Prognostic and predictive markers in recurrent high-grade glioma (HGG): Results from the BR12 randomized trial.

Abstract

2035 Background: BR12 randomised 447 chemo-naïve pts with recurrent HGG between PCV and TMZ, subrandomising TMZ between 200 mg/m2 for 5 days (TMZ5) and 100 mg/m2 for 21 days (TMZ21). Tumour samples were requested on all pts; 354 (79%) samples were obtained, 314 sufficient for molecular analysis of potential prognostic and predictive markers (mkrs). Methods: DNA was isolated from micro-dissected sections of tumour in paraffin blocks. Array- CGH data using a custom tiled path array of chromosome (chr) 1 and 19 incorporated into a 1 Mb genome-wide array determined locus copy number. IDH1 and IDH2 mutation was identified by pyrosequencing and MGMT methylation (meth) by bisulfite modification followed by PCR and pyrosequencing reporting % meth at each of 16 CpGs. The following mkrs were assessed: chr 1, 1p, 1p36, 7, 10, 19, 19q and 19q13 status; PTEN, MGMT and CDKN2A copy number; EGFR, MDM2, CDK4 and PDGFRA amplification; TP53, IDH1 and IDH2 mutation. Each was added to a Cox regression survival model including age, gender, tumour grade and WHO performance status. An initial exploratory analysis of MGMT meth status has been carried out using mean % meth across all 16 CpGs. Further analyses will examine individual CpG data. Results: MGMT pyrosequencing succeeded for 91% of pts on whom it was attempted, aCGH; 93% and 87% for TP53 and IDH1. Total loss of 1p was noted in 2%, (95% CI 0.5%, 4.7%); loss of 1p36 in 23%, (95% CI 18%, 28%). IDH1 mutation, PTEN copy number, EGFR amplification, chr 10 status and MGMT meth were individually prognostic but only IDH1 mutation (hazard ratio [HR] mutated vs. normal = 0.54, p = 0.008); and MGMT meth% (HR > 10% vs ≤ 10% = 0.57, p = 0.001) were independent of each other and the clinical factors. There was no evidence of a predictive effect for benefit of TMZ over PCV for any of these mrks or for TMZ5 over TMZ21 for MGMT meth. Conclusions: In this cohort IDH1 mutation and MGMT meth are strong, independent prognostic factors. Initial analysis suggests a prognostic but not predictive role for meth status in this setting with prolonged administration of TMZ21 failing to overcome the prognostic relevance of unmethylated MGMT. Further analysis and modeling of the overall and individual CpG data may provide further clarification. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Bristol-Myers Squibb, Roche Schering-Plough