2091 Molecular Classification Refines Surgical and Radiotherapeutic Decision Making in Meningioma and Prospective Validation

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INTRODUCTION: Treatment of the tumor and dural margin, most commonly with surgery and sometimes radiation, are cornerstones of therapy for meningioma. Molecular classifications have provided insights into the biology of disease. However, response to treatment remains heterogeneous. METHODS: Data were collected from 10 different institutions. Meningiomas were re-graded in accordance with 2021 WHO classification and stratified to Molecular Groups based on previously published methodologies utilizing DNA methylation alone or combined with RNA sequencing. Propensity score matching (PSM) was used to mimic a randomized control trial for comparison of treatment arms. RESULTS: Gross total tumor resection (GTR) was associated with significantly longer progression-free-survival (PFS) across all Molecular Groups, and longer overall survival (OS) in Proliferative meningiomas (STR vs GTR HR 1.90, 95% CI 1.28-2.82, p=0.00155). Following PSM of key covariates including WHO grade, tumor location, and Molecular Group, the addition of dural margin treatment (Simpson grade 1 or 2) prolonged PFS compared to GTR alone (Simpson grade 3; HR 1.64, 95% CI 1.03-2.62, p=0.038). When considering the effect of adjuvant radiotherapy (RT) following PSM, Immunogenic, NF2-wt, and Hypermetabolic meningiomas obtained a PFS benefit from the addition of RT but Proliferative meningiomas were RT-resistant. These findings were validated in meningiomas from the RTOG-0539 trial. To obtain an individualized prediction of RT-responsiveness, we leveraged meningiomas from the RTOG-0539 trial to build a DNA methylation and gene-expression model that was able to predict response to RT better than standard of care clinical covariates (AUC 0.81, 95% CI 0.72-0.90 vs 0.67, 95% CI 0.57-0.77). CONCLUSIONS: This study highlights the potential for molecular profiling to meaningfully refine surgical and RT decision-making.

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