Molecular Study of Malignant Gliomas Treated with Epidermal Growth Factor Receptor Inhibitors: Tissue Analysis from North American Brain Tumor Consortium Trials 01-03 and 00-01

• Published in: Clinical cancer research Vol. 11; no. 21; pp. 7841 - 7850
• Main Authors: LASSMAN, Andrew B, ROSSI, Michael R, WILSON, Richard, NOWAK, Norma J, COWELL, John K, DEANGELIS, Lisa M, WEN, Patrick, GILBERT, Mark R, CHANG, Susan, YUNG, W. A, PRADOS, Michael, HOLLAND, Eric C, RAZIER, Jeffrey R, ABREY, Lauren E, LIEBERMAN, Frank S, GREFE, Chelsea N, LAMBORN, Kathleen, PAO, William, SHIH, Alan H, KUHN, John G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-11-2005
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Blotting, Western; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Clinical Trials as Topic; Cluster Analysis; Disease Progression; EGFR inhibitor; Erlotinib Hydrochloride; Exons; Gene Deletion; Gene Expression Regulation, Neoplastic; Genome; Glioma; Glioma - drug therapy; Glioma - metabolism; Glioma - pathology; Humans; Lung Neoplasms - metabolism; Medical sciences; Models, Biological; Mutation; Neurology; Nucleic Acid Hybridization; Pharmacology. Drug treatments; Protein Kinase Inhibitors - pharmacology; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Sequence Analysis, DNA; Time Factors; tissue analysis; Tumors of the nervous system. Phacomatoses; United States; North America; America; Malignant glioma; Intracranial; Nervous system diseases; Growth factor receptor; Treatment; Central nervous system disease; Clinical trial; Inhibitor; Malignant tumor; Intracranial tumor; Epidermal growth factor receptor; Cerebral disorder
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0421

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.