Minimal Residual Disease (MRD) and the Role of Circulating Tumor DNA (ctDNA) in Sarcomas

🧬 A New Era in Sarcoma: Monitoring MRD with ctDNA

Sarcomas arise from bone and soft tissue, with more than 70 histological subtypes, and are rare but aggressive cancers. Despite treatment advances, high recurrence and metastasis rates heavily affect survival and quality of life. Conventional surveillance waits for disease to become apparent, so microscopic residual disease (MRD, minimal residual disease) may be missed.

Circulating tumor DNA (ctDNA)-based MRD detectionis attracting attention for its potential to fill this gap. We examine its role, benefits and limitations in sarcoma monitoring.

Minimal Residual Disease (MRD)means tumor cells remaining after treatment in numbers too small for imaging detection.

• These cells are the main source of recurrence and metastasis.
• Detecting MRD is critical for determining whether disease has entered complete remission .
• In high-risk cancers such as sarcoma, early MRD detection offers the opportunity to predict recurrence and intervene promptly .

Circulating tumor DNA (ctDNA)is genetic material released into blood through tumor cell apoptosis, necrosis or active secretion.

These fragments carry the tumor's genetic mutations and reveal its biological signature . ctDNA thus acts as a unique “fingerprint” of cancer.

Through a simple blood test, liquid biopsy , these fingerprints can be isolated and analyzed. Even when tissue biopsy is impossible, ctDNA can reveal the disease's genetic profile .

Serial ctDNA measurementscan reflect changes in tumor burden in real time .

Sarcomas' genetic diversity and high recurrence riskmake ctDNA-based MRD monitoring particularly relevant.

Recent research shows promise for early recurrence detection and treatment response assessment :

In a Stanford University study, Signatera , a tumor-specific ctDNA test, was evaluated in 16 high-risk sarcoma patients. Concordance between ctDNA and radiological recurrence was 87.5% .

In 5 of 6 relapsing patients (83.3%), ctDNA became positive before imaging findings, on average 66 (pleomorphic liposarcoma), 49 and 14 (both leiomyosarcoma) days earlier . This shows that molecular progression may be identified much earlier than radiological disease.

Sensitivity: 83.3%
Specificity: 90%

These findings support ctDNA as an early warning tool in sarcoma surveillance.

A Natera study presented at ASCO 2025, with the largest sarcoma cohort to date, analyzed:

• Approximately 200 patients and 2100+ plasma samples .
• The Signatera testdetected recurrence with:
  • Sensitivity: 89%
  • Specificity: 100%
• In leiomyosarcoma, sensitivity was 93% .

Conclusion: These rates suggest ctDNA may be a reliable monitoring tool , particularly for subtypes such as leiomyosarcoma.

Changes in ctDNA levels may allow real-time monitoring of treatment response .

In Natera's study, leiomyosarcoma patients showed a correlation between ctDNA kinetics (rate of change) and treatment response of 90% .

Yiwei Fu and colleaguescreated personalized tumor-informed MRD panels and assessed 84 sarcoma patients:

• Successful MRD panel construction: 78.6%
• Bone tumors: 85.1% – Soft tissue sarcomas: 75%

Postoperatively, 8 of 27 patients described as ctDNA-positive (30%) tested positive. In 3 of these patients, recurrence was confirmed 12, 30 and 101 days after ctDNA positivity on imaging.

In two patients receiving neoadjuvant treatment, changes in ctDNA allele frequency paralleled tumor size:

• Stable allele frequency : The tumor continued growing.
• Decreasing allele frequency : Tumor shrinkage was observed.

These data suggest ctDNA may predict not only recurrence but also treatment efficacy .

ctDNA testing may support patient-specific treatment planning .

• ctDNA-negative patients have lower recurrence risk, potentially allowing avoidance of unnecessary, toxic adjuvant treatment.
• Persistently ctDNA-positive patients may undergo treatment intensification or alternative strategies .

This approach may improve efficacy and also quality of life while reducing treatment costs potentially.

Answer: Yes, patients can remain ctDNA-negative and nevertheless relapse; this does occur. Called a “false negative,” it relates to test sensitivity.

• In the Stanford study, 1 of 6 patients relapsed despite negative ctDNA, giving a 16.7% false-negative rate.
• Overall sensitivity in the Natera study: 89% → ctDNA may miss recurrence in approximately 11 of every 100 patients.

Reasons:

• Low tumor burden → May remain below the detection threshold.
• Heterogeneous shedding → Not all tumors release equal ctDNA.
• Tumor location → Brain tumors, for example, release limited ctDNA into circulation.
• Test sensitivity → The minimum detectable allele frequency is critical.

Note: ctDNA surveillance must therefore be performed alongside radiological imaging .

Yes. Sarcomas' broad genetic diversity makes monitoring more complex. Tumor-specific, personalized ctDNA panels should therefore be preferred.

• Tumor-informed testsare more sensitive than general panels.
• TMB (mutation burden) may be low in some types, reducing ctDNA detectability.
• Fusion genes in sarcomas may be better monitored with specialized tests.

Because approximately 64% of sarcoma mutations are patient-specific, tumor-informed MRDappears superior to panel-based MRD. This individual variation suggests tumor-specific personalized panels provide more sensitive and effective monitoring.

Ewing Sarcoma: Carrying fusion genes such as EWSR1-FLI1, this tumor allows ctDNA monitoring with high sensitivity .

• Techniques such as ddPCR can monitor these genes in ctDNA.
• ctDNA clearance is associated with good prognosis; persistence with poor prognosis.

GIST: Generally carries KIT or PDGFRA mutations.

• These mutations can be monitored for TKI response and resistance .
• In MRD and treatment monitoring, ctDNA may support clinical decisions in high-risk patients.

Summary: In sarcoma subtypes with distinct genetic markers, ctDNA monitoring is more effective and targeted as a strategy.

Several barriers remain before ctDNA-based MRD detection can enter routine sarcoma care:

• Lack of Standardization: Methods are not yet harmonized.
• High Cost: Tumor-specific personalized ctDNA tests remain expensive.
• Lack of Prospective Data: Large prospective studies and clinical guidelines are needed.

🔬 Growing interest in liquid biopsy and technological advances make these limitations likely to be overcome in the near future.

With cheaper, more sensitive and accessible tests, ctDNA monitoring in oncology may become a standard surveillance tool.

Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detectionhas the potential to open a new chapter in sarcoma follow-up.

• Early recurrence detection gives patients more time,
• Dynamically assesses response,
• Supports personalized treatment decisions.

Future large studies will accelerate this technology's integration into clinical decision algorithms , offering tangible benefits in survival and quality of life.

We will continue following and reporting this transformation.