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Updated: Jul 31, 2025
Detection and Monitoring of Tumor Associated Circulating DNA in Patient Biofluids
Published on: June 8, 2019
Monitoring Sarcoma Response to Immune Checkpoint Inhibition and Local Cryotherapy with Circulating Tumor DNA Analysis
Nam Q Bui1, Neda Nemat-Gorgani2, Ajay Subramanian2
1Division of Oncology, Department of Medicine, Stanford University, Stanford, California.
Purpose:
Immune checkpoint inhibition has led to promising responses in soft tissue sarcomas (STS), but the majority of patients do not respond and biomarkers of response will be crucial. Local ablative therapies may augment systemic responses to immunotherapy. We evaluated circulating tumor DNA (ctDNA) as a biomarker of response in patients treated on a trial combining immunotherapy with local cryotherapy for advanced STS.
Patients And Methods:
We enrolled 30 patients with unresectable or metastatic STS to a phase II clinical trial. Patients received ipilimumab and nivolumab for four doses followed by nivolumab alone with cryoablation performed between cycles 1 and 2. The primary endpoint was objective response rate (ORR) by 14 weeks. Personalized ctDNA analysis using bespoke panels was performed on blood samples collected prior to each immunotherapy cycle.
Results:
ctDNA was detected in at least one sample for 96% of patients. Pretreatment ctDNA allele fraction was negatively associated with treatment response, progression-free survival (PFS), and overall survival (OS). ctDNA increased in 90% of patients from pretreatment to postcryotherapy, and patients with a subsequent decrease in ctDNA or undetectable ctDNA after cryotherapy had significantly better PFS. Of the 27 evaluable patients, the ORR was 4% by RECIST and 11% by irRECIST. Median PFS and OS were 2.7 and 12.0 months, respectively. No new safety signals were observed.
Conclusions:
ctDNA represents a promising biomarker for monitoring response to treatment in patients with advanced STS, warranting future prospective studies. Combining cryotherapy and immune checkpoint inhibitors did not increase the response rate of STS to immunotherapy.
Insights
Circulating tumor DNA (ctDNA) shows promise as a biomarker for tracking treatment response in advanced soft tissue sarcomas (STS). However, combining cryotherapy with immune checkpoint inhibitors did not improve response rates in this study.
Area of Science:
- Oncology
- Immunotherapy
- Biomarker Discovery
Background:
- Immune checkpoint inhibitors (ICIs) show promise in soft tissue sarcomas (STS), but response rates are limited.
- Biomarkers are crucial for predicting patient response to ICI therapy.
- Local ablative therapies are being investigated to enhance systemic immunotherapy efficacy.
Purpose of the Study:
- To evaluate circulating tumor DNA (ctDNA) as a predictive biomarker for treatment response in advanced STS.
- To assess the efficacy of combining ICIs (ipilimumab and nivolumab) with cryotherapy in advanced STS patients.
Main Methods:
- A phase II clinical trial enrolled 30 patients with unresectable or metastatic STS.
- Patients received ipilimumab and nivolumab, followed by nivolumab alone, with cryoablation between cycles 1 and 2.
- Personalized ctDNA analysis was performed on serial blood samples; objective response rate (ORR) was the primary endpoint.
Main Results:
- ctDNA was detected in 96% of patients; higher pretreatment ctDNA levels correlated with poorer outcomes (response, PFS, OS).
- A significant increase in ctDNA post-cryotherapy was observed in 90% of patients, with subsequent decreases predicting better progression-free survival (PFS).
- The ORR was low (4% RECIST, 11% irRECIST), with median PFS of 2.7 months and median overall survival (OS) of 12.0 months.
Conclusions:
- ctDNA is a promising biomarker for monitoring treatment response in advanced STS.
- The combination of cryotherapy and ICIs did not enhance the response rate in this STS cohort.
- Further prospective studies are warranted to validate ctDNA as a biomarker in STS immunotherapy.
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