Two Decades of Advances in Hepatocellular Carcinoma Research

Liver disease is an active field of knowledge in which advances have been produced at a very rapid pace. Major breakthroughs have dramatically improved the understanding of the molecular mechanisms and pathophysiology of several entities. Without any doubt, hepatocellular carcinoma (HCC) is among those areas that have experienced a most intense evolution in terms of research and clinical practice. Two decades ago, HCC was considered a very infrequent cancer in the West and, as such, deserved a limited interest. In addition, it was seen as a neoplasm that would unequivocally carry a grim prognosis. Indeed, it was usually diagnosed at an advanced, symptomatic phase and the sole treatment option considered was surgical resection. Research conducted over the past 20 years has subverted this scenario.

HCC has a heterogeneous geographic incidence and data from several registries show that its incidence is significantly increasing worldwide. In the West, the incidence rate is not expected to reach a plateau until 2020. Liver cancer is the third cause of cancer-related death, and prospective studies in cirrhotic patients have determined that HCC development now constitutes the main cause of death in this population. Primary prevention has become a reality with universal HBV vaccination policies, an approach leading to an effective reduction of cases. Permanent eradication of HCV infection in early phases of chronic hepatitis has been shown to prevent development of advanced fibrosis and cirrhosis, ultimately leading to a decrease in HCC occurrence. In addition, early detection of small tumors in the target population (i.e., cirrhotic patients) has been made feasible through the development of ultrasonography. This noninvasive and sensitive technique is the backbone of surveillance programs aiming to detect and treat HCC at a stage when long-term survival and cure are feasible. Ideally, tumors should be detected when solitary and less than 2 cm in size, which represents a major diagnostic challenge. Expert biopsy examination and state-of-the-art imaging techniques are available to face this issue.

Major advances in surgical and ablative techniques have changed the landscape of curative therapeutic approaches to HCC. Selection of candidates has emerged as a key step to achieve optimal results with resection. Liver transplantation now constitutes conventional clinical cancer care, and tumor ablation by radiofrequency or ethanol injection have proven efficacy in studies from both East and West. These three therapies are fully consolidated for patients with early tumors, but even patients diagnosed at a more advanced stage can currently receive effective treatments that are able to improve the natural outcome according to evidence-based principles. Randomized controlled trials demonstrated that chemoembolization benefits patients with liver-only cancer, while patients at more advanced stages will benefit from the multikinase inhibitor sorafenib. This drug is the first systemic therapy able to improve survival in those afflicted with this neoplasm, a feature that has primed a blossom of activity in the field of molecular targeted therapies. Several other molecular agents are now undergoing clinical assessment in first or second line mode. It is important to note that this consolidated decision-making approach for each evolutionary stage has been based on an accurate integration of the knowledge of the natural history of the disease and the available evidence-based data. This integration has been accomplished by the BCLC staging system and treatment algorithm (first reported in Seminars in Liver Disease in 1999), which is endorsed by several scientific associations and entities. As a result, for instance, this classification refined the confusing term “nonsurgical” HCC into three additional stages that almost certainly will be modified in the future as more data are published.

In parallel to all these clinical improvements, major advancements have also been achieved in basic and translational research. Even considering that our knowledge in the pathogenesis of HCC is still elementary, some major achievements should be pointed out. First, critical signaling pathways have been proven to be involved in hepatocarcinogenesis, including Wnt signaling, p53, IGF, Ras, EGFR, Akt/TOR, c-MET, VEGFR, and FGF, among others. Specific associations between main carcinogens and molecular aberrations have been unraveled. Recent data have now emerged on the role of miRNA in the pathogenesis and even prognostic prediction of this neoplasm. As a result of high-throughput genomic data and integrative genomic analysis various attempts have been produced to define a common molecular classification of this cancer. Current technology allows interrogating the whole transcriptome using paraffin-embedded tissue, which surely will prime the production of major information to complete the seminal contributions that have recently been made available. Cancer stem cells will also gain recognition as the ultimate cell niche to be tackled to achieve long-term cure. In all this effort, genetically-engineered models and cell lines will still be of paramount importance to delineate pathway activation and abrogation, but more importantly to first test molecules aimed at correcting their abnormal situation. Nonetheless, major milestone advancements are expected from discoveries by using such newly available technologies as deep whole-genome sequencing, which not only will improve our understanding of the main drivers of the disease but also will lead the development of a more personalized medicine approach.

In the current issue of Seminars in Liver Disease we have assembled a superb panel of experts to expose the current status in all the aspects that have been briefly summarized above. The chapters provide a comprehensive update on the major aspects of research and practice in HCC. It is clear that knowledge will keep evolving, but the content offered here should serve to frame where we stand today and what needs to be faced in the next few years. Hopefully, readers will be stimulated to join us in the area of HCC and team up in the effort to fully transform what was seen as an unknown and deadly disease some years ago into an entity that can be not only prevented by avoiding the well-established risk factors for its development, but also be effectively treated to offer long-term survival.