Everett Moding, Assistant Professor of Radiation Oncology at Stanford University, shared on X:
“Soft tissue sarcomas (STS) have few recurrent mutations, making ctDNA testing a challenge. In our new paper in Journal of Clinical Oncology, we show that personalized ctDNA analysis achieves high detection rates and can track treatment response in localized STS.
Title: Personalized Circulating Tumor DNA Analysis for Predicting Outcomes and Tracking Response to Radiotherapy and Pembrolizumab in Localized Sarcomas: Analysis of the SU2C-SARC032 Trial
Authors: Ajay Subramanian, Serey C.L. Nouth, Neda Nemat-Gorgani, Shaghayegh Soudi, Karla V. Ballman, Rachel S. Heise, Claire Johns, Timothy J. Sears, Siyer Roohani, Reinhardt Krcek, Angela M. Hong, Kent J. Weinhold, Matt van de Rijn, Brian E. Brigman, Richard F. Riedel, Yvonne M. Mowery, David G. Kirsch, Everett J. Moding
We analyzed 313 plasma samples collected pretreatment, after radiotherapy but before surgery, and after surgery from 106 patients treated in the SU2C-SARC032 randomized trial.
Using custom, tumor-informed assays, we tracked a median of 46 somatic mutations per patient.
Personalized ctDNA profiling detected baseline ctDNA in 85% of patients, a substantial improvement over prior studies in STS using fixed gene panels or low-pass whole-genome sequencing.
Pre-treatment ctDNA levels were higher in patients with larger tumors, grade 3 disease, and pleomorphic liposarcoma histology, all features associated with an increased risk of metastasis in STS.
ctDNA levels pre-treatment were strongly associated with disease-free and overall survival, even after adjusting for established clinical risk factors.
Patients treated with pembrolizumab, who had significantly better disease-free survival in SU2C-SARC032, had a greater decrease in their ctDNA levels after neoadjuvant therapy, suggesting that ctDNA dynamics could provide an early readout of treatment efficacy.
Detection of ctDNA MRD at 3 months post-surgery was strongly associated with both disease-free and overall survival, raising the possibility that ctDNA analysis can identify patients who may benefit from additional systemic therapy after radiation and surgery.
Because our panels track all clonal and subclonal tumor mutations, we could follow individual tumor clones noninvasively. We were interested to find that patients with multiple clones detected after surgery had worse outcomes even when their ctDNA levels were similar.
We are excited about the potential for personalized ctDNA analysis to guide treatment decisions in STS! This work was led by co-first authors Ajay Subramanian, Serey Nouth, and Neda Nemat-Gorgani.
Grateful to David Kirsch, Yvonne Mowery, Richard Riedel, and Brian Brigman for leading a hugely impactful trial with rich correlative samples. Thank you to all our co-authors for making this possible!
Thank you to SARC for sponsoring and conducting this trial at 20 sites around the world. This work was supported by a Stand Up To Cancer Catalyst Grant with support from Merck, National Cancer Institute, and the DoD. Finally, we are grateful to patients and their caregivers for participating.”
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