Journal of Clinical Oncology SEPTEMBER 09, 2026

Personalized Circulating Tumor DNA Analysis for Predicting Outcomes and Tracking Response to Radiotherapy and Pembrolizumab in Localized Sarcomas: Analysis of the SU2C-SARC032 Trial

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

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Bottom Line

Tumor-informed personalized ctDNA profiling successfully detected baseline circulating tumor DNA in 85% of patients with localized soft tissue sarcomas and provided independent prognostic information for disease-free and overall survival throughout the perioperative period.

Key Findings

1. Personalized ctDNA profiling successfully detected baseline circulating tumor DNA in 85% of the 106 analyzed patients with localized soft tissue sarcomas, tracking a median of 46 somatic mutations per patient.

2. Baseline ctDNA levels significantly correlated with larger tumor size, histologic grade 3 disease, and the expression of genes related to hypoxia and the cell cycle.

3. ctDNA levels at multiple timepoints—pretreatment, after radiotherapy with or without immunotherapy (prior to surgery), and postsurgery—were strongly associated with both disease-free survival (DFS) and overall survival (OS) on both univariable and multivariable analyses.

4. Patients treated with neoadjuvant pembrolizumab, who experienced significantly better DFS compared to the control arm, exhibited a greater magnitude of decrease in their ctDNA levels following neoadjuvant therapy.

5. Personalized ctDNA analysis enabled noninvasive subclone tracking, revealing that patients who had multiple tumor clones detected by ctDNA after surgery experienced inferior clinical outcomes.

Study Design

Design

Secondary Biomarker Analysis

Open-Label

Sample

106

Patients

Duration

50.7 mo

Median

Setting

Multicenter, International

Population Patients with high-risk, localized, stage III soft tissue sarcoma (undifferentiated pleomorphic sarcoma or dedifferentiated/pleomorphic liposarcoma of the extremity) from the phase II SU2C-SARC032 trial.

Intervention Personalized, tumor-informed ctDNA tracking combined with preoperative radiotherapy and perioperative pembrolizumab (the experimental arm).

Comparator Standard of care preoperative radiotherapy alone (control arm), with comparisons mapped against ctDNA clearance/positivity.

Outcome Association of dynamic ctDNA levels (pretreatment, postradiotherapy/presurgery, and postsurgery) with disease-free survival (DFS) and overall survival (OS).

Study Limitations

• As a secondary, exploratory biomarker analysis of the phase II SU2C-SARC032 trial, the study is inherently limited by the parent trial's sample size (n=106 evaluated for ctDNA).

• Soft tissue sarcomas are rare and heterogeneous tumors with generally low mutational burdens, meaning that personalized tumor-informed assays (requiring prior whole-exome sequencing of tumor and germline DNA) remain technically challenging, time-consuming, and costly to implement across diverse subtypes.

• Because ctDNA monitoring was purely observational in this trial, the findings cannot determine whether actively modifying clinical treatment based on ctDNA dynamics would improve patient outcomes.

• The results require validation in prospective, ctDNA-guided interventional trials before these personalized liquid biopsy assays can be routinely adopted in standard sarcoma care.

Clinical Significance

This analysis represents a major milestone in sarcoma precision oncology by validating the feasibility and prognostic utility of tumor-informed ctDNA tracking in localized soft tissue sarcomas. By establishing that dynamic changes in ctDNA correlate strongly with long-term survival and immunotherapeutic response, these findings support utilizing ctDNA monitoring to identify high-risk patients who might benefit most from personalized, tailored adjuvant systemic therapies.

Historical Context

While liquid biopsies have transformed the management of common solid tumors like lung and colorectal cancers, their application in soft tissue sarcomas has lagged severely due to the rarity, extreme molecular heterogeneity, and typically low mutational burden of these diseases. The parent SU2C-SARC032 trial was a landmark randomized study that recently demonstrated the addition of perioperative pembrolizumab to radiotherapy and surgery significantly improved DFS in high-risk localized sarcomas. This 2026 biomarker analysis leverages that robust dataset to provide some of the first definitive evidence that customized ctDNA assays can successfully track microscopic disease and reflect immunotherapy response in this challenging setting.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the biological difference between a tumor-informed and a tumor-agnostic approach to detecting circulating tumor DNA (ctDNA), and why might a tumor-informed approach be particularly important in soft tissue sarcomas?

Key Response

Sarcomas have high genomic heterogeneity and diverse fusion genes or mutations compared to epithelial tumors. Tumor-informed assays sequence the primary tumor first to design a custom panel, increasing sensitivity for the specific mutations present in that patient's sarcoma, whereas agnostic panels might miss rare or unique sarcoma-specific variants.

Resident

If a patient with a localized high-grade extremity soft tissue sarcoma tests positive for ctDNA after completing neoadjuvant radiotherapy and pembrolizumab but before surgical resection, how might this finding influence your counseling regarding their prognosis?

