PURPOSE: Circulating tumor DNA (ctDNA) has emerged as a noninvasive biomarker for minimal residual disease (MRD) detection in many solid tumors. However, the role of ctDNA in MRD monitoring for melanoma remains unexplored. In this retrospective study, we aim to assess the sensitivity of a commercially available, tumor-informed, exome-based, ctDNA assay to detect recurrence or relapse of melanoma. METHODS: Fifty-six patients with a history of stage II to IV melanoma with no evidence of disease and a seronegative (0 MTM/mL) ctDNA result that preceded histologic or radiologic confirmation of melanoma recurrence were identified. The overall sensitivity of ctDNA detection at recurrence or relapse was evaluated and further stratified based on anatomic sites of relapse. RESULTS: The ctDNA assay demonstrated an overall sensitivity of 53.6%. The odds of detecting ctDNA at relapse or recurrence were significant among patients with lymph node metastases (odds ratios [ORs], 12.0 [95% CI, 2.40 to 60.05]; P = .001) and patients with multiple anatomic sites (2+) of metastases (OR, 9.52 [95% CI, 1.10 to 82.44]; P = .027). Sensitivity for ctDNA detection of recurrence was 33.3% in the brain ( P = .248), 37.5% in skin or muscle ( P = .317), 61.5% in lung metastases ( P = .405), 75% in bone ( P = .625), 87.5% in liver was ( P = .034), and 87.5% in lymph node metastases ( P = .003). CONCLUSION: ctDNA monitoring shows potential for detecting relapse in patients with melanoma. The location of melanoma recurrence or relapse may affect shedding of ctDNA and its detection. Larger studies are needed to refine the role of ctDNA in recurrence detection and to improve its diagnostic performance to optimize oncologic surveillance.

CtDNA is evolving as an important biomarker for ICI treatment response assessment in advanced melanoma. However, the utility of ctDNA monitoring during concurrent ICI with RT remains incompletely explored. In this multicenter, retrospective study, patients with unresectable stage III/IV melanoma treated with ICI and palliative RT were identified. Patients had retrospectively collected, tumor-informed, exome-based, ctDNA monitoring within 3 months following RT. 50 patients treated with ICI and palliative RT were analyzed. Patients with ctDNA clearance had significantly longer OS (HR 2.10, 95% CI 1.16-3.80, p=0.014) compared to those with increasing or decreasing and detectable ctDNA following RT. One-year OS was 85.9% with ctDNA clearance, 30.6% with decreasing ctDNA, and 22.0% for increasing ctDNA. In a multivariable analysis, both decreasing and increasing ctDNA were associated with worse OS compared with ctDNA clearance (HR 5.08 [95% CI, 1.26–20.48, p=0.022] and HR 9.83 [95% CI, 2.69–35.94, p< 0.001], respectively). Among patients with advanced melanoma treated with ICI and palliative RT, ctDNA clearance is associated with significantly improved OS compared to patients with detectable ctDNA within 3 months following RT. Ongoing studies are needed to understand the role of ctDNA in this population.

Circulating tumor DNA (ctDNA) has rapidly emerged over the last several years as a sensitive biomarker for minimal residual disease (MRD), cancer that remains in the body but is undetectable by conventional imaging. Studies have shown its clinical utility across several cancer types, including colorectal cancer. However, its role in MRD detection and treatment monitoring for melanoma remains an evolving area of research. While multiple commercially available ctDNA assays exist, none have been clinically validated specifically for melanoma as of 2025. This chapter will explore the emerging landscape of blood-based biomarkers, such as ctDNA, for patients with melanoma and its role in clinical practice.

Background/Objectives: ctDNA is evolving as an important biomarker for prognostic assessment in advanced melanoma. However, the utility of ctDNA monitoring during concurrent ICI with RT remains incompletely explored. Methods: In this multicenter retrospective study, patients with unresectable stage III/IV melanoma treated with ICI and palliative RT were identified. Patients had retrospectively collected, tumor-informed, exome-based, ctDNA monitoring within 3 months following RT. Results: A total of 50 patients treated with ICI and palliative RT were analyzed. Compared with ctDNA clearance, ctDNA detectable and increasing was associated with worse OS (adjusted HR 2.52, 95% CI 1.20–5.29; p = 0.015), whereas ctDNA detectable and decreasing was not significantly different from ctDNA clearance (adjusted HR 1.58, 95% CI 0.69–3.65; p = 0.282). One-year OS was 87.5% with persistently undetectable ctDNA, 83.3% for ctDNA clearance, 46.3% for detectable and decreasing ctDNA, and 21.4% for detectable and increasing ctDNA. In a multivariable analysis, detectable and increasing ctDNA was associated with worse OS compared with ctDNA clearance (HR 2.52, 95% CI, 1.20–5.29, p = 0.015). Conclusions: Among patients with advanced melanoma treated with ICI and palliative RT, ctDNA clearance is associated with significantly improved OS compared to patients with detectable and increasing ctDNA within 3 months following RT. Ongoing prospective studies are needed to understand the role of ctDNA in this population.