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Cancer Therapy: Clinical |
Authors' Affiliations: Departments of 1 Neurology, 2 Cancer Biology and Genetics, 3 Medicine, and 4 Surgery (Neurosurgery), Memorial Sloan Kettering Cancer Center, New York, New York; 5 Roswell Park Cancer Institute, Buffalo, New York; 6 Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois; 7 University of Pittsburgh Medical Center Cancer Pavilion, Pittsburgh, Pennsylvania; 8 Neuro-Oncology Services, University of California-San Francisco, San Francisco, California; 9 University of Texas Health Science Center, San Antonio, Texas; 10 Genome Sequencing Center, Washington University School of Medicine, St. Louis, Missouri; 11 Department of Neurology, Dana-Farber Cancer Institute, Boston, Massachusetts; and 12 Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Andrew B. Lassman, Department of Neurology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-6037; Fax: 212-717-3519; E-mail: lassmana{at}mskcc.org.
Purpose: We investigated the molecular effect of the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib in vivo on all available tumors from patients treated on North American Brain Tumor Consortium trials 01-03 and 00-01 for recurrent or progressive malignant glioma.
Experimental Design: EGFR expression and signaling during treatment with erlotinib or gefitinib were analyzed by Western blot and compared with pre–erlotinib/gefitinib–exposed tissue or unexposed controls. Tumors were also analyzed for EGFR mutations and for other genomic abnormalities by array-based comparative genomic hybridization. Clinical data were used to associate molecular features with tumor sensitivity to erlotinib or gefitinib.
Results: Erlotinib and gefitinib did not markedly affect EGFR activity in vivo. No lung signature mutations of EGFR exons 18 to 21 were observed. There was no clear association between erlotinib/gefitinib sensitivity and deletion or amplification events on array-based comparative genomic hybridization analysis, although novel genomic changes were identified.
Conclusions: As erlotinib and gefitinib were generally ineffective at markedly inhibiting EGFR phosphorylation in these tumors, other assays may be needed to detect molecular effects. Additionally, the mechanism of erlotinib/gefitinib sensitivity likely differs between brain and lung tumors. Finally, novel genomic changes, including deletions of chromosomes 6, 21, and 22, represent new targets for further research.
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