Liquid Biopsy in Hepatocellular Carcinoma: Where Are We Now?

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is one of the mostly lethal cancers, with a prognosis which is still very poor. Novel reliable biomarkers, useful in early diagnosis and prognosis assessment, are urgently needed in order to improve HCC patient survival. In recent years, several studies focused on liquid biopsy, the molecular analysis of circulating cancer by-products, as a source of novel biomarkers. Extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA provided very interesting results in a large number of studies published recently, but none of them has entered the clinical routine. In this review we will summarize the available evidence on these novel circulating biomarkers as diagnostic, prognostic, and predictive tools. Liquid biopsy proved to be a very useful source of biomarkers, some of which will probably be applied soon in clinical practice. ABSTRACT: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer related death worldwide. Diagnostic, prognostic, and predictive biomarkers are urgently needed in order to improve patient survival. Indeed, the most widely used biomarkers, such as alpha-fetoprotein (AFP), have limited accuracy as both diagnostic and prognostic tests. Liver biopsy provides an insight on the biology of the tumor, but it is an invasive procedure, not routinely used, and not representative of the whole neoplasia due to the demonstrated intra-tumoral heterogeneity. In recent years, liquid biopsy, defined as the molecular analysis of cancer by-products, released by the tumor in the bloodstream, emerged as an appealing source of new biomarkers. Several studies focused on evaluating extracellular vesicles, circulating tumor cells, cell-free DNA and non-coding RNA as novel reliable biomarkers. In this review, we aimed to provide a comprehensive overview on the most relevant available evidence on novel circulating biomarkers for early diagnosis, prognostic stratification, and therapeutic monitoring. Liquid biopsy seems to be a very promising instrument and, in the near future, some of these new non-invasive tools will probably change the clinical management of HCC patients.