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.

Purpose: This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including promoter methylation and mutations in , , , , and , in NRG/RTOG 0424 using long-term follow-up data.

Methods: Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and 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.

Results: We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were mutant/co-deleted, 28 (35%) were mutant/non-co-deleted, and 26 (32.5%) were wild-type. Upon single-marker MVA, both mutant subgroups were associated with significantly better OS and PFS ( values < .001), compared with the wild-type subgroup. promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that promoter methylation was statistically significant for OS ( value < .001) and PFS ( value = .003). In a multimarker MVA, one WHO subgroup comparison (mutant/co-deleted wild-type) was significant for OS ( value = .045), whereas methylation did not retain significance.

Conclusion: This study reports the long-term prognostic effect of the WHO molecular subgroups, promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and both serve as strong prognostic indicators, but that does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond and 1p/19q status.