Clinically-actionable Mutations in Posterior Skull Base Meningiomas

Background: Meningiomas are the most common intracranial tumor. Standard therapy for meningiomas is surgery with radiation used as salvage therapy. There are limited chemotherapeutic options for meningiomas. Meningiomas located in the skull base have limited surgical access and resection is associated with a higher morbidity. Mutations in the tumor suppressor gene, NF2, has been known to occur in approximately half of meningiomas; however, other oncogenic drivers have only recently been discovered. Among others, activating mutations in SMO and AKT1 have been identified in meningiomas, especially in the skull base, and are clinically relevant, as targeted therapies have been successful in the treatments of other neoplasms that bare these mutations. Vismodegib and afuresertib inhibit SMO and AKT1, respectively, and are currently under evaluation in a national Phase II study of progressive or recurrent meningioma (NCT02523014). In this study, we sought to analyze the frequency, clinical characteristics, and outcomes associated with SMO and AKT1 mutations in posterior skull base tumors.

Methods: We performed targeted sequencing of 160 known cancer drivers in a cohort of 75 posterior skull base WHO grade I and II meningiomas to better define the frequency of SMO, AKT, and other clinically actionable mutations in these tumors. We then correlated these findings with clinical and survival data.

Results: We confirmed a high prevalence of NF2 mutations, which were present in 40% of our posterior skull base meningioma cohort. Moreover, 10% had AKT1 E17K mutations. Notably, there were no posterior skull base tumors with oncogenic SMO mutations that have been described in anterior skull base meningiomas. We did, nonetheless, find a high prevalence of other mutations characterized in known cancer-associated genes, including CREBBP, PTEN, PIK3CA, and MTOR.

Conclusions: Meningiomas with clinically-actionable AKT1 mutations comprise a significant portion of posterior skull base tumors. In addition, other known cancer associated genes are also clearly implicated in their etiology. Interestingly, no posterior skull base tumors had SMO mutations. This strengthens the theory that SMO mutations are confined to the anterior skull base, where the SHH pathway, of which SMO is a part, contributes to craniofacial patterning. Overall, the identification of AKT1 and other targetable mutations in meningiomas of this surgically challenging area of the skull base will be the first step in developing early treatment with AKT1-inhibitors and provide options for patients who fail standard therapy.