Originally published as JCO Early Release 10.1200/JCO.2005.02.7078 on October 3 2005

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Epidermal Growth Factor Receptor Mutations and Gene Amplification in Non–Small-Cell Lung Cancer: Molecular Analysis of the IDEAL/INTACT Gefitinib Trials

From the Massachusetts General Hospital Cancer Center and Department of Pathology, Harvard Medical School, Charlestown, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN; Free University Hospital, Amsterdam, the Netherlands; The University of Texas M.D. Anderson Cancer Center, Houston, TX; Heidelberg University Medical Centre, Mannheim, Germany; Kinki University School of Medicine, Osaka, Japan; Memorial Sloan-Kettering Cancer Center, New York, NY; Vall d'Hebron University Hospital, Barcelona, Spain; and AstraZeneca Pharmaceuticals, Wilmington, DE

Address reprint requests to Daniel A. Haber, MD, MGH Cancer Center, CNY7, 149, 13th St, Charlestown, MA 02129; e-mail: haber{at}helix.mgh.harvard.edu

PURPOSE: Most cases of non–small-cell lung cancer (NSCLC) with dramatic responses to gefitinib have specific activating mutations in the epidermal growth factor receptor (EGFR), but the predictive value of these mutations has not been defined in large clinical trials. The goal of this study was to determine the contribution of molecular alterations in EGFR to response and survival within the phase II (IDEAL) and phase III (INTACT) trials of gefitinib.

PATIENTS AND METHODS: We analyzed the frequency of EGFR mutations in lung cancer specimens from both the IDEAL and INTACT trials and compared it with EGFR gene amplification, another genetic abnormality in NSCLC.

RESULTS: EGFR mutations correlated with previously identified clinical features of gefitinib response, including adenocarcinoma histology, absence of smoking history, female sex, and Asian ethnicity. No such association was seen in patients whose tumors had EGFR amplification, suggesting that these molecular markers identify different biologic subsets of NSCLC. In the IDEAL trials, responses to gefitinib were seen in six of 13 tumors (46%) with an EGFR mutation, two of seven tumors (29%) with amplification, and five of 56 tumors (9%) with neither mutation nor amplification (P = .001 for either EGFR mutation or amplification v neither abnormality). Analysis of the INTACT trials did not show a statistically significant difference in response to gefitinib plus chemotherapy according to EGFR genotype.

CONCLUSION: EGFR mutations and, to a lesser extent, amplification appear to identify distinct subsets of NSCLC with an increased response to gefitinib. The combination of gefitinib with chemotherapy does not improve survival in patients with these molecular markers.

Supported by Grant No. NIH PO1 95281 (D.W.B., D.A.H.), and the Doris Duke Foundation Distinguished Clinical Investigator Award (DAH), and a research grant from AstraZeneca, Wilmington, DE.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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				E. L. Kwak, J. Jankowski, S. P. Thayer, G. Y. Lauwers, B. W. Brannigan, P. L. Harris, R. A. Okimoto, S. M. Haserlat, D. R. Driscoll, D. Ferry, et al. Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas. Clin. Cancer Res., July 15, 2006; 12(14): 4283 - 4287. [Abstract] [Full Text] [PDF]

				R. Dziadziuszko, F. R. Hirsch, M. Varella-Garcia, and P. A. Bunn Jr. Selecting Lung Cancer Patients for Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by Immunohistochemistry and Fluorescence In situ Hybridization--Why, When, and How? Clin. Cancer Res., July 15, 2006; 12(14): 4409s - 4415s. [Abstract] [Full Text] [PDF]

				C. Ho, G. Bebb, and N. Murray In Reply J. Clin. Oncol., July 1, 2006; 24(19): 3214 - 3215. [Full Text] [PDF]

				P. A. Bunn Jr., R. Dziadziuszko, M. Varella-Garcia, W. A. Franklin, S. E. Witta, K. Kelly, and F. R. Hirsch Biological Markers for Non-Small Cell Lung Cancer Patient Selection for Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy. Clin. Cancer Res., June 15, 2006; 12(12): 3652 - 3656. [Full Text] [PDF]

				J. Baselga Is There a Role for the Irreversible Epidermal Growth Factor Receptor Inhibitor EKB-569 in the Treatment of Cancer? A Mutation-Driven Question J. Clin. Oncol., May 20, 2006; 24(15): 2225 - 2226. [Full Text] [PDF]

				S. Goodin Erlotinib: optimizing therapy with predictors of response? Clin. Cancer Res., May 15, 2006; 12(10): 2961 - 2963. [Full Text] [PDF]

				R. Dziadziuszko, S. E. Witta, F. Cappuzzo, S. Park, K. Tanaka, P. V. Danenberg, A. E. Baron, L. Crino, W. A. Franklin, P. A. Bunn Jr., et al. Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non-small cell lung cancer. Clin. Cancer Res., May 15, 2006; 12(10): 3078 - 3084. [Abstract] [Full Text] [PDF]

				E. Calvo and J. Baselga Ethnic Differences in Response to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors J. Clin. Oncol., May 10, 2006; 24(14): 2158 - 2163. [Abstract] [Full Text] [PDF]

				S. Van Schaeybroeck, J. Kyula, D. M. Kelly, A. Karaiskou-McCaul, S. A. Stokesberry, E. Van Cutsem, D. B. Longley, and P. G. Johnston Chemotherapy-induced epidermal growth factor receptor activation determines response to combined gefitinib/chemotherapy treatment in non-small cell lung cancer cells Mol. Cancer Ther., May 1, 2006; 5(5): 1154 - 1165. [Abstract] [Full Text] [PDF]

				S. Marsh and H. L. McLeod Pharmacogenomics: from bedside to clinical practice. Hum. Mol. Genet., April 15, 2006; 15(suppl_1): R89 - R93. [Abstract] [Full Text] [PDF]

				J. R. Jett and Y. E. Miller Update in lung cancer 2005. Am. J. Respir. Crit. Care Med., April 1, 2006; 173(7): 695 - 697. [Full Text] [PDF]

				T. Takano, Y. Ohe, I. Sekine, H. Kunitoh, T. Yoshida, and T. Tamura In Reply: J. Clin. Oncol., March 1, 2006; 24(7): 1221 - 1221. [Full Text] [PDF]

				D.A. HABER, D.W. BELL, R. SORDELLA, E.L. KWAK, N. GODIN-HEYMANN, S.V. SHARMA, T.J. LYNCH, and J. SETTLEMAN Molecular Targeted Therapy of Lung Cancer: EGFR Mutations and Response to EGFR Inhibitors Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 419 - 426. [Abstract] [PDF]

				L.C. AMLER, A.D. GODDARD, and K.J. HILLAN Predicting Clinical Benefit in Non-Small-Cell Lung Cancer Patients Treated with Epidermal Growth Factor Tyrosine Kinase Inhibitors Cold Spring Harb Symp Quant Biol, January 1, 2005; 70(0): 483 - 488. [Abstract] [PDF]