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

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:

We conducted genome-wide methylation profiling of 115 samples included in the EORTC-26951 trial and extracted the CpG island hypermethylated phenotype (CIMP) and MGMT promoter 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 review diagnosis in the model. CIMP+ and MGMT-STP27 methylated tumors showed a clear benefit from adjuvant PCV chemotherapy: the median OS of 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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 19 Pg. 5513-22 (Oct 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23948976 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2013 AACR.

Chemical References

• Biomarkers
• Tumor Suppressor Proteins
• Procarbazine
• Vincristine
• Lomustine
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes

Topics

• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Biomarkers
• Cluster Analysis
• CpG Islands
• DNA Methylation
• DNA Modification Methylases (genetics)
• DNA Repair Enzymes (genetics)
• Female
• Gene Expression Profiling
• Humans
• Lomustine (administration & dosage)
• Male
• Oligodendroglioma (drug therapy, genetics, mortality)
• Phenotype
• Procarbazine (administration & dosage)
• Prognosis
• Promoter Regions, Genetic
• Treatment Outcome
• Tumor Suppressor Proteins (genetics)
• Vincristine (administration & dosage)