© 2005 Oxford University Press
ARTICLE |
Epidermal Growth Factor Receptor Gene and Protein and Gefitinib Sensitivity in NonSmall-Cell Lung Cancer
Affiliations of authors: University of Colorado Health Sciences Center and University of Colorado Cancer Center, Aurora, CO (FC, FRH, LB, JH, SW, WAF, PAB, MVG); Bellaria Hospital, Bologna, Italy (FC, SB, EM, LC); CINECA Interuniversity Consortium, Bologna, Italy (ER, ID); Scientific Institute University Hospital San Raffaele, Milan, Italy (GLC, VG, CD); Response Genetic, Inc., Los Angeles, CA (KD); Policlinico Monteluce, Perugia, Italy (VL, AS, MT)
Correspondence to: Fred R. Hirsch, MD, PhD, University of Colorado Cancer Center, Department of Medicine and Pathology, 12801 E. 17th Ave., P.O. Box 6511, Mail Stop 8111, Aurora, CO 80010 (e-mail: fred.hirsch{at}uchsc.edu).
Background: Gefitinib is a selective inhibitor of the epidermal growth factor (EGFR) tyrosine kinase, which is overexpressed in many cancers, including nonsmall-cell lung cancer (NSCLC). We carried out a clinical study to compare the relationship between EGFR gene copy number, EGFR protein expression, EGFR mutations, and Akt activation status as predictive markers for gefitinib therapy in advanced NSCLC. Methods: Tumors from 102 NSCLC patients treated daily with 250 mg of gefitinib were evaluated for EGFR status by fluorescence in situ hybridization (FISH), DNA sequencing, and immunohistochemistry and for Akt activation status (phospho-Akt [P-Akt]) by immunohistochemistry. Time to progression, overall survival, and 95% confidence intervals (CIs) were calculated and evaluated by the KaplanMeier method; groups were compared using the log-rank test. Risk factors associated with survival were evaluated using Cox proportional hazards regression modeling and multivariable analysis. All statistical tests were two-sided. Results: Amplification or high polysomy of the EGFR gene (seen in 33 of 102 patients) and high protein expression (seen in 58 of 98 patients) were statistically significantly associated with better response (36% versus 3%, mean difference = 34%, 95% CI = 16.6 to 50.3; P<.001), disease control rate (67% versus 26%, mean difference = 40.6%, 95% CI = 21.5 to 59.7; P<.001), time to progression (9.0 versus 2.5 months, mean difference = 6.5 months, 95% CI = 2.8 to 10.3; P<.001), and survival (18.7 versus 7.0 months, mean difference = 11.7 months, 95% CI = 2.1 to 21.4; P = .03). EGFR mutations (seen in 15 of 89 patients) were also statistically significantly related to response and time to progression, but the association with survival was not statistically significant, and 40% of the patients with mutation had progressive disease. In multivariable analysis, only high EGFR gene copy number remained statistically significantly associated with better survival (hazard ratio = 0.44, 95% CI = 0.23 to 0.82). Independent of EGFR assessment method, EGFR+/P-Akt+ patients had a statistically significantly better outcome than EGFR, P-Akt, or EGFR+/P-Akt patients. Conclusions: High EGFR gene copy number identified by FISH may be an effective molecular predictor for gefitinib efficacy in advanced NSCLC.
Editorial about this Article
- A Curious Link Between Epidermal Growth Factor Receptor Amplification and Survival: Effect of "Allele Dilution" on Gefitinib Sensitivity?
