Biomarkers for diagnosis and therapeutic options in hepatocellular carcinoma

Abstract

Liver cancer is a global health challenge, causing a significant social-economic burden. Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, which is highly heterogeneous in terms of molecular and cellular signatures. Early-stage or small tumors are typically treated with surgery or ablation. Currently, chemotherapies and immunotherapies are the best treatments for unresectable tumors or advanced HCC. However, drug response and acquired resistance are not predictable with the existing systematic guidelines regarding mutation patterns and molecular biomarkers, resulting in sub-optimal treatment outcomes for many patients with atypical molecular profiles. With advanced technological platforms, valuable information such as tumor genetic alterations, epigenetic data, and tumor microenvironments can be obtained from liquid biopsy. The inter- and intra-tumoral heterogeneity of HCC are illustrated, and these collective data provide solid evidence in the decision-making process of treatment regimens. This article reviews the current understanding of HCC detection methods and aims to update the development of HCC surveillance using liquid biopsy. Recent critical findings on the molecular basis, epigenetic profiles, circulating tumor cells, circulating DNAs, and omics studies are elaborated for HCC diagnosis. Besides, biomarkers related to the choice of therapeutic options are discussed. Some notable recent clinical trials working on targeted therapies are also highlighted. Insights are provided to translate the knowledge into potential biomarkers for detection and diagnosis, prognosis, treatment response, and drug resistance indicators in clinical practice.

Keywords: Artificial intelligence; Biomarkers; Cancer diagnosis; Cancer surveillance; Cancer treatment; Cell-free DNA; Circulating tumor DNA; Circulating tumor cells; Clinical trials; HAIC; Hepatocellular carcinoma; Immunotherapies; Liquid biopsy; Liver transplantation; Local ablation; Metabolomics; Methylation; Non-coding RNAs; Serological biomarkers; Surgical resection; TACE; Targeted therapies; Therapeutic option; Tissue biopsy; Tumor-derived vesicles.

Fig. 1

Biomarkers of HCC diagnosis. The current surveillance methodology for Hepatocellular Carcinoma (HCC) primarily involves ultrasound and serum AFP measurements, sometimes supplemented with imaging techniques. In instances where diagnosis or treatment options are ambiguous, tissue biopsy is often employed to confirm the histological structure of the tumor. Liquid biopsy offers a minimally invasive alternative for gaining insights into tumor heterogeneity. Recent research has identified potential biomarkers from diverse sources, including serological components, genetic materials, cells, and vesicles. Among these candidate biomarkers, circulating tumor DNAs and omics stand out due to their ability to reflect the complexity of HCC tumors. These technologies offer great promise in understanding the intricacies of HCC and developing more effective and personalized treatment strategies

Fig. 2

Biomarkers for therapeutic options. To facilitate the decision on the best treatment for HCC patients, biomarkers predicting therapeutic response to different treatments, including surgical resection, TACE, HAIC, liver transplantation, targeted therapies, and immunotherapies, are being investigated. Some of the significant aspects of the studies are highlighted in the illustration, and the predicted response and correlated clinical outcomes are drawn on the diagram