EGFR Amplification/Overexpression Associated With Improved Response of Glioblastoma to Metronomic Temozolomide

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In a study reported in Journal of the National Cancer Institute, Cominelli and colleagues found that EGFR amplification/overexpression was associated with improved response of glioblastoma to adjuvant metronomic (every day of a 28 day cycle at a dosing of 50-75 mg/m2) but not standard (5 consecutive days of temozolomide in a 28 day cycle at a dosing of 150-200 mg/m2) temozolomide schedules.

Analysis of a cohort of glioblastoma patients showed no relationship of survival with gene classifiers associated with molecular glioblastoma subtypes in those receiving temozolomide in a standard schedule. However, EGFR amplification/overexpression was associated with significantly better progression-free survival and overall survival (hazard ratio = 0.22, P = .001, for high vs low) in those receiving metronomic treatment. Long-term survival in those receiving metronomic treatment was independent of MGMT and EGFRvIII-mutant status and was more likely in those with EGFR overexpression with PTEN loss.

In studies in vitro, temozolomide-treated EGFR-positive human-derived glioblastoma cancer stem cells exhibited selective dose- and time-dependent reductions in survival, mediated by inhibition of NF-κB (nuclear factor kappa B) transcriptional activity. Analysis of samples from recurrent metronomic-treated ­EGFR-overexpressing patients showed reductions in EGFR-amplified cells and NF-κB/p65 ­expression.

The investigators concluded: ­“EGFR-amplified/overexpressing glioblastomas strongly benefit from metronomic temozolomide-based therapies.” ■

Cominelli M, et al: J Natl Cancer Inst 107:pii: djv041, 2015.





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