Clinical Significance of Molecular Alterations and Systemic Therapy for Meningiomas: Where Do We Stand?

SIMPLE SUMMARY: Meningiomas are the most frequent intracranial tumors and comprise a heterogeneous spectrum of diseases, ranging from small, asymptomatic tumors that do not need treatment to large, symptomatic ones causing seizures or neurological deficits that require surgery and/or radiotherapy. Systemic therapy is reserved for progressive or recurrent meningiomas when surgery and/or radiotherapy options have been exhausted, with only modest activity in terms of disease control and survival. Novel molecular alterations are correlated with grading, location, and prognosis of meningiomas. Moreover, some of these driver alterations regulate meningioma growth and progression and may be targeted by specific drugs that are under investigation in clinical trials. Lastly, the microenvironment surrounding meningiomas may also contribute to regulating tumor growth: in particular, PD-L1 and/or M2 macrophage expression may represent a target for immunotherapy. ABSTRACT: Meningiomas are common intracranial tumors that can be treated successfully in most cases with surgical resection and/or adjuvant radiotherapy. However, approximately 20% of patients show an aggressive clinical course with tumor recurrence or progressive disease, resulting in significant morbidity and increased mortality. Despite several studies that have investigated different cytotoxic agents in aggressive meningiomas in the past several years, limited evidence of efficacy and clinical benefit has been reported thus far. Novel molecular alterations have been linked to a particular clinicopathological phenotype and have been correlated with grading, location, and prognosis of meningiomas. In this regard, SMO, AKT, and PIK3CA mutations are typical of anterior skull base meningiomas, whereas KLF4 mutations are specific for secretory histology, and BAP1 alterations are common in progressive rhabdoid meningiomas. Alterations in TERT, DMD, and BAP1 correlate with poor outcomes. Moreover, some actionable mutations, including SMO, AKT1, and PIK3CA, regulate meningioma growth and are under investigation in clinical trials. PD-L1 and/or M2 macrophage expression in the microenvironment provides evidence for the investigation of immunotherapy in progressive meningiomas.