Abstract
Simple SummaryMelanoma, like other solid tumors, releases DNA molecules that are referred to as circulating tumor DNA (ctDNA), into the blood and other biological fluids. ctDNA analysis performed with molecular biology techniques can provide important information on the aggressiveness of the disease and its genetic characteristics. This review aims to highlight all the possible clinical applications of ctDNA analysis that can contribute to an improvement in the diagnosis and therapy of melanoma.Malignant melanoma accounts for about 1% of all skin cancers, but it causes most of the skin cancer-related deaths. Circulating tumor DNA (ctDNA) testing is emerging as a relevant tool for the diagnosis and monitoring of cancer. The availability of highly sensitive techniques, including next generation sequencing (NGS)-based panels, has increased the fields of application of ctDNA testing. While ctDNA-based tests for the early detection of melanoma are not available yet, perioperative ctDNA analysis in patients with surgically resectable melanoma offers relevant prognostic information: i) the detection of ctDNA before surgery correlates with the extent and the aggressiveness of the disease; ii) ctDNA testing after surgery/adjuvant therapy identifies minimal residual disease; iii) testing ctDNA during the follow-up can detect a tumor recurrence, anticipating clinical/radiological progression. In patients with advanced melanoma, several studies have demonstrated that the analysis of ctDNA can better depict tumor heterogeneity and provides relevant prognostic information. In addition, ctDNA testing during treatment allows assessing the response to systemic therapy and identifying resistance mechanisms. Although validation in prospective clinical trials is needed for most of these approaches, ctDNA testing opens up new scenarios in the management of melanoma patients that could lead to improvements in the diagnosis and therapy of this disease.
Highlights
Melanoma is an aggressive and deadly disease that is responsible for the largest number of skin cancer-related deaths, it comprises less than 10% of skin cancers
The quantification with droplet digital PCR (ddPCR) of mutant BRAF-V600E copies in cell-free DNA (cfDNA) from 20 patients with metastatic melanoma showed a direct relationship between the BRAF-V600E copy numbers and clinical outcomes, where basal concentrations
Some studies have reported a very early spike in Circulating tumor DNA (ctDNA) concentration occurring 24/48 h after starting treatment with BRAF inhibitors [19,64]. This early spike is probably related to a massive release of tumor DNA due to treatment-induced tumor cell lysis. These findings strongly suggest that monitoring BRAF mutations in the cfDNA
Summary
Melanoma is an aggressive and deadly disease that is responsible for the largest number of skin cancer-related deaths, it comprises less than 10% of skin cancers. The therapeutic strategies for advanced melanoma have significantly improved in the past few years thanks to the introduction of targeted agents and immune checkpoint inhibitors. Both targeted therapy and immunotherapy have shown to reduce the rate of recurrence in patients with resectable, locally advanced disease. Mechanisms of intrinsic and acquired resistance greatly limit the activity of therapies in melanoma, especially in the most advanced phases of disease For this reason, the identification of non-invasive biomarkers could be key for facilitating early detection, patient stratification, and monitoring the response and resistance to therapy
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