- Frederic J. Kaye
J Natl Cancer Inst 2005 97: 621-623.[Extract] [Full Text] [PDF]
Related Memo to the Media
- Press Release: Study Identifies Possible Marker for Efficacy of Gefitinib in Lung Cancer Patients
- Sarah L. Zielinski
J Natl Cancer Inst 2005 97: 617.[Extract] [Full Text]
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I. I. Na, B. H. Byun, H. J. Kang, G. J. Cheon, J. S. Koh, C. H. Kim, D. H. Choe, B.-Y. Ryoo, J. C. Lee, S. M. Lim, et al. 18F-Fluoro-2-Deoxy-Glucose Uptake Predicts Clinical Outcome in Patients with Gefitinib-Treated Non-Small Cell Lung Cancer Clin. Cancer Res., April 1, 2008; 14(7): 2036 - 2041. [Abstract] [Full Text] [PDF] |
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M. J. Fidler, A. Argiris, J. D. Patel, D. H. Johnson, A. Sandler, V. M. Villaflor, J. Coon IV, L. Buckingham, K. Kaiser, S. Basu, et al. The Potential Predictive Value of Cyclooxygenase-2 Expression and Increased Risk of Gastrointestinal Hemorrhage in Advanced Non-Small Cell Lung Cancer Patients Treated with Erlotinib and Celecoxib Clin. Cancer Res., April 1, 2008; 14(7): 2088 - 2094. [Abstract] [Full Text] [PDF] |
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F. Ciardiello and G. Tortora EGFR Antagonists in Cancer Treatment N. Engl. J. Med., March 13, 2008; 358(11): 1160 - 1174. [Full Text] [PDF] |
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F. Pinter, J. Papay, A. Almasi, Z. Sapi, E. Szabo, M. Kanya, A. Tamasi, B. Jori, E. Varkondi, J. Moldvay, et al. Epidermal Growth Factor Receptor (EGFR) High Gene Copy Number and Activating Mutations in Lung Adenocarcinomas Are Not Consistently Accompanied by Positivity for EGFR Protein by Standard Immunohistochemistry J. Mol. Diagn., March 1, 2008; 10(2): 160 - 168. [Abstract] [Full Text] [PDF] |
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P. C. Black, G. A. Brown, T. Inamoto, M. Shrader, A. Arora, A. O. Siefker-Radtke, L. Adam, D. Theodorescu, X. Wu, M. F. Munsell, et al. Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells Clin. Cancer Res., March 1, 2008; 14(5): 1478 - 1486. [Abstract] [Full Text] [PDF] |
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D. A. Eberhard, G. Giaccone, and B. E. Johnson Biomarkers of Response to Epidermal Growth Factor Receptor Inhibitors in Non-Small-Cell Lung Cancer Working Group: Standardization for Use in the Clinical Trial Setting J. Clin. Oncol., February 20, 2008; 26(6): 983 - 994. [Abstract] [Full Text] [PDF] |
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A. A. Brandes, E. Franceschi, A. Tosoni, M. E. Hegi, and R. Stupp Epidermal Growth Factor Receptor Inhibitors in Neuro-oncology: Hopes and Disappointments Clin. Cancer Res., February 15, 2008; 14(4): 957 - 960. [Abstract] [Full Text] [PDF] |
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N. B. Merchant, I. Voskresensky, C. M. Rogers, B. LaFleur, P. J. Dempsey, R. Graves-Deal, F. Revetta, A. C. Foutch, M. L. Rothenberg, M. K. Washington, et al. TACE/ADAM-17: A Component of the Epidermal Growth Factor Receptor Axis and a Promising Therapeutic Target in Colorectal Cancer Clin. Cancer Res., February 15, 2008; 14(4): 1182 - 1191. [Abstract] [Full Text] [PDF] |
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A. Cavazzoni, R. R. Alfieri, C. Carmi, V. Zuliani, M. Galetti, C. Fumarola, R. Frazzi, M. Bonelli, F. Bordi, A. Lodola, et al. Dual mechanisms of action of the 5-benzylidene-hydantoin UPR1024 on lung cancer cell lines Mol. Cancer Ther., February 1, 2008; 7(2): 361 - 370. [Abstract] [Full Text] [PDF] |
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P. A. Bunn Jr. and N. Thatcher Introduction Oncologist, January 1, 2008; 13(suppl_1): 1 - 4. [Abstract] [Full Text] [PDF] |
