Liquid biopsy utility for the surveillance of cutaneous malignant melanoma patients

Abstract

Cutaneous melanoma is one of the highest incident-rate cancers with increasing prevalence in Western societies. Despite the advent of new approved therapeutics, the 5-year overall survival rate of stage IV melanoma patients remains below 15%. Current treatments for late stage disease have shown higher efficacy when treated at a lower disease burden. Thus, blood-based biomarkers capable of detecting melanoma prior to clinically evident distant metastasis, will improve the treatment and outcomes for melanoma patients. To that end, effective treatment of melanoma necessitates identification of patients at risk for developing distant metastases. Furthermore, employing blood biomarkers that monitor cancer progression over the course of treatment is a promising solution to post-treatment drug resistance often developed in melanoma patients. Non-invasive blood biomarker assays allow for regular dynamic monitoring of disease. "Liquid Biopsy" of blood, which exploits circulating tumor cells (CTCs), cell-free circulating tumor DNA (ctDNA) and cell-free circulating microRNA (cmiRNA), has been shown to detect prognostic factors for relapse in AJCC stage III and stage IV melanoma patients. Moreover, molecular characterization of CTC and analysis of various forms of ctDNA present promising potential in development of individualized therapy for melanoma patients. New approaches such as massive parallel sequencing (MPS) provide a comprehensive view of the disease progression, allowing for the selection of therapeutic options for individual patients. With advancements of improving molecular assays, liquid biopsy analysis as a powerful, routine clinical assay for melanoma patients, is highly promising prospective.

Keywords: Cell-free DNA; Cell-free circulating tumor DNA; Cell-free microRNA; Circulating tumor cells; Liquid biopsy; Melanoma.

Figure 1

(1) Kaplan–Meier survival curves for stage III melanoma patients with CTC biomarker detection in pre‐treatment blood (baseline). (1A) Distant metastasis‐free and disease‐free survival was significantly worse for patients with ≥2 vs. 0–1 positive biomarkers (p = 0.025). (1B) Melanoma‐specific survival was significantly worse for patients with ≥2 vs. 0–1 positive biomarkers (p = 0.031) (Hoshimoto et al., 2012c). (2) Kaplan–Meier survival curves for stage IV melanoma patients with CTC biomarker detection in pre‐treatment blood (baseline). (2A) Overall survival tended to be worse for patients with >0 vs. 0 positive biomarkers (p = 0.028). (2B) Disease‐free survival was significantly worse for patients with >0 vs. 0 positive biomarkers (p = 0.002) (Hoshimoto et al., 2012a). (3) Kaplan–Meier survival curves for stage III melanoma patients with the detection of cmiR‐210 in plasma. cmiR‐210 expression was significantly related to disease outcome (3A) DFS and (3B) MSS: Comparison of melanoma patients with either >1 dCq increase in cmiR‐210 levels from baseline to prior to clinical recurrence bleed (n = 24 patients) vs. patients without such an increase (n = 64 patients). Blue line: No increase in cmiR‐210. Red line: Increase in cmiR‐210 (Ono et al., 2015b).