(P 342) THE ROLE OF MYELOPEROXIDASE IN SARCOMA TREATMENT

Objective: High-grade sarcoma is a difficult to treat disease for many reasons including heterogeneity and lack of response to therapy. Traditional chemotherapies for sarcoma are toxic, have minimal response, and do not have a durable effect. Approximately one-third of patients with advanced stage sarcoma have a targetable mutation, but the role of targeted therapy and immune checkpoint therapy (ICT) are understudied. Despite advances in many other cancer types, the French PEMBROSARC trial looking at ICT in sarcoma was underwhelming with minimal response. Immune suppressing myeloid cells have increased production of reactive oxygen species leading to less response to ICT. Myeloperoxidase (MPO) is a major source of reactive oxygen species and has previously been shown to contribute to ICT resistance in other solid organ tumors. Here we look at the potential role of MPO in sarcoma.

Methods: This study is a single-center retrospective review of high-grade sarcomas including synovial, dedifferentiated liposarcoma (DDLS), and undifferentiated pleomorphic sarcomas (UPS) biopsied at our institution from 2019-2024. Formalin fixed paraffin embedded tumor samples were stained for MPO and examined by a pathologist blinded to patient data who specializes in sarcoma.

Results: Fourteen patients had tumor available and were included in this study. Seven (50%) patients were female. Median age was 58.5 years at diagnosis. Two were Stage II, five Stage IIIA, and five Stage IIIB. Five patients with synovial cancer, one with UPS, and eight with DDLS. Five (35.7%) had no MPO in samples. Nine (64.3%) had >1% and four (28.6%) had > 5% MPO staining. All, but two patients required chemotherapy either in the neoadjuvant setting or for recurrence. Only two patients had next generation sequencing and neither had targetable mutations. Two others progressed on ICT.

Conclusion: As demonstrated by our patients, these sarcomas can be aggressive and systemic therapy is often required for unresectable, recurrent, or metastatic disease. The effect is, however, not durable. Neither of the patients who received next generation sequencing had a useful mutation as most targets seen in sarcomas are only found in a small subset of patients. Here, we found MPO in approximately two-thirds of patients. ICT is generally a well-tolerated treatment. MPO inhibitors are currently in trial for FDA approval and have the potential to convert ICT non-responders to responders. This is the first step to a potential new treatment for sarcoma. Further clinical trials will be needed to support this.