;Paez et al, 2004;Pao et al, 2004; Sasaki et al, 2006;Kosaka et al, 2007;Yoshida et al, 2007;see Gazdar, 2009).…”

Epidermal growth factor receptor mutations detected by denaturing high‐performance liquid chromatography in nonsmall cell lung cancer

“…The other is a point mutation in exon 21 (2573T>G) that results in substitution of leucine by arginine at codon 858 (L858R). [4][5][6][7][8][9][10] Other much less common mutations have also been described in exons 18, 20, and 21.…”