Originally published as JCO Early Release 10.1200/JCO.2005.01.388 on February 14 2005

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Predictive and Prognostic Impact of Epidermal Growth Factor Receptor Mutation in Non–Small-Cell Lung Cancer Patients Treated With Gefitinib

Sae-Won Han, Tae-You Kim, Pil Gyu Hwang, Soohyun Jeong, Jeongmi Kim, In Sil Choi, Do-Youn Oh, Jee Hyun Kim, Dong-Wan Kim, Doo Hyun Chung, Seock-Ah Im, Young Tae Kim, Jong Seok Lee, Dae Seog Heo, Yung-Jue Bang, Noe Kyeong Kim

From the Department of Internal Medicine, Department of Pathology, and Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital; Department of Internal Medicine, Seoul Municipal Boramae Hospital; Department of Internal Medicine, Seoul National University Bundang Hospital; Cancer Research Institute, Seoul National University College of Medicine; Petagen Inc, Seoul, Korea

Address reprint requests to Tae-You Kim, MD, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu Seoul, 110-744 Korea; e-mail: kimty{at}snu.ac.kr.

PURPOSE: This study was undertaken to investigate the effects of epidermal growth factor receptor (EGFR) mutation and its downstream signaling on response and survival in non–small-cell lung cancer (NSCLC) patients treated with gefitinib.

PATIENTS AND METHODS: For 90 consecutive NSCLC patients who had received gefitinib, EGFR mutation was analyzed by DNA sequencing of exons 18, 19, 21, and 23 in the EGFR tyrosine kinase domain. Expressions of phosphorylated (p) -Akt and p-Erk were determined via immunohistochemistry. Response rate, time to progression (TTP), and overall survival were compared between each group according to EGFR mutation, as well as p-Akt and p-Erk expression.

RESULTS: Seventeen patients (18.9%; 95% CI, 10.8 to 27.0) harbored EGFR mutations. These mutations include deletions in exon 19 in seven patients, L858R in six patients, G719A in three patients, and a novel A859T in one patient. Response rate in patients with EGFR mutation was 64.7% (11 of 17 patients; 95% CI, 42.0 to 87.4), in contrast to 13.7% (10 of 73 patients; 95% CI, 5.8 to 21.6) in patients without mutation (P < .001). Moreover, these 17 patients with EGFR mutation had significantly prolonged TTP (21.7 v 1.8 months; P < .001) and overall survival (30.5 v 6.6 months; P < .001) compared with the remaining 73 patients without mutation. Although no significant correlation was detected between EGFR mutation and expressions of p-Akt or p-Erk, p-Akt overexpression was associated with prolonged TTP in patients with EGFR mutation.

CONCLUSION: Our data further support the importance of EGFR mutation with regard to gefitinib sensitivity. In addition to its predictive role, EGFR mutation confers significant survival benefits on NSCLC patients treated with gefitinib.

Supported in part by a grant from the Korean Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (03-PJ10-PG13-GD01-0002); and by AstraZeneca Pharmaceuticals, Seoul, Korea.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

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

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				L. V. Sequist, V. A. Joshi, P. A. Janne, D. W. Bell, P. Fidias, N. I. Lindeman, D. N. Louis, J. C. Lee, E. J. Mark, J. Longtine, et al. Epidermal growth factor receptor mutation testing in the care of lung cancer patients. Clin. Cancer Res., July 15, 2006; 12(14): 4403s - 4408s. [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]

				P. A. Janne and B. E. Johnson Effect of epidermal growth factor receptor tyrosine kinase domain mutations on the outcome of patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. Clin. Cancer Res., July 15, 2006; 12(14): 4416s - 4420s. [Abstract] [Full Text] [PDF]

				D. H. Johnson Targeted therapies in combination with chemotherapy in non-small cell lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4451s - 4457s. [Abstract] [Full Text] [PDF]

				Y. Yatabe, T. Hida, Y. Horio, T. Kosaka, T. Takahashi, and T. Mitsudomi A Rapid, Sensitive Assay to Detect EGFR Mutation in Small Biopsy Specimens from Lung Cancer J. Mol. Diagn., July 1, 2006; 8(3): 335 - 341. [Abstract] [Full Text] [PDF]

				M. Sonobe, T. Manabe, H. Wada, and F. Tanaka Lung Adenocarcinoma Harboring Mutations in the ERBB2 Kinase Domain J. Mol. Diagn., July 1, 2006; 8(3): 351 - 356. [Abstract] [Full Text] [PDF]

				M. Hidalgo, M. L. Amador, A. Jimeno, H. Mezzadra, P. Patel, A. Chan, M. E. Nielsen, A. Maitra, and S. Altiok Assessment of gefitinib- and CI-1040-mediated changes in epidermal growth factor receptor signaling in HuCCT-1 human cholangiocarcinoma by serial fine needle aspiration. Mol. Cancer Ther., July 1, 2006; 5(7): 1895 - 1903. [Abstract] [Full Text] [PDF]

				D. W. Bell and D. A. Haber A Blood-Based Test for Epidermal Growth Factor Receptor Mutations in Lung Cancer. Clin. Cancer Res., July 1, 2006; 12(13): 3875 - 3877. [Full Text] [PDF]

				D. M. Jackman, B. Y. Yeap, L. V. Sequist, N. Lindeman, A. J. Holmes, V. A. Joshi, D. W. Bell, M. S. Huberman, B. Halmos, M. S. Rabin, et al. Exon 19 Deletion Mutations of Epidermal Growth Factor Receptor Are Associated with Prolonged Survival in Non-Small Cell Lung Cancer Patients Treated with Gefitinib or Erlotinib. Clin. Cancer Res., July 1, 2006; 12(13): 3908 - 3914. [Abstract] [Full Text] [PDF]