Key Response

Persistent ctDNA post-neoadjuvant therapy strongly correlates with inferior disease-free and overall survival, indicating a high risk of micrometastatic disease. While it currently may not mandate a change in standard surgical management outside a trial, it informs the patient of a higher recurrence risk and underscores the importance of close postoperative surveillance.

Fellow

Given that the SU2C-SARC032 trial evaluated neoadjuvant pembrolizumab and radiotherapy, how might radiation-induced tumor necrosis and inflammation confound the interpretation of ctDNA clearance or spikes during the neoadjuvant window compared to systemic chemotherapy alone?

Key Response

Radiation causes profound cell death and can lead to a transient surge in cell-free DNA (including ctDNA) due to tumor lysis, which immune checkpoint inhibitors might exacerbate. Interpreting ctDNA kinetics requires understanding that an initial spike might represent effective therapy rather than progression, necessitating careful timing of blood draws to accurately assess true molecular response.

Attending

As ctDNA profiling moves closer to routine practice in localized soft tissue sarcomas, how should we ethically and practically manage 'molecular relapse' (ctDNA positivity without radiographic evidence of disease) in the adjuvant setting, given the current lack of proven targeted interventions for many STS subtypes?

Key Response

This highlights the clinical dilemma of lead-time bias. Detecting molecular relapse months before radiographic relapse causes significant patient anxiety. Until we have trials demonstrating that initiating systemic therapy at the time of molecular relapse improves overall survival compared to waiting for radiographic progression, we risk overtreating patients without a proven survival benefit.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In designing a tumor-informed ctDNA assay for a genetically diverse group like soft tissue sarcomas, how does the choice of variant calling algorithms and the threshold for the number of tracked mutations affect the assay's positive predictive value and sensitivity, particularly when accounting for clonal hematopoiesis of indeterminate potential (CHIP)?

Key Response

STS can have lower mutational burdens than melanoma or lung cancer. Tracking too few mutations reduces sensitivity, while tracking too many without stringent filtering increases false positives from CHIP or sequencing artifacts. Utilizing matched buffy coat sequencing to filter CHIP and employing consensus sequencing with unique molecular identifiers are critical methodological steps to ensure high PPV.

Journal Editor

When reviewing the survival analyses of the SU2C-SARC032 trial, what critical confounding variables regarding patient heterogeneity must be adjusted for in the multivariable Cox proportional hazards model to confirm that ctDNA is a truly independent prognostic biomarker?

Key Response

Soft tissue sarcoma is an umbrella term for distinct histologies with vastly different natural histories. A rigorous review would flag whether the prognostic value of ctDNA holds true across subtypes (e.g., undifferentiated pleomorphic sarcoma vs. liposarcoma) and whether it merely acts as a surrogate for known high-risk features like large size or high histological grade.

Guideline Committee

Current NCCN guidelines for localized soft tissue sarcomas rely on tumor size, grade, and depth for risk stratification and do not mandate routine ctDNA testing. Based on the 85% detection rate and prognostic value demonstrated in this study, what specific evidentiary milestones must be met before guidelines incorporate ctDNA testing to direct the use of adjuvant systemic therapy?

Key Response

While this study establishes analytical and clinical validity (prognostic value), guideline integration requires clinical utility. Guidelines require randomized controlled trial data demonstrating that escalating or de-escalating therapy based on ctDNA status improves outcomes like DFS or OS compared to standard of care. Until utility is proven, it remains an investigational tool.

Clinical Landscape

Noteworthy Related Trials

2017

SARC028 Trial

n = 86 · Lancet Oncol

Tested

Pembrolizumab 200mg every 3 weeks

Population

Patients with advanced soft-tissue and bone sarcomas

Comparator

None (Single-arm)

Endpoint

Objective response rate

Key result: Pembrolizumab showed meaningful clinical activity in specific sarcoma subtypes like undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma.

2020

STRASS Trial

n = 266 · Lancet Oncol

Tested

Neoadjuvant radiotherapy followed by surgery

Population

Patients with primary retroperitoneal sarcoma

Comparator

Surgery alone

Endpoint

Abdominal recurrence-free survival

Key result: Preoperative radiotherapy did not significantly improve abdominal recurrence-free survival compared to surgery alone in the overall cohort, highlighting a need for improved systemic combinations.

2021

IMvigor010 ctDNA Analysis

n = 581 · Nature

Tested

Adjuvant atezolizumab

Population

Patients with high-risk muscle-invasive urothelial carcinoma

Comparator

Observation

Endpoint

Disease-free survival and overall survival by ctDNA status

Key result: Patients who were positive for ctDNA showed improved disease-free and overall survival with immunotherapy, whereas ctDNA-negative patients did not derive significant benefit.

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