TY - JOUR
T1 - Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma
AU - Tesileanu, C. Mircea S.
AU - Van Den Bent, Martin J.
AU - Sanson, Marc
AU - Wick, Wolfgang
AU - Brandes, Alba A.
AU - Clement, Paul M.
AU - Erridge, Sara C.
AU - Vogelbaum, Michael A.
AU - Nowak, Anna K.
AU - Baurain, Jean F.
AU - Mason, Warren P.
AU - Wheeler, Helen
AU - Chinot, Olivier L.
AU - Gill, Sanjeev
AU - Griffin, Matthew
AU - Rogers, Leland
AU - Taal, Walter
AU - Rudà, Roberta
AU - Weller, Michael
AU - McBain, Catherine
AU - Van Linde, Myra E.
AU - Sabedot, Thais S.
AU - Hoogstrate, Youri
AU - Von Deimling, Andreas
AU - De Heer, Iris
AU - Van Ijcken, Wilfred F.J.
AU - Brouwer, Rutger W.W.
AU - Aldape, Kenneth
AU - Jenkins, Robert B.
AU - Dubbink, Hendrikus J.
AU - Kros, Johan M.
AU - Wesseling, Pieter
AU - Cheung, Kin Jip
AU - Golfinopoulos, Vassilis
AU - Baumert, Brigitta G.
AU - Gorlia, Thierry
AU - Noushmehr, Houtan
AU - French, Pim J.
N1 - Funding Information:
This study was supported by MSD (educational grant, provision of temozolomide), the NRG (grants U10CA180868 and U10CA180822), Cancer Research UK (grant CRUK/07/028), and Cancer Australia (grants 1026842 and 1078655). The molecular analysis was funded by The Brain Tumour Charity (grant GN- 000577), the Dutch Cancer Society (grant 10685), the Vereniging Heino "Strijd van Salland," and the USA Department of Defence (grant CA170278).
Publisher Copyright:
© 2021 The Author(s) 2021.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85111541007&partnerID=8YFLogxK
U2 - 10.1093/neuonc/noab088
DO - 10.1093/neuonc/noab088
M3 - Article
C2 - 33914057
AN - SCOPUS:85111541007
SN - 1522-8517
VL - 23
SP - 1547
EP - 1559
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - 9
ER -
