Abstract
BACKGROUND: Response to targeting and non-targeting agents is variable and molecular information remains poorly described in patients with recurrent sonic-hedgehog-driven medulloblastoma (SHH-MB). MATERIALS AND METHODS: Clinical and PET/CT findings during treatment with successive hedgehog antagonists and temozolomide monotherapies are described in a heavily pre-treated patient with recurrent extraneural metastases from PTCH1 mutated/ wild type smoothened (SMO) CNS SHH-MB. Molecular tests were prospectively performed in tissue from two extraneural sites at progression. RESULTS: Sustained clinical/metabolic response was obtained to vismodegib. At progression, itraconazole was ineffective, but salvage temozolomide treatment results in a response similar to vismodegib. At further progression, acquired SMO and PIK3CA mutations were identified in bone (G477L and H1047A, respectively) and epidural (L412P and H1065L, respectively) metastases. No response was observed with subsequent sonidegib treatment. CONCLUSIONS: This is the first clinical report of recurrent extraneural PTCH1 mutated SHH-MB exhibiting: 1) a sustained response to vismodegib and temozolomide, and 2) inter-metastatic molecular heterogeneity and acquired SMO-G477L, SMO-L412P, and PIK3CA-H1065L mutations at progression, highlighting the need for a multitarget treatment approach.