Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma

Abstract

Background Survival in patients with IDH1/2 mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients. Methods The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumour classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using one of two glioma-tailored NGS panels. The primary endpoint was overall survival measured from date of randomization. Results Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumours. Of these, 432 tumours were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazards model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication. Conclusion Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification

Sex Differences in Glioblastoma—Findings from the Swedish National Quality Registry for Primary Brain Tumors between 1999–2018

“…According to the CBTRUS report, anaplastic astrocytoma (now astrocytoma grade 3) (A3) were more frequent in males, with no significant survival difference between males and females [37]. In line with findings from the CATNON trial, also in the CBTRUS data, the majority of A3 patients were surely IDHmut [16]. We note that the CBTRUS findings for A3 are similar to that of IDHwt GBM, with male dominance, but with small differences in survival between sexes, if any.…”

“…A change with a larger impact occurred in 2016, when the WHO guidelines for primary brain tumors were updated to include molecular markers [5]. This led to many tumors previously diagnosed as grade 3 glioma being reclassified as IDH wildtype (IDHwt) GBM, for example in the NOA-04 and CATNON studies, where around 30% were found to be IDHwt tumors [15,16]. Approximately 10% of GBMs have been identified as IDH mutated (IDHmut), these previously being secondary GBMs [5], but according to the latest guidelines they are now astrocytoma grade 4 [17,18].…”

Treatment of anaplastic gliomas: evidences and controversies

“…The unfavorable prognosis of patients with astrocytoma, IDHmt, WHO grade 4 could justify a more aggressive radiotherapy approach with the glioblastoma regimen of 30×2.0Gy. In the CATNON trial, 4-year survival in patients with tumors with a homozygous deletion of CDKN2A/B was around 40% [24]. These survival data support a 33×1.8Gy regime because of the supposed lower risk of long-term toxicity relevant for a considerable percentage of these often young patients [22].…”

Tumor-Associated Microenvironment of Adult Gliomas: A Review

“…Almost all astrocytomas present p53 (94%) alterations, ATRX (86%) loss, or CDKN2A/CDKN2B (cyclin-dependent kinase inhibitor 2A/2B, 10%) homozygous deletion ( 16 , 17 ). Curiously, astrocytomas present often non-canonical IDH1 mutations that are associated with improved survival ( 18 – 20 ).…”