The Promise of Liquid Biopsy to Predict Response to Immunotherapy in Metastatic Melanoma

Abstract

Metastatic melanoma is the deadliest form of skin cancer whose incidence has been rising dramatically over the last few decades. Nowadays, the most successful approach in treating advanced melanoma is immunotherapy which encompasses the use of immune checkpoint blockers able to unleash the immune system’s activity against tumor cells. Immunotherapy has dramatically changed clinical practice by contributing to increasing long term overall survival. Despite these striking therapeutic effects, the clinical benefits are strongly mitigated by innate or acquired resistance. In this context, it is of utmost importance to develop methods capable of predicting patient response to immunotherapy. To this purpose, one major step forward may be provided by measuring non-invasive biomarkers in human fluids, namely Liquid Biopsies (LBs). Several LB approaches have been developed over the last few years thanks to technological breakthroughs that have allowed to evaluate circulating components also when they are present in low abundance. The elements of this so-called “circulome” mostly encompass: tumor DNA, tumor and immune cells, soluble factors and non-coding RNAs. Here, we review the current knowledge of these molecules as predictors of response to immunotherapy in metastatic melanoma and predict that LB will soon enter into routine practice in order to guide clinical decisions for cancer immunotherapy.

Liquid biopsy: a step closer to transform diagnosis, prognosis and future of cancer treatments

“…Moreover, the establishment of non-coding RNA signatures in the blood is more challenging than other common biomarkers due to their low abundance in body fluids, lack of suitable housekeeping non-coding RNA reference analytes, and high intra-patient variability. These limitations lead to a lack of consistency between biomarkers identified in different studies [ 227 ]. Laboratories performing LB assays might also need an initial histological examination by tissue biopsy to avoid over-interpretation of the diagnostic data.…”

Harnessing Liquid Biopsies to Guide Immune Checkpoint Inhibitor Therapy

“…The invasive nature of tissue biopsies also makes it unreasonable to obtain multiple samples throughout treatment. To overcome these challenges and complement invasive tissue biopsies, minimally invasive liquid biopsy—the sampling of blood or other bodily fluids containing tumour-derived entities analysable for biomarkers—is an attractive alternative [ 21 , 23 , 24 ]. Liquid biopsy also holds promise to better reflect tumor heterogeneity compared to tissue biopsies since the tumour derived entities might originate from different tumor sites and reflect characterstics from the primary tumor site as well as from metastatic sites.…”

“…Importantly, capturing these tumor biomarkers in blood provide a tumour snapshot in real time, and when assessed sequentially, it provides a holistic information of the tumor allowing for successive monitoring of the entire tumor heterogeneity and tumor evolution during the course of the treatment [ 22 ]. Tumour-derived entities present in blood may include circulating proteins, circulating tumor DNA (ctDNA) and RNA (ctRNA), extracellular vesicles (EVs) and circulating tumor cells (CTCs) [ 17 , 23 , 24 ] ( Figure 2 ). Recently, circulating immune cells can be used to detect biomarkers corresponding to patient-specific pathological information and function as relevant cancer biomarkers [ 24 , 25 ].…”

Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways

“…However, the responses are typically incomplete and short-lived due to intrinsic and extrinsic resistance mechanisms. Immunotherapies have also increased melanoma survival but it remains difficult to predict responses [4]. The drug therapy of brain metastases is further hampered by a limited drug penetration beyond the blood-brain barrier (BBB) [5,6].…”