Validation, translation, and clinical implementation of a gene expression biomarker to predict meningioma outcomes and radiotherapy responses

PROJECT SUMMARY Meningiomas comprise 40% of primary intracranial tumors and approximately 1% of humans will develop a meningioma in their lifetime. Meningioma treatments are largely restricted to surgery and radiotherapy (RT), and systemic therapies remain ineffective or experimental. The World Health Organization (WHO) has historically graded meningiomas according to histological features. According to WHO criteria, many grade 1 meningiomas can be effectively treated with surgery or RT, but many WHO grade 2 or grade 3 meningiomas are resistant to treatment and cause significant neurological morbidity and mortality. Approximately 30% of WHO grade 1 meningiomas develop recurrences that cannot be predicted from histological features, and some WHO grade 2 or grade 3 meningiomas are unexpectedly well controlled with surgery and RT. These data indicate that improvements in meningioma risk stratification are needed, but limited understanding of meningioma biology and the misconception that all meningiomas are “benign” has encumbered medical advances for patients. Postoperative RT improves local control of meningiomas, but the benefits of meningioma radiation must be weighed against long-term toxicities, which can include neurocognitive deficits and secondary cancers. Most meningioma patients survive 5 years or more after diagnosis and are therefore at risk of long-term side effects of ionizing radiation on the normal brain, including white matter change, microvascular damage, and cognitive deficit. In recognition of the controversies surrounding meningioma risk stratification and treatment, clinical trials in North America and in Europe currently randomize patients with newly diagnosed WHO grade 2 meningiomas to postoperative surveillance or postoperative RT after gross total resection. Thus, there are unmet needs for improved risk stratification and prediction of postoperative RT responses for meningioma patients. To address this, we performed molecular profiling on 1856 frozen or formalin-fixed paraffin-embedded meningiomas from 12 institutions across 3 continents to develop a predictive 34-gene expression biomarker that outperforms all other risk stratification systems and identifies tumors that benefit from postoperative RT. The clinical and analytical validity of this biomarker were established in external cohorts and archival samples from NRG/RTOG 0539, the only successful prospective study of RT for meningiomas in North America. Despite these advances, all our meningioma gene expression profiling was performed in research laboratories, and our biomarker calculations largely relied on a hybridization and barcode-based platform for transcript quantification that is not widely available in the clinic. Our central hypothesis is that gene expression profiling will enable biomarker detection in clinical meningioma samples in a CLIA/CAP-certified setting. To test this, we will deploy two platforms for transcript quantification that rely on hybridization and barcoding, or on RNA sequencing, to test archival (Aim 1) or prospective (Aim 2) meningiomas. Successful completion of this proposal sets the stage for biomarker-stratified clinical trials that are currently under development for meningiomas through NRG Oncology.