11574 Background: The integration of liquid biopsies into clinical guidelines is revolutionizing the management of late-stage cancer. A notable advancement is the use of broad genomic analysis of circulating tumor DNA (ctDNA) for quantifying tumor fraction (TF). While TF's prognostic relevance in carcinomas has been explored, its significance in sarcomas remains unclear. Methods: This study involved patients with advanced sarcomas from two precision medicine studies (BIP, Institut Bergonié, Bordeaux, France; STING, Gustave Roussy, Villejuif, France) across two French Sarcoma Group sites. All participating patients underwent comprehensive genomic profiling with the FDA approved FoundationOne Liquid CDx assay. TF was measured using single-nucleotide polymorphism-based aneuploidy analysis as previously described (Reichert et al. 2023). Progression-free survival (PFS) and overall survival (OS) were assessed from treatment commencement (PFS) or the date of ctDNA profiling (OS) to disease progression, death, or last patient contact. Univariate analysis examined variables such as age, gender, tumor grade, metastatic sites, performance status (PS), and prior treatment lines. Results: 195 patients (103 males, 92 females) entered the study. The three most frequent histological subtypes were leiomyosarcomas, dedifferentiated liposarcomas, and undifferentiated pleiomorphic sarcomas. Median age was 56 (range 18-91). Thirty patients (15.4%) had high TF (≥ 10%). Among the 189 patients who underwent systemic treatment post-ctDNA profiling, elevated TF correlated with significantly poorer PFS (2.6 vs 4.3 months, p=0.018) and OS (6.7 vs 14.1 months, p=0.005). Multivariate analysis identified TF and ECOG performance status as independent predictors of OS. Conclusions: Plasma ctDNA TF is a practical and independent prognostic biomarker in advanced sarcoma patients. Its integration into treatment paradigms can facilitate precision therapeutic strategies tailored to individual tumor biology.