Molecular Predictors of Progression-Free and Overall Survival in Patients With Newly Diagnosed Glioblastoma: A Prospective Translational Study of the German Glioma Network

Abstract

Purpose The prognostic value of genetic alterations characteristic of glioblastoma in patients treated according to present standards of care is unclear. Patients and Methods Three 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. Results Median 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. Conclusion Molecular 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.

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

“…10,11,13,38,40,41 The 2 year and 5 year survival rates in patients with a methylated MGMT promoter treated with concomitant and adjuvant temozolomide were 49% and 14%, respectively, while the corresponding figures for patients initially treated with radiotherapy only were 24% and 5%. Of patients with an unmethylated MGMT promoter, 15% and 8% were alive at 2 years and 5 years, respectively, after treatment with combined chemoradiotherapy, compared with 2% and 0% in those initially treated with radiotherapy alone.…”

Prognostic value of preoperative von Willebrand factor plasma levels in patients with Glioblastoma

“…Putative genetic and epigenetic prognostic factors have been investigated in order to optimize treatment strategies. These include 1p/19q codeletion, isocitrate dehydrogenase (IDH) 1 and 2 gene ( IDH1/2 ) mutations, and methylation of the O(6)‐methylguanine‐DNA methyltransferase (MGMT) promoter 2, 3, which confer a better responsiveness to radio‐ and chemotherapy 4, 5, 6, even the disease is still incurable. A prominent feature of GBM is the aberrant angiogenesis.…”

Genetic alterations of IDH1 and Vegf in brain tumors

“…Thus, this gene is strongly involved in the biology of gliomagenesis (Ducray et al., 2011; Takano et al., 2012). The IDH1 gene may be the key in the pathogenic processes associated with the R132H mutation and those caused by the accumulation of R2‐HG (Ducray et al., 2011; Mellai et al., 2011; Parsons et al., 2008; Thota et al., 2012; Weller et al., 2009). This accumulation produces a high intracellular metabolic stress, so cells need to get adapted to this condition to facilitate survival and tumor progression (Van Lith et al., 2014).…”

“…Regarding the survival analysis, previous studies demonstrated the prognostic significance of IDH1 mutations (Arita et al., 2015; Brennan et al., 2013; Ducray et al., 2011; Hartmann et al., 2010; Killela et al., 2014; Lewandowska et al., 2014; Mellai et al., 2011; Olar et al., 2012; Parsons et al., 2008; Polivka et al., 2014; Sanson et al., 2009; Shibahara et al., 2011; Sun et al., 2013; Takano et al., 2012; Weller et al., 2009). Some authors observed that OS and PFS in IDH mutated cases were about twice longer than in wild‐type patients (Arita et al., 2015; Polivka et al., 2014), and others showed that mutation in IDH1 was an independent factor for a favorable prognosis (Brennan et al., 2013; Ducray et al., 2011; Polivka et al., 2014; Sanson et al., 2009; Shibahara et al., 2011).…”

“…IDH1 R132H mutation overexpression has been shown to decrease cell proliferation (Parsons et al., 2008). Several studies show the presence of the IDH1 R132H mutation in 70–90% of secondary GBMs and 10% primary GBMs, both cases associated with young patients and a higher overall survival rate (Bleeker et al., 2012; Carrillo et al., 2012; Mellai et al., 2011; Weller et al., 2009). The median survival of patients with IDH1 mutation is 3.8 years compared with 1.1 years in patients with wild‐type IDH1 (Parsons et al., 2008).…”