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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

Authors :
Kazuhiko Mishima
Atsushi Natsume
Yasuo Iwadate
Takanori Onishi
Toshihiko Wakabayashi
Tomokazu Aoki
Kazuhiko Sugiyama
Tamio Ito
Eiichi Ishikawa
Yusuke Okuno
Yoshitaka Narita
Toshihiro Kumabe
Takaaki Beppu
Ryo Nishikawa
Koji Yoshimoto
Masaki Hirano
Kenichiro Asano
Kaoru Kurisu
Kazuya Motomura
Hideo Nakamura
Yoshiki Arakawa
Nobusada Shinoura
Minako Sumi
Kosuke Aoki
Shinya Sato
Fumiyuki Yamasaki
Akio Asai
Tatsuya Abe
Soichiro Shibui
Motoo Nagane
Hiroyuki Kobayashi
Takayuki Matsuo
Akitake Mukasa
Hikaru Sasaki
Yoshihiro Muragaki
Atsuo Yoshino
Akira Matsumura
Fumiharu Ohka
Yoko Nakasu
Sachi Maeda
Mizuhiko Terasaki
Hirofumi Hirano
Alimu Adilijiang
Takamasa Kayama
Naoya Hashimoto
Takashi Maruyama
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.

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