Molecular and immunological paradigms of hepatocellular carcinoma: Special reference to therapeutic approaches

• Published in: Journal of hepato-biliary-pancreatic sciences 2021-01, Vol.28 (1), p.62-75
• Main Authors: Kabashima, Ayano, Shimada, Shu, Shimokawa, Masahiro, Akiyama, Yoshimitsu, Tanabe, Minoru, Tanaka, Shinji
• Format: Article
• Language: English
• Subjects: Clinical trials; combination therapy; hepatocellular carcinoma; immunotherapy; Liver cancer; molecular targeted therapy; subclass classification
• ISSN: 1868-6974; 1868-6982
• DOI: 10.1002/jhbp.874

The development of hepatocellular carcinoma (HCC) is a multistep process with a complex interaction of various genetic backgrounds and the tumor microenvironment. In addition to the development of rational approaches to epidemiologic research, early detection, and diagnosis, considerable progress has been made in systemic treatment with molecular‐targeted agents for patients with advanced HCC. Moreover, encouraging reports of recent clinical trials of combination therapy with immune‐checkpoint inhibitors (ICIs) has raised high hopes. Each HCC is the result of a unique combination of somatic alterations, including genetic, epigenetic, transcriptomic, and metabolic events, leading to conclusive tumoral heterogeneity. Recent advances in comprehensive genetic analysis have accelerated molecular classification and defined subtypes with specific characteristics, including immune‐associated molecular profiles reflecting the immune reactivity in the tumor. In considering the development of therapeutic strategies in combination with immunotherapy, proper interpretation of molecular pathological characterization could lead to effective therapeutic deployment and enable individualization of the management of HCC. Here, we review distinctive molecular alterations in the subtype classification of HCC, current therapies, and representative clinical trials with alternative immune‐combination approaches from a molecular pathological point. Highlight Advances in molecular pathology have shifted the paradigm of hepatocellular carcinoma treatment. Comprehensive gene stratification analysis advances our understanding of molecular pathology, ultimately leading to precision medicine. Kabashima and colleagues reviewed our current knowledge from a perspective of molecular pathology, including the characterization of sub‐classifications, molecular targeted therapies and immunological therapies.