Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals☆
Introduction
Lung cancer is the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC), 70–80% of which is diagnosed at an advanced stage, accounts for about 85% of the total cases. At present, chemotherapy is the first-line treatment for advanced cases, with a median overall objective response rate of 17% [1]. NSCLC shows a promising response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib, which target the molecular pathways of tumor cell growth and survival. The objective response rate to EGFR-TKIs was higher in patients harboring somatic EGFR mutations [2], [3].
Mutations of EGFR are found in fewer than 10% of non-Asian patients but occur in 30% of East Asians [4], [5], [6]. The two most important mutations are L858R in exon 21, which involves a thymine-to-guanine transversion that replaces leucine with arginine, and exon 19 deletion, which eliminates a leucine-arginine-glutamate-alanine motif. These two account for more than 80% of EGFR mutations [4], [7], [8], [9]. The altered structure of the EGFR kinase domain allows TKIs binding more tightly to the receptor. Both in vivo and in vitro studies have shown that these mutations increase the sensitivity of NSCLC patients to EGFR-TKIs [10], [11], [12].
An individual patient data (IPD) meta-analysis, conducted by Wu et al., showed that the clinical selected population for gefitinib are non-smokers with adenocarcinoma and that a more favorable response occurred in patients with somatic EGFR mutations [5]. Moreover, patients with exon 19 deletions survived longer than those with exon 21 point mutations, consistent with previous studies [13], [14], [15]. Few in vitro studies were found to have specifically investigated the mechanism of the distinction. We hypothesized that these two mutations might affect the autophosphorylation of residues in EGFR, probably via changes in the kinase domain structure. It would lead to a different activation model of downstream signaling, causing a biological alteration [8], [16]. Therefore, to further understand different types of mutations in EGFR and downstream signals, we mimicked the biological behavior of the two mutations by generating EGFR mutation cell line, which originally did not express EGFR. Thus the transfected mutant EGFR, instead of other genes, should be the cause of the difference.
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Patients
Our retrospective analysis examined 57 patients with advanced NSCLC who had received gefitinib therapy and the specimen were available at Guangdong Provincial People’s Hospital and Peking Union Medical College Hospital from July 2002 to January 2005. In the NSCLC patients, tumor tissues obtained either from paraffin-embedded or frozen and mutations in EGFR exons 18–21 were analyzed by direct sequencing as previously described [17], [18]. In this study, patients of refractory NSCLC with
Patient characteristics
The two most common EGFR mutations, exon 19 deletion and exon 21 point mutation, were identified in 26 (45.6%) of the 57 NSCLC patients who had received gefitinib therapy. Exon 21 point mutation group included 11 patients with L858R, one with L861Q, and one with A871G. Three patients with double mutation in exon 19 and exon 21 (5.3%) had been reported in our previous work [18]. Table 1 shows the characteristics of the included patients.
Response to gefitinib
All patients were classified into four groups, namely:
Discussion
EGFR mutations and its correlation with gefitinib therapy have aroused great interest among oncologists. On comparing the two most common EGFR mutations, we found that overall survival was longer in those patients with exon 19 deletions than with exon 21 point mutations. The in vitro transfection studies indicated that exon 19 deletion might produce greater sensitivity to gefitinib through Akt and Erk1/2 signals.
The EGFR mutation rate in our study was 50.9% (29/57), which is relatively higher
Acknowledgments
We thank the patients who participated in the study and Dr. Long-Yun Li and Dr. Xiao-Tong Zhang from Peking Union Medical College Hospital for providing the patient data.
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Grant support: National Natural Science Foundation of China 30772531, China Postdoctoral Science Foundation 20060400781, Foundation of the Bureau of Health of Guangdong Province A2007039, and grant from Chinese Lung Cancer Research Foundation.