Optimal Clinical Management and the Molecular Biology of Angiosarcomas

Simple Summary Angiosarcomas are a group of a rare vascular cancers transformed from endothelial cells that could occur in any body part. Most angiosarcomas have unknown aetiology but secondary angiosarcomas could occur after radiation exposure or chronic lymphedema. The optimal treatment for localized angiosarcoma is complete surgical resection but neoadjuvant therapy may be helpful for some patients. For advanced angiosarcoma, systemic treatment including chemotherapy, anti-angiogenic therapy, and immunotherapies are options. We also review the molecular alterations that are associated with the pathogenesis of angiosarcoma, including c-Myc, TP53, vascular endothelial growth factor receptors, and others. This clinical management and molecular biology review will provide both clinicians and researchers of angiosarcoma with insights to help patients and move the field forward. Angiosarcomas comprise less than 3% of all soft tissue sarcomas but have a poor prognosis. Most angiosarcomas occur without obvious risk factors but secondary angiosarcoma could arise after radiotherapy or chronic lymphedema. Surgery remains the standard treatment for localized angiosarcoma but neoadjuvant systemic treatment may improve the curability. For advanced angiosarcoma, anthracyclines and taxanes are the main chemotherapy options. Anti-angiogenic agents have a substantial role but the failure of a randomized phase 3 trial of pazopanib with or without an anti-endoglin antibody brings a challenge to future trials in angiosarcomas. Immune checkpoint inhibitors as single agents or in combination with oncolytic virus may play an important role but the optimal duration remains to be investigated. We also report the current understanding of the molecular pathways involved in angiosarcoma pathogenesis including MYC amplification, activation of angiogenic pathways and different molecular alterations that are associated with angiosarcomas of different aetiology. The success of the patient-partnered Angiosarcoma Project (ASCProject) has provided not only detailed insights into the molecular features of angiosarcomas of different origins but also offers a template for future fruitful collaborations between patients, physicians, and researchers. Lastly, we provide our perspective of future developments in optimizing the clinical management of angiosarcomas.