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

Abstract

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. 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. 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. 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. Meningiomas are brain tumors that can behave very differently from one patient to another. After surgery, the main additional treatment available is radiation therapy, but it does not work equally well for everyone. Doctors currently have limited ways to predict which tumors will respond well to radiation. In this study, researchers analyzed tumor samples from 100 patients enrolled in the NRG/RTOG-0539 clinical trial, which assigned radiation treatment based on patients’ clinical risk. Using modern laboratory methods, they studied changes in the tumors’ DNA and examined which genes were more or less active. The goal was to find biological features linked to how well tumors respond to radiation. The researchers found that using updated tumor grading rules that include certain genetic features would change how about 10% of tumors are classified. In about 7% of patients, this could have changed which treatment group they were placed in. Tumors that did not respond well to radiation were more likely to have losses of specific parts of their chromosomes (called 1p and 14q) and to show a larger number of overall genetic changes. Tumors that responded better to radiation showed signs of stronger immune activity. In contrast, tumors that did not respond tended to show signs of faster cell growth. The researchers also identified a specific biological subtype of meningioma, called the Proliferative group, that was strongly linked to the risk of the tumor coming back after radiation. This group predicted recurrence better than the traditional tumor grading system currently used in clinical practice. Overall, the results suggest that testing tumors for these molecular features could help doctors better predict which patients are most likely to benefit from radiation therapy. These findings may also help guide future clinical trials and support the development of new treatments for more aggressive meningiomas.