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Clinical Trial
. 2023 Oct 2;29(19):3892-3900.
doi: 10.1158/1078-0432.CCR-23-0926.

Prognostic Markers of DNA Methylation and Next-Generation Sequencing in Progressive Glioblastoma from the EORTC-26101 Trial

Tobias Kessler  1   2 , Daniel Schrimpf  3   4 , Laura Doerner  3 , Ling Hai  1   2 , Leon D Kaulen  1   2 , Jakob Ito  1 , Martin van den Bent  5 , Martin Taphoorn  6   7 , Alba A Brandes  8 , Ahmed Idbaih  9 , Julien Dômont  10 , Paul M Clement  11 , Mario Campone  12 , Martin Bendszus  13 , Andreas von Deimling  3   4 , Felix Sahm  3   4 , Michael Platten  14   15 , Wolfgang Wick  1   2 , Antje Wick  2
Affiliations
Clinical Trial

Prognostic Markers of DNA Methylation and Next-Generation Sequencing in Progressive Glioblastoma from the EORTC-26101 Trial

Tobias Kessler et al. Clin Cancer Res. .

Abstract

Purpose: The EORTC-26101 study was a randomized phase II and III clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. Other than for progression-free survival (PFS), there was no benefit from addition of bevacizumab for overall survival (OS). However, molecular data allow for the rare opportunity to assess prognostic biomarkers from primary surgery for their impact in progressive glioblastoma.

Experimental design: We analyzed DNA methylation array data and panel sequencing from 170 genes of 380 tumor samples of the EORTC-26101 study. These patients were comparable with the overall study cohort in regard to baseline characteristics, study treatment, and survival.

Results: Of patients' samples, 295/380 (78%) were classified into one of the main glioblastoma groups, receptor tyrosine kinase (RTK)1, RTK2 and mesenchymal. There were 10 patients (2.6%) with isocitrate dehydrogenase mutant tumors in the biomarker cohort. Patients with RTK1 and RTK2 classified tumors had lower median OS compared with mesenchymal (7.6 vs. 9.2 vs. 10.5 months). O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation was prognostic for PFS and OS. Neurofibromin (NF)1 mutations were predictive of response to bevacizumab treatment.

Conclusions: Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.

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Figures

Figure 1. Methylation classes in progressive glioblastoma of the EORTC-26101 study. Circos blot showing methylation classification according to the v11b4 and v12.5 version of the methylation classifier (n = 380).
Figure 1.
Methylation classes in progressive glioblastoma of the EORTC-26101 study. Circos blot showing methylation classification according to the v11b4 and v12.5 version of the methylation classifier (n = 380).
Figure 2. Prognostic effect of the main glioblastoma methylation classes and MGMT promoter methylation status. A, OS of patients with the three main glioblastoma groups (RTK1, RTK2, and MES, n = 295) identified with classifier v12.5. B, PFS of the same patient cohort as in A (n = 295). C, OS according to MGMT promoter methylation (n = 313). Patients with MGMT promoter methylation status of “undeterminable” were excluded from the analysis. D, PFS according to MGMT promoter methylation (n = 313).
Figure 2.
Prognostic effect of the main glioblastoma methylation classes and MGMT promoter methylation status. A, OS of patients with the three main glioblastoma groups (RTK1, RTK2, and MES, n = 295) identified with classifier v12.5. B, PFS of the same patient cohort as in A (n = 295). C, OS according to MGMT promoter methylation (n = 313). Patients with MGMT promoter methylation status of “undeterminable” were excluded from the analysis. D, PFS according to MGMT promoter methylation (n = 313).
Figure 3. Impact of somatic mutations in the EORTC-26101 cohort. A, Oncoplot with SNVs and indels in the 20 most frequently affected genes in the complete EORTC-26101 biomarker cohort (n = 380). B, OS according to PTEN mutation status (n = 380).
Figure 3.
Impact of somatic mutations in the EORTC-26101 cohort. A, Oncoplot with SNVs and indels in the 20 most frequently affected genes in the complete EORTC-26101 biomarker cohort (n = 380). B, OS according to PTEN mutation status (n = 380).
Figure 4. NF1 mutation is a prognostic factor for response to bevacizumab therapy. A, OS of patients with NF1 mutations according to treatment (n = 28). B, OS of patients with NF1 wild-type according to treatment (n = 260). Bev, bevacizumab.
Figure 4.
NF1 mutation is a prognostic factor for response to bevacizumab therapy. A, OS of patients with NF1 mutations according to treatment (n = 28). B, OS of patients with NF1 wild-type according to treatment (n = 260). Bev, bevacizumab.
Figure 5. Features of patients with long and short OS. A, Clinical characteristics of patients with the 10% shortest (n = 39) and longest (n = 39) OS. B, Distribution of methylation classification in patients with short (n = 39) and long (n = 39) OS. C, Oncoplot of patients with the 10% shortest OS (n = 39). D, Oncoplot of patients with the 10% longest OS (n = 39).
Figure 5.
Features of patients with long and short OS. A, Clinical characteristics of patients with the 10% shortest (n = 39) and longest (n = 39) OS. B, Distribution of methylation classification in patients with short (n = 39) and long (n = 39) OS. C, Oncoplot of patients with the 10% shortest OS (n = 39). D, Oncoplot of patients with the 10% longest OS (n = 39).
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