Case Report: A case series on actionable genomic alterations guiding effective targeted therapy in rare sarcomas.

Background: Advanced sarcomas have limited systemic therapy options, but genomic profiling can uncover actionable mutations. This case series illustrates the promise and limitations of next-generation sequencing (NGS) and targeted therapies in clinical practice across three sarcoma histologies. Case presentations: Case 1: A 36-year-old woman received local therapies for an angiosarcoma in her breast. Six months later, she developed osseous metastatic disease, and NGS revealed a Discussion: Three patients with advanced sarcomas achieved partial responses to NGS-guided targeted therapies, with disease control lasting from 1 to over 5 years. Two cases involved novel, targetable mutations not previously identified in these sarcoma subtypes. However, the limitations of targeted therapies are highlighted by one patient's lack of response to a novel ROS1 G2032R-directed treatment, and another patient's repeated oligometastatic progression despite using an ALK inhibitor without resistance mutations. Simply suppressing a driver-mutation clone with targeted therapy may be insufficient for long-term disease control in sarcoma. Local therapies can be critical adjuvants in achieving improved outcomes for aggressive sarcomas. We recommend careful consideration of NGS testing for all sarcomas as we continue to explore their vast mutational landscape, response to targeted therapies, and mechanisms of resistance.