Can Early ctDNA Changes Predict Immunotherapy Response in Colorectal Cancer?
In this article
Immune checkpoint inhibitors (immunotherapies)have transformed treatment for metastatic colorectal cancer (mCRC), particularly when tumors show dMMR/MSI-H as a biomarker.
dMMR/MSI-His a biomarker arising from disruption of the DNA mismatch repair (MMR) system, characterized by microsatellite instability (MSI-H) and mismatch repair deficiency (dMMR).
This increases sensitivity to immunotherapies by making it easier for the immune system to recognize the tumor .
Approximately 5% of patients with metastatic colorectal cancer have a dMMR/MSI-H profile.
Although dMMR/MSI-H tumors respond well to immunotherapies, two critical questions remain unanswered:
- Which patients show a lack of response to initial treatment (primary resistance)?
- When should treatment be stopped in patients who respond?
Answering these questions is crucial for preventing unnecessary side effects and the rational use of costly treatments .
New hope: The change in ctDNA (circulating tumor DNA) levels just 1 month after treatment begins!
These findings were reported on July 18, 2025, in JAMA Oncology in a study published by Taïeb J. and colleagues.
SAMCO-PRODIGE 54 Trial
- Phase 2 randomized clinical trial
- Participants: dMMR/MSI-H mCRC patients (99 patients)
- Two arms:
- Avelumab (anti–PD-L1 immunotherapy)
- Standard chemotherapy ± targeted therapy
- Blood samples were collected before treatment (V1) and at month 1 (V2)
- ctDNA was analyzed using the WIF1 and NPY methylation markers, with the ddPCR method
📊 Main Findings
- Baseline ctDNA presencewas not associated with survival.
- However, a ≥86% ctDNA reduction at month 1:
- Progression-free survival (PFS): A 3-fold lower risk of progression (HR: 2.98; p < .001)
- Overall survival (OS): A 3.6-fold lower risk of death (HR: 3.61; p < .001)
- In the Avelumab arm: Patients with a poor ctDNA response had a 17-fold higher risk of death (HR: 17.40; p < .001)
- Concordance between a good ctDNA response and radiological response was over 90%
Clinical Interpretation
- After just 1 month, a blood test can show whether the treatment is working
- If an early ctDNA decrease is absent → consider alternative treatment
- If a strong ctDNA response is present → treatment duration may be shortened
- Combining ctDNA response with radiological assessment (RECIST) can provide much stronger and more reliable predictions about the disease course.
📉 Summary in Numbers
| Patient Group | PFS (months) | OS (months) | Hazard Ratio (HR) |
|---|---|---|---|
| Good ctDNA Response (≥86% reduction) | 12.0 | Not reached | Reference |
| Poor ctDNA Response (<86%) | 2.4 | 14.0 | PFS HR: 2.98; OS HR: 3.61 |
| Avelumab + poor ctDNA response | 2.3 | 15.0 | OS HR: 17.40 |
⚠️ Limitations
- The number of participants was relatively small (99 patients)
- ctDNA was measured only at month 1 in this assessment
- Only Avelumab was tested; other immunotherapies were not included in the trial
Conclusion: ctDNA Monitoring May Be a New Compass
SAMCO-PRODIGE 54 showed that, in immunotherapy-treated dMMR/MSI-H mCRC patients, early changes in ctDNA levels may be useful for predicting:
- Treatment response
- Development of drug resistance
- Long-term survival
as a powerful biomarker.
💡 ctDNA data, when assessed alongside conventional radiological imaging , may usher in a new era in personalized oncology .
🔍 Technology Behind the ctDNA Test Used
There are two main approaches to ctDNA analysis:
-
Tumor-informed: Specifically designed according to unique genetic mutations in the patient’s tumor tissue. Sensitivity is high, but time and cost may be limiting.
-
Tumor-agnostic: Requires no tumor-specific information. Relies on universal genetic or epigenetic markers. Faster and more suitable for clinical implementation.
📌 This study used a tumor-agnostic approach. That is, analysis used ctDNA methylation markers (WIF1 and NPY) without patient-specific mutation analysis.
🧪 Method Used
- Markers: WIF1 and NPY (methylation patterns)
- Technology: Bisulfite conversion + droplet digital PCR (ddPCR)
- Timing: Before treatment (V1) and month 1 (V2)
Because it does not require mutation analysis of tumor tissue, this method is considered fast, affordable and easy to implement clinically .
💡 Tumor-Agnostic vs Tumor-Informed Comparison
| Feature | Tumor-Informed | Tumor-Agnostic (This study) |
|---|---|---|
| Is tumor tissue required? | Yes | No |
| Individually designed? | Yes (based on specific mutations) | No (universal methylation markers) |
| Sensitivity | Very high (LOD < 0.01%) | Moderate (LOD ~0.2%) |
| Suitable patient profile | MRD / early-stage patients | Metastatic disease, high tumor burden |
| Clinical feasibility | Difficult, time-consuming | Easy, fast, cost-effective |
✅ Why Was the Tumor-Agnostic Method Chosen?
- In metastatic CRC patients, ctDNA levels are generally high → ddPCR is sufficient
- Rapid, inexpensive implementation offers a clinical advantage
- Goal: Detect the early response to treatment
🎯 ctDNA and MRD in Solid Tumors: New Horizons
Although this trial produced strong signals, some unanswered questions remain important:
- What is the best ctDNA testing strategy?
- What are the optimal monitoring intervals?
- Does ctDNA negativity always mean a good prognosis?
- If ctDNA and RECIST disagree, which should guide decisions?
Larger, prospective studies with multiple time points are needed to answer these questions.
However: The data already obtained provide a strong foundation for integrating ctDNA into clinical decision support tools in practice.
Sources
Was this article helpful?
Your feedback helps us improve our content.
Reader comments
Share your comment
Your name and comment are published only after administrator approval. Your email address is never shown to visitors.
Be the first to comment.