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F. de Marinis and F. Grossi Clinical Evidence for Second- and Third-Line Treatment Options in Advanced Non-Small Cell Lung Cancer Oncologist, January 1, 2008; 13(suppl_1): 14 - 20. [Abstract] [Full Text] [PDF] |
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P. A. Bunn Jr. and N. Thatcher Conclusion Oncologist, January 1, 2008; 13(suppl_1): 37 - 46. [Abstract] [Full Text] [PDF] |
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J. A. Engelman, K. Zejnullahu, C.-M. Gale, E. Lifshits, A. J. Gonzales, T. Shimamura, F. Zhao, P. W. Vincent, G. N. Naumov, J. E. Bradner, et al. PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models with EGFR and ERBB2 Mutations that Are Resistant to Gefitinib Cancer Res., December 15, 2007; 67(24): 11924 - 11932. [Abstract] [Full Text] [PDF] |
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F. Thomas, P. Rochaix, A. Benlyazid, J. Sarini, M. Rives, J. L. Lefebvre, B. C. Allal, F. Courbon, E. Chatelut, and J.-P. Delord Pilot Study of Neoadjuvant Treatment with Erlotinib in Nonmetastatic Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., December 1, 2007; 13(23): 7086 - 7092. [Abstract] [Full Text] [PDF] |
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T. Schlomm, P. Kirstein, L. Iwers, B. Daniel, T. Steuber, J. Walz, F. H.K. Chun, A. Haese, J. Kollermann, M. Graefen, et al. Clinical Significance of Epidermal Growth Factor Receptor Protein Overexpression and Gene Copy Number Gains in Prostate Cancer Clin. Cancer Res., November 15, 2007; 13(22): 6579 - 6584. [Abstract] [Full Text] [PDF] |
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W. Liu, X. Wu, W. Zhang, R. C. Montenegro, D. L. Fackenthal, J. A. Spitz, L. M. Huff, F. Innocenti, S. Das, E. H. Cook, Jr., et al. Relationship of EGFR Mutations, Expression, Amplification, and Polymorphisms to Epidermal Growth Factor Receptor Inhibitors in the NCI60 Cell Lines Clin. Cancer Res., November 15, 2007; 13(22): 6788 - 6795. [Abstract] [Full Text] [PDF] |
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M. Loprevite, M. Tiseo, M. Chiaramondia, M. Capelletti, C. Bozzetti, B. Bortesi, N. Naldi, R. Nizzoli, P. Dadati, A. Kunkl, et al. Buccal Mucosa Cells as In vivo Model to Evaluate Gefitinib Activity in Patients with Advanced Non Small Cell Lung Cancer Clin. Cancer Res., November 1, 2007; 13(21): 6518 - 6526. [Abstract] [Full Text] [PDF] |
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M. Suzuki, H. Shigematsu, T. Nakajima, R. Kubo, S. Motohashi, Y. Sekine, K. Shibuya, T. Iizasa, K. Hiroshima, Y. Nakatani, et al. Synchronous Alterations of Wnt and Epidermal Growth Factor Receptor Signaling Pathways through Aberrant Methylation and Mutation in Non Small Cell Lung Cancer Clin. Cancer Res., October 15, 2007; 13(20): 6087 - 6092. [Abstract] [Full Text] [PDF] |
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R. S. Herbst, A. M. Davies, R. B. Natale, T. P. Dang, J. H. Schiller, L. L. Garland, V. A. Miller, D. Mendelson, A. D. Van den Abbeele, Y. Melenevsky, et al. Efficacy and Safety of Single-Agent Pertuzumab, a Human Epidermal Receptor Dimerization Inhibitor, in Patients with Non Small Cell Lung Cancer Clin. Cancer Res., October 15, 2007; 13(20): 6175 - 6181. [Abstract] [Full Text] [PDF] |
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T. Takano, Y. Ohe, K. Tsuta, T. Fukui, H. Sakamoto, T. Yoshida, U. Tateishi, H. Nokihara, N. Yamamoto, I. Sekine, et al. Epidermal Growth Factor Receptor Mutation Detection Using High-Resolution Melting Analysis Predicts Outcomes in Patients with Advanced Non Small Cell Lung Cancer Treated with Gefitinib Clin. Cancer Res., September 15, 2007; 13(18): 5385 - 5390. [Abstract] [Full Text] [PDF] |
