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Published Online April 29, 2004
Science DOI: 10.1126/science.1099314

Reports

Submitted on April 16, 2004
Accepted on April 21, 2004

EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy

J. Guillermo Paez 1, Pasi A. Jänne 1, Jeffrey C. Lee 2, Sean Tracy 3, Heidi Greulich 1, Stacey Gabriel 4, Paula Herman 3, Frederic J. Kaye 5, Neal Lindeman 6, Titus J. Boggon 2, Katsuhiko Naoki 3, Hidefumi Sasaki 7, Yoshitaka Fujii 7, Michael J. Eck 2, William R. Sellers 8*, Bruce E. Johnson 1*, Matthew Meyerson 9*

1 Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115 USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
2 Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115 USA; Departments of Pathology and Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
3 Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115 USA.
4 The Broad Institute at MIT and Harvard, Cambridge, MA 02142, USA.
5 Genetics Branch, National Cancer Institute, National Naval Medical Center, Bethesda, MD 20889, USA.
6 Department of Pathology, Brigham and Women's Hospital, Boston MA 02115, USA.
7 Department of Surgery 2, Nagoya City University Medical School, Nagoya 467-8601, Japan.
8 Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115 USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; The Broad Institute at MIT and Harvard, Cambridge, MA 02142, USA.
9 Departments of Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115 USA; Departments of Pathology and Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; The Broad Institute at MIT and Harvard, Cambridge, MA 02142, USA.

* To whom correspondence should be addressed.
William R. Sellers , E-mail: William_Sellers{at}dfci.harvard.edu
Bruce E. Johnson , E-mail: Bruce_Johnson{at}dfci.harvard.edu
Matthew Meyerson , E-mail: Matthew_Meyerson{at}dfci.harvard.edu

Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.


