Detecting ctDNA Using Personalized Structural Variants to Forecast Recurrence in Localized Soft-Tissue Sarcoma

Soft-tissue sarcoma (STS) is a heterogeneous disease characterized by high prevalence of structural variants (SV). Despite surgery and radiation, ∼50% of patients with localized STS recur; the role of adjuvant systemic therapy remains controversial. We assessed circulating tumor DNA (ctDNA) tracking tumor-informed SVs throughout the perioperative course and surveillance to detect molecular residual disease.

Patients with localized, high-risk STS (size ≥5 cm, grade ≥2) were enrolled. Bespoke assays targeting 4 to 16 SV breakpoints per patient were generated to detect ctDNA. Blood was collected at diagnosis, after radiation, postoperatively (≤8 weeks), and during follow-up with radiologic surveillance; ctDNA dynamics were correlated with clinical outcomes.

228 plasma samples from 32 patients were analyzed with a median ctDNA surveillance spanning 20.1 months and a median clinical follow-up of 43.8 months. Sensitivity of the assay was 97% (31/32) at baseline. Twenty-two patients received preoperative radiation and had blood collected within the 8-week postoperative window. ctDNA was detectable within this period in 4 of 22 (18%) patients. All 4 (100%) developed metastatic disease within 1 year (median: 153 days). Three of 18 (17%) patients who were ctDNA negative in the 8-week window developed metastatic recurrence (median: 521 days), which was preceded by detectable ctDNA. Longitudinal assessment of the entire cohort showed that ctDNA concentration correlated with oncologic treatment and radiologic response.

SV-based personalized ctDNA detection is feasible and highly sensitive in localized STS. In this proof-of-principle study, ctDNA detection in the 8-week postoperative window was associated with early recurrence. These data inform future trial design of personalized adjuvant systemic therapy for localized STS.