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P. A. Janne, J. von Pawel, R. B. Cohen, L. Crino, C. A. Butts, S. S. Olson, I. A. Eiseman, A. A. Chiappori, B. Y. Yeap, P. F. Lenehan, et al. Multicenter, Randomized, Phase II Trial of CI-1033, an Irreversible Pan-ERBB Inhibitor, for Previously Treated Advanced Non Small-Cell Lung Cancer J. Clin. Oncol., September 1, 2007; 25(25): 3936 - 3944. [Abstract] [Full Text] [PDF] |
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A. Ogino, H. Kitao, S. Hirano, A. Uchida, M. Ishiai, T. Kozuki, N. Takigawa, M. Takata, K. Kiura, and M. Tanimoto Emergence of Epidermal Growth Factor Receptor T790M Mutation during Chronic Exposure to Gefitinib in a Non Small Cell Lung Cancer Cell Line Cancer Res., August 15, 2007; 67(16): 7807 - 7814. [Abstract] [Full Text] [PDF] |
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S. Khambata-Ford, C. R. Garrett, N. J. Meropol, M. Basik, C. T. Harbison, S. Wu, T. W. Wong, X. Huang, C. H. Takimoto, A. K. Godwin, et al. Expression of Epiregulin and Amphiregulin and K-ras Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab J. Clin. Oncol., August 1, 2007; 25(22): 3230 - 3237. [Abstract] [Full Text] [PDF] |
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D. H. Lee, G. K. Lee, S.-y. Kong, M. C. Kook, S. K. Yang, S. Y. Park, S. H. Park, B. Keam, D. J. Park, B. Y. Cho, et al. Epidermal growth factor receptor status in anaplastic thyroid carcinoma J. Clin. Pathol., August 1, 2007; 60(8): 881 - 884. [Abstract] [Full Text] [PDF] |
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P. D. Bonomi, L. Buckingham, and J. Coon Selecting Patients for Treatment with Epidermal Growth Factor Tyrosine Kinase Inhibitors Clin. Cancer Res., August 1, 2007; 13(15): 4606s - 4612s. [Abstract] [Full Text] [PDF] |
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B. E. Johnson, D. Jackman, and P. A. Janne Rationale for a Phase I Trial of Erlotinib and the Mammalian Target of Rapamycin Inhibitor Everolimus (RAD001) for Patients with Relapsed Non Small Cell Lung Cancer Clin. Cancer Res., August 1, 2007; 13(15): 4628s - 4631s. [Abstract] [Full Text] [PDF] |
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M. V. Karamouzis, J. R. Grandis, and A. Argiris Therapies Directed Against Epidermal Growth Factor Receptor in Aerodigestive Carcinomas JAMA, July 4, 2007; 298(1): 70 - 82. [Abstract] [Full Text] [PDF] |
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J. K. Wiencke, S. Zheng, N. Jelluma, T. Tihan, S. Vandenberg, T. Tamguney, R. Baumber, R. Parsons, K. R. Lamborn, M. S. Berger, et al. Methylation of the PTEN promoter defines low-grade gliomas and secondary glioblastoma Neuro-oncol, July 1, 2007; 9(3): 271 - 279. [Abstract] [Full Text] [PDF] |
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D. A. Torigian, S. S. Huang, M. Houseni, and A. Alavi Functional Imaging of Cancer with Emphasis on Molecular Techniques CA Cancer J Clin, July 1, 2007; 57(4): 206 - 224. [Abstract] [Full Text] [PDF] |
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K. E. Finberg, L. V. Sequist, V. A. Joshi, A. Muzikansky, J. M. Miller, M. Han, J. Beheshti, L. R. Chirieac, E. J. Mark, and A. J. Iafrate Mucinous Differentiation Correlates with Absence of EGFR Mutation and Presence of KRAS Mutation in Lung Adenocarcinomas with Bronchioloalveolar Features J. Mol. Diagn., July 1, 2007; 9(3): 320 - 326. [Abstract] [Full Text] [PDF] |
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