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T. Takano, T. Fukui, Y. Ohe, K. Tsuta, S. Yamamoto, H. Nokihara, N. Yamamoto, I. Sekine, H. Kunitoh, K. Furuta, et al. (2008)
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A phase I study of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors.
E. T. Lam, C. L. O'Bryant, M. Basche, D. L. Gustafson, N. Serkova, A. Baron, S. N. Holden, J. Dancey, S. G. Eckhardt, and L. Gore (2008)
Mol. Cancer Ther. 7, 3685-3694
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HER-2 Gene Amplification, HER-2 and Epidermal Growth Factor Receptor mRNA and Protein Expression, and Lapatinib Efficacy in Women with Metastatic Breast Cancer.
M. F. Press, R. S. Finn, D. Cameron, A. Di Leo, C. E. Geyer, I. E. Villalobos, A. Santiago, R. Guzman, A. Gasparyan, Y. Ma, et al. (2008)
Clin. Cancer Res. 14, 7861-7870
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Good Response to Gefitinib in Lung Adenocarcinoma of Complex Epidermal Growth Factor Receptor (EGFR) Mutations with the Classical Mutation Pattern.
S.-G. Wu, Y.-L. Chang, Y.-C. Hsu, J.-Y. Wu, C.-H. Yang, C.-J. Yu, M.-F. Tsai, J.-Y. Shih, and P.-C. Yang (2008)
Oncologist 13, 1276-1284
   Abstract »    Full Text »    PDF »
Genetic Predictors of MEK Dependence in Non-Small Cell Lung Cancer.
C. A. Pratilas, A. J. Hanrahan, E. Halilovic, Y. Persaud, J. Soh, D. Chitale, H. Shigematsu, H. Yamamoto, A. Sawai, M. Janakiraman, et al. (2008)
Cancer Res. 68, 9375-9383
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Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor-Activating Mutations.
S. Yano, W. Wang, Q. Li, K. Matsumoto, H. Sakurama, T. Nakamura, H. Ogino, S. Kakiuchi, M. Hanibuchi, Y. Nishioka, et al. (2008)
Cancer Res. 68, 9479-9487
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[18F]Fluorothymidine Positron Emission Tomography before and 7 Days after Gefitinib Treatment Predicts Response in Patients with Advanced Adenocarcinoma of the Lung.
H.-J. Sohn, Y.-J. Yang, J.-S. Ryu, S. J. Oh, K. C. Im, D. H. Moon, D. H. Lee, C. Suh, J.-S. Lee, and S.-W. Kim (2008)
Clin. Cancer Res. 14, 7423-7429
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Acquired Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors Associated with a Novel T854A Mutation in a Patient with EGFR-Mutant Lung Adenocarcinoma.
J. Bean, G. J. Riely, M. Balak, J. L. Marks, M. Ladanyi, V. A. Miller, and W. Pao (2008)
Clin. Cancer Res. 14, 7519-7525
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Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors.
M. S. Anglesio, J. M. Arnold, J. George, A. V. Tinker, R. Tothill, N. Waddell, L. Simms, B. Locandro, S. Fereday, N. Traficante, et al. (2008)
Mol. Cancer Res. 6, 1678-1690
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Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study.
M. A. Villalona-Calero, G. A. Otterson, M. G. Wientjes, F. Weber, T. Bekaii-Saab, D. Young, A. J. Murgo, R. Jensen, T.-K. Yeh, Y. Wei, et al. (2008)
Ann. Onc. 19, 1903-1909
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Reduced Erlotinib Sensitivity of Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer following Cisplatin Exposure: A Cell Culture Model of Second-line Erlotinib Treatment.
T. M. Chin, M. P. Quinlan, A. Singh, L. V. Sequist, T. J. Lynch, D. A. Haber, S. V. Sharma, and J. Settleman (2008)
Clin. Cancer Res. 14, 6867-6876
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Autocrine Production of Amphiregulin Predicts Sensitivity to Both Gefitinib and Cetuximab in EGFR Wild-type Cancers.
K. Yonesaka, K. Zejnullahu, N. Lindeman, A. J. Homes, D. M. Jackman, F. Zhao, A. M. Rogers, B. E. Johnson, and P. A. Janne (2008)
Clin. Cancer Res. 14, 6963-6973
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Effects of Erlotinib in EGFR Mutated Non-Small Cell Lung Cancers with Resistance to Gefitinib.
D. B. Costa, K.-S. H. Nguyen, B. C. Cho, L. V. Sequist, D. M. Jackman, G. J. Riely, B. Y. Yeap, B. Halmos, J. H. Kim, P. A. Janne, et al. (2008)
Clin. Cancer Res. 14, 7060-7067
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Bevacizumab and Erlotinib: A Promising New Approach to the Treatment of Advanced NSCLC.
R. S. Herbst and A. Sandler (2008)
Oncologist 13, 1166-1176
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Gefitinib First or Gefitinib Second: Is Timing Everything in the Treatment of EGFR Mutant Non-Small Cell Lung Cancer?.
P. A. Janne (2008)
Am. J. Respir. Crit. Care Med. 178, 783-785
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First- or Second-line Therapy with Gefitinib Produces Equal Survival in Non-Small Cell Lung Cancer.
J.-Y. Wu, C.-J. Yu, C.-H. Yang, S.-G. Wu, Y.-H. Chiu, C.-H. Gow, Y.-C. Chang, Y.-C. Hsu, P.-F. Wei, J.-Y. Shih, et al. (2008)
Am. J. Respir. Crit. Care Med. 178, 847-853
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Establishment of Patient-Derived Non-Small Cell Lung Cancer Xenografts as Models for the Identification of Predictive Biomarkers.
I. Fichtner, J. Rolff, R. Soong, J. Hoffmann, S. Hammer, A. Sommer, M. Becker, and J. Merk (2008)
Clin. Cancer Res. 14, 6456-6468
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Regression of Drug-Resistant Lung Cancer by the Combination of Rosiglitazone and Carboplatin.
G. D. Girnun, L. Chen, J. Silvaggi, R. Drapkin, L. R. Chirieac, R. F. Padera, R. Upadhyay, S. B. Vafai, R. Weissleder, U. Mahmood, et al. (2008)
Clin. Cancer Res. 14, 6478-6486
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Frequent epidermal growth factor receptor gene mutations in malignant pleural effusion of lung adenocarcinoma.
S-G. Wu, C-H. Gow, C-J. Yu, Y-L. Chang, C-H. Yang, Y-C. Hsu, J-Y. Shih, Y-C. Lee, and P-C. Yang (2008)
Eur. Respir. J. 32, 924-930
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Laser Capture Microdissection and Protein Microarray Analysis of Human Non-small Cell Lung Cancer: Differential Epidermal Growth Factor Receptor (EGPR) Phosphorylation Events Associated with Mutated EGFR Compared with Wild Type.
A. J. VanMeter, A. S. Rodriguez, E. D. Bowman, J. Jen, C. C. Harris, J. Deng, V. S. Calvert, A. Silvestri, C. Fredolini, V. Chandhoke, et al. (2008)
Mol. Cell. Proteomics 7, 1902-1924
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Gamma-aminobutyric acid, a potential tumor suppressor for small airway-derived lung adenocarcinoma.
H. M. Schuller, H. A.N. Al-Wadei, and M. Majidi (2008)
Carcinogenesis 29, 1979-1985
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The Use of Genomics in Clinical Trial Design.
R. Simon (2008)
Clin. Cancer Res. 14, 5984-5993
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Epidermal growth factor receptor-targeted therapy.
C M West, L Joseph, and S Bhana (2008)
Br. J. Radiol. 81, S36-S44
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