Recurrent extraneural sonic hedgehog medulloblastoma exhibiting sustained response to vismodegib and temozolomide monotherapies and inter-metastatic molecular heterogeneity at progression

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.

Keywords: PIK3CA mutation; smoothened mutation; sonic hedgehog medulloblastoma; temozolomide; vismodegib.

Figure 1

Whole body projections from F¹⁸–fluorodeoxyglucose PET scans showing (A) baseline examination before vismodegib, (B) partial response to vismodegib, (C) disease progression under vismodegib, (D) further progression under itraconazole, (E) partial response to temozolomide, (F) progression under temozolomide, and (G) progression after sonidegib with response in 6th thoracic and 3rd lumbar locally treated lesions.

Figure 2. Axial F¹⁸–fluorodeoxyglucose PET/CT images at the pelvic level showing the right sacral alae lesion (arrow) chosen as a target for molecular analyses after progression to temozolomide

(A) Before vismodegib monotherapy, (B) partial response to vismodegib, (C) disease progression under vismodegib, (D) further lesion size progression under itraconazole, (E) partial response to temozolomide, and (F) progression under temozolomide when the CT scan-guided biopsy was performed (F’).

Figure 3. PTCH1 (top-left), SMO (top-right), and PIK3CA (bottom) sequence analysis in the primary CNS tumor and two extraneural metastases after progression to vismodegib and temozolomide

Figure 4

(A) Thoracic epidural metastasis (arrow) detected on PET/CT at progression under temozolomide. T2-weighted MRI scan of the spine at (B) baseline, (C) ten days after starting sonidegib showing tumor progression, and (D) after surgical decompression (raw sagittal and axial images on top and bottom, respectively).