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NCOG-08. NEUROCOGNITIVE FUNCTIONING IN EORTC BRAIN TUMOR GROUP RANDOMIZED PHASE II TAVAREC TRIAL (EORTC 26091, NCT01164189) ON TEMOZOLOMIDE WITH OR WITHOUT BEVACIZUMAB in 1p/19q INTACT RECURRENT GRADE II AND III GLIOMAS

ABSTRACT: Abstract BACKGROUND EORTC study 26091 showed that addition of bevacizumab (BEV) to temozolomide (TMZ) does not improve overall survival (OS) or progression-free survival (PFS) in recurrent grade II and III 1p/19q intact gliomas; regardless of isocitrate dehydrogenase (IDH) mutational status. This abstract reports the neurocognitive functioning (NCF) outcomes. METHODS NCF was evaluated before randomization and at every 12 weeks during treatment using Hopkins Verbal Learning Test (Free Recall, Delayed Recall, and Delayed Recognition), Trail Making Test (TMT A/B); and Controlled Oral Word Association Test (COWA). RESULTS 148/155 patients had at least one NCF assessment. Compliance was 91.5% at baseline and dropped to 61.9% at week 60. Primary analysis (at 5% significance level) compared NCF at the last disease assessment before or at week 60 in patients who had at least one NCF assessment after baseline. Patients in the temozolomide+bevacizumab arm did not differ from patients in the temozolomide only arm. Except for Delayed Recognition, all NCF outcomes were positively associated with WHO performance status. TMT A (p=0.03), TMT B (p=0.006) and COWA (p<0.0001) were significantly worse in patients receiving steroids at study entry. Furthermore, delayed recognition was worse in patients with larger tumors (>26.5 vs <=26.5 mm; p=0.04). Memory performance was poorer in patients with tumors in the left hemisphere (Free Recall; p=0.0002), Delayed Recall; p<0.0001, Delayed Recognition; p=0.004). Except for Free Recall and Delayed Recognition, all other baseline raw scores were associated with OS in univariate analyses. In a multivariate Cox regression model, TMT B and tumor size were identified as independent OS prognostic factors while baseline WHO performance status and steroids use were not included. CONCLUSION At the group level patients in the temozolomide+bevacizumab arm do not differ from patients with temozolomide only, individual patients’ verbal memory capacity might negatively be affected by tumor volume and tumor location.

SUBMITTER: Klein M

PROVIDER: S-EPMC5693186 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Project description:High-grade gliomas are malignant neuroepithelial tumors. The current WHO classification for adult-type diffuse gliomas is based on IDH1/2 mutational and 1p/19q-codeletion status, which can be refined by emerging genomics, transcriptomics, and methylomics approaches. Nevertheless, therapy has been dominated by radiochemotherapy for about 15 years and progressed little in efficacy or precision through advanced molecular patient stratification. Glioma proteome alterations remain undercharacterized despite their promise for a better stratification and, in particular, the identification of therapeutic targets. Here, we used mass spectrometry (MS) to characterize 42 formalin-fixed, paraffin-embedded (FFPE) samples from IDH-wildtype (IDHwt), IDH-mutant (IDHmut) gliomas with and without 1p/19q-codeletion, and non-neoplastic brain tissue controls. Based on more than 5500 quantified proteins and 5000 phospho-sites, gliomas separated according to IDH1/2 mutational status and reflected loss of proteins encoded on 1p/19q in IDHmut, gains on chromosome 7 and losses on chromosome 10 in IDHwt. Unexpectedly, the 1p/19q-codeletion resulted in minor proteome changes. Instead, two proteomic subtypes of IDHmut gliomas showed major perturbations of mitochondrial DNA-encoded proteins, aerobic/anaerobic energy metabolism, RNA metabolism, chromatin dynamics, the extracellular matrix as well as tumor suppressor and oncoproteins. Reanalysis of three glioma proteomics studies independently validate the observed hallmarks and associate these proteomic subtypes with the well-established proneural and classic/mesenchymal IDHwt glioma subtypes. These results suggest an alternative stratification of IDHmut gliomas as part of common phenotypic subtypes independent of the IDH status, with broad therapeutic implications for patients with IDHmut gliomas in the future. Altogether, our study provides a rich protein and phospho-site resource restratifying glioma subtypes and supporting future mechanism of action and target discovery investigations.

Dataset Information

NCOG-08. NEUROCOGNITIVE FUNCTIONING IN EORTC BRAIN TUMOR GROUP RANDOMIZED PHASE II TAVAREC TRIAL (EORTC 26091, NCT01164189) ON TEMOZOLOMIDE WITH OR WITHOUT BEVACIZUMAB in 1p/19q INTACT RECURRENT GRADE II AND III GLIOMAS

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