Analysis of EGFR Gene Amplification, Protein Over-expression and Tyrosine Kinase Domain Mutation in Recurrent Glioblastoma

Abstract

Gefitinib and erlotinib are both selective EGFR tyrosine kinase inhibitors (EGFR-TKIs) that have produced responses in a small subgroup of lung cancer patients. The strongest evidence for a role of EGFR in the biology of glioblastoma stems from clinical trials in which 15-20% of recurrent glioblastoma patients experienced significant tumour regression in response to these small-molecule EGFR kinase inhibitors. We examined the protein-kinase domain of the EGFR gene, EGFR protein expression and EGFR gene amplification in 20 cases of recurrent GBMs. EGFR protein over-expression was found in 65% of cases. EGFR protein over-expression was associated with EGFR gene amplification in 35% of cases, and with high polysomy in 15% of cases. No mutations were found in the TK domain of the EGFR gene. Our results confirm that mutations in the kinase domain are absent in recurrent GBM, and this might be a preponderant factor in the lack of major clinical responses of TKIs in GBM, recent studies have suggested that responsiveness to EGFR kinase inhibitors was strongly associated with coexpression of EGFRvIII and PTEN. Further prospective validation of EGFRvIII and PTEN as predictors of the clinical response to EGFR kinase inhibitors in recurrent GBM is strongly anticipated.

Multiple Microsurgical Resections for Repeated Recurrence of Glioblastoma Multiforme

“…[35][36][37] Data on the effect of reirradiation, applied as normofractionated or hypofractionated stereotactic small volume radiotherapy are limited regarding further tumor growth, but it may aggravate neurological toxicity. [38][39][40][41][42][43][44][45][46][47] In long-term survivors, there are concerns regarding radiation-induced late sequelae, in particular delayed leukoencephalopathy with neurocognitive dysfunction or radiation necrosis.…”

Glioblastoma-Derived Epidermal Growth Factor Receptor Carboxyl-Terminal Deletion Mutants Are Transforming and Are Sensitive to EGFR-Directed Therapies

“…In addition, various exon deletion mutations including exon 25–27 and exon 25–28 deletion mutations, which result in the truncation of the C-terminal domain of EGFR, have been identified in GBM patients although their oncogenic potential has not yet been characterized (17, 18). Furthermore, EGFR gene amplification and/or EGFR protein overexpression commonly occur in approximately 50% of GBM patients, suggesting that an increased abundance of the EGFR may also be responsible for tumorigenesis in primary GBM (7, 19). Interestingly, somatic mutations within the EGFR kinase domain, which are frequently identified in non-small cell lung cancer, have only rarely been identified in GBM (8, 14, 20).…”

Anti-cancer Therapies in High Grade Gliomas

“…Numerous studies have identified epidermal growth factor receptor as a common genetically altered gene in primary GBM [35-37], by: i) amplifications [35, 38] ii) exon deletions affecting either the extracellular, either cytoplasmatic domain [39-41] iii) point mutations within the extracellular domain of EGFR [42]. These genetic alterations have been shown to lead to oncogenic activation of the mutant receptor independent of ligand stimulation and, consequently, induce cellular transformation.…”