Using personalized medicine in gliomas: a genomic approach to diagnosis and overcoming treatment resistance in a case with pleomorphic xanthoastrocytoma

Abstract

Introduction: A patient who was initially considered to have a glioblastoma (GBM) had molecular analysis, showing that it was a pleomorphic xanthoastrocytoma (PXA). Up to 78% of PXA tumors have BRAF V600E mutations. Primary brain tumors with BRAF mutations can have a good response to BRAF MEK inhibitors (BRAF MEKi), and there may be a synergistic response when combined with autophagy inhibitors. Presentation of the case: A 20-year-old man found to have a large brain mass with midline shift underwent resection. He was diagnosed with “GBM” and treated with radiation and temozolomide with subsequent disease recurrence. Review of histology showed malignant PXA with BRAF V600E mutation. Treatment with Dabrafenib and Trametinib was started, and tumor size increased in size after 14 months of treatment. Given studies showing that resistance to BRAF inhibition can be overcome by autophagy inhibition, chloroquine was added. Patient has been on “triple” therapy for 15 months and has radiographically Stable Disease. At MCC, 3% of patients with gliomas have BRAF mutations who could potentially benefit from this combination therapy. Conclusion: This is the first report of a PXA patient receiving therapy with BRAF MEKi and an autophagy inhibitor with prolonged stable disease. This patient highlights the importance of a molecular interrogation in gliomas to provide an integrated diagnosis and effective treatment. This may be useful in up to 3% of glioma patients with BRAF mutations. Molecular testing in neuro-oncology is providing new avenues of diagnosis and treatment, and detailed molecular interrogation should be considered routine.