INNV-09. Disease stabilization in atypical schwannomatosis with BAP1 and PIK3CA mutations treated with olaparib and alpelisib

Abstract Atypical schwannomatosis is a rare, non-syndromic peripheral nerve sheath tumor disorder characterized by multiple schwannomas, often with uncertain malignant potential. Malignant transformation and metastatic behavior are exceptionally rare, and there is no standard systemic therapy for progressive or disseminated disease. We report a case of a 62-year-old woman with a longstanding history of schwannomatosis, initially diagnosed in 2009, who presented with worsening dyspnea and was found to have multiple progressing pulmonary and pelvic schwannomas. Tumor resections and next-generation sequencing revealed somatic BAP1 and PIK3CA mutations in clonally related but genetically divergent lesions, consistent with metastatic behavior. Her disease progressed rapidly following standard treatments, including temozolomide, doxorubicin, and cabozantinib. In October 2024, she began treatment with the PARP inhibitor olaparib, which showed further progression by December 2024. In January 2025, alpelisib, a PI3K inhibitor, was added based on molecular profiling and expert consultation. Follow-up CT imaging in February 2025 demonstrated an overall decrease in tumor burden and lesion enhancement, although a few nodules progressed. Clinically, the patient noted improved respiratory symptoms, including reduced cough and shortness of breath, though she remained on oxygen therapy. Treatment-related adverse events included weight loss, nausea, and diarrhea, which were manageable. The patient remained on combination therapy without interruption for over 12 weeks, with radiographic progression noted in May 2025. This case demonstrates that combination therapy targeting somatic BAP1 and PIK3CA mutations with olaparib and alpelisib can achieve temporary disease stabilization in aggressive, non-syndromic schwannomatosis. It supports the consideration of molecularly guided targeted therapies in rare, treatment-refractory peripheral nerve sheath tumors with atypical or metastatic behavior. Further studies are needed to evaluate the role of precision medicine in managing atypical schwannomatosis and related low-grade spindle cell neoplasms.