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ATF6α activation in human and preclinical models of hepatocellular carcinoma is significantly associated with an aggressive tumour phenotype characterized by reduced survival, glycolytic reprogramming and local immunosuppression.

Saturation genome editing of a cancer mutation hotspot in CTNNB1, the gene encoding β-catenin, reveals a gradient of effects of missense mutations on Wnt signaling.

Since the publication of the first issue of Nature Reviews Clinical Oncology, we have witnessed advances in multiple research areas that have culminated in improved outcomes for many cancer types, although substantial unmet needs remain for a majority of patients worldwide. Here, we have asked experts in several key specialities to reflect on the progress from the past 20 years and propose the next steps to enable further advances. Although we are aware that this Viewpoint cannot provide full coverage of the vast field that is clinical oncology, we hope that these messages inspire a diverse range of readers.

As the burden of hepatocellular carcinoma (HCC) continues to increase, attention turns to the appropriate management of the disease. In this Review, the authors discuss and critique the currently available medical interventions for the treatment and management of HCC, as well as introduce future developments in the field.

Immune-checkpoint inhibitors have revolutionized the management of hepatocellular carcinoma. Currently, anti-PD-(L)-1 antibodies combined with either bevacizumab or anti-CTLA4 antibodies are the standard of care for advanced-stage tumours. Now, two phase III studies (CheckMate 9DW and APOLLO) have reported positive survival results in the first-line setting, although with distinct implications for clinical practice.

Unexpected data from new studies show that direct-acting antiviral agents might promote tumour occurrence in patients with cirrhosis, or recurrence in patients with presumed cure of hepatocellular carcinoma. In view of the potential clinical implications, this controversy calls for a thorough and expeditious consideration of the hypothetical oncogenic activity of novel HCV drugs.

A large-scale comprehensive analysis of hepatocellular carcinoma (HCC) based on the integration of six distinct data platforms has pinpointed novel oncogenic processes and prognostic subgroups. These findings confirm previously identified molecular subclasses and fuel the need for a clear strategy of precision medicine in HCC.

Next-generation sequencing analysis and characterization of the microenvironment 'field-effect' that promotes hepatocellular carcinoma (HCC) development has revealed critical players and potential targets for chemoprevention. A biomarker-based drug development strategy is needed to improve future HCC clinical trials and therapies.

As proof of principle, an analysis using a suite of human-aligned immunocompetent mouse models of hepatocellular carcinoma identifies a promising therapeutic candidate, cladribine, which acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.

In this Review, Llovet and colleagues discuss advances in our knowledge of the pathogenesis and clinical management of nonalcoholic steatohepatitis-related hepatocellular carcinoma. They also discuss future prospects and unmet needs.

Llovet and colleagues review recent advances in hepatocellular carcinoma therapy and the clinical workflows for the selection and monitoring of patients undergoing systemic therapies and immunotherapy.

Intrahepatic cholangiocarcinoma is an aggressive cancer of the bile duct with few treatment options and a below 10% five-year survival rate. Here Sia et al. show a novel FGFR2–PPHLN1 fusion and ARAFmutations that may represent future potential therapeutic targets.

Hepatocellular carcinoma is a difficult-to-treat cancer and, after numerous phase III trials assessing kinase inhibitors have failed to meet their end points, sorafenib is the only accepted treatment for advanced stages of the disease. Now, the trial EVOLVE-1 has shown a lack of benefit for everolimus in the second-line treatment setting.

The revolution of immunotherapies in oncology has not been matched by the development of companion diagnostic biomarkers able to identify the ideal target populations. Aside from the established pathways for regulatory approval relying on predefined biomarkers, a novel approach based on post hoc biomarker analysis could potentially be instrumental in enhancing the cost-effectiveness of cancer immunotherapy.

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and has well-known risk factors, including cirrhosis and viral hepatitis. Here, Llovet and colleagues discuss the challenges and recent advances in HCC molecular characterization, diagnosis and management.

In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Guccione and colleagues identify and characterize a sorafenib derivative, WNTinib, with therapeutic efficacy in β-catenin-mutated hepatocellular carcinoma and identify EZH2 as important for the activity of the inhibitor.

