Abstract
We evaluated the prognostic and predictive value of a range of molecular changes in the setting of a randomised trial comparing standard PCV (procarbazine, CCNU (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea) and vincristine) chemotherapy with the standard temozolomide (TMZ) 5-day (200 mg/m2/day) schedule and a 21-day (100 mg/m2/day) schedule in chemo-naïve, high-grade glioma (non-oligodendroglial tumours; WHO (World Health Organisation) grades III and IV) patients at first progression following radiotherapy.354 samples (79.2%) from the first operation of the 447 randomised patients provided enough tumour DNA for some or all parts of the study. Genome-wide array comparative genomic hybridisation (aCGH), mutation analysis of IDH1/2 and TP53 and methylation analyses of the MGMT CpG-island was done.84% of grade III tumours and 17% of grade IV had IDH1 or IDH2 mutations that conferred a better prognosis in both; MGMT methylation (defined as average value across 16 CpGs ≥ 10%) occurred in 75% of tumours and was also associated with improved survival. Both were of independent prognostic value after accounting for clinical factors and tumour grade. None of the molecular changes investigated gave clear evidence of a predictive benefit of TMZ over PCV or 21-day TMZ over 5-day TMZ although power was limited and a role for MGMT methylation could not be ruled out. Loss of 1p and 19q was seen in only 4 patients although hemizygous loss of 1p36 occurred in 20%.The findings support reports that IDH1/2 mutations and MGMT methylation can be used in addition to tumour grade and clinical factors to predict survival in patients with recurrent high grade gliomas when treated with any of the therapy regimes used.
Highlights
Randomised clinical trials provide a basis for successful evaluation of biomarkers
To date methylation of the O6methylguanine-DNA methyltransferase (MGMT) gene is the only molecular marker that can be mechanistically linked to a response to alkylating agent chemotherapy
The value of MGMT methylation has not been tested in patients treated with PCV (Procarbazine, CCNU and Vincristine), a recognised effective regimen in the treatment of recurrent high grade glioma used as standard therapy prior to the introduction of temozolomide
Summary
Randomised clinical trials provide a basis for successful evaluation of biomarkers. To date methylation of the O6methylguanine-DNA methyltransferase (MGMT) gene is the only molecular marker that can be mechanistically linked to a response to alkylating agent chemotherapy. We evaluated the prognostic and predictive value of a range of molecular changes reported for adult brain tumours in the setting of a randomised trial in chemo-naïve, recurrent high-grade astrocytic gliomas (WHO grades III and IV) including anaplastic astrocytoma (AA), anaplastic oligoastrocytoma (AOA), glioblastoma (GB) and gliosarcoma (GS) following previous radiotherapy, comparing PCV (procarbazine, CCNU and vincristine) chemotherapy with two temozolomide schedules; the standard 5-day (200 mg/m2/day) schedule and a 21-day (100 mg/m2/day) schedule. The results of this trial have been published elsewhere [7]. The sub-randomisation between 5-day and 21-day schedules in this trial provided a framework for the investigation of the hypothesis that higher intensity of temozolomide treatment might be required for a response, if one or two unmethylated copies of the MGMT gene are present
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