A prospective study of tumor-informed ctDNA minimal residual disease detection in bone and soft tissue sarcomas.

3057 Background: The high recurrence and metastasis rates lead to poor survival of patients with sarcoma. Conventional imaging often detects relapse at a relatively late stage. In our previous study, circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection demonstrated strong prognostic value in osteosarcoma, enabling earlier detection of recurrence compared with radiographic surveillance. However, whether this approach is applicable to soft tissue sarcomas and the broader sarcoma population remains unclear. Methods: Between August 2020 and March 2024, patients with sarcoma were prospectively enrolled at a single center. Tumor-informed MRD assays were designed using whole-exome sequencing of paired tumor–normal samples. Longitudinal postoperative plasma samples were collected for ctDNA analysis. Survival outcomes were assessed using Kaplan–Meier analysis with log-rank tests. Multivariable Cox proportional hazards regression was performed adjusting for age, sex, tumor necrosis score, and histologic subtype (osteosarcoma vs non-osteosarcoma). Results: A total of 121 patients were included, comprising 74 bone-origin sarcomas (72 osteosarcomas) and 47 soft tissue sarcomas; 77 patients were male and 44 were female. With a median follow-up of 21.7 months, postoperative ctDNA positivity was strongly associated with inferior survival. Median relapse-free survival was 6 months in ctDNA-positive patients versus 43 months in ctDNA-negative patients (P < 0.001). This prognostic separation remained significant across early (≤1 month), intermediate (1–6 months), and late (>6 months) postoperative time windows. In multivariable Cox analysis, postoperative ctDNA status remained an independent prognostic factor (HR = 5.20, 95% CI: 2.07–13.08; P < 0.001). In 19 patients, ctDNA positivity preceded radiographic evidence of recurrence, with a mean lead time of approximately 3 months. Notably, 56 patients with persistently negative postoperative ctDNA experienced no recurrence or metastasis during follow-up. Conclusions: Tumor-informed ctDNA-based MRD detection is applicable to a broad range of sarcoma subtypes and provides robust prognostic information following surgery. These findings support the role of ctDNA as an early biomarker for disease recurrence in sarcoma. Clinical trial information: ChiCTR2400083045.