Prognostic significance of HMGB1 expression as a biomarker of immunogenic cell death in patients with leiomyosarcoma and undifferentiated pleomorphic sarcoma treated with chemo-immuno–based regimens.

Abstract

e23526 Background: Immunogenic cell death (ICD) is a functionally unique form of apoptosis that triggers a robust tumor-specific immune response by releasing damage-associated molecular patterns (DAMPs). High Mobility Group Box 1 (HMGB1) is a canonical DAMP and a key biomarker of ICD. Anthracycline-based chemotherapy, the standard of care for soft-tissue sarcomas (STS) such as leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS), is a known inducer of ICD. We sought to determine the prognostic value of HMGB1 expression variation for predicting progression-free survival (PFS) in patients treated with an anthracycline-based chemotherapy regimen combined with an anti-PD-1 inhibitor. Methods: We analyzed HMGB1 expression levels in a cohort of 32 patients with LMS and UPS undergoing anthracycline-based treatment combined with nivolumab, within the IMMUNOSARC clinical trial. Maximally selected log-rank statistics (Maxstat) were utilized to identify the optimal cut-off for HMGB1 expression variation (percentage of variation between baseline and the first radiologic evaluation) to segregate patients into two distinct prognostic groups for PFS. The variation in HMGB1 expression was also correlated with overall survival (OS). Results: The Maxstat analysis identified an optimal prognostic cut-off for HMGB1 expression variation at 13.2%. The group with HMGB1 expression variation > 13.2% demonstrated significantly superior PFS compared to the HMGB1 expression variation ≤13.2% group (13.5 months [95% CI, 11.1-16.0] vs. 8.4 months [95% CI, 6.2-10.5], p = 0.006). This threshold did not demonstrate significant prognostic value for OS (not reached, vs. 17.7 months [95% CI, not reached], p = 0.076). Conclusions: Increased variation in HMGB1 expression is a significant predictor of improved PFS in patients with LMS and UPS treated with chemo-immunotherapy regimens, suggesting that HMGB1 may serve as a valuable circulatory biomarker to monitor treatment efficacy and guide clinical decision-making. Ongoing analyses are evaluating HMGB1 variation at the time of disease progression to determine if the dynamic expression of this protein can predict clinical progression.