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
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DOI：
10.1007/s11060-020-03505-9
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发表时间：
2020-05-04
影响因子：
3.9
通讯作者：
Wakabayashi, Toshihiko
中科院分区：
文献类型：
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作者：
Natsume, Atsushi;Aoki, Kosuke;Wakabayashi, Toshihiko
目的本研究旨在探讨基因改变，并确定良好的反应者在实验组的肿瘤样本从新诊断的胶质母细胞瘤（GBM）患者入组JCOG 0911;一个随机的II期临床试验进行比较干扰素β（IFN β）联合替莫唑胺（TMZ）的疗效与TMZ单药。实验设计在122个肿瘤中，我们分别对95、91、91和72个肿瘤进行了深度靶向测序以确定体细胞突变、拷贝数变异和肿瘤突变负荷;对O-6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）启动子甲基化进行焦磷酸测序;对端粒酶逆转录酶（TERT）启动子进行桑格测序;以及微卫星不稳定性（MSI）测试。我们进行了多变量考克斯回归分析，使用向后逐步选择的变量，包括临床因素（性别，年龄，体力状态，切除后残留肿瘤，肿瘤位置）和遗传改变。结果深度测序检测到13例肿瘤（14%）存在IDH 1突变。通过定量焦磷酸测序在41%的肿瘤中观察到MGMT启动子甲基化。在69%的肿瘤中观察到TERT启动子突变。虽然在四个肿瘤中观察到高肿瘤突变负荷（> 10个突变/兆碱基），但没有一个肿瘤显示MSI高。被认为是独立的有利预后因素的临床和遗传因素是大体全切除（风险比[HR]：0.49，95%置信区间，0.30-0.81，P = 0.0049）和MGMT启动子甲基化（HR：0.43，0.21-0.88，P = 0.023）。而肿瘤位于颞叶（HR：1.90，1.22-2.95，P = 0.0046）是独立的预后不良因素。TMZ + IFN β +放疗（RT）group. Conclusion JCOG 0911新诊断GBM患者中的额外的子分析研究表明，肿瘤位置在颞叶，总切除，MGMT启动子甲基化是显着的预后因素，虽然没有特定的IFN β添加因素被确定。
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 interferon beta (IFN beta) plus temozolomide (TMZ) with that of TMZ alone. Experimentaldesign Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O-6-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 + IFN beta + 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 IFN beta addition were identified.