DDDR-28. Selumetinib in NF1-associated high-grade astrocytoma with piloid features

Abstract Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder that predisposes individuals to a range of neoplasms, including optic gliomas, astrocytomas, neurofibromas, breast carcinomas, and leukemias. The condition affects approximately 1 in 3,000 individuals and results from mutations in the NF1 gene on chromosome 17q11.2. This gene encodes neurofibromin, a tumor suppressor protein that regulates cell growth through the RAS/MAPK pathway. High-grade astrocytoma with piloid features (HGAP) is a rare tumor, with only 42 reported NF1-associated cases. It is a recently recognized primary brain tumor entity. Histologically, it has overlapping features of pilocytic astrocytoma and glioblastoma. Definitive diagnosis is primarily dependent on its global DNA methylation signature or epigenetic profile. The average age of onset is 44 years, and median survival is 15 months. We report two additional NF-1 associated HGAP cases. Patient 1, a 34-year-old woman with an unresectable left basal ganglia tumor, underwent biopsy, radiation, and chemotherapy. Molecular analysis showed NF1 and ATRX mutations, CDKN2A loss, and a methylation profile consistent with HGAP. Patient 2, a 51-year-old man with a right pontine tumor, had 70% resection followed by adjuvant therapy. Pathology revealed NF1 and ATRX mutations, CDKN2A and p16 loss, and methylation profiling consistent with HGAP. Both patients received selumetinib, a MEK inhibitor which targets the RAS/MAPK pathway. Patient 1 has stable disease at 15 months; patient 2 remained stable for 18 months before passing of pneumonia. He survived 5 years after diagnosis of HGAP. Of prior HGAP cases, none received selumetinib, though one was treated with trametinib, another MEK inhibitor, with 8.5 months survival. Given the rarity of NF1-associated HGAP, large scale studies are difficult. These cases suggest MEK inhibitors may offer therapeutic benefit. Collaborative research is needed to better understand the disease’s molecular profile and optimize treatment strategies.