Originally published as JCO Early Release 10.1200/JCO.2005.01.2823 on July 5 2005

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Increased Epidermal Growth Factor Receptor Gene Copy Number Detected by Fluorescence In Situ Hybridization Associates With Increased Sensitivity to Gefitinib in Patients With Bronchioloalveolar Carcinoma Subtypes: A Southwest Oncology Group Study

From the University of Colorado Health Sciences Center, Denver, CO; Southwest Oncology Group Statistical Center, San Antonio, TX; Puget Sound Oncology Consortium, Seattle, WA; and University of California, Davis Cancer Center, Sacramento, CA

Address reprint requests to Fred R. Hirsch, MD, PhD, Department of Medicine and Pathology, University of Colorado Cancer Center, 12801 E 17th Ave, PO Box 6511, Mail 8111, Aurora, CO 80010; e-mail: Fred.Hirsch{at}uchsc.edu

PURPOSE: Bronchioloalveolar carcinoma (BAC) and adenocarcinomas with BAC features seem to be increasing in incidence, particularly in younger, never-smoking women. Epidermal growth factor receptor (EGFR) inhibitors demonstrated response rates of 20% to 30% in patients with advanced BAC subtypes, but selection methods for patient therapy are not established.

PATIENTS AND METHODS: EGFR and HER2 gene copy numbers were assessed by fluorescence in situ hybridization (FISH) in 81 patients treated with gefitinib 500 mg/d (Southwest Oncology Group protocol S0126) and were correlated to treatment outcome. Tumors were classified into two main strata: FISH-positive (high polysomy/gene amplification) and FISH-negative (disomy/low polysomy).

RESULTS: In 81 patients, the median survival time for EGFR/FISH-negative patients was 8 months and not yet reached for FISH-positive patients (but approaching 18 months; hazard ratio [HR] = 2.02; P = .042). Median progression-free survival time for EGFR/FISH-positive patients was 9 months versus 4 months for the FISH-negative patients (HR = 1.67; P = .072). In multivariate analysis, EGFR copy number by FISH remained a significant predictive factor for survival after accounting for smoking status, sex, histology, and performance status. Fifty-five patients were evaluated for response using Response Evaluation Criteria in Solid Tumors Group, and 12 of 19 EGFR/FISH-positive patients (63%) demonstrated disease control versus 14 (39%) of 36 patients in the FISH-negative group (P = .087). No association was found between HER2 gene copy number and response (n = 39 patients) or survival (n = 56 patients; P > .10).

CONCLUSION: Increased EGFR gene copy number detected by FISH is associated with improved survival after gefitinib therapy in patients with advanced BAC, suggesting FISH methodology can be used to assess survival potential in patients treated with EGFR tyrosine kinase inhibitors.

Supported in part by the following Public Health Service Cooperative Agreement Grant No. awarded by the National Cancer Institute, United States Department of Health and Human Services: NCI CCSG P30-CA46934, Lung SPORE P50 CA058187, CA38926, and CA32102.

F.R.H. and M.V.-G. contributed equally to this work.

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

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				A. Araujo, R. Ribeiro, I. Azevedo, A. Coelho, M. Soares, B. Sousa, D. Pinto, C. Lopes, R. Medeiros, and G. V. Scagliotti Genetic Polymorphisms of the Epidermal Growth Factor and Related Receptor in Non-Small Cell Lung Cancer--A Review of the Literature Oncologist, February 1, 2007; 12(2): 201 - 210. [Abstract] [Full Text] [PDF]

				L. Toschi and F. Cappuzzo Understanding the New Genetics of Responsiveness to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Oncologist, February 1, 2007; 12(2): 211 - 220. [Abstract] [Full Text] [PDF]

				I. K. Mellinghoff, T. F. Cloughesy, and P. S. Mischel PTEN-Mediated Resistance to Epidermal Growth Factor Receptor Kinase Inhibitors Clin. Cancer Res., January 15, 2007; 13(2): 378 - 381. [Abstract] [Full Text] [PDF]

