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Research Articles: Therapeutics, Targets, and Development
Predicting gefitinib responsiveness in lung cancer by fluorescence in situ hybridization/chromogenic in situ hybridization analysis of EGFR and HER2 in biopsy and cytology specimens
1 Department of Biomedical Sciences and Human Oncology and 2 Center for Experimental Research and Medical Studies, University of Turin; and 3 Medical Oncology, Azienda Sanitaria Ospedaliera San Giovanni Battista, Molinette, Turin, Italy
Requests for reprints: Anna Sapino, Department of Biomedical Sciences and Human Oncology, University of Turin, Via Santena 7, 10126 Turin, Italy. Phone: 39-011-633-4274; Fax: 39-011-663-5267. E-mail: anna.sapino{at}unito.it
Abstract
In non–small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutational analysis is an excellent predictor of responsiveness to treatment with tyrosine kinase inhibitors, such as gefitinib. In up to 80% of NSCLCs, cytologic samples or endoscopic biopsies are the only specimens available for molecular analysis, but PCR amplification of DNA from small fixed and paraffin-embedded samples may create artifactual mutations. Fluorescence in situ hybridization (FISH) of EGFR and HER2 has been proposed as an alternative method of analysis. This project aimed to determine the optimal scoring method for FISH or chromogenic in situ hybridization (CISH) assays when analyzing small NSCLC samples to predict response. FISH or CISH analysis of EGFR and HER2 genes was done on 42 small samples derived from NSCLC patients treated with gefitinib. EGFR mutational analysis was done after quantity and quality controls of DNA. In seven of seven cases, a balanced increase in EGFR gene and chromosome 7 number was found to correlate with the presence of specific EGFR mutations. In addition, seven of seven cases with balanced EGFR/HER2 polysomy and two of three cases with balanced EGFR/HER2 trisomy responded to gefitinib (75% of responders). Instead, the EGFR mutations predicted only 7 of 12 (58%) of gefitinib-responsive patients. When only endoscopic biopsies or cytologic specimens are available, we propose using FISH/CISH for EGFR and HER2 as the test of choice for selecting patients for treatment with gefitinib and to consider as negative predictive factor the absence of EGFR/HER2 gene gain. [Mol Cancer Ther 2007;6(4):1223–9]
Grant support: Ministry for Universities, Instruction and Research, Rome, Italy; Ministero dell'Università e della Ricerca Scientifica e Tecnologica (ex 60%), Rome, Italy; Compagnia di San Paolo/FIRMS, Turin, Italy; and Regione Piemonte "Ricerca Scientifica Applicata" 2004.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
5 Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
Received 11/21/06; revised 1/25/07; accepted 2/20/07.
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  F C Schmitt, A Longatto-Filho, A Valent, and P Vielh Molecular techniques in cytopathology practice J. Clin. Pathol., March 1, 2008; 61(3): 258 - 267. [Abstract] [Full Text] [PDF]
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 W. Wu, M. S. O'Reilly, R. R. Langley, R. Z. Tsan, C. H. Baker, N. Bekele, X. M. Tang, A. Onn, I. J. Fidler, and R. S. Herbst Expression of epidermal growth factor (EGF)/transforming growth factor-{alpha} by human lung cancer cells determines their response to EGF receptor tyrosine kinase inhibition in the lungs of mice Mol. Cancer Ther., October 1, 2007; 6(10): 2652 - 2663. [Abstract] [Full Text] [PDF]
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