Early on-treatment ctDNA dynamics and response by imaging in patients with sarcoma.

Abstract

11537 Background: ctDNA holds promise as a prognostic and predictive biomarker for risk stratification and treatment response monitoring across multiple tumor types. However, the optimal timepoints and cutoffs for interpretation of ctDNA results are not well defined. Here we explored the ctDNA dynamics in patients with sarcomas on cytotoxic chemotherapy, with a focus on early time points to predict response. Methods: All sarcoma patients at the Wilmot Cancer Institute who had ctDNA (SignateraTM, Natera, Inc.) requested clinically from 03/01/22 – 12/31/25 were screened. Patients who had a positive baseline and at least 2 cycles of cytotoxic chemotherapy with serial ctDNA monitoring and response evaluation were selected for further analysis. Response was determined by imaging reports (CT, MRI, or PET) after 2-4 cycles of therapy. Results: One hundred and twenty-four patients were identified on initial screening, and 112 were able to generate a bespoke assay. Twenty-two patients met criteria for early on-treatment response analysis and 4 had results available from a second line of chemotherapy, for a total of 26 evaluations. Seventeen patients had metastatic disease while 5 were on neoadjuvant chemotherapy for high risk localized sarcomas. The most common sarcoma subtype was LMS (5), followed by undifferentiated small round cell sarcoma (Ewing, other EWSR1 fusions, BCOR; 4 patients), and osteosarcoma (3). Most patients, including those who progressed, showed some early decrease in ctDNA levels, but no patients whose ctDNA result converted to negative within the first two cycles progressed on the first reassessment. In this series a log10 fold change of -1.25 or greater by the end of cycle 2 separated responders and progressors. Conclusions: ctDNA is promising as an early biomarker of response across a wide variety of sarcoma subtypes and chemotherapy regimens. ctDNA dynamics may provide particular clinical utility in interpreting scans showing stable disease, as well as when response is difficult to capture on imaging, such as bony primaries or metastasis, or infiltrative malignancies such as angiosarcoma. Larger data sets and multi-institutional collaboration are needed to verify optimal time points and cutoffs for guiding patient care and interventional trials. Log10 change in ctDNA from baseline at end of cycle 1 and cycle 2 chemotherapy by initial imaging response. Initial Response Cycle 1 median log change Cycle 1 log change range Cycle 2 median log change Cycle 2 log change range Progression -0.17 -1.01— +0.16 -0.36 -1.23— +0.21 Stable disease (SD) -0.18 ND (Not Detected) — +0.27 -0.88 ND — +1.00 Partial response (PR) -1.62 ND — -0.21 -2.42 ND — -1.26 Complete response (CR) -2.72 ND — -1.00 -3.12 ND — -2.35 PR + CR -2.35 ND — -2.01 -2.08 ND — +1.00 SD + PR + CR -1.80 ND — +0.27 -2.47 ND — -1.26