MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951.
OBJECTIVE
O6-methylguanine-methyltransferase (MGMT) promoter methylation has been shown to predict survival of patients with glioblastomas if temozolomide is added to radiotherapy (RT). It is unknown if MGMT promoter methylation is also predictive to outcome to RT followed by adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy in patients with anaplastic oligodendroglial tumors (AOT).


METHODS
In the European Organisation for the Research and Treatment of Cancer study 26951, 368 patients with AOT were randomly assigned to either RT alone or to RT followed by adjuvant PCV. From 165 patients of this study, formalin-fixed, paraffin-embedded tumor tissue was available for MGMT promoter methylation analysis. This was investigated with methylation specific multiplex ligation-dependent probe amplification.


RESULTS
In 152 cases, an MGMT result was obtained, in 121 (80%) cases MGMT promoter methylation was observed. Methylation strongly correlated with combined loss of chromosome 1p and 19q loss (P = .00043). In multivariate analysis, MGMT promoter methylation, 1p/19q codeletion, tumor necrosis, and extent of resection were independent prognostic factors. The prognostic significance of MGMT promoter methylation was equally strong in the RT arm and the RT/PCV arm for both progression-free survival and overall survival. In tumors diagnosed at central pathology review as glioblastoma, no prognostic effect of MGMT promoter methylation was observed.


CONCLUSIONS
In this study, on patients with AOT MGMT promoter methylation was of prognostic significance and did not have predictive significance for outcome to adjuvant PCV chemotherapy. The biologic effect of MGMT promoter methylation or pathogenetic features associated with MGMT promoter methylation may be different for AOT compared with glioblastoma.
van den Bent
Martin J
MJ
Department of Neuro-Oncology and Pathology, Daniel den Hoed Cancer Center and Erasmus University Medical Center, Rotterdam, the Netherlands. m.vandenbent@erasmusmc.nl
Dubbink
Hendrikus J
HJ
Sanson
Marc
M
van der Lee-Haarloo
Cathleen R
CR
Hegi
Monika
M
Jeuken
Judith W M
JW
Ibdaih
Ahmed
A
Brandes
Alba A
AA
Taphoorn
Martin J B
MJ
Frenay
Marc
M
Lacombe
Denis
D
Gorlia
Thierry
T
Dinjens
Winand N M
WN
Kros
Johan M
JM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001254:Astrocytoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D017024:Chemotherapy, Adjuvant; D002872:Chromosome Deletion; D002878:Chromosomes, Human, Pair 1; D002888:Chromosomes, Human, Pair 19; D018899:CpG Islands; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D018572:Disease-Free Survival; D005060:Europe / Q000453:epidemiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008130:Lomustine / Q000008:administration & dosage; D008875:Middle Aged; D009837:Oligodendroglioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy; D016133:Polymerase Chain Reaction / Q000379:methods; D011344:Procarbazine / Q000008:administration & dosage; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014750:Vincristine / Q000008:administration & dosage
D025521:Tumor Suppressor Proteins; D011344:Procarbazine; D014750:Vincristine; D008130:Lomustine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes