55 Insights Into Meningioma Biology and Radiotherapy Response Through Molecular Characterization of Rtog-0539 Clinical Trial

Brain Tumour Foundation of Canada Travel Award Recipient BACKGROUND Meningiomas are the most common primary intracranial tumors. Radiotherapy (RT) is an adjunct treatment following surgical resection, but response varies. RTOG-0539 is the first prospective phase 2 clinical trial to stratify patients into risk groups for adjuvant RT, establishing key benchmarks for RT outcomes. This study provides the first molecular characterization of an RT clinical trial in meningiomas to identify biological insights into RT response and tumor behavior. METHODS Tumor tissue from 100meningioma patients enrolled in the RTOG-0539 trial was analyzed using DNA methylation profiling, RNA sequencing, and whole-exome sequencing. Copy number variations, mutational landscapes, and gene expression patterns were examined to identify molecular correlates of tumor aggressiveness and RT response. Consensus pathway analysis was performed to determine biological processes associated with differential RT sensitivity. RESULTS High-risk meningiomas demonstrated significant cell cycle dysregulation and upregulation of hypermetabolic pathways. Specific genomic alterations, including 1p loss and 1q gain, were associated with aggressive tumor behavior. Co-occurrence of NF2 and non-NF2 mutations was identified in select high-risk cases, suggesting distinct molecular subgroups. Notably, molecular profiling led to reclassification of several tumors, revealing discrepancies between histopathologic grading and underlying biology. CONCLUSION This is the first study to comprehensively define the molecular landscape of meningiomas treated with RT in a prospective clinical trial. Multi-omic integration refined risk stratification beyond histopathologic grading, with implications for genomically guided treatment strategies. These findings align with ongoing precision medicine trials and emphasize the importance of prospective tumor banking to facilitate biomarker-driven approaches in meningioma management.