The Mutational Landscape of Angiosarcoma: Challenges and Opportunities to Design Management Strategies.

Angiosarcoma is a rare, highly aggressive endothelial malignancy comprising less than 1% of soft tissue sarcomas, with a 5-year overall survival of only 41-43%. Despite advances in cancer therapeutics, angiosarcoma remains critically understudied due to limited case prevalence, perpetuating a knowledge gap in molecular mechanisms and therapeutic strategies. Recent clinical trials (Axi-STS, TAPPAS) demonstrated that single-agent anti-angiogenic inhibitors (axitinib, pazopanib) achieve modest efficacy (median progression-free survival (PFS) 3.0-4.3 months, response rates 5-13%), underscoring angiosarcoma's complex, multipathway-driven pathogenesis. This review synthesizes the mutational landscape and molecular crosstalk of angiosarcoma, emphasizing four key mechanisms - (1) genepathway interactions-MYC amplification (>95% in radiation-associated angiosarcoma (RAAS)), TP53 mutations, and PIK3CA alterations converging to drive aggressive angiogenesis; (2) endothelial-specific dysregulation-TP53-driven disruption of VEcadherin junctions, VEGF-induced vascular permeability, and endothelial-tomesenchymal transition; (3) microenvironmental contributions- Transforming Growth Factor-Beta (TGF-β), IL-10, and VEGF-mediated immunosuppression and tumor progression; and (4) emerging biomarker-driven combinations-dual Vascular Endothelial Growth Factor (VEGF) + endoglin inhibition, chemotherapy + anti-PD-L1 immunotherapy, and multi-targeted TKI + Immune Checkpoint Inhibitors (ICI) strategies showing improved outcomes. Environmental exposures (vinyl chloride, thorotrast, radiation) drive distinct angiosarcoma subtypes with subtype-specific mutational profiles. We propose that precision-medicine approaches integrating molecular stratification, pathway crosstalk analysis, and biomarker-guided combination therapies represent the rational next steps to overcome therapeutic resistance and improve clinical outcomes in this lethal malignancy.