				J. Zhang, S. Kalyankrishna, M. Wislez, N. Thilaganathan, B. Saigal, W. Wei, L. Ma, I. I. Wistuba, F. M. Johnson, and J. M. Kurie Src-Family Kinases Are Activated in Non-Small Cell Lung Cancer and Promote the Survival of Epidermal Growth Factor Receptor-Dependent Cell Lines Am. J. Pathol., January 1, 2007; 170(1): 366 - 376. [Abstract] [Full Text] [PDF]

				L. V. Sequist, V. A. Joshi, P. A. Janne, A. Muzikansky, P. Fidias, M. Meyerson, D. A. Haber, R. Kucherlapati, B. E. Johnson, and T. J. Lynch Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist, January 1, 2007; 12(1): 90 - 98. [Abstract] [Full Text] [PDF]

				M. Ono and M. Kuwano Molecular Mechanisms of Epidermal Growth Factor Receptor (EGFR) Activation and Response to Gefitinib and Other EGFR-Targeting Drugs Clin. Cancer Res., December 15, 2006; 12(24): 7242 - 7251. [Abstract] [Full Text] [PDF]

				N. Personeni Epidermal Growth Factor Receptor Gene Copy Number in Esophageal Cancer and Outcome Prediction to Gefitinib: Does Intratumoral Heterogeneity Matter? J. Clin. Oncol., December 1, 2006; 24(34): 5465 - 5465. [Full Text] [PDF]

				P Ceppi, M Volante, S Novello, I Rapa, K. Danenberg, P. Danenberg, A Cambieri, G Selvaggi, S Saviozzi, R Calogero, et al. ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine Ann. Onc., December 1, 2006; 17(12): 1818 - 1825. [Abstract] [Full Text] [PDF]

				F. R. Hirsch, M. Varella-Garcia, P. A. Bunn Jr, W. A. Franklin, R. Dziadziuszko, N. Thatcher, A. Chang, P. Parikh, J. R. Pereira, T. Ciuleanu, et al. Molecular Predictors of Outcome With Gefitinib in a Phase III Placebo-Controlled Study in Advanced Non-Small-Cell Lung Cancer J. Clin. Oncol., November 1, 2006; 24(31): 5034 - 5042. [Abstract] [Full Text] [PDF]

				H.-J. Lenz, E. Van Cutsem, S. Khambata-Ford, R. J. Mayer, P. Gold, P. Stella, B. Mirtsching, A. L. Cohn, A. W. Pippas, N. Azarnia, et al. Multicenter Phase II and Translational Study of Cetuximab in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin, and Fluoropyrimidines J. Clin. Oncol., October 20, 2006; 24(30): 4914 - 4921. [Abstract] [Full Text] [PDF]

				T. Dragovich, S. McCoy, C. M. Fenoglio-Preiser, J. Wang, J. K. Benedetti, A. F. Baker, C. B. Hackett, S. G. Urba, K. S. Zaner, C. D. Blanke, et al. Phase II Trial of Erlotinib in Gastroesophageal Junction and Gastric Adenocarcinomas: SWOG 0127 J. Clin. Oncol., October 20, 2006; 24(30): 4922 - 4927. [Abstract] [Full Text] [PDF]

				P. A. Bunn Jr. Can a single pill replace doublet chemotherapy in first-line therapy of advanced non-small cell lung cancer? Clin. Cancer Res., October 15, 2006; 12(20): 5919 - 5920. [Full Text] [PDF]

				C. H. Chung, K. Ely, L. McGavran, M. Varella-Garcia, J. Parker, N. Parker, C. Jarrett, J. Carter, B. A. Murphy, J. Netterville, et al. Increased Epidermal Growth Factor Receptor Gene Copy Number Is Associated With Poor Prognosis in Head and Neck Squamous Cell Carcinomas J. Clin. Oncol., September 1, 2006; 24(25): 4170 - 4176. [Abstract] [Full Text] [PDF]

