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.

Figure 1.

A) Molecular pathogenesis of HCC: step-by-step process, genomic hits and clonal evolution. Both genetic and epigenetic mechanisms (TERT promoter mutations, chromosomal aberrations and methylation events) are thought to function as gatekeepers for malignant transformation of dysplastic nodules. Hepatocarcinogenesis requires a tumour-initiation event such as mutations in TERT, TP53 and CTNNB1, which are already present in 51% of small HCC tumors. Further acquired genetic alterations and changes to the tumour microenvironment enable these tumors to progress to advanced stages under the constant pressure of evolutional selection, leading to vast intratumoral heterogeneity. HBV, hepatitis B virus; HCV, hepatitis C virus; HGDN, high-grade dysplastic nodules; LGDN, low-grade dysplastic nodules; TERTp, TERT promoter. B) Molecular depiction of systemic therapies in HCC. Tumor cells, liver sinusoidal endothelial cells and lymphocytes are represented in relation to tyrosine kinase inhibitors, immunotherapies and monoclonal antibodies approved in HCC based on phase III data. Therapy names in bold black indicate positive results based on phase III trials, either with a superiority design (atezolizumab plus bevacizumab, sorafenib, regorafenib, cabozantinib and ramucirumab) or with a non-inferiority design (lenvatinib). Therapy names in bold blue designate other FDA-approved drugs based on non-randomized phase II trials (pembrolizumab and nivolumab plus ipilimumab). Grey boxes indicate combination therapies.

Figure 2.

A) BCLC treatment algorithm with new systemic agents. Treatment strategy in the management of HCC is guided by the Barcelona Clinic Liver Cancer (BCLC) staging system, which consists of five stages depending on tumour burden features, liver function and performance status. Asymptomatic patients with low tumour burden and good liver function (BCLC 0/A) should be treated with local curative treatments (resection, ablation or transplantation, depending on the presence of portal hypertension, number of nodules and liver function). Asymptomatic patients with multinodular disease and adequate liver function (BCLC B) should receive chemoembolization and patients with portal thrombosis or extrahepatic spread (BCLC C) should be treated with systemic therapies. HCC, Hepatocellular carcinoma; ECOG PS, Eastern Cooperative Oncology Group performance status; LT, liver transplantation; M1, distant metastasis; N1, lymph node metastasis; SBRT, Stereotactic Body Radiation Therapy; TACE, Transarterial Chemoembolization; TARE; Transarterial Radioembolization. Adapted with permission from [ref. 23], Wiley. #: Based on high level of evidence studies. ##: Based on low/moderate level of evidence studies. *: see Figure 2b. [AU: we have initiated the collection of permissions to adapt and re-use parts of this figure] B) Treatment strategy for HCC with systemic therapies. Green: Regulatory approved regimes based on phase III studies. Orange: positive combinations vs sorafenib, but drugs not yet approved. Yellow: treatments that got FDA accelerated approval based on phase II studies. (*) Around 70–80% of patients are expected to receive this regime. (**) COSMIC-312 phase III trial reported superior PFS for the combination of cabozantinib plus atezolizumab versus sorafenib, but final analysis on benefit on OS is not yet available. BCLC, Barcelona Clinic Liver Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; PD, Progressive Disease.