BACKGROUND: Soft tissue sarcoma (STS) is a heterogeneous disease characterized by high prevalence of structural variants (SV). Despite surgery and radiation, ~50% of 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. METHODS: Patients with localized, high-risk STS (size ≥5cm, grade ≥2) were enrolled. Bespoke assays targeting 4-16 SV-breakpoints per patient were generated to detect ctDNA. Blood was collected at diagnosis, post-radiation, postoperatively (≤8-weeks), and during follow-up with radiologic surveillance; ctDNA dynamics were correlated with clinical outcomes. RESULTS: 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. 22 patients received preoperative radiation and had blood collected within the 8-week postoperative window. ctDNA was detectable within this period in 4/22 patients (18%). All 4 (100%) developed metastatic disease within 1 year (median 153 days). 3/18 patients (17%) 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. CONCLUSION: 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.
Park et al. (Thu,) studied this question.