Early assessment of response to chemotherapy via ctDNA in soft tissue sarcoma.

Abstract

11531 Background: Chemotherapy remains the cornerstone for treatment of soft tissue sarcomas (STS). Biomarkers are needed to enhance timely assessment of chemotherapy efficacy to limit toxicity and guide patient management including estimating prognosis and duration of chemotherapy. Methods: This retrospective study includes patients with STS who received chemotherapy in the neoadjuvant or unresectable/metastatic setting at Stanford Sarcoma Center between May 2021 and January 2025. ctDNA was tested with Natera’s CLIA lab using a personalized, tumor-informed ctDNA assay (Signatera, bespoke mPCR, NGS assay). Longitudinal changes in peripheral blood ctDNA were correlated with radiographic response and survival. ctDNA response was defined as > 50% decrease in MTM/mL from baseline, with a second confirmatory measurement. Radiographic response was defined as stable disease or partial response on first re-staging assessment after starting therapy. Overall survival (OS) was defined as time from initiation of chemotherapy to death or last clinical follow up. Progression-free survival (PFS) was defined as time from initiation of chemotherapy to radiographic disease progression, death, or last clinical follow up. Results: Twenty-six patients (median age at diagnosis = 63 years [range 26 – 78]) were included. Histological subtypes consisted of leiomyosarcoma (uterine [n = 10], extrauterine [n = 4]), malignant peripheral nerve sheath tumor (n = 2), undifferentiated pleomorphic sarcoma (n = 2), angiosarcoma (n = 2), and other (Ewing’s sarcoma, malignant phyllodes tumor, perivascular epithelioid cell tumor, low grade myoepithelial carcinoma, high grade uterine sarcoma not otherwise specified, and small round blue cell neoplasm with EWSR1 rearrangement, each n = 1). Chemotherapy consisted of doxorubicin-containing regimens (n = 9), gemcitabine/docetaxel (n = 9), temozolomide-containing regimens (n = 5), and other (cyclophosphamide/topotecan, paclitaxel, and trabectedin, each n = 1). Median follow-up time after initiation of chemotherapy was 12.9 months. 16 of 26 patients had radiographic response. Substantial agreement was observed between ctDNA response and radiographic response (Cohen’s kappa coefficient 0.752). Median OS was longer for ctDNA responders (n = 17) than non-responders (n = 9), at 43.8 months vs 20.6 months (p = 0.03). Median PFS was longer for ctDNA responders than non-responders, at 11.4 months vs 2.0 months (p < 0.001). In the metastatic cohort (n = 22), time on chemotherapy regimen was longer for ctDNA responders than non-responders, median 5.0 vs 2.6 months, p = 0.016 by Wilcoxon rank sum test. Conclusions: Early decline in ctDNA after initiation of chemotherapy correlates with radiographic response and survival in STS. Research is ongoing to evaluate these findings in a prospective study.