EGFR amplified and overexpressing glioblastomas and association with better response to adjuvant metronomic temozolomide.

Abstract

BACKGROUND:

Lack of robust predictive biomarkers, other than MGMT promoter methylation, makes temozolomide responsiveness in newly diagnosed glioblastoma (GBM) patients difficult to predict. However, we identified patients with long-term survival (≥35 months) within a group of newly diagnosed GBM patients treated with standard or metronomic adjuvant temozolomide schedules. We thus investigated possible molecular profiles associated with longer survival following temozolomide treatment.

METHODS:

We investigated the association of molecular features with progression-free (PFS) and overall survival (OS). Human-derived GBM cancer stem cells (CSCs) were used to investigate in vitro molecular mechanisms associated with temozolomide responsiveness. Surgically removed recurrences allowed investigation of molecular changes occurring during therapy in vivo. Statistical analyses included one- and two-way analysis of variance, Student's t test, Cox proportional hazards, and the Kaplan-Meier method. All statistical tests were two-sided.

RESULTS:

No association was found between survival and gene classifiers associated with different molecular GBM subtypes in the standard-treated group, while in metronomic-treated patients robust association was found between EGFR amplification/overexpression and PFS and OS (OS, EGFR-high vs low: hazard ratiodeath = 0.22, 95% confidence interval = 0.09 to 0.55, P = .001). The result for OS remained statistically significant after Bonferroni correction (P interaction < .0005). Long-term survival following metronomic temozolomide was independent from MGMT and EGFRvIII status and was more pronounced in EGFR-overexpressing GBM patients with PTEN loss. In vitro findings confirmed a selective dose- and time-dependent decrease in survival of temozolomide-treated EGFR+ human-derived glioblastoma CSCs, which occurred through inhibition of NF-κB transcriptional activity. In addition, reduction in EGFR-amplified cells, along with a statistically significant decrease in NF-κB/p65 expression, were observed in specimens from recurrent metronomic-treated EGFR-overexpressing GBM patients.

CONCLUSIONS:

EGFR-amplified/overexpressing glioblastomas strongly benefit from metronomic temozolomide-based therapies.

• Authors: Manuela Cominelli, Salvatore Grisanti, Stefania Mazzoleni, Caterina Branca, Luciano Buttolo, Daniela Furlan, Barbara Liserre, Maria Fausta Bonetti, Daniela Medicina, Vilma Pellegrini, Michela Buglione, Roberto Liserre, Serena Pellegatta, Gaetano Finocchiaro, Piero Dalerba, Fabio Facchetti, Marina Pizzi, Rossella Galli, Pietro Luigi Poliani
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 107 Issue 5 (May 2015) ISSN: 1460-2105 [Electronic] United States
• PMID: 25739547 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents, Alkylating
• Dacarbazine
• EGFR protein, human
• ErbB Receptors
• Temozolomide

Topics

• Administration, Metronomic
• Adult
• Analysis of Variance
• Antineoplastic Agents, Alkylating (administration & dosage, therapeutic use)
• Brain Neoplasms (drug therapy, metabolism, surgery)
• Chemotherapy, Adjuvant
• Dacarbazine (administration & dosage, analogs & derivatives, therapeutic use)
• Disease-Free Survival
• ErbB Receptors (genetics)
• Female
• Gene Amplification
• Gene Expression Regulation, Neoplastic
• Glioblastoma (drug therapy, metabolism, surgery)
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplastic Stem Cells (drug effects)
• Odds Ratio
• Proportional Hazards Models
• Temozolomide
• Up-Regulation