				K. C. Halling, O. B. Rickman, B. R. Kipp, A. R. Harwood, C. H. Doerr, and J. R. Jett A comparison of cytology and fluorescence in situ hybridization for the detection of lung cancer in bronchoscopic specimens. Chest, September 1, 2006; 130(3): 694 - 701. [Abstract] [Full Text] [PDF]

				M. P. Cunningham, H. Thomas, Z. Fan, and H. Modjtahedi Responses of Human Colorectal Tumor Cells to Treatment with the Anti-Epidermal Growth Factor Receptor Monoclonal Antibody ICR62 Used Alone and in Combination with the EGFR Tyrosine Kinase Inhibitor Gefitinib. Cancer Res., August 1, 2006; 66(15): 7708 - 7715. [Abstract] [Full Text] [PDF]

				B. Rubio-Viqueira, A. Jimeno, G. Cusatis, X. Zhang, C. Iacobuzio-Donahue, C. Karikari, C. Shi, K. Danenberg, P. V. Danenberg, H. Kuramochi, et al. An In vivo Platform for Translational Drug Development in Pancreatic Cancer Clin. Cancer Res., August 1, 2006; 12(15): 4652 - 4661. [Abstract] [Full Text] [PDF]

				A. Inoue, T. Suzuki, T. Fukuhara, M. Maemondo, Y. Kimura, N. Morikawa, H. Watanabe, Y. Saijo, and T. Nukiwa Prospective Phase II Study of Gefitinib for Chemotherapy-Naive Patients With Advanced Non-Small-Cell Lung Cancer With Epidermal Growth Factor Receptor Gene Mutations J. Clin. Oncol., July 20, 2006; 24(21): 3340 - 3346. [Abstract] [Full Text] [PDF]

				P. A. Janne Gefitinib for Epidermal Growth Factor Receptor Mutant Lung Cancers: Searching for a Weapon of Mass Destruction J. Clin. Oncol., July 20, 2006; 24(21): 3319 - 3321. [Full Text] [PDF]

				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]

				C. Swanton, A. Futreal, and T. Eisen Her2-targeted therapies in non-small cell lung cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4377s - 4383s. [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]

				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]

				A. Italiano, F. B. Vandenbos, J. Otto, J. Mouroux, D. Fontaine, P.-Y. Marcy, N. Cardot, A. Thyss, and F. Pedeutour Comparison of the epidermal growth factor receptor gene and protein in primary non-small-cell-lung cancer and metastatic sites: implications for treatment with EGFR-inhibitors Ann. Onc., June 1, 2006; 17(6): 981 - 985. [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]

				H. L. West, W. A. Franklin, J. McCoy, P. H. Gumerlock, R. Vance, D. H.M. Lau, K. Chansky, J. J. Crowley, and D. R. Gandara Gefitinib Therapy in Advanced Bronchioloalveolar Carcinoma: Southwest Oncology Group Study S0126 J. Clin. Oncol., April 20, 2006; 24(12): 1807 - 1813. [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. S. Ettinger Clinical Implications of EGFR Expression in the Development and Progression of Solid Tumors: Focus on Non-Small Cell Lung Cancer. Oncologist, April 1, 2006; 11(4): 358 - 373. [Abstract] [Full Text] [PDF]

				L. Paz-Ares, J.-Y. Douillard, P. Koralewski, C. Manegold, E. F. Smit, J. M. Reyes, G.-C. Chang, W. J. John, P. M. Peterson, C. K. Obasaju, et al. Phase III Study of Gemcitabine and Cisplatin With or Without Aprinocarsen, a Protein Kinase C-Alpha Antisense Oligonucleotide, in Patients With Advanced-Stage Non-Small-Cell Lung Cancer J. Clin. Oncol., March 20, 2006; 24(9): 1428 - 1434. [Abstract] [Full Text] [PDF]

				F. A. Shepherd and M.-S. Tsao Unraveling the Mystery of Prognostic and Predictive Factors in Epidermal Growth Factor Receptor Therapy J. Clin. Oncol., March 1, 2006; 24(7): 1219 - 1220. [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]