PROGNOSTIC SIGNIFICANCE OF EPIGENETIC SUBTYPES AND CPGS ASSOCIATED WITH PROGRESSION TO G-CIMP LOW IN THE EORTC RANDOMIZED PHASE III INTERGROUP CATNON

Abstract BACKGROUND Uncontrolled studies have suggested that methylation-based epigenetic subtypes can be used for prognostication of glioma. We used the prospective randomized CATNON trial to validate the clinical relevance of these epigenetic subtypes. METHODS The phase III CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant TMZ. CNV data and methylation data were derived from Infinium MethylationEPIC arrays. Epigenetic subtyping and risk of progression to G-CIMP low were determined from random forest models and 7 specific CpGs (PMID: 29642018). IDH1/2 status was determined with a glioma-tailored NGS panel. Overall survival (OS) was measured from date of randomization. RESULTS Methylation analysis was performed on 654 tumors: 440 were IDH1/2mt, 204 IDH1/2wt and of 10 IDH1/2 status was unknown; 8 IDH1/2mt were 1p/19q codeleted. Based on methylation, tumors were classified as G-CIMP high (n=409), G-CIMP low (n=19), codel-like (n=18), mesenchymal-like (n=107), classic-like (n=48), and PA-like tumors (n=53). Median OS between these epigenetic subtypes varied considerably: codel-like 9.1 yrs, G-CIMP high 9.5 yrs, G-CIMP low 2.8 yrs, mesenchymal-like 1.3 yrs, classic-like 1.6 yrs, and PA-like 2.8 yrs. The difference in OS of the IDH1/2mt astrocytoma subgroup patients was prominent [G-CIMP low vs G-CIMP high: HR 4.12, 95% CI 2.37-7.19, p < 0.001]. Within the IDH1/2mt G-CIMP high astrocytoma patients, 115 tumors were predicted to have risk of progression to G-CIMP low and patients with such tumors indeed had poorer survival [risk vs no-risk: HR 1.59, 95% CI 1.10-2.31, p = 0.02]. Median OS in G-CIMP high tumors with (n=37) and without (n=366) CDKN2A/B HD was 3.3 yrs versus not reached [p< 0.001], in G-CIMP low tumors it was 1.2 yrs (n=6) versus 4.4 yrs (n=12) [p=0.008]. CONCLUSIONS In IDH1/2mt anaplastic astrocytoma, G-CIMP status and CDKN2A/B HD are of independent prognostic value.