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

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 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 GOPC-ROS1 fusion. She had a partial response to crizotinib. This ROS1 inhibitor and one course of radiation for oligometastatic progression controlled her disease for 12 months. Subsequent lines of therapy included pembrolizumab for high PD-L1 status, with suspected hyperprogression. Repotrectinib was trialed to overcome her ROS1 G2032R resistance mutation, but it had limited efficacy. She ultimately succumbed to her disease. Case 2: A 30-year-old woman with Neurofibromatosis Type 1 developed a high-grade, ALK-rearranged peripheral malignant nerve sheath tumor at her left antecubital fossa. Following resection, pulmonary metastases were identified. RNA transcriptome analysis revealed an EML4-ALK rearrangement. She had a prolonged partial response to alectinib. The ALK inhibitor and two courses of radiation for oligoprogression have continued to control her disease at 48 months. Case 3: A 51-year-old woman with uterine leiomyosarcoma developed pulmonary metastases shortly after completing adjuvant radiation. NGS revealed a BRCA2 deep deletion. After progressing on multiple lines of systemic therapies, her widely metastatic disease has been controlled for 62 months with niraparib and local therapies for oligoprogression. 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.