Table 1.

Most important tumor alterations investigable in circulating biomarkers by sequential LB analysis.

LB Biomarkers	Type of Evaluation	Results	Reference(s)
CTCs	Enumeration	Correlation between increased CTCs number and worse OS.	[37]
		Significant correlation among baseline levels of CTCs and PD.	[38]
		Association of CTCs detection with a shorter RFS.	[39]
		Correlation between CTCs number and BRAF and MEK inhibitors responses.	[40]
	Molecular characterization	Favorable effects in CTCs/PDL1+ patients in terms of PFS.	[41]
		Early assessment of response to immunotherapies by means of a 19-gene signature.	[42]
ctDNA	Mutation detection	Association between lower levels of circulating BRAF, NRAS, and c-KIT mutations at baseline and/or during anti-PDL1 treatment and better OS.	[43]
	Quantification	Higher levels of circulating genetic material correlated with significantly decreased PFS.	[44]
		Correlation among higher blood concentrations of ctDNA and better survival ranges withanti-PD1/CTLA-4 inhibitors treatment.	[45]
		Detection of changes in ctDNA blood levels between the onset of PD and treatment response.	[46]
	DNA methylation	Correlation between methylation of TFPI2 with metastatic melanoma.	[47]
Exsosomes	Proteomic characterization	Higher expression of immunosuppressive proteins in exosomes from the blood of melanoma patients than those of healthy donors.	[48]
		Significant increase in circulating PDL1 compared with healthy controls.	[49]
		Significant association between high S100B and MIA exosomal concentrations and shorter PFS.	[50]
	Circulating exsosomal miRNA	High-power diagnostic assessment of apEV-miRNAs panel (miR-412-3p, miR-507, miR-1203, and miR-362-3p).	[51]
ct-miRNA	Quantification	Prediction of target therapy responses with specific ct-miRNAs (miR-579-3p and miR-4488).	[52]
		Stratification of stage I–IV melanoma patients by a combination of 38 miRNAs (MEL38).	[53]
		Detection of tumor burden increase through a panel of seven melanoma-related biomarkers (MELmiR-7).	[54]
		Correlation between levels of miR-199a-5p, miR-877-3p, miR-1228-3p, miR-3613-5p, miR-182-5p, and higher melanoma stages.	[55]
		Correlation between ct-miRNAs in metastatic melanoma samples and poor clinical outcome, associated to immune evasion and tumor microenvironment response.	[56]
		Prediction of treatment response in melanoma stage IV patients with a panel of ct-miRNA (miR-1234-3p, miR-4649-3p, and miR-615-3p).	[57]