Liquid Biopsy in Hepatocellular Carcinoma: Opportunities and Challenges for Immunotherapy

Abstract

Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. HCC is often diagnosed at a late stage when the therapeutic options are very limited. However, even at the earlier stages, the best treatment is liver transplantation, surgical resection or ablation. Surgical resection and ablation may carry a high risk of tumor recurrence. The recent introduction of immunotherapies resulted in clinical responses for a subgroup of patients, but there were still no effective predictive markers for response to immunotherapy or for recurrence after surgical therapy. The identification of biomarkers that could correlate and predict response or recurrence would require close monitoring of the patients throughout and after the completion of treatment. However, this would not be performed efficiently by repeated and invasive tissue biopsies. A better approach would be to use liquid biopsies including circulating tumor DNA (ctDNA), circulating RNA (e.g., microRNAs), circulating tumor cells (CTC) and extracellular vesicles (EVs) (e.g., exosomes) for disease monitoring in a non-invasive manner. In this review, we discuss the currently available technology that can enable the use of liquid biopsy as a diagnostic and prognostic tool. Moreover, we discuss the opportunities and challenges of the clinical application of liquid biopsy for immunotherapy of HCC.

Non-Invasive Biomarkers for Immunotherapy in Patients with Hepatocellular Carcinoma: Current Knowledge and Future Perspectives

“…A liquid biopsy can overcome these limitations. It is a non-invasive approach of detecting tumor-derived products that can be performed at different time points, drawing a personalized and dynamic picture of HCC’s evolution and response to therapy [ 23 ]. There are various tumor by-products that can be measured in the bloodstream alone or in combination [ 24 ], some of which are well-known and traditionally linked to the mechanisms of carcinogenesis (e.g., cytokines and alpha-fetoprotein), while others have only recently been studied (e.g., circulating tumor cells, DNA, RNA, and exosomes).…”

Immunotherapy for nonalcoholic fatty liver disease-related hepatocellular carcinoma: Lights and shadows

“…Hence, biomarkers identified through liquid biopsy, such as circulating tumor DNA[ 102 ], miRNAs[ 103 ], tumor cells[ 104 ], and extracellular vesicles[ 105 ], have been considered. However, no biological marker has demonstrated a strong predictive value in patients with HCC[ 106 ]. Scheiner et al [ 107 ] developed and proposed the C-reactive protein and -fetoprotein in immunotherapy (CRAFITY) score as an easily applicable clinical tool to predict response to ICIs in patients with HCC.…”

“…Furthermore, the composition of the gut microbiota changes over time during immunotherapy, which might be associated with a modification in the expression of immunomodulating pathways or vice versa may be a result of the modulating effect of the immune system on the gut microenvironment. Whether these modifications can predict responses that are essential for making further treatment decisions[ 106 ] needs further confirmation. Based on these findings, the oral administration of Akkermansia muciniphila was suggested to enhance the effect of ICIs[ 110 ].…”

Personalized treatment for hepatocellular carcinoma: Current status and future perspectives

“…The increasing availability of sequencing panel has also led to wider adoption of biopsy procedures in clinical trials for research on biomarkers 15 . Apart from tissue‐based genomic sequencing, the rapid advances on the technology of sequencing circulating nucleic acid could also enable non‐invasive assessment of tumor‐related genome in HCC 16,17 . Recently, there are growing preclinical and clinical data on the heterogeneity of tumor and tumor microenvironment on HCC, which are crucial to developing precision medicine for HCC.…”

“…15 Apart from tissue-based genomic sequencing, the rapid advances on the technology of sequencing circulating nucleic acid could also enable non-invasive assessment of tumor-related genome in HCC. 16,17 Recently, there are growing preclinical and clinical data on the heterogeneity of tumor and tumor microenvironment on HCC, which are crucial to developing precision medicine for HCC. In this review, focus will be put on recent advances and future direction on the approach personalized treatment on HCC.…”