Sarcomas are a rare and heterogeneous group of malignancies that affect patients of all ages and arise from mesenchymal cells throughout the body.1,2 Soft tissue sarcomas (STSs) account for 80% of all new sarcoma diagnoses, while the remainder of sarcomas develop from the bone.3 Sarcomas have historically been classified based on the normal tissue they most closely resemble with genomic characterization more recently helping to refine histologic subtypes and identify new sarcoma entities.3,4 Although the etiology of sarcomas are largely unknown, factors such as genetic syndromes, environmental exposures, and iatrogenic causes including radiation therapy and chemotherapy are known to increase the risk of sarcoma development.5, 6, 7 The primary management of most localized sarcomas involves surgical resection and risk-adapted addition of radiation therapy.8 In some sarcoma centers, systemic therapy is utilized for high-risk localized disease. In patients with metastatic disease, anthracycline-based chemotherapy remains the first line option for most sarcoma histologies.9 However, mutation-targeted therapies have shown promise for a small subset of patients with sarcomas,10 and up to a third of patients with oligometastatic sarcoma can be cured with metastasis-directed therapy.11 Although the rarity and complexity of sarcomas represent a substantial therapeutic challenge, the wide range of tumor biology across patients offers a unique opportunity to personalize cancer treatment to optimize patient outcomes.

New genomic and proteomic technologies have started to unravel the key molecular events that underly tumorigenesis and response to therapy across sarcoma subtypes.12 In addition to guiding the development of new therapies, insights into the genetic alterations and gene expression changes in sarcomas have helped to identify new prognostic and predictive biomarkers. In particular, liquid biopsies to noninvasively track analytes such as circulating tumor DNA (ctDNA) promise to revolutionize the way sarcomas are diagnosed, treated, and monitored (Figure). For example, radiation therapy is standard of care for patients with large, high grade STSs to reduce the risk of local recurrence.13 However, the majority of patients do not benefit from radiation therapy because more than two-thirds of these STSs will not recur locally after surgery alone. Similarly, although up to 50% of patients with large, high grade STSs will develop metastatic disease, the use of adjuvant chemotherapy remains controversial.14 Here, we review the current and future applications of molecular biomarkers to address these challenges and other important issues in contemporary sarcoma care. We emphasize the clinical applications of ctDNA analysis and highlight the challenges for developing sensitive and specific liquid biopsies for sarcomas.