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Updated: Dec 22, 2025
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in
Atsushi Natsume1, Kosuke Aoki2, Fumiharu Ohka2
1Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. anatsume@med.nagoya-u.ac.jp.
Purpose:
This study aimed to explore the genetic alterations and to identify good responders in the experimental arm in the tumor samples from newly diagnosed glioblastoma (GBM) patients enrolled in JCOG0911; a randomized phase II trial was conducted to compare the efficacy of interferonβ (IFNβ) plus temozolomide (TMZ) with that of TMZ alone.
Experimental:
DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation; Sanger sequencing for the telomerase reverse transcriptase (TERT) promoter; and microsatellite instability (MSI) testing in 95, 91, 91 and 72 tumors, respectively. We performed a multivariable Cox regression analysis using backward stepwise selection of variables including clinical factors (sex, age, performance status, residual tumor after resection, tumor location) and genetic alterations.
Results:
Deep sequencing detected an IDH1 mutation in 13 tumors (14%). The MGMT promoter methylation by quantitative pyrosequencing was observed in 41% of the tumors. A mutation in the TERT promoter was observed in 69% of the tumors. While high tumor mutation burden (> 10 mutations per megabase) was seen in four tumors, none of the tumors displayed MSI-high. The clinical and genetic factors considered as independent favorable prognostic factors were gross total resection (hazard ratio [HR]: 0.49, 95% confidence interval, 0.30-0.81, P = 0.0049) and MGMT promoter methylation (HR: 0.43, 0.21-0.88, P = 0.023). However, tumor location at the temporal lobe (HR: 1.90, 1.22-2.95, P = 0.0046) was an independent unfavorable prognostic factor. No predictive factors specific to the TMZ + IFNβ + Radiotherapy (RT) group were found.
Conclusion:
This additional sub-analytical study of JCOG0911 among patients with newly diagnosed GBM showed that tumor location at the temporal lobe, gross total resection, and MGMT promoter methylation were significant prognostic factors, although no factors specific to IFNβ addition were identified.
Insights
Gross total resection and MGMT promoter methylation are favorable prognostic factors for glioblastoma (GBM) patients. Temporal lobe location is an unfavorable factor, but no predictors for interferon-beta treatment efficacy were identified.
Area of Science:
- Neuro-oncology
- Molecular Genetics
- Clinical Trial Analysis
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
- The JCOG0911 trial evaluated interferon-beta (IFNβ) plus temozolomide (TMZ) versus TMZ alone for newly diagnosed GBM.
- Understanding genetic alterations can help identify prognostic and predictive factors.
Purpose of the Study:
- To explore genetic alterations in newly diagnosed GBM patient tumors from the JCOG0911 trial.
- To identify factors associated with treatment response in the experimental arm (TMZ + IFNβ).
- To correlate genetic and clinical factors with patient prognosis.
Main Methods:
- Deep targeted sequencing, pyrosequencing for MGMT promoter methylation, Sanger sequencing for TERT promoter, and MSI testing were performed on tumor samples.
- Multivariable Cox regression analysis was used to identify prognostic factors, including clinical and genetic variables.
- The study analyzed 122 tumors for various genetic alterations and clinical data.
Main Results:
- IDH1 mutations were found in 14% of tumors. MGMT promoter methylation was present in 41%, and TERT promoter mutations in 69%.
- Gross total resection (HR: 0.49) and MGMT promoter methylation (HR: 0.43) were independent favorable prognostic factors.
- Temporal lobe tumor location (HR: 1.90) was an independent unfavorable prognostic factor. No predictive factors for IFNβ efficacy were identified.
Conclusions:
- Gross total resection and MGMT promoter methylation are significant prognostic factors in newly diagnosed GBM.
- Tumor location, specifically the temporal lobe, is a significant unfavorable prognostic factor.
- This study did not identify specific biomarkers predicting response to the addition of IFNβ to TMZ therapy.
