Comprehensive Molecular Analysis in NRG Oncology/RTOG 9813: A Phase 3 Study of Radiation and Temozolomide Versus Radiation and BCNU/CCNU in Anaplastic Astrocytoma

PURPOSE:There is a need to better understand the molecular features that characterize grade 3 astrocytomas and their significance in predicting clinical outcomes. The aim of this study was to determine the significance of the 2021 World Health Organization (WHO)-defined molecular subgroups, along with MGMT promoter methylation, and other alterations in NRG Oncology/RTOG 9813. METHODS AND MATERIALS:Mutation status was determined by immunohistochemistry and/or next-generation sequencing. Copy number alterations and MGMT methylation were determined by Affymetrix Oncoscan and/or Illumina 450K arrays. Progression-free survival and overall survival were estimated using the Kaplan-Meier method and tested using the log-rank test. Multivariable analyses used Cox proportional hazards models. RESULTS:Application of the 2021 WHO-defined criteria resulted in the reclassification of 26/79 (33%) patients to grade 4 astrocytoma, IDH-mutant or glioblastoma. When looking at newly assigned molecular grade, grade 3 patients experienced longer survival outcomes compared to grade 4 patients. As individual biomarkers, IDH1/2 mutations, MGMT promoter methylation, and ATRX mutations were each associated with longer survival, whereas TERT promoter mutations, EGFR amplification, and gain of chromosome 7/loss of 10 (Chr+7/-10) were associated with shorter survival. Similar survival outcomes were observed for MGMT methylated patients treated with radiation therapy (RT) and temozolomide (TMZ) or RT and BCNU/CCNU, and MGMT unmethylated patients treated with RT and TMZ. Additionally, IDH-mutant patients seemed to respond well to the addition of TMZ. CONCLUSIONS:This study demonstrated the importance of classifying patients according to the 2021 WHO-defined criteria. The majority of IDH-wildtype anaplastic astrocytomas (grade 3) were reclassified as glioblastoma (grade 4). These analyses also shed light on the efficacy of TMZ in certain molecular subgroups, where the addition of TMZ to RT appeared to benefit patients regardless of MGMT methylation status.