Circulating Tumor DNA as a Biomarker for Melanoma Prognosis and Therapy.

With more than 300,000 new cases diagnosed in 2022 and a projected rise in incidence until the year 2040, malignant melanoma remains a major global health challenge. Of note, immunotherapy has substantially improved survival outcomes, even in advanced stages. Nevertheless, reliable biomarkers for early relapse detection, risk stratification, and treatment monitoring remain an unmet clinical need. Conventional surveillance tools, including imaging, lactate dehydrogenase (LDH), and S100B, are limited by their sensitivity and specificity, particularly in patients with low tumor burden. The use of liquid biopsy, the analysis of body fluids such as blood, with its wide range of analytes and highly sensitive analysis methods, may represent a novel strategy to overcome the limitations of conventional biomarkers. In particular, the analysis of circulating cell-free nucleic acids from the tumor released to the blood, referred to as circulating tumor DNA (ctDNA), has emerged as a minimally invasive approach capable of capturing tumor-derived molecular information from plasma in solid tumors. ctDNA holds promise as a tool for the detection of minimal residual disease (MRD), early relapse, clonal evolution, and actionable genomic alterations. Technological advances have expanded ctDNA applications from single-mutation assays to comprehensive personalized NGS strategies and multi-modal approaches incorporating methylation profiling and fragmentomics. Clinical studies increasingly demonstrate that ctDNA detection and ctDNA dynamics provide prognostic and potentially predictive information across both (neo)adjuvant and advanced melanoma settings. In this review, we summarize the current methodological approaches and clinical evidence supporting ctDNA as a biomarker for prognosis, risk stratification, and therapy monitoring in melanoma.