				H. Kimura, K. Kasahara, M. Kawaishi, H. Kunitoh, T. Tamura, B. Holloway, and K. Nishio Detection of Epidermal Growth Factor Receptor Mutations in Serum as a Predictor of the Response to Gefitinib in Patients with Non-Small-Cell Lung Cancer. Clin. Cancer Res., July 1, 2006; 12(13): 3915 - 3921. [Abstract] [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]

				K.-H. Lee, S.-W. Han, P. G. Hwang, D.-Y. Oh, D.-W. Kim, D. H. Chung, S.-A. Im, T.-Y. Kim, D. S. Heo, and Y.-J. Bang Epidermal Growth Factor Receptor Mutations and Response to Chemotherapy in Patients with Non-Small-Cell Lung Cancer. Jpn. J. Clin. Oncol., June 1, 2006; 36(6): 344 - 350. [Abstract] [Full Text] [PDF]

				S. Ramalingam and A. B. Sandler Salvage therapy for advanced non-small cell lung cancer: factors influencing treatment selection. Oncologist, June 1, 2006; 11(6): 655 - 665. [Abstract] [Full Text] [PDF]

				K. Politi, M. F. Zakowski, P.-D. Fan, E. A. Schonfeld, W. Pao, and H. E. Varmus Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors Genes & Dev., June 1, 2006; 20(11): 1496 - 1510. [Abstract] [Full Text] [PDF]

				C.-K. Toh, F. Gao, W.-T. Lim, S.-S. Leong, K.-W. Fong, S.-P. Yap, A. A.L. Hsu, P. Eng, H.-N. Koong, A. Thirugnanam, et al. Never-Smokers With Lung Cancer: Epidemiologic Evidence of a Distinct Disease Entity J. Clin. Oncol., May 20, 2006; 24(15): 2245 - 2251. [Abstract] [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.-W. Han, T.-Y. Kim, Y. K. Jeon, P. G. Hwang, S.-A. Im, K.-H. Lee, J. H. Kim, D.-W. Kim, D. S. Heo, N. K. Kim, et al. Optimization of Patient Selection for Gefitinib in Non-Small Cell Lung Cancer by Combined Analysis of Epidermal Growth Factor Receptor Mutation, K-ras Mutation, and Akt Phosphorylation Clin. Cancer Res., April 15, 2006; 12(8): 2538 - 2544. [Abstract] [Full Text] [PDF]

				D. Pham, M. G. Kris, G. J. Riely, I. S. Sarkaria, T. McDonough, S. Chuai, E. S. Venkatraman, V. A. Miller, M. Ladanyi, W. Pao, et al. Use of Cigarette-Smoking History to Estimate the Likelihood of Mutations in Epidermal Growth Factor Receptor Gene Exons 19 and 21 in Lung Adenocarcinomas J. Clin. Oncol., April 10, 2006; 24(11): 1700 - 1704. [Abstract] [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]

				E. Conde, B. Angulo, M. Tang, M. Morente, J. Torres-Lanzas, A. Lopez-Encuentra, F. Lopez-Rios, and M. Sanchez-Cespedes Molecular Context of the EGFR Mutations: Evidence for the Activation of mTOR/S6K Signaling Clin. Cancer Res., February 1, 2006; 12(3): 710 - 717. [Abstract] [Full Text] [PDF]

				G. J. Riely, W. Pao, D. Pham, A. R. Li, N. Rizvi, E. S. Venkatraman, M. F. Zakowski, M. G. Kris, M. Ladanyi, and V. A. Miller Clinical Course of Patients with Non-Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated with Gefitinib or Erlotinib Clin. Cancer Res., February 1, 2006; 12(3): 839 - 844. [Abstract] [Full Text] [PDF]

				E. K. Bergsland When Does the Presence of the Target Predict Response to the Targeted Agent? J. Clin. Oncol., January 10, 2006; 24(2): 213 - 216. [Full Text] [PDF]

				D. W. Bell, T. J. Lynch, S. M. Haserlat, P. L. Harris, R. A. Okimoto, B. W. Brannigan, D. C. Sgroi, B. Muir, M. J. Riemenschneider, R. B. Iacona, et al. Epidermal Growth Factor Receptor Mutations and Gene Amplification in Non-Small-Cell Lung Cancer: Molecular Analysis of the IDEAL/INTACT Gefitinib Trials J. Clin. Oncol., November 1, 2005; 23(31): 8081 - 8092. [Abstract] [Full Text] [PDF]

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				B. E. Johnson and P. A. Janne Selecting Patients for Epidermal Growth Factor Receptor Inhibitor Treatment: A FISH Story or a Tale of Mutations? J. Clin. Oncol., October 1, 2005; 23(28): 6813 - 6816. [Full Text] [PDF]

				M. G. Kris How Today's Developments in the Treatment of Non-Small Cell Lung Cancer Will Change Tomorrow's Standards of Care Oncologist, October 1, 2005; 10(suppl_2): 23 - 29. [Abstract] [Full Text] [PDF]

				B. E. Johnson and P. A. Janne Epidermal Growth Factor Receptor Mutations in Patients with Non-Small Cell Lung Cancer Cancer Res., September 1, 2005; 65(17): 7525 - 7529. [Abstract] [Full Text] [PDF]

				A. P. Dicker and U. Rodeck Predicting the Future From Trials of the Past: Epidermal Growth Factor Receptor Expression and Outcome of Fractionated Radiation Therapy Trials J. Clin. Oncol., August 20, 2005; 23(24): 5437 - 5439. [Full Text] [PDF]