Citation
Miller DM, Sondak VK, Chandra S, Tsai KY, Kaufman HL, Gupta S, Brownell I, Saito Y, Silk AW, Thakuria M, Nghiem PT. The evolving role of ctDNA in Merkel cell carcinoma: Challenges and opportunities. Journal of Cutaneous Oncology. 2025;3(1). doi:10.59449/joco.2025.04.02.
Why this article matters
Surveillance after definitive treatment for Merkel cell carcinoma remains challenging. Imaging is effective but costly, logistically burdensome, and associated with radiation exposure, while existing blood-based biomarkers are not informative for every patient.
Tumor-informed circulating tumor DNA offers a potential molecular measure of minimal residual disease that can be used in both virus-positive and virus-negative MCC. The key question is no longer whether ctDNA is associated with recurrence, but how clinicians should incorporate that signal into surveillance and treatment decisions.
ctDNA is emerging as a powerful surveillance biomarker in MCC, particularly because serial negative results provide strong short-term reassurance and positive results identify patients at markedly increased recurrence risk. Its role in initiating systemic therapy, however, remains unproven.
The featured study at a glance
Patients across discovery and validation cohorts
The study enrolled 167 patients in the discovery cohort and 152 in the validation cohort.
Positive versus negative post-treatment ctDNA
Early positivity after curative-intent therapy identified patients at substantially greater risk of recurrence.
Negative predictive value at 135 days
A negative result was strongly associated with remaining recurrence free over the following several months.
What the study establishes
- Post-treatment ctDNA positivity is strongly associated with recurrence.
- The recurrence signal persists after adjustment for stage, immunosuppression, sex, and age.
- Serial negative ctDNA results provide meaningful short-term reassurance.
- ctDNA can become positive before recurrence is apparent on imaging or physical examination.
- Tumor-informed testing is applicable to both virus-positive and virus-negative MCC.
Where ctDNA may add value
Risk-adapted surveillance
Persistently negative results may support longer imaging intervals, while new positivity may justify earlier imaging or intensified follow-up.
Earlier recurrence detection
Molecular recurrence may be identified before disease is visible using conventional radiographic or clinical assessment.
Monitoring treatment response
Serial changes in ctDNA may provide a dynamic measure of disease burden during systemic or locoregional therapy.
Informing treatment duration
Persistent positivity may eventually help identify patients in whom treatment discontinuation would carry greater risk.
The unresolved clinical question
A positive ctDNA test in a clinically disease-free patient creates a new category of uncertainty: molecular evidence of disease without radiographic or pathologic confirmation. Although preemptive immunotherapy is conceptually appealing, treatment based on ctDNA alone could expose patients to toxicity without proof that earlier intervention improves outcomes.
Surveyed clinicians were generally comfortable using ctDNA to shape surveillance but remained reluctant to initiate immune checkpoint blockade solely because of molecular positivity. Most wanted prospective evidence demonstrating that ctDNA-directed treatment improves clinically meaningful outcomes.
ctDNA has crossed the threshold from investigational biomarker to clinically useful surveillance tool. It has not yet crossed the threshold required to serve as a stand-alone indication for systemic therapy.
What clinicians reported
- Surveillance was the most common real-world use of ctDNA.
- Far fewer clinicians used ctDNA to guide systemic treatment decisions.
- More than one-third reported regular surveillance use, with additional selective use in high-risk cases.
- Most respondents viewed ctDNA as valuable, although uncertainty remained about its precise role.
- No surveyed clinicians had initiated systemic therapy solely on the basis of ctDNA positivity without additional clinical context.
Barriers to implementation
Cost and coverage
Reimbursement, patient financial responsibility, and long-term cost-effectiveness remain difficult to predict.
Operational complexity
Tumor-informed testing requires pathology retrieval, specialized sample handling, vendor coordination, and longitudinal result tracking.
Guideline uncertainty
Recognition as a surveillance option does not yet provide detailed guidance on imaging substitution, testing intervals, or treatment action thresholds.
Outcome validation
Demonstrating earlier detection is not the same as proving that ctDNA-guided intervention improves survival, quality of life, or treatment burden.
The most defensible current use of ctDNA is to complement—not automatically replace—clinical examination and imaging. Negative results may support de-escalation, while positive results should trigger intensified evaluation rather than reflexive treatment.
What comes next
- Prospective trials of ctDNA-guided surveillance intensity.
- Studies testing whether molecularly triggered intervention improves outcomes.
- Standardized thresholds, timing, and interpretation across assays.
- Clearer reimbursement pathways and integration into electronic health records.
- Consensus guidance distinguishing surveillance use from treatment-directed use.
Authors
David M. Miller, Vernon K. Sondak, Sunandana Chandra, Kenneth Y. Tsai, Howard L. Kaufman, Sameer Gupta, Isaac Brownell, Yoshine Saito, Ann W. Silk, Manisha Thakuria, and Paul T. Nghiem.