# Targeted and Personalized Therapy for Difficult Benign Brain Tumors: A Review

## TL;DR

This review explores personalized treatment options for difficult benign brain tumors, focusing on molecular profiling and targeted therapies to improve outcomes.

## Contribution

The paper highlights the use of DNA methylation models and functional testing to guide individualized treatment for benign brain tumors.

## Key findings

- DNA methylation-based models predict post-surgical outcomes and radiotherapy responses in benign brain tumors.
- Target-directed treatments like cMET blockade and brigatinib show promise in preclinical models of schwannomas and PitNETs.
- Molecular profiling and functional assays are recommended to guide clinical decisions for difficult benign brain tumors.

## Abstract

Background: Difficult benign intracranial tumors (including meningiomas, schwannomas, neurofibromatosis-related tumors, and pituitary neuroendocrine tumors) have substantial morbidity in patients. Due to their limited treatment options, there is a need for individualized treatment beyond histological and surgical approaches. Objective: To summarize how novel treatment innovations have been implemented for these tumors, meningiomas and schwannomas are prioritized, followed by NF-associated neoplasms, and then pituitary neuroendocrine tumors in comparison to low-grade gliomas. Methods: We summarize the current knowledge relating to targeted therapies for gliomas, meningiomas, schwannomas, neurofibromatosis (NF) tumors, and pituitary neuroendocrine tumors to investigate an individual’s treatment options for difficult benign brain tumors. This review synthesizes evidence on tumor genomics and molecular markers, supported by methylation-based classification, immunohistochemistry, and functional assays, emphasizing current clinical applications. Evidence Synthesis: The recent data show that DNA methylation-based models can predict post-surgical outcomes and radiotherapy responses, enabling risk stratification and radiotherapy benefit prediction. Early signals support target-directed treatment, including cMET blockade that radiosensitizes NF2 schwannoma models, brigatinib-associated tumor shrinkage in NF2-deficient models, and PitNET organoid data. Conclusions: We support clinical decision-making that utilizes molecular profiling with functional testing to guide targeted treatment. We also identify evidence gaps such as biomarker-defined prospective trials that are needed for broader clinical implementation.