Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial

Y. Gao, B. Weenink, M. J. van den Bent, L. Erdem-Eraslan, J. M. Kros, P. A. E. Sillevis Smitt, K. Hoang-Xuan, A. A. Brandes, M. Vos, F. Dhermain, R. Enting, G. F. Ryan, O. Chinot, M. Ben Hassel, M. E. van Linde, W. P. Mason, J. M. M. Gijtenbeek, C. Balana, A. von Deimling, Th GorliaR. Stupp, M. E. Hegi, B. G. Baumert, P. J. French*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    13 Citations (Scopus)

    Abstract

    Introduction: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response.

    Methods: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays.

    Results: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although followup time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitoretype immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified.

    Conclusion: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples. (C) 2018 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)168-178
    Number of pages11
    JournalEuropean Journal of Cancer
    Volume94
    DOIs
    Publication statusPublished - May-2018

    Keywords

    • Low grade glioma
    • Intrinsic subtype
    • Pilocytic astrocytoma
    • Gene expression profiling
    • Immunophenotype
    • BELOB
    • OLIGODENDROGLIAL BRAIN-TUMORS
    • CENTRAL-NERVOUS-SYSTEM
    • PHASE-III TRIAL
    • RANDOMIZED-TRIAL
    • VINCRISTINE CHEMOTHERAPY
    • PILOCYTIC ASTROCYTOMAS
    • ADJUVANT PROCARBAZINE
    • RADIATION-THERAPY
    • EORTC 22033-26033
    • MGMT METHYLATION

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