Long-Term Report of a Comprehensive Molecular and Genomic Analysis in NRG Oncology/RTOG 0424: A Phase II Study of Radiation and Temozolomide in High-Risk Grade II Glioma.

Abstract

This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including <i>MGMT</i> promoter methylation and mutations in <i>ATRX</i>, <i>CIC</i>, <i>FUBP1</i>, <i>TERT</i>, and <i>TP53</i>, in NRG/RTOG 0424 using long-term follow-up data. Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and <i>MGMT</i> promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were <i>IDH</i>mutant/co-deleted, 28 (35%) were <i>IDH</i>mutant/non-co-deleted, and 26 (32.5%) were <i>IDH</i>wild-type. Upon single-marker MVA, both <i>IDH</i>mutant subgroups were associated with significantly better OS and PFS (<i>P</i> values < .001), compared with the <i>IDH</i>wild-type subgroup. <i>MGMT</i> promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that <i>MGMT</i> promoter methylation was statistically significant for OS (<i>P</i> value < .001) and PFS (<i>P</i> value = .003). In a multimarker MVA, one WHO subgroup comparison (<i>IDH</i>mutant/co-deleted <i>v IDH</i>wild-type) was significant for OS (<i>P</i> value = .045), whereas <i>MGMT</i> methylation did not retain significance. This study reports the long-term prognostic effect of the WHO molecular subgroups, <i>MGMT</i> promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and <i>MGMT</i> both serve as strong prognostic indicators, but that <i>MGMT</i> does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond <i>IDH</i> and 1p/19q status.