Improved prognostic stratification of patients with isocitrate dehydrogenase-mutant astrocytoma

Michael Weller; Jörg Felsberg; Bettina Hentschel; Dorothee Gramatzki; Nadezhda Kubon; Marietta Wolter; Matthias Reusche; Patrick Roth; Dietmar Krex; Ulrich Herrlinger; Manfred Westphal; Joerg C Tonn; Luca Regli; Claude-Alain Maurage; Andreas von Deimling; Torsten Pietsch; Emilie Le Rhun; Guido Reifenberger

doi:10.1007/s00401-023-02662-1

Improved prognostic stratification of patients with isocitrate dehydrogenase-mutant astrocytoma

Acta Neuropathol. 2024 Jan 6;147(1):11. doi: 10.1007/s00401-023-02662-1.

Authors

Michael Weller^{1

2}, Jörg Felsberg³, Bettina Hentschel⁴, Dorothee Gramatzki⁵, Nadezhda Kubon³, Marietta Wolter³, Matthias Reusche⁴, Patrick Roth^{5

6}, Dietmar Krex⁷, Ulrich Herrlinger⁸, Manfred Westphal⁹, Joerg C Tonn^{10

11}, Luca Regli^{12

13}, Claude-Alain Maurage¹⁴, Andreas von Deimling^{15

16}, Torsten Pietsch¹⁷, Emilie Le Rhun^{5

6

12

13

18}, Guido Reifenberger^{3

19}

Affiliations

¹ Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland. michael.weller@usz.ch.
² Department of Neurology, University of Zurich, Zurich, Switzerland. michael.weller@usz.ch.
³ Institute of Neuropathology, Heinrich Heine University, Medical Faculty, and University Hospital Düsseldorf, Düsseldorf, Germany.
⁴ Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Leipzig, Germany.
⁵ Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, 8091, Zurich, Switzerland.
⁶ Department of Neurology, University of Zurich, Zurich, Switzerland.
⁷ Faculty of Medicine, Department of Neurosurgery, Technische Universität Dresden, University Hospital Carl Gustav Carus, Dresden, Germany.
⁸ Department of Neurology, University of Bonn, Bonn, Germany.
⁹ Department of Neurosurgery, University of Hamburg, Hamburg, Germany.
¹⁰ Department of Neurosurgery, Ludwig-Maximilians-University Munich, Munich, Germany.
¹¹ German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.
¹² Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
¹³ Department of Neurosurgery, University of Zurich, Zurich, Switzerland.
¹⁴ Department of Pathology, Centre Biologie Pathologie, Lille University Hospital, Hopital Nord, Lille, France.
¹⁵ Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.
¹⁶ Clinical Cooperation Unit Neuropathology, German Cancer Center (DKFZ), and German Cancer Consortium (DKTK), Partner Site Heidelberg, Heidelberg, Germany.
¹⁷ Department of Neuropathology, University of Bonn Medical Center, DGNN Brain Tumor Reference Center, Bonn, Germany.
¹⁸ Department of Neurosurgery, Lille University Hospital, Lille, France.
¹⁹ German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Düsseldorf, Germany.

Abstract

Prognostic factors and standards of care for astrocytoma, isocitrate dehydrogenase (IDH)-mutant, CNS WHO grade 4, remain poorly defined. Here we sought to explore disease characteristics, prognostic markers, and outcome in patients with this newly defined tumor type. We determined molecular biomarkers and assembled clinical and outcome data in patients with IDH-mutant astrocytomas confirmed by central pathology review. Patients were identified in the German Glioma Network cohort study; additional cohorts of patients with CNS WHO grade 4 tumors were identified retrospectively at two sites. In total, 258 patients with IDH-mutant astrocytomas (114 CNS WHO grade 2, 73 CNS WHO grade 3, 71 CNS WHO grade 4) were studied. The median age at diagnosis was similar for all grades. Karnofsky performance status at diagnosis inversely correlated with CNS WHO grade (p < 0.001). Despite more intensive treatment upfront with higher grade, CNS WHO grade was strongly prognostic: median overall survival was not reached for grade 2 (median follow-up 10.4 years), 8.1 years (95% CI 5.4-10.8) for grade 3, and 4.7 years (95% CI 3.4-6.0) for grade 4. Among patients with CNS WHO grade 4 astrocytoma, median overall survival was 5.5 years (95% CI 4.3-6.7) without (n = 58) versus 1.8 years (95% CI 0-4.1) with (n = 12) homozygous CDKN2A deletion. Lower levels of global DNA methylation as detected by LINE-1 methylation analysis were strongly associated with CNS WHO grade 4 (p < 0.001) and poor outcome. MGMT promoter methylation status was not prognostic for overall survival. Histomolecular stratification based on CNS WHO grade, LINE-1 methylation level, and CDKN2A status revealed four subgroups of patients with significantly different outcomes. In conclusion, CNS WHO grade, global DNA methylation status, and CDKN2A homozygous deletion are prognostic in patients with IDH-mutant astrocytoma. Combination of these parameters allows for improved prediction of outcome. These data aid in designing upcoming trials using IDH inhibitors.

Keywords: Brain; CDKN2A; CNS WHO grade; IDH; LINE-1; Molecular.

MeSH terms

Astrocytoma* / genetics
Astrocytoma* / therapy
Cohort Studies
Homozygote
Humans
Isocitrate Dehydrogenase* / genetics
Prognosis
Retrospective Studies
Sequence Deletion

Substances

Isocitrate Dehydrogenase
IDH1 protein, human