MGMT-STP27 methylation status as predictive marker for response to PCV in anaplastic oligodendrogliomas and oligoastrocytomas. A report from EORTC study 26951

Martin J. Van Den Bent, Lale Erdem-Eraslan, Ahmed Idbaih, Johan De Rooi, Paul H.C. Eilers, Wim G.M. Spliet, Wilfred F.A. Den Dunnen, Cees Tijssen, Pieter Wesseling, Peter A.E. Sillevis Smitt, Johan M. Kros, Thierry Gorlia, Pim J. French

Research output: Contribution to journalArticlepeer-review

106 Citations (Scopus)

Abstract

Purpose: The long-term follow-up results from the EORTC-26951 trial showed that the addition of procarbazine, CCNU, and vincristine (PCV) after radiotherapy increases survival in anaplastic oligodendrogliomas/ oligoastrocytomas (AOD/AOA). However, some patients appeared to benefit more from PCV treatment than others. Experimental Design:Weconducted genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted theCpGisland hypermethylated phenotype (CIMP) andMGMTpromoter methylation (MGMT-STP27) status. Results: We first show that methylation profiling can be conducted on archival tissues with a performance that is similar to snap-frozen tissue samples. We then conducted methylation profiling on EORTC-26951 clinical trial samples. Univariate analysis indicated that CIMP? or MGMT-STP27 methylated tumors had an improved survival compared with CIMP- and/or MGMT-STP27 unmethylated tumors [median overall survival (OS), 1.05 vs. 6.46 years and 1.06 vs. 3.8 years, both P < 0.0001 for CIMP and MGMT-STP27 status, respectively]. Multivariable analysis indicates that CIMP and MGMT-STP27 are significant prognostic factors for survival in presence of age, sex, performance score, and reviewdiagnosis in themodel. CIMP?andMGMTSTP27methylated tumors showed a clear benefit fromadjuvantPCVchemotherapy: themedianOSof CIMP? samples in the RT and RT-PCV arms was 3.27 and 9.51 years, respectively (P = 0.0033); for MGMT-STP27 methylated samples, it was 1.98 and 8.65 years. There was no such benefit for CIMP- or for MGMT-STP27 unmethylated tumors. MGMT-STP27 status remained significant in an interaction test (P = 0.003). Statistical analysis of microarray (SAM) identified 259 novel CpGs associated with treatment response. Conclusions:MGMT-STP27 may be used to guide treatment decisions in this tumor type.

Original languageEnglish
Pages (from-to)5513-5522
Number of pages10
JournalClinical Cancer Research
Volume19
Issue number19
DOIs
Publication statusPublished - 1 Oct 2013
Externally publishedYes

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