A new study proposes a modelling strategy to identify reactions, genes and metabolites relevant in hepatocellular carcinoma using in silico and in vivo analyses. The proposed genome-scale metabolic model integrates genomic and proteomic information, and points to statins, among others, as potential chemopreventive and anticancer drugs.

Liver cancer mortality has increased in the past 20 years, and estimates indicate that the global health burden of this disease will continue to grow. Advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with hepatocellular carcinoma (HCC). In this Review, the authors summarize the molecular concepts of progression of HCC, discuss the potential reasons for clinical trial failure, and propose new concepts of drug development.

Blockade of intrahepatic accumulation and function of platelets represents a potential approach to treat non-alcoholic steatohepatitis (NASH) and prevent subsequent progression to hepatocellular carcinoma

Keng et al. characterize the mouse hepatocellular carcinoma genome by using tissue-specific recombinase expression to restrict mobilization of the Sleeping Beauty transposon to the liver. High throughput sequencing of >100,000 insertions sites in mouse tumor nodules identifies potential therapeutic targets.

Immune-mediated selection pressures impact the clonal evolution of tumours. Here, in hepatocellular carcinoma the authors map spatio-temporal interactions between tumor and immune cells, highlighting the regulatory substrate of intra-tumoural heterogeneity that correlates with regional adaptive immune responses.

Immunotherapy is revolutionizing the treatment of many cancers and hepatocellular carcinoma (HCC) is no exception. This Review describes the heterogeneous immune microenvironments of HCC as well as their links with the various aetiologies underlying this malignancy and with response or resistance to immunotherapies. In addition, the authors provide an overview of the current landscape of clinical trials evaluating immunotherapies across all stages of HCC.

Patients with early stage hepatocellular carcinoma typically undergo resection, liver transplantation or local ablation; however, 30–50% will have disease recurrence at 3 years. The authors of this Review describe the tumour immune microenvironment and mechanism of action of immunotherapies, and discuss the available evidence from phase II/III trials of neoadjuvant and adjuvant treatment approaches in this setting.

Locoregional therapies, defined as imaging-guided liver tumour-directed procedures, play a leading part in the management of hepatocellular carcinoma. This Review analyses data from randomized and uncontrolled studies reported with ablative and locoregional techniques and examines the expected effects of combinations with systemic treatments, exploring their distinct mechanisms of action.

Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is one of the leading causes of cancer-related death in the world. This Primer summarizes the current knowledge on the epidemiology, pathogenetic mechanisms and diagnosis of HCC and provides an update on key advancements in the management of this disease.

Molecular profiling studies are providing novel insights into the biology of hepatocellular carcinoma, although these remain to be translated into novel effective therapies. Nevertheless, therapeutic advances have been made in the past few years, and further advancements are expected in the near future, including biomarker-driven treatments and immunotherapies, as discussed in this Review.

George Daley and colleagues show that Lin28 and Lin28B promote cellular transformation by repressing let-7 family members, leading to derepression of let-7 targets. They also find that LIN28 and LIN28B are overexpressed in ∼15% of primary human tumors and cancer cell lines and that their expression is associated with aggressive disease and poor prognosis across multiple tumor types.

Gain-of-function mutations in isocitrate dehydrogenase (IDH) are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly cancer of the liver bile ducts; now mutant IDH is shown to block liver cell differentiation through the suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence, leading to expansion of liver progenitor cells primed for progression to IHCC.

Jessica Zucman-Rossi and colleagues report exome sequences of 243 hepatocellular carcinomas. They identify mutational signatures associated with specific risk factors such as alcohol, tobacco and aflatoxin B1 and find genetic alterations potentially targetable by FDA-approved drugs in 28% of the tumors.

Hepatocellular carcinoma (HCC) is among the most common causes of cancer-related death globally, and despite improvements in prevention and treatment strategies, continued increases in HCC incidence and mortality are predicted. Cirrhosis remains the major risk factor for HCC, although the underlying aetiology is shifting from virus-related to non-viral liver diseases. In this Review, the authors discuss the changing trends in HCC epidemiology and their implications for screening, prevention and therapy, including opportunities to further improve the management of patients with, or at high risk of, HCC.