title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. lassmana@mskcc.org
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Lassman
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rossi
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Raizer
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Razier
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Abrey
authors.forename: Frank S
authors.initials: FS
authors.lastname: Lieberman
authors.forename: Chelsea N
authors.initials: CN
authors.lastname: Grefe
authors.forename: Kathleen
authors.initials: K
authors.lastname: Lamborn
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Alan H
authors.initials: AH
authors.lastname: Shih
authors.forename: John G
authors.initials: JG
authors.lastname: Kuhn
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.forename: Norma J
authors.initials: NJ
authors.lastname: Nowak
authors.forename: John K
authors.initials: JK
authors.lastname: Cowell
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DeAngelis
authors.forename: Patrick
authors.initials: P
authors.lastname: Wen
authors.forename: Mark R
authors.initials: MR
authors.lastname: Gilbert
authors.forename: Susan
authors.initials: S
authors.lastname: Chang
authors.forename: W A
authors.initials: WA
authors.lastname: Yung
authors.forename: Michael
authors.initials: M
authors.lastname: Prados
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002986:Clinical Trials as Topic; D016000:Cluster Analysis; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005091:Exons; D000077156:Gefitinib; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009693:Nucleic Acid Hybridization; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib