Faculty Collaboration Database

Comprehensive Molecular Analysis in NRG Oncology/RTOG 9813: A Phase 3 Study of Radiation and Temozolomide Versus Radiation and BCNU/CCNU in Anaplastic Astrocytoma. Int J Radiat Oncol Biol Phys 2025 Sep 01;123(1):84-92

Date

04/01/2025

Pubmed ID

40164352

DOI

10.1016/j.ijrobp.2025.03.043

Scopus ID

2-s2.0-105012631632 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

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.

Author List

Fleming JL, Pugh SL, Chang SM, McElroy JP, Becker AP, Aldape KD, Shih HA, Ashby LS, Hunter GK, Bahary JP, Schultz CJ, Kavanagh BD, Puduvalli VK, Robins HI, Werner-Wasik M, Mehta M, Chakravarti A

Author

Christopher J. Schultz MD Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antineoplastic Agents, Alkylating
Astrocytoma
Brain Neoplasms
Chemoradiotherapy
DNA Methylation
DNA Modification Methylases
DNA Repair Enzymes
ErbB Receptors
Female
Glioblastoma
Humans
Isocitrate Dehydrogenase
Male
Middle Aged
Mutation
Promoter Regions, Genetic
Telomerase
Tumor Suppressor Proteins
X-linked Nuclear Protein