Selecting Patients for Epidermal Growth Factor Receptor Inhibitor Treatment: A FISH Story or a Tale of Mutations?
Authors: Bruce E. Johnson, Pasi A. Jänne
Journal: Journal of Clinical Oncology (2005)

The two articles that appear in this issue of the Journal of Clinical Oncology provide additional information about the role of the mutated epidermal growth factor receptor (EGFR) and gene copy number of EGFR in the response, time to progression, and survival of patients with non–small-cell lung cancer treated with gefitinib. The article by Takano et al includes information on 66 patients with non–small-cell lung cancer (NSCLC) from Japan whose tumors underwent sequencing of exons 18 to 24 of EGFR and determination of EGFR gene copy number by quantitative, real-time polymerase chain reaction (PCR). The article by Hirsch et al extends these observations on EGFR copy number assessed by fluorescence in situ hybridization (FISH) and its relationship to response, time to progression, and survival to an additional subset of 81 patients with bronchioloalveolar carcinoma (BAC). The article by Hirsch et al reinforces the role of gene copy number assessed by FISH in assessing outcome following treatment with gefitinib, while the article by Takano et al provides evidence that the presence of mutations of EGFR—rather than copy number—is more important in determining outcome with gefitinib therapy. Although both of these articles used gefitinib as the EGFR tyrosine kinase inhibitor (EGFR-TKI), some of this Editorial will include some observations with the other EGFR-TKI commonly used for patients with NSCLC, erlotinib. The research community is appropriately left to wonder if EGFR mutations, EGFR copy number, EGFR immunohistochemistry or a combination of these tests should be used to help predict which patients are most likely to respond to gefitinib therapy, and which tests should be done to help identify the appropriate candidates for gefitinib therapy. It is important to point out that there are different end points for successful treatment, with a minority of patients demonstrating a partial response to treatment with gefitinib and erlotinib and a greater proportion with prolonged stable disease that ultimately contribute to a survival benefit. In addition to the two articles in this issue of the Journal of Clinical Oncology, there are two other manuscripts on EGFR mutations in patients from Asia and two manuscripts by the group from the University of Colorado that are particularly pertinent to determining whether this is a FISH story or a tale of mutations, or both. The data on somatic mutations of EGFR in patients with NSCLC in the article by Takano et al are consistent with that of the two other articles that have appeared in 2005. These studies have been limited to patients from Japan and Korea, where the somatic mutations of EGFR are detected approximately three times more often than in the United States and Europe. The design of the three studies was similar. The patients treated with gefitinib were retrospectively identified, their tumor retrieved from the tumor banks from a previous resection or biopsy, and some or all of exons 18 to 24 of EGFR underwent sequencing of the DNA extracted from the tumor blocks. The differences in response rates, time to progression, and survival were consistent in those with and without EGFR mutations and were highly statistically significant (P .0053 to 0.0001, respectively; Table 1). The study by Takano et al also confirmed the presence of an increased EGFR mutation frequency in specific subgroups of patients, namely in nonsmokers and in those whose tumors have BAC features. In addition, all of the mutations described by Takano et al (exon 19 deletions, L858R and G719S/C) have been previously identified in patients with dramatic clinical responses when treated with gefitinib. Three additional mutations were detected (L703V, E709K, and S768I), but all occurred in concert with one of the mutations described above, and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 28 OCTOBER 1 2005