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Molecular pathogenesis and systemic therapies for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) remains one of the most prevalent and deadliest cancers. The poor outcome associated with HCC is dramatically changing due to the advent of effective systemic therapies. Here we discuss the molecular pathogenesis of HCC, molecular classes and determinants of heterogeneity. In addition, effective single-agent and combination systemic therapies involving immunotherapies as standard of care are analyzed. Finally, we propose a flowchart of sequential therapies, explore mechanisms of resistance and address the need for predictive biomarkers.

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Fig. 1: Molecular pathogenesis of HCC: step-by-step process, genomic hits and clonal evolution.
Fig. 2: Molecular depiction of systemic therapies in HCC.
Fig. 3: Staging system and treatment allocation for HCC.

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Acknowledgements

We thank M. Piqué and F. Castet, members of J.M.L.’s laboratory, for their support in the production of this manuscript. J.M.L. is supported by grants from Cancer Research UK, the Fondazione AIRC and the Fundación Científica de la Asociación Española Contra el Cáncer (HUNTER, reference C9380/A26813), the NIH (RO1DK56621 and RO1DK128289), the Samuel Waxman Cancer Research Foundation, EIT Health (CRISH2, reference 18053), the Generalitat de Catalunya (AGAUR, SGR-1358), the Spanish National Health Institute (MICINN, PID2019-105378RB-I00) and the Acadèmia de Ciències Mèdiques i de la Salut de Catalunya i de Balears (reference BECA_ACADEMIA21_001). X.W.W. is supported by grants (Z01 BC 010877, Z01 BC 010876, Z01 BC 010313 and ZIA BC 011870) from the intramural research program of the Center for Cancer Research, National Cancer Institute of the US.

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Correspondence to Josep M. Llovet.

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J.M.L. received research support from Bayer HealthCare Pharmaceuticals, Eisai, Boehringer Ingelheim and Ipsen and consulting fees from Merck, Eli Lilly, Eisai, Bayer HealthCare Pharmaceuticals, Bristol Myers Squibb, Ipsen, Genentech, Roche, Glycotest, Nucleix, Omega Therapeutics, Iylon, Mina Alpha, Boston Scientific and AstraZeneca. H.L.R. has acted in an advisory capacity for Boston Scientific and Sirtex, and received speaker fees from Eisai and Bayer. A.V. has received consulting fees from Boehringer Ingelheim, FirstWorld, Natera, Cambridge Healthcare Research and Genentech; advisory board fees from Bristol Myers Squibb, Gilead and NGM Pharmaceuticals; and research support from Eisai. R.K.K. received research support from Agios, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, EMD Serono, Exelixis, Genentech–Roche, Merck, Partner Therapeutics, Novartis, QED, Relay Therapeutics, Surface Oncology and Taiho; and consulting and/or advisory fees from Exact Sciences, Genentech–Roche and Gilead. A.E.-K. has received research support from Astex, AstraZeneca and Fulgent; advisory or consulting fees from Bayer, Bristol Myers Squibb, Eisai, Merck, Exelixis, AstraZeneca, Roche–Genentech, Agenus, ABL Bio, QED, Gilead, CytomX, Pieris and EMD Serono. G.J.G., X.W.W. and R.P. have no competing interests.

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Llovet, J.M., Pinyol, R., Kelley, R.K. et al. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma. Nat Cancer 3, 386–401 (2022). https://doi.org/10.1038/s43018-022-00357-2

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