Treatment of metastatic melanoma has undergone tremendous changes over the past few years. There are now highly effective systemic therapies available: targeted therapy with BRAF and MEK inhibitors in BRAF-V600-mutant melanoma and immunotherapies, including PD-1 antibodies with or without CTLA-4 antibody, that can be used regardless of mutational status. However, long-term tumor control is only achieved in a minority of patients. Liquid biopsy using circulating tumor cells, circulating tumor DNA (ctDNA), circulating mRNA and micro-RNA might represent valuable biomarkers, e.g. in the setting of systemic treatment for metastatic melanoma. Pre-treatment detection of BRAF V600-mutant ctDNA has been shown to be a prognostic factor in patients receiving BRAF/MEK inhibitor treatment. Furthermore, monitoring of ctDNA of known driver mutations can be used for treatment monitoring and detection of acquired resistance. However, results of the currently available studies need to be interpreted with caution as multiple approaches were used that are hardly comparable. So far, even with advancement of methods, there are only prognostic but no predictive biomarkers available.

1.
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al.: Cancer incidence and mortality patterns in europe: Estimates for 40 countries in 2012. Eur J Cancer 2013;49:1374-1403.
2.
Tsao H, Atkins MB, Sober AJ: Management of cutaneous melanoma. N Engl J Med 2004;351:998-1012.
3.
Karimkhani C, Green AC, Nijsten T, et al.: The global burden of melanoma: Results from global burden of disease study 2015. Br J Dermatol 2017 [Epub ahead of print].
4.
Larkin J, Ascierto PA, Dreno B, et al.: Combined vemurafenib and cobimetinib in braf-mutated melanoma. N Engl J Med 2014;371:1867-1876.
5.
Long GV, Stroyakovskiy D, Gogas H, et al.: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: A multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015;386:444-451.
6.
Larkin J, Chiarion-Sileni V, Gonzalez R, et al.: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 2015;373:23-34.
7.
Robert C, Long GV, Brady B, et al.: Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 2015;372:320-330.
8.
Robert C, Schachter J, Long GV, et al.: Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 2015;372:2521-2532.
9.
Andtbacka RH, Ross M, Puzanov I, et al.: Patterns of clinical response with Talimogene laherparepvec (T-VEC) in patients with melanoma treated in the OPTiM phase III clinical trial. Ann Surg Oncol 2016;23:4169-4177.
10.
Rosenberg SA, Yang JC, Sherry RM, et al.: Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011;17:4550-4557.
11.
Rafique I, Kirkwood JM, Tarhini AA: Immune checkpoint blockade and interferon-alpha in melanoma. Semin Oncol 2015;42:436-447.
12.
Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol 2015;16:522-530.
13.
Gogas H, Eggermont AM, Hauschild A, et al.: Biomarkers in melanoma. Ann Oncol 2009;20 Suppl 6:vi8-13.
14.
Schwarzenbach H, Hoon DS, Pantel K: Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011;11:426-437.
15.
Wan JC, Massie C, Garcia-Corbacho J, et al.: Liquid biopsies come of age: Towards implementation of circulating tumour DNA. Nat Rev Cancer 2017;17:223-238.
16.
Smith B, Selby P, Southgate J, et al.: Detection of melanoma cells in peripheral blood by means of reverse transcriptase and polymerase chain reaction. Lancet 1991;338:1227-1229.
17.
Rodic S, Mihalcioiu C, Saleh RR: Detection methods of circulating tumor cells in cutaneous melanoma: A systematic review. Crit Rev Oncol Hematol 2014;91:74-92.
18.
Palmirotta R, Lovero D, Silvestris E, et al.: Next-generation sequencing (NGS) analysis on single circulating tumor cells (CTCs) with no need of whole-genome amplification (WGA). Cancer Genomics Proteomics 2017;14:173-179.
19.
Ramskold D, Luo S, Wang YC, et al.: Full-length mRNA-Seq from single-cell levels of RNA and individual circulating tumor cells. Nat Biotechnol 2012;30:777-782.
20.
Koyanagi K, Kuo C, Nakagawa T, et al.: Multimarker quantitative real-time pcr detection of circulating melanoma cells in peripheral blood: Relation to disease stage in melanoma patients. Clin Chem 2005;51:981-988.
21.
Garbe C, Leiter U, Ellwanger U, et al.: Diagnostic value and prognostic significance of protein S-100beta, melanoma-inhibitory activity, and tyrosinase/MART-1 reverse transcription-polymerase chain reaction in the follow-up of high-risk melanoma patients. Cancer 2003;97:1737-1745.
22.
Hoshimoto S, Shingai T, Morton DL, et al.: Association between circulating tumor cells and prognosis in patients with stage III melanoma with sentinel lymph node metastasis in a phase iii international multicenter trial. J Clin Oncol 2012;30:3819-3826.
23.
Hoshimoto S, Faries MB, Morton DL, et al.: Assessment of prognostic circulating tumor cells in a phase III trial of adjuvant immunotherapy after complete resection of stage iv melanoma. Ann Surg 2012;255:357-362.
24.
Fusi A, Collette S, Busse A, et al.: Circulating melanoma cells and distant metastasis-free survival in stage III melanoma patients with or without adjuvant interferon treatment (EORTC 18991 side study). Eur J Cancer 2009;45:3189-3197.
