Cabozantinib for PDGFRB Mutant High-Grade Uterine Sarcoma: A Precision Oncology Case Report

High-grade uterine sarcomas (HGUS) with myogenic differentiation pose significant therapeutic challenges, especially when metastasized. Pazopanib remains the only FDA-approved multi-kinase inhibitor for advanced soft tissue sarcoma after progression on standard chemotherapy, although outcomes remain limited. PDGFRB mutations have been detected in up to 37% of uterine sarcomas. We present a case of metastatic HGUS with PDGFRB mutations that exhibited sustained responses in most metastatic lesions to cabozantinib, a well-tolerated multi-kinase inhibitor utilized in other sarcoma subtypes.

A 37-year-old woman presented with abdominal pain and one month of abnormal uterine bleeding. Imaging revealed a large pelvic mass (22.7 x 13.7 x 19.2 cm) and bilateral lung metastases. She underwent a radical hysterectomy with bilateral salpingo-oophorectomy and was diagnosed with Stage IVb HGUS. Standard first-line gemcitabine/docetaxel led to disease progression after 3 cycles. Next-generation sequencing identified PDGFRB N666K and W566C mutations. Due to insurance denial for imatinib, cabozantinib 40 mg daily was initiated. Within 10 weeks, imaging showed a marked reduction in pulmonary metastases and complete resolution of pelvic recurrence. At months 17 and 23, new metastases in the soft tissue were resected; both lacked original PDGFRB mutations but showed mutations in SMARCA2, CDKN2A/B homozygous deletion as well as MTAP loss, suggesting clonal evolution. Side effects included hypertension and port thrombus that were medically managed. Patient remained on cabozantinib therapy for the past 25 months with no new adverse effects, with all existing lesions decreasing in size or remaining stable.

This report represents the first documented case of PDGFRB mutated HGUS with myogenic differentiation showing sustained response to cabozantinib. It could be that HGUS with myogenic differentiation harboring PDGFRB activating mutations may represent a distinct subset of sarcomas sensitive to multiple kinase inhibitors. The case supports the utility of molecular profiling and highlights cabozantinib as a promising targeted therapy for advanced undifferentiated uterine sarcomas.