Abstract 642: A hypermethylated phenotype as predictive marker for response to PCV in anaplastic oligodendrogliomas. A report from EORTC study 26951.
Authors: French Pim J. , Erdem-Eraslan Lale , Idbaih Ahmed , Spliet Wim , den Dunnen Wilfred , Teepen Johannes L. , Wesseling Pieter , Sillevis Smitt Peter A. , Kros Johan M. , Gorlia Thierry , van den Bent Martin 
Published: August 2014

Abstract
Introduction: In 1995 a large European phase III clinical trial (‘EORTC 26951’) was initiated to examine the effects of adjuvant procarbazine, CCNU and vincristine (PCV) chemotherapy in anaplastic oligodendrogliomas (AOD and AOA). This trial showed that the addition of 6 cycles PCV after 59.4 Gy RT increases overall survival (OS) and progression free survival (PFS) in these tumors. However, some patients appeared to benefit more from the addition of PCV treatment than others. In current study, we aimed to identify the patients in this trial that benefit from adjuvant PCV treatment using genome wide methylation profiling.
Methods: Methylation profiles of a total of 115 samples were generated, 49 of which were reported previously.
Results: Most (59/66) samples were formalin-fixed and embedded in paraffin (FFPE). Our first experiment was therefore aimed at determining the performance of methylation arrays using such tissue. Paired snap frozen (FF)-FFPE sample analysis on six glioma samples demonstrated that the correlation between FF and FFPE samples was high: 0.961±0.023. Between FFPE technical replicates it was 0.987±0.009. These results demonstrate that methylation profiling can be performed on DNA isolated from FFPE samples. We then performed methylation profiling on an additional 66 samples of the EORTC26951 trial (59 FFPE, 7 FF) and combined the data with those of the 49 FF samples previously analyzed. The cohort analyzed for methylation profiling had similar characteristics as the entire EORTC26951 cohort. However, OS within the RT-only treatment arm of included patients was worse compared to OS in patients not included. Univariate analysis indicated that CIMP (CpG island methylator phenotype) status was a favorable prognostic marker for OS with CIMP+ tumors having a more favorable prognosis than CIMP- tumors (median OS 1.05 v. 6.46 years HR 0.225 95% CI [0.138, 0.369], P&lt;0.0001. Multivariate analysis indicates that CIMP status is a prognostic factor for overall survival that is independent of clinical and histological parameters (age, sex, performance score and review diagnosis). IDH1 mutations (39/51), 1p19q LOH (29/63) and MGMT promoter methylation (45/52) were predominantly identified in CIMP+ tumors whereas EGFR amplification was predominantly identified in the CIMP- subtype (20/42, 48%). When stratified for treatment, CIMP+ tumors showed a clear benefit from adjuvant PCV chemotherapy, both for OS and PFS. Median OS of CIMP+ samples in the RT and RT-PCV arms was 3.27 and 9.36 years respectively (HR: 0.409; 95% CI [0.224,0.746], P=0.0036). There was no such benefit for CIMP- tumors.
Conclusion: Our results suggest that CIMP status is predictive for benefit from adjuvant PCV in AODs and AOAs in samples of the EORTC 26951 clinical trial. Further validation of these results is urgently required.
Citation Format: Pim J. French, Lale Erdem-Eraslan, Ahmed Idbaih, Wim Spliet, Wilfred den Dunnen, Johannes L. Teepen, Pieter Wesseling, Peter A. Sillevis Smitt, Johan M. Kros, Thierry Gorlia, Martin van den Bent. A hypermethylated phenotype as predictive marker for response to PCV in anaplastic oligodendrogliomas. A report from EORTC study 26951. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 642. doi:10.1158/1538-7445.AM2013-642