Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Radiation Oncology Department, Cancer Institute Hospital, Tokyo, Japan.
J Neurooncol. 2020 May;148(1):17-27. doi: 10.1007/s11060-020-03505-9. Epub 2020 May 4.
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.
DESIGN: Of 122 tumors, we performed deep targeted sequencing to determine the somatic mutations, copy number variations, and tumor mutation burden; pyrosequencing for O-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.
本研究旨在探索新诊断胶质母细胞瘤（GBM）患者肿瘤样本中的遗传改变，并确定实验组的良好应答者。JCOG0911 是一项随机 II 期试验，旨在比较干扰素β（IFNβ）联合替莫唑胺（TMZ）与 TMZ 单药治疗的疗效。
设计：在 122 例肿瘤中，我们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担；焦磷酸测序检测 O-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）启动子甲基化；桑格测序检测端粒酶逆转录酶（TERT）启动子；95、91、91 和 72 例肿瘤分别进行微卫星不稳定性（MSI）检测。我们使用包括临床因素（性别、年龄、表现状态、切除后残余肿瘤、肿瘤位置）和遗传改变在内的变量进行向后逐步选择的多变量 Cox 回归分析。
深度测序检测到 13 例肿瘤（14%）存在 IDH1 突变。通过定量焦磷酸测序检测到 41%的肿瘤存在 MGMT 启动子甲基化。69%的肿瘤存在 TERT 启动子突变。虽然有 4 例肿瘤存在高肿瘤突变负担（>10 个突变/兆碱基），但没有肿瘤表现出 MSI 高。被认为是独立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）。然而，颞叶（HR：1.90，1.22-2.95，P=0.0046）肿瘤位置是独立的不利预后因素。未发现 TMZ+IFNβ+放疗（RT）组的特定预测因素。
JCOG0911 中对新诊断 GBM 患者的这项附加亚分析表明，颞叶肿瘤位置、大体全切除和 MGMT 启动子甲基化是显著的预后因素，尽管未发现 IFNβ 加用的特定因素。
