Modern Molecular Profiling Recontextualizes the NRG/RTOG 0539 Trial and Reveals Hidden High-Risk and Radiotherapy Resistant Meningiomas

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ID: 313582
2026
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Abstract
Abstract Background Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response. Methods Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death within 3 years. Results Modern grading criteria, including brain invasion, TERT mutation, CDKN2A/B deletion, and 1p/1q status, would reclassify 10% of tumors and alter treatment group assignment in 7%. Non-responders to RT exhibited more frequent 1p and 14q loss, and more copy number alterations. Transcriptomic and epigenetic profiling revealed immune-related signatures in responders and cell cycle–related pathways in non-responders, several of which overlapped with targets of vorinostat, a histone deacetylase inhibitor previously validated in aggressive meningioma models. The Proliferative Molecular Group was an independent predictor of post-RT recurrence in multivariable analysis, outperforming WHO grade. Conclusion Multi-omic analysis of the NRG/RTOG-0539 cohort shows that updated WHO grading criteria, incorporating molecular and cytogenetic features, improve risk stratification. However, molecular classification, particularly the Proliferative group, remains an independent and stronger predictor of RT response. These findings support integrating molecular biomarkers alongside modern grading frameworks to guide treatment and trial design in meningioma.
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Authors Leeor S Yefet, Alexander Landry, C Leland Rogers, J WANG, Jeff Liu, Vikas Patil, Chloe Gui, Andrew Ajisebutu, Yosef Ellenbogen, Qingxia Wei, Olivia Singh, Sheila Mansouri, Christopher Szot, Richard C. Jordan, Igor J. Barani, Michael Straza, Hui-Kuo G Shu, Kelli B. Pointer, Grant Hunter, Valérie Panet-Raymond, Wenyin Shi, Haley K. Perlow, Brian D. Kavanagh, Tyler Gunter, Clifford Robinson, Stephanie L. Pugh, Adam P. Dicker, Minesh P Mehta, Arnab Chakravarti, Farshad Nassiri, Kenneth Aldape, G Z Zadeh
Journal journal of neuro-oncology
Year 2026
DOI
10.1093/neuonc/noag081
URL
https://doi.org/10.1093/neuonc/noag081
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