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

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

Research output: Contribution to journalArticle

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

Original languageEnglish
Article numberdjv041
JournalJournal of the National Cancer Institute
Volume107
Issue number5
DOIs
Publication statusPublished - May 1 2015

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temozolomide
Glioblastoma
Survival
Neoplastic Stem Cells
Methylation
Analysis of Variance
Appointments and Schedules

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Cominelli, M., Grisanti, S., Mazzoleni, S., Branca, C., Buttolo, L., Furlan, D., ... Poliani, P. L. (2015). EGFR amplified and overexpressing glioblastomas and association with better response to adjuvant metronomic temozolomide. Journal of the National Cancer Institute, 107(5), [djv041]. https://doi.org/10.1093/jnci/djv041

EGFR amplified and overexpressing glioblastomas and association with better response to adjuvant metronomic temozolomide. / Cominelli, Manuela; Grisanti, Salvatore; Mazzoleni, Stefania; Branca, Caterina; Buttolo, Luciano; Furlan, Daniela; Liserre, Barbara; Bonetti, Maria Fausta; Medicina, Daniela; Pellegrini, Vilma; Buglione, Michela; Liserre, Roberto; Pellegatta, Serena; Finocchiaro, Gaetano; Dalerba, Piero; Facchetti, Fabio; Pizzi, Marina; Galli, Rossella; Poliani, Pietro Luigi.

In: Journal of the National Cancer Institute, Vol. 107, No. 5, djv041, 01.05.2015.

Research output: Contribution to journalArticle

Cominelli, M, Grisanti, S, Mazzoleni, S, Branca, C, Buttolo, L, Furlan, D, Liserre, B, Bonetti, MF, Medicina, D, Pellegrini, V, Buglione, M, Liserre, R, Pellegatta, S, Finocchiaro, G, Dalerba, P, Facchetti, F, Pizzi, M, Galli, R & Poliani, PL 2015, 'EGFR amplified and overexpressing glioblastomas and association with better response to adjuvant metronomic temozolomide', Journal of the National Cancer Institute, vol. 107, no. 5, djv041. https://doi.org/10.1093/jnci/djv041
Cominelli, Manuela ; Grisanti, Salvatore ; Mazzoleni, Stefania ; Branca, Caterina ; Buttolo, Luciano ; Furlan, Daniela ; Liserre, Barbara ; Bonetti, Maria Fausta ; Medicina, Daniela ; Pellegrini, Vilma ; Buglione, Michela ; Liserre, Roberto ; Pellegatta, Serena ; Finocchiaro, Gaetano ; Dalerba, Piero ; Facchetti, Fabio ; Pizzi, Marina ; Galli, Rossella ; Poliani, Pietro Luigi. / EGFR amplified and overexpressing glioblastomas and association with better response to adjuvant metronomic temozolomide. In: Journal of the National Cancer Institute. 2015 ; Vol. 107, No. 5.
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AU - Grisanti, Salvatore

AU - Mazzoleni, Stefania

AU - Branca, Caterina

AU - Buttolo, Luciano

AU - Furlan, Daniela

AU - Liserre, Barbara

AU - Bonetti, Maria Fausta

AU - Medicina, Daniela

AU - Pellegrini, Vilma

AU - Buglione, Michela

AU - Liserre, Roberto

AU - Pellegatta, Serena

AU - Finocchiaro, Gaetano

AU - Dalerba, Piero

AU - Facchetti, Fabio

AU - Pizzi, Marina

AU - Galli, Rossella

AU - Poliani, Pietro Luigi

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N2 - 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

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