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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
Lassman AB, Rossi MR, Razier JR, Abrey LE,
Lieberman FS, Grefe CN, Lamborn K, Pao W, Shih
AH, Kuhn JG, Wilson R, Nowak NJ, Cowell JK,
Deangelis LM, Wen P, Gilbert MR, Chang S, Yung
WA, Prados M, Holland EC
Departments of Neurology, Cancer Biology and Genetics, Medicine,
and Surgery (Neurosurgery), Memorial Sloan Kettering Cancer Center,
New York, New York
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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