Molecular Predictors of Progression-Free and Overall Survival in Patients With Newly Diagnosed Glioblastoma: A Prospective Translational Study of the German Glioma Network
Molecular Predictors of Progression-Free and Overall Survival in Patients With Newly Diagnosed Glioblastoma: A Prospective Translational Study of the German Glioma Network
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DOI：
10.1200/jco.2009.23.0805
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发表时间：
2009-12-01
影响因子：
45.3
通讯作者：
Loeffler, Markus
中科院分区：
文献类型：
--
作者：
Weller, Michael;Felsberg, Joerg;Loeffler, Markus
研究对象与方法2004年10月至2006年12月，在德国胶质瘤网络的临床中心，前瞻性地收集了31例胶质母细胞瘤患者。258名患者接受了放射治疗，199名患者接受了替莫唑胺治疗，189名患者同时接受了放射治疗，7名患者接受了另一种化疗作为初始治疗。检测肿瘤组织中TP53基因突变、p53免疫反应性、表皮生长因子受体、细胞周期蛋白依赖性激酶CDK4或小鼠双分钟2扩增、CDKN2A纯合子缺失、染色体臂1p、9p、10q和19q等位基因缺失、O6-甲基鸟嘌呤甲基转移酶(MGMT)启动子甲基化和异柠檬酸脱氢酶1(IDH1)突变。多因素分析显示，年龄较小、表现评分较高、MGMT启动子甲基化和替莫唑胺放化疗是与较长OS相关的独立因素。在接受替莫唑胺治疗的患者中，MGMT启动子甲基化与较长的PFS(相对风险[RR]，0.5；95%CI，0.38至0.68；P<；.001)和OS(RR，0.39；95%CI，0.28至0.54；P<；.001)相关。IDH1突变与PFS延长(RR，0.42；95%CI，0.19至0.91；P=.028)和OS延长的趋势(RR，0.43；95%CI，0.15至1.19；P=.10)相关。没有其他分子因素与结果相关。结论根据目前的治疗标准，与胶质瘤形成相关的分子变化不能预测胶质母细胞瘤患者的治疗反应。MGMT启动子甲基化和IDH1突变状态允许分层为预测不同的亚组。
PurposeThe prognostic value of genetic alterations characteristic of glioblastoma in patients treated according to present standards of care is unclear.Patients and MethodsThree hundred one patients with glioblastoma were prospectively recruited between October 2004 and December 2006 at the clinical centers of the German Glioma Network. Two hundred fifty-eight patients had radiotherapy, 199 patients had temozolomide, 189 had both, and seven had another chemotherapy as the initial treatment. The tumors were investigated for TP53 mutation, p53 immunoreactivity, epidermal growth factor receptor, cyclin-dependent kinase CDK 4 or murine double minute 2 amplification, CDKN2A homozygous deletion, allelic losses on chromosome arms 1p, 9p, 10q, and 19q, O6-methylguanine methyltransferase (MGMT) promoter methylation, and isocitrate dehydrogenase 1 (IDH1) mutations.ResultsMedian progression-free (PFS) and overall survival (OS) were 6.8 and 12.5 months. Multivariate analysis revealed younger age, higher performance score, MGMT promoter methylation, and temozolomide radiochemotherapy as independent factors associated with longer OS. MGMT promoter methylation was associated with longer PFS ( relative risk [RR], 0.5; 95% CI, 0.38 to 0.68; P < .001) and OS (RR, 0.39; 95% CI, 0.28 to 0.54; P < .001) in patients receiving temozolomide. IDH1 mutations were associated with prolonged PFS ( RR, 0.42; 95% CI, 0.19 to 0.91; P = .028) and a trend for prolonged OS (RR, 0.43; 95% CI, 0.15 to 1.19; P = .10). No other molecular factor was associated with outcome.ConclusionMolecular changes associated with gliomagenesis do not predict response to therapy in glioblastoma patients managed according to current standards of care. MGMT promoter methylation and IDH1 mutational status allow for stratification into prognostically distinct subgroups.