The role of circulating tumor DNA in the management of melanoma: a literature review

Circulating tumor DNA (ctDNA) is an emerging noninvasive biomarker in melanoma, yet its clinical relevance varies by disease stage and tumor biology. This literature review integrates mechanistic concepts with clinical evidence to clarify where ctDNA provides meaningful insight for melanoma management. A comprehensive review of recent literature was conducted to evaluate biological mechanisms, detection methods, and clinical applications of ctDNA in melanoma care. Across multiple studies, detectable baseline ctDNA was consistently associated with worse overall and PFS, with hazard ratios generally ranging from 2 to 3. Low or undetectable pretreatment ctDNA correlated with improved outcomes in patients receiving immune checkpoint inhibitors and targeted therapies. Early ctDNA decline or clearance during treatment was associated with radiographic response, whereas persistent detectability suggested intrinsic resistance. Serial monitoring enabled identification of emerging resistance mutations, including NRAS, MEK1, and PI3K-pathway alterations, frequently preceding radiographic progression. In resected stage III melanoma, postoperative ctDNA positivity strongly predicted relapse, with hazard ratios approaching 10, and molecular recurrence often preceded clinical recurrence by several months. By contrast, early-stage melanoma demonstrated low ctDNA detection rates, often below 15%, reflecting limited tumor burden and low DNA shedding. Evidence is emerging to position ctDNA as a dynamic biomarker that complements conventional melanoma staging by capturing real-time tumor burden, treatment response, and residual disease. Its clinical utility is most robust in high-risk and advanced melanoma, where ctDNA reliably informs prognosis, molecular residual disease, and early relapse, while sensitivity constraints limit its current role in early-stage disease with low tumor burden.