25.
Koyanagi K, Mori T, O'Day SJ, et al.: Association of circulating tumor cells with serum tumor-related methylated DNA in peripheral blood of melanoma patients. Cancer Res 2006;66:6111-6117.
26.
Khoja L, Lorigan P, Zhou C, et al.: Biomarker utility of circulating tumor cells in metastatic cutaneous melanoma. J Invest Dermatol 2013;133:1582-1590.
27.
Klinac D, Gray ES, Freeman JB, et al.: Monitoring changes in circulating tumour cells as a prognostic indicator of overall survival and treatment response in patients with metastatic melanoma. BMC Cancer 2014;14:423.
28.
Shinozaki M, O'Day SJ, Kitago M, et al.: Utility of circulating B-RAF DNA mutation in serum for monitoring melanoma patients receiving biochemotherapy. Clin Cancer Res 2007;13:2068-2074.
29.
Fujiwara Y, Chi DD, Wang H, et al.: Plasma DNA microsatellites as tumor-specific markers and indicators of tumor progression in melanoma patients. Cancer Res 1999;59:1567-1571.
30.
Taback B, O'Day SJ, Boasberg PD, et al.: Circulating DNA microsatellites: Molecular determinants of response to biochemotherapy in patients with metastatic melanoma. J Natl Cancer Inst 2004;96:152-156.
31.
Lo Nigro C, Wang H, McHugh A, et al.: Methylated tissue factor pathway inhibitor 2 (TFPI2) DNA in serum is a biomarker of metastatic melanoma. J Invest Dermatol 2013;133:1278-1285.
32.
Mori T, O'Day SJ, Umetani N, et al.: Predictive utility of circulating methylated DNA in serum of melanoma patients receiving biochemotherapy. J Clin Oncol 2005;23:9351-9358.
33.
Board RE, Ellison G, Orr MC, et al.: Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study. Br J Cancer 2009;101:1724-1730.
34.
Daniotti M, Vallacchi V, Rivoltini L, et al.: Detection of mutated BRAFV600E variant in circulating DNA of stage III-IV melanoma patients. Int J Cancer 2007;120:2439-2444.
35.
Gray ES, Rizos H, Reid AL, et al.: Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma. Oncotarget 2015;6:42008-42018.
36.
Santiago-Walker A, Gagnon R, Mazumdar J, et al.: Correlation of BRAF mutation status in circulating-free DNA and tumor and association with clinical outcome across four BRAFi and MEKi clinical trials. Clin Cancer Res 2016;22:567-574.
37.
Gonzalez-Cao M, Mayo-de-Las-Casas C, Molina-Vila MA, et al.: BRAF mutation analysis in circulating free tumor DNA of melanoma patients treated with BRAF inhibitors. Melanoma Res 2015;25:486-495.
38.
Schreuer M, Meersseman G, Van Den Herrewegen S, et al.: Quantitative assessment of BRAF V600 mutant circulating cell-free tumor DNA as a tool for therapeutic monitoring in metastatic melanoma patients treated with BRAF/MEK inhibitors. J Transl Med 2016;14:95.
39.
Xi L, Pham TH, Payabyab EC, et al.: Circulating tumor DNA as an early indicator of response to T-cell transfer immunotherapy in metastatic melanoma. Clin Cancer Res 2016;22:5480-5486.
40.
Bettegowda C, Sausen M, Leary RJ, et al.: Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014;6:224ra224.
41.
Girotti MR, Gremel G, Lee R, et al.: Application of sequencing, liquid biopsies, and patient-derived xenografts for personalized medicine in melanoma. Cancer Discov 2016;6:286-299.
42.
Tsao SC, Weiss J, Hudson C, et al.: Monitoring response to therapy in melanoma by quantifying circulating tumour DNA with droplet digital PCR for BRAF and NRAS mutations. Sci Rep 2015;5:11198.
43.
Quaglino P, Osella-Abate S, Cappello N, et al.: Prognostic relevance of baseline and sequential peripheral blood tyrosinase expression in 200 consecutive advanced metastatic melanoma patients. Melanoma Res 2007;17:75-82.
44.
Best MG, Sol N, Kooi I, et al.: RNA-Seq of tumor-educated platelets enables blood-based pan-cancer, multiclass, and molecular pathway cancer diagnostics. Cancer Cell 2015;28:666-676.
45.
Fogli S, Polini B, Carpi S, et al.: Identification of plasma microRNAs as new potential biomarkers with high diagnostic power in human cutaneous melanoma. Tumour Biol 2017;39:1010428317701646.
46.
Ono S, Oyama T, Lam S, et al.: A direct plasma assay of circulating microRNA-210 of hypoxia can identify early systemic metastasis recurrence in melanoma patients. Oncotarget 2015;6:7053-7064.
47.
Huang SK, Hoon DS: Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients. Mol Oncol 2016;10:450-463.
48.
De Giorgi V, Pinzani P, Salvianti F, et al.: Circulating benign nevus cells detected by ISET technique: Warning for melanoma molecular diagnosis. Arch Dermatol 2010;146:1120-1124.
49.
Gray ES, Reid AL, Bowyer S, et al.: Circulating melanoma cell subpopulations: Their heterogeneity and differential responses to treatment. J Invest Dermatol 2015;135:2040-2048.
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