Prognostic or predictive value of MGMT promoter methylation in gliomas depends on IDH1 mutation.
OBJECTIVE
To explore whether the isocitrate dehydrogenase 1 (IDH1) or 1p/19q status determines the prognostic vs predictive role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in the Neuro-Oncology Working Group of the German Cancer Society (NOA)-04 trial anaplastic glioma biomarker cohort.


METHODS
Patients (n = 183) of the NOA-04 trial with known MGMT and IDH1 status were analyzed for interdependency of the prognostic vs predictive role of MGMT promoter methylation from IDH1 or 1p/19q status and treatment, using progression-free survival (PFS) as an endpoint. An independent validation cohort of the German Glioma Network (n = 75) and the NOA-08 trial (n = 34) served as a confirmation cohort.


RESULTS
In tumors with IDH1 mutation, MGMT promoter methylation was associated with prolonged PFS with chemotherapy ± radiotherapy (RT) or RT-only groups, and is thus prognostic. In tumors without IDH1 mutation, MGMT promoter methylation was associated with increased PFS in patients treated with chemotherapy, but not in those who received RT alone as the first-line treatment, and is thus chemotherapy-predictive. In contrast, 1p/19q codeletions showed no such association with the prognostic vs predictive value of MGMT.


CONCLUSIONS
MGMT promoter methylation is a predictive biomarker for benefit from alkylating agent chemotherapy in patients with IDH1-wild-type, but not IDH1-mutant, malignant gliomas of World Health Organization grades III/IV. Combined IDH1/MGMT assessment may help to individualize clinical decision-making in neuro-oncology.
From the Departments of Neuro-oncology (W.W., M.P., A.S., B.W., M. Weiler) and Neuropathology (A.v.D.), University of Heidelberg; German Cancer Consortium (DKTK) (W.W., B.W., M. Weiler), Clinical Cooperation Unit Neuro-oncology and Clinical Cooperation Unit Neuropathology (A.v.D.), German Cancer Research Center, Heidelberg; Department of Medical Biometry (C.M.), University of Tübingen; Institute for Medical Informatics, Statistics and Epidemiology (B.H., M.L.), University Leipzig; Departments of Neurosurgery (M.C.S.) and Neuropathology (G.R.), Heinrich-Heine-University and DKTK (G.R.), Düsseldorf; Department of Neurology (S.K.), University of Essen Medical School; Department of Neurosurgery (R.K.), Saarland University, Homburg, Germany; Department of Neurology (G.T., D.G., M. Weller), University Hospital Zurich, Switzerland; Department of Neurosurgery (M. Westphal), University Clinic Hamburg Eppendorf, Hamburg; Department of Neurosurgery (G.S.) and DKTK (G.S.), Technical University Dresden; and Department of Neurosurgery (M.S.), University of Bonn, Germany.
Wolfgang
W
Wick
Christoph
C
Meisner
Bettina
B
Hentschel
Michael
M
Platten
Alissa
A
Schilling
Benedikt
B
Wiestler
Michael C
MC
Sabel
Susanne
S
Koeppen
Ralf
R
Ketter
Markus
M
Weiler
Ghazaleh
G
Tabatabai
Andreas
A
von Deimling
Dorothee
D
Gramatzki
Manfred
M
Westphal
Gabriele
G
Schackert
Markus
M
Loeffler
Matthias
M
Simon
Guido
G
Reifenberger
Michael
M
Weller
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D005819:Genetic Markers; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000532:radiotherapy; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016032:Randomized Controlled Trials as Topic; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
D005819:Genetic Markers; D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes