Here we use targeted gene expression profiling to develop and validate a polygenic biomarker that provides additional information for meningioma outcomes compared to recent classification systems, including prediction of postoperative radiotherapy responses. The gene expression biomarker we report is independently prognostic across all clinical, histological, and molecular contexts tested5,16,17,19, 21–24, including WHO 2021 grade11, the current standard of care. When incorporated into clinical risk groups defined by contemporary trials7–9 that are consistent with consensus NCCN and EANO guidelines4,35, the gene expression biomarker re-classifies up to 52.0% of meningiomas and potentially refines postoperative management for 29.8% of patients.
DNA methylation profiling21–24, 36, CNV analysis16–18, DNA sequencing12–15, and RNA sequencing18–20, 22 have improved understanding of meningioma biology. Unsupervised bioinformatic analyses paired with mechanistic and functional approaches have identified molecular groups and subgroups of meningiomas with distinct biologic drivers, therapeutic vulnerabilities, and clinical outcomes18,19,21,22. Supervised bioinformatic models incorporating clinical endpoints have refined risk stratification for meningioma local recurrence16,17,24,36. The gene expression biomarker reported here provides additional prognostic information for local recurrence and overall survival when combined with all unsupervised or supervised meningioma molecular classification systems tested. These findings are concordant with pan-cancer analyses examining gene expression, CNV, DNA methylation, protein expression, and DNA sequencing data in 10,884 patients, which suggest gene expression encodes the greatest prognostic information across cancer types28. In support of these data, targeted gene expression biomarkers and continuous risk scores have proven successful for multiple cancers25–27, 37–39, particularly for breast cancer where polygenic biomarkers are standard of care25,30. Previous efforts to reduce meningioma molecular classification systems to immunohistochemical stains have thus far not been reproducible40. More broadly, qualitative or semi-quantitative protein expression is unlikely to capture the quantitative signal of a gene expression continuous risk score, especially when incorporating non-protein coding genes, as is the case for the biomarker we report (Fig. 1E, Table S3).
Current indications for postoperative radiotherapy for patients with meningiomas are controversial, particularly for patients with primary WHO grade 2 meningiomas who are randomized to postoperative surveillance or postoperative radiotherapy on NRG BN-003 and EORTC 1308 after GTR3,6. Conflicting retrospective series have variably reported a benefit9, 41–48 or no benefit from radiotherapy in this setting47, 49–56, which has fueled debate and inspired these international Phase III clinical trials of radiotherapy for patients with meningiomas. The gene expression biomarker reported here improves risk stratification for primary WHO grade 2 meningiomas and may identify favorable WHO grade 2 meningiomas where postoperative radiotherapy could be safely omitted in favor of close surveillance. The gene expression biomarker also identifies primary WHO grade 1 meningiomas with elevated risk of recurrence (Figure S8E). Indeed, 6.4% of primary WHO grade 1 meningiomas in the multicenter retrospective clinical validation cohort were classified as gene expression high risk (N = 27), with 5-year LFFR of 43.0%. Of these, only 1 patient received postoperative radiotherapy (3.7%). The gene expression biomarker also identified 59 primary WHO grade 1 meningiomas (13.9%) with subtotal resection in the multicenter retrospective clinical validation cohort as intermediate risk, and this unfavorable combination was associated with 5-year LFFR of 65.1%. Of these, only 3 patients (5.1%) received postoperative radiotherapy. In sum, 20.3% of primary WHO grade 1 meningiomas in the multicenter retrospective clinical validation cohort (N = 86 of 423) were re-classified as unfavorable using biomarker/surgical strata, and the overwhelming majority of these patients did not receive postoperative radiotherapy (95.3%). To address these missed opportunities for refined risk stratification, the performance characteristics, rate of re-classification, and rate of potential refinement of postoperative management offered by the gene expression biomarker reported here compare favorably to well-established biomarkers in routine clinical use for patients with other cancers29,30,57,58.
Previous meningioma molecular classification studies have largely not reported overall survival outcomes. A prospective trial of trabectedin in 90 patients with recurrent WHO grade 2 or grade 3 meningiomas examined DNA methylation families in multivariate analysis without including WHO grade as a covariate, and found meningiomas in the malignant DNA methylation family had worse overall survival compared to non-malignant families, although all families (including benign and intermediate) experienced poor outcomes59. The data we present using meningiomas from RTOG 0539 demonstrate the gene expression biomarker was prognostic for overall survival both before and after adjusting for WHO grade on multivariate analysis, and that outcomes remained well-calibrated in this prospective, investigator-blinded validation cohort. For patients with meningiomas, prospective trials such as these will be critical to distinguish conventionally higher risk cases that may safely undergo postoperative surveillance (Figures S8F, S8G), elucidate which biomarker(s) could be used for stratification (Figures S8H, S8I), and determine whether the timing of postoperative radiotherapy or other interventions improves overall survival (Figure S8J). As clinical trials develop, we do not anticipate targeted gene expression profiling will obviate longstanding and robust meningioma classification systems, such as WHO grade11, or more recent classification systems that are tractable across multiple brain tumor types, such DNA methylation profiling which elucidates biological drivers and vulnerabilities to molecular therapy for meningiomas21,22,60. Rather, if incorporated alongside other meningioma classification systems and clinical factors such as extent of resection that are already in widespread use, the gene expression biomarker reported here may offer additional benefit to patients with the most common primary intracranial tumor1, particularly in terms of postoperative radiotherapy response.
This study should be interpreted in the context of its limitations. First, clinical data in the discovery and multicenter validation cohorts were obtained retrospectively, suggesting our results are susceptible to biases inherent to retrospective research. To address this limitation, we provide additional investigator-blinded, independent validation using meningiomas and clinical data that were prospectively collected from patients enrolled on RTOG 0539. Second, pathology and radiology reviews were performed independently at each institution for meningiomas in the retrospective discovery and validation cohorts. Nevertheless, inter-observer concordance for meningioma WHO grade and imaging characteristics are high61–63, and any heterogeneity in clinical review across independent cohorts may better represent the heterogeneity intrinsic to routine clinical practice than might be anticipated from central review. To further address this limitation, the meningiomas from RTOG 0539 that were included in this study underwent central pathology and radiology review7–9, 63.