Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma

authors

• Tesileanu C Mircea S
• van den Bent Martin
• Sanson Marc
• Wick Wolfgang
• Brandes Alba
• Clement Paul
• Erridge Sara
• Vogelbaum Michael
• Nowak Anna
• Baurain Jean
• Mason Warren
• Wheeler Helen
• Chinot Olivier
• Gill Sanjeev
• Griffin Matthew
• Rogers Leland
• Taal Walter
• Rudà Roberta
• Weller Michael
• Mcbain Catherine
• van Linde Myra
• Sabedot Thais
• Hoogstrate Youri
• von Deimling Andreas
• de Heer Iris
• van Ijcken Wilfred
• Brouwer Rutger
• Aldape Kenneth
• Jenkins Robert
• Dubbink Hendrikus
• Kros Johan
• Wesseling Pieter
• Cheung Kin Jip
• Golfinopoulos Vassilis
• Baumert Brigitta
• Gorlia Thierry
• Noushmehr Houtan
• French Pim

document type

abstract

Abstract Background Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. Methods The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/− concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization. Results Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Conclusion Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.

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