Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
J Hepatobiliary Pancreat Sci. 2021 Jan;28(1):62-75. doi: 10.1002/jhbp.874. Epub 2021 Jan 5.
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.
肝细胞癌 (HCC) 的发生发展是一个多步骤的过程，涉及多种遗传背景与肿瘤微环境的复杂相互作用。除了制定合理的流行病学研究、早期检测和诊断方法外，针对晚期 HCC 患者的分子靶向药物系统治疗也取得了相当大的进展。此外，免疫检查点抑制剂 (ICI) 联合治疗的近期临床试验令人鼓舞的报告也带来了很高的期望。每个 HCC 都是体细胞改变的独特组合的结果，包括遗传、表观遗传、转录组和代谢事件，导致明确的肿瘤异质性。全面遗传分析的最新进展加速了分子分类，并定义了具有特定特征的亚型，包括反映肿瘤免疫反应的免疫相关分子特征。在考虑与免疫疗法联合开发治疗策略时，对分子病理特征的正确解释可能会导致有效的治疗部署，并实现 HCC 管理的个体化。在这里，我们从分子病理的角度回顾 HCC 亚型分类中的独特分子改变、当前治疗方法以及具有替代免疫联合方法的代表性临床试验。
