Abstract
Circulating tumor DNA (ctDNA) tumor fraction (TF), the proportion of ctDNA within total cell-free DNA, is emerging as a simple and powerful biomarker across cancers. While recent studies in carcinomas established its prognostic value, its role in sarcomas remains unknown. We analyzed 192 patients with advanced soft tissue sarcomas enrolled in the French BIP (NCT02534649) and STING (NCT04932525) precision medicine programs, using the FoundationOne® Liquid CDx assay to quantify TF. Patients were stratified at a 10% cutpoint, consistent with prior reports. Median overall survival was 6.3 months for patients with TF ≥ 10% compared to 12.9 months for those with TF < 10% (p = 0.01). On multivariate analysis adjusting for histology, grade, performance status, and metastatic burden, high TF remained an independent predictor of poor survival (HR 2.0, 95% CI 1.1–3.5, p = 0.017). Unlike carcinomas, sarcomas currently lack validated circulating biomarkers. Our findings demonstrate that ctDNA TF provides non-invasive, real-time prognostic information in this rare and heterogeneous tumor type, with potential applications for patient stratification, treatment planning, and clinical trial design. Prospective validation is warranted to define standardized TF thresholds and support its integration into sarcoma care.
Supplementary Information
The online version contains supplementary material available at 10.1007/s10238-026-02069-8.
Dear Editor,
Recent data underline the prognostic significance of circulating tumor DNA (ctDNA) tumor fraction (TF) in several carcinomas [1]. However, a critical gap remains in understanding the prognostic value of TF in sarcomas, a diverse and aggressive group of tumors.
Our research aimed to fill this gap by exploring the prognostic significance of ctDNA TF in advanced sarcoma patients. Sarcomas, due to their heterogeneity and complex clinical behavior, pose significant challenges in prognostic assessment. Our study, which included 192 patients with advanced soft tissue sarcoma (STS) from two institutional molecular profiling studies, provides compelling evidence of the independent prognostic value of ctDNA TF in this tumor type (see Supplementary Methods for details and Supplementary Table 1 for patients characteristics).
We utilized hybrid capture-based next-generation sequencing (NGS) with the 324-gene FoundationOne® Liquid CDx assay to quantify ctDNA TF [2]. The patient cohort was stratified based on TF at a 10% cutpoint, and overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan–Meier plots and Cox proportional hazardgrs models, controlling for known prognostic scores such as histology, grade, number of metastatic sites and performance status.
Our analysis demonstrated that a high TF (≥ 10%) was significantly associated with worse OS (median overall survival 6.3 months 95% CI:0.3–12.2 vs. 12.9 months 95% CI: 10.2–15.7, p = 0.01) (Fig.1). These associations persisted independently of performance status, grade, histological subtype and and number of metastatic sites, on multivariate analysis (HR = 2 [CI95%: 1.1–3.5, p = 0.017) (Supplementary Table 2). This suggests that ctDNA TF is a potent prognostic biomarker in sarcoma, offering a non-invasive, dynamic measure of tumor burden that can reflect real-time disease progression.
Fig. 1.
Kaplan-Meier curve of overall survival in 217 patients with advanced soft-tissue sarcomas according to tumor fraction (blue line: tumor fraction ≥ 10, tumor fraction < 10)
A critical aspect that underscores the importance of our findings is the current lack of established circulating biomarkers for sarcomas. Unlike carcinomas, which benefit from specific circulating markers such as PSA for prostate cancer and CA 15 − 3 for breast cancer, sarcomas have no such biomarkers to aid in prognosis and monitoring. The integration of ctDNA TF as a prognostic tool in sarcomas could significantly enhance clinical decision-making. Traditional imaging and clinical assessments often fail to capture the full extent of tumor heterogeneity and progression in sarcomas. The ability to quantify tumor burden through ctDNA TF offers a novel approach that could guide treatment strategies, facilitating more personalized and timely therapeutic interventions, such as more aggressive chemotherapy regimens in patients with high TF. Moreover, the application of TF in clinical trials involving sarcoma patients could improve stratification and outcome prediction. Identifying patients with high TF may highlight those who would benefit from more aggressive treatment regimens or novel therapeutic approaches. Conversely, patients with low TF might be suitable for less intensive treatments, thereby sparing them from unnecessary toxicity.
Our findings align with and extend the work of Reichert et al. [1], reinforcing the value of ctDNA TF as a universal prognostic biomarker across various cancer types, including sarcomas. Further prospective validation studies are warranted to establish standardized TF cutpoints and integrate this biomarker into routine clinical practice for sarcoma patients.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We thank the patients and their families for participating in the BIP (NCT02534649) and STING (NCT04932525) programs.
Author contributions
AI conceived the study. All authors performed data collection and ctDNA TF analysis. ST performed the statistical analyses. AI drafted the manuscript. All authors revised the manuscript critically for important intellectual content and approved the final version. All authors agree to be accountable for all aspects of the work.
Funding
This work was supported by Fondation Bergonié and Fondation Gustave Roussy. The funders had no role in the design of the study, data collection, analysis, interpretation, or manuscript writing.
Data availability
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. Supporting data, including supplementary tables and figures, are included in the supplementary information files.
Declarations
Competing interests
The authors declare no competing interests.
Ethics approval and consent to participate
This study was conducted in accordance with the Declaration of Helsinki and approved by the local ethics committee of Institut Bergonié (Comité de Protection des Personnes – Sud-Ouest et Outre-Mer III). All patients provided written informed consent for molecular profiling and study participation.
Consent for publication
Not applicable. This manuscript does not contain any individual person’s data.
Footnotes
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References
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Associated Data
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Supplementary Materials
Data Availability Statement
The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. Supporting data, including supplementary tables and figures, are included in the supplementary information files.