PROGNOSTIC AND PREDICTIVE BIOMARKER-BASED SUBGROUPS IN THE NOA-04 TRIAL

Abstract

BACKGROUND: The WHO classification, based on morphological criteria, may be increasingly supplemented with defined molecular aberrations. These might help to resolve the discrepancy between classification and clinical outcome. Molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion, mutations and (consequently) loss of expression of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) and O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation, improve prognostication and may even guide treatment decisions in patients with anaplastic gliomas. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) allow the determination of large-scale methylation profiles and genome-wide DNA copy number changes, enabling molecular subgrouping of tumors. In addition, algorithms have been developed to detect the glioma CpG island methylator phenotype (G-CIMP) associated with IDH1/2 mutation, 1p/19q codeletion and MGMT promoter methylation using this assay. METHODS: In the biomarker cohort of the NOA-04 trial, the diagnostic and prognostic performance of these molecular markers using single tests, HM450 data and HM450-based algorithms has been investigated to propose biological subgroups, which reflect outcomes and potentially influence treatment decisions. RESULTS: Loss of ATRX expression was detected in 45% of anaplastic astrocytomas (AA), 27% of anaplastic oligoastrocytomas (AOA) and 10% of anaplastic oligodendrogliomas (AO). It was mostly restricted to IDH mutant tumors and almost mutually exclusive with 1p/19q co-deletion. In tumors with IDH1 mutation, MGMT promoter methylation was associated with prolonged progression-free survival (PFS) with chemotherapy or radiotherapy (RT), and thus prognostic. In tumors without IDH1 mutation, MGMT promoter methylation was associated with increased PFS in patients treated with chemotherapy, too, but not in those who received RT alone as the first-line treatment, and is thus chemotherapy-predictive. Comparisons of single assays and HM450-based algorithms revealed a high concordance for IDH and 1p/19q status. The HM450-derived MGMT-STP27 model to calculate MGMT promoter methylation probability revealed this aberration in a significantly higher fraction of cases as conventional methylation-specific PCR, with 87/91 G-CIMP-positive tumors predicted as MGMT promoter-methylated. CONCLUSIONS: ATRX loss is a hallmark and favorable prognosticator of astrocytic tumors allowing a better definition of the clinically and morphologically mixed group of AOA. MGMT promoter methylation is a predictive biomarker for benefit from alkylating agent chemotherapy in patients with IDH1-wildtype, but not IDH1-mutant malignant gliomas of WHO grades III/IV. Combined IDH1/ MGMT assessment may help to individualize clinical decision making in neurooncology. G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and associated with prognosis in the NOA-04 trial. HM450 arrays allowed clustering of anaplastic gliomas into relevant subgroups. SECONDARY CATEGORY: Tumor Biology.