Durable disease control in a radiation-induced high-grade glioma harboring NF1 and PTPN11 co-mutations

Abstract Radiation-induced gliomas (RIGs) are rare and aggressive secondary brain tumors arising years after cranial irradiation. Their management remains challenging due to prior radiation exposure, which limits additional radiation, and a lack of effective chemotherapies. Recent studies have revealed distinct molecular profiles in RIGs with unclear clinical implications. This study presents the case of an individual who developed a high-grade glioma three decades after curative craniospinal radiation for medulloblastoma. He was treated with repeat radiation and temozolomide chemotherapy but developed recurrence with disseminated leptomeningeal disease thereafter. Molecular profiling of the tumor revealed a loss-of-function NF1 mutation and a gain-of-function PTPN11 mutation, two convergent alterations in the MAPK pathway. Based on these findings, the patient was treated with a MEK inhibitor, trametinib, and achieved durable disease control for 20 months until progression. This case underscores the importance of genomic profiling in RIGs and potential utility of molecularly targeted approaches in this population.