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Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone
Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone
- Source :
- Journal of Neuro-Oncology. 148:17-27
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- 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. 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. 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. 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.
- Subjects :
- Adult
Male
Oncology
Cancer Research
medicine.medical_specialty
Methyltransferase
Antineoplastic Agents
Deep sequencing
Young Adult
03 medical and health sciences
symbols.namesake
0302 clinical medicine
Internal medicine
Temozolomide
Humans
Medicine
Telomerase reverse transcriptase
DNA Modification Methylases
Telomerase
Aged
Sanger sequencing
Performance status
Brain Neoplasms
business.industry
Tumor Suppressor Proteins
Hazard ratio
Microsatellite instability
Interferon-beta
Middle Aged
medicine.disease
Isocitrate Dehydrogenase
DNA Repair Enzymes
Treatment Outcome
Neurology
030220 oncology & carcinogenesis
symbols
Female
Neurology (clinical)
Glioblastoma
business
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 15737373 and 0167594X
- Volume :
- 148
- Database :
- OpenAIRE
- Journal :
- Journal of Neuro-Oncology
- Accession number :
- edsair.doi.dedup.....f80d06a9931a94d58c444b87a9554d05
- Full Text :
- https://doi.org/10.1007/s11060-020-03505-9