Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib

Abstract

The new england journal of medicine 1260 n engl j med 351;12 www.nejm.org september 16, 2004 by Schnyder et al. did not include subjects with homocysteine levels higher than 13.5 µmol per liter. Studies are needed that will test the efficacy of homocysteine-lowering vitamin regimens containing betaine instead of folate. EGFR Mutations and Sensitivity to Gefitinibto the editor: The important study by Dr. Lynch and colleagues (May 20 issue) 1 suggests that specific mutations in the epidermal growth factor receptor (EGFR) characterize a subgroup of non-smallcell lung cancers that may be highly responsive to gefitinib therapy. Do these mutations predict a greater sensitivity to chemotherapy as well? The overall objective response rate to first-line combination chemotherapy for metastatic non-small-cell lung cancer is about 20 percent. 2 Only tumors from a small cohort of patients who had a response to gefitinib were studied for the specific mutations, but all patients except one had also received prior chemotherapy. Although the authors describe Patient 6 as "representative" of the cohort, the percentage of other patients who previously had a response to chemotherapy is not reported. If the rate of response to first-line chemotherapy was high for the other patients in the cohort who had a response to gefitinib, the specific mutations may be predictive of either chemotherapy or gefitinib sensitivity, thus identifying a distinct subgroup of patients with non-smallcell lung cancer. to the editor: Lynch et al. and Paez et al. 1 report that mutations in the EGFR kinase domain in lung cancers are associated with responsiveness to gefitinib. We performed a mutational analysis of the EGFR kinase region on tumor tissue from nine patients with an event-free survival of more than 24 weeks in our phase 2 trial of gefitinib in patients with glioblastoma. 2 No mutations affecting the amino acid sequence in the kinase region were detected. However, our experience with EGFR immunolocalization in brain and lung tumors indicates that the cytoplasmic and membranous localization of wild-type EGFR and the constitutively active mutant EGFRvIII in brain tumors as compared with only membranous localization in lung tumors supports additional differences in the biology of EGFR between these tumor systems (McLendon R: personal communication). In summary, EGFR in glioblastoma did not have mutations in the kinase region, and any activity of gefitinib in glioblastoma would occur through an alternative mechanism reflective of important pathophysiological differences between glioblastomas and lung carcinomas.

Molecular pathology of lung cancer: key to personalized medicine

“…5,6,14,63,64 In adenocarcinomas, the majority of mutations have been identified in exons 18-21 of the EGFR gene. 9,65,66 These mutations can be roughly classified into three major categories: in-frame deletions in exon 19, insertion mutations in exon 20, and missense mutations in exons 18-21 ( Figure 2).…”

“…Exons 18-21 in the tyrosine kinase region of the EGFR gene are scaled up; a detailed list of EGFR mutations in these exons associated with sensitivity (green) or resistance (orange) to EGFR TKI. 6,12,[67][68][69][70][71][80][81][82][83][84]195 The frequency of the mutations is labeled to the side of the color-coded bars. The most prevalent EGFR mutations are in-frame deletions of exon 19 (45%), followed by L858R substitution in exon 21 (41%).…”

“…These mutations are also most frequently associated with either sensitivity or resistance to EGFR TKIs ( Figure 2). 6,[80][81][82][83][84] The response-associated mutations are linked with response rates of 470% in patients treated with either erlotinib or gefitinib. 85,86 However, upto 25% of patients with TKI resistanceassociated mutations will also respond to the therapy.…”

“…85 EGFR mutations are generally associated with sensitivity to TKI therapy. 71,87 Both retrospective and prospective studies have demonstrated that lung adenocarcinoma patients carrying such an EGFR mutation and who were treated with TKIs had significantly higher response rates and longer progression-free survival than patients without an EGFR mutation, [5][6][7]25,29,71,83,85,87,88 with some patients experiencing rapid, complete, or partial responses that were persistant. 55 Jackman et al 85 studied 223 chemotherapy-naïve patients with advanced lung cancer of non-small cell type, among which 86% were adenocarcinomas.…”

“…4 In recent years, attention has been paid to the role that 'driver mutations,' such as epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), have in the tumorigenesis of adenocarcinomas, and their potential use as targets for therapy. [5][6][7][8][9] Recent data suggest EGFR may also serve as a prognostic factor, in addition to its role as a predictive factor, as patients-bearing EGFR mutations have shown favorable clinical outcomes even with conventional chemotherapy. [10][11][12][13] EGFR and members of its family have an important role in carcinogenesis through their involvement in the modulation of cell proliferation, apoptosis, cell motility, and neovascularization.…”