title: Prognostic and predictive markers in recurrent high grade glioma; results from the BR12 randomised trial.
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.
authors: Department of Pathology, Division of Molecular Histopathology, University of Cambridge, Cambridge, UK. Vpc20@cam.ac.uk.
authors: Vincent Peter
authors: VP
authors: Collins
authors: Koichi
authors: K
authors: Ichimura
authors: Ying
authors: Y
authors: Di
authors: Danita
authors: D
authors: Pearson
authors: Ray
authors: R
authors: Chan
authors: Lindsay C
authors: LC
authors: Thompson
authors: Rhian
authors: R
authors: Gabe
authors: Michael
authors: M
authors: Brada
authors: Sally P
authors: SP
authors: Stenning
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005910:Glioma / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008130:Lomustine / Q000627:therapeutic use; D008297:Male; D011237:Predictive Value of Tests; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D014750:Vincristine / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D014750:Vincristine; D008130:Lomustine; D003606:Dacarbazine; D007521:Isocitrate Dehydrogenase; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide