Over the past year we have solicited and assembled a partial collection of articles from talented investigators that we believe provides a strong sampling on state-of-the-art advances in this field of hepatobiliary cancers. These contributions are focused on the fundamental understanding and implementation of research in the epidemiology, genomics, molecular pathogenesis, diagnostic, predictive and prognostic biomarkers, surgical, loco-regional and systemic treatment, and clinical trial design for hepatobiliary cancers. Special consideration is given to the tumor microenvironment and the emerging fields of immunotherapy and the liver immune microenvironment. The articles also provide a look forward to highlight the pressing questions to be answered. We realize that many additional important areas of investigation, from other talented scientists, were not included in this edition due to space constraints, and we apologize for this.
The collection begins with an update on epidemiology that reviews recent results and highlights the diversity of risk and protective factors for liver cancers in different geographic, cultural, and socioeconomic settings. This is followed by a series of articles on pathogenesis that covers genetic diversity and tumor heterogeneity, provides a detailed review of the pathogenic mechanisms of chronic hepatitis B and C–mediated liver carcinogenesis, highlights recent studies of regulatory RNAs in HCC, and includes an in-depth description of the current state of basic and translational science for the mammalian target of rapamycin pathway, a central and as yet incompletely characterized translational target in HCC. Next, a pair of articles is provided that focus on the biology of cholangiocarcinoma, including molecular targets and the role of the tumor microenvironment in cholangiocarcinoma progression. In-depth coverage of the rapidly expanding field of liver cancer immunity, the immune microenvironment, and translation to immunotherapy follows. We then pivot to articles that focus on clinical translation and the current state of clinical care, addressing biomarkers for hepatobiliary cancers, surgical treatment of hepatobiliary cancers, local and regional therapies for HCC, and the rapid evolution of advances in systemic therapy. Finally, the collection is anchored by a detailed and comprehensive analysis of the state of clinical trial design and endpoints for studies of primary liver cancers.
After many years of robust discussion, a consensus has emerged that surveillance for HCC in at-risk groups saves lives. Furthermore, imaging criteria for the diagnosis of small HCC have been validated and standardized and recall algorithms established for indeterminate lesions. A wide variety of treatment options are available for patients with early HCC, as extensively reviewed in this issue of Hepatology. Hence, early diagnosis can be linked to effective therapies. This exposes a number of practical questions: How do we most efficiently define the at-risk population in different geographic settings? How do we identify the most cost-effective methods of surveillance, and couple these to improved access to care in low-resource settings?
There is increasing hope that improvements in technology will facilitate the development of highly accurate low-cost surveillance systems. These systems are most needed in the communities in Asia and Africa with the highest burdens of chronic liver disease, but also in Europe and North America, where ineffective systems for identifying those at risk and enrolling them in comprehensive surveillance have resulted in limited benefit in otherwise well-endowed health care systems. These issues are of increasing importance as we face profound increases in liver disease risk from fatty liver and diabetes and reckon with an apparent increase in HCC diagnosis in persons without cirrhosis. The emergence of novel blood-based surveillance tests and algorithms incorporating combinations of epigenetic and protein markers developed through more sophisticated algorithms also provides hope for simplified rapid point-of-care testing, which may improve compliance with long-term repeated surveillance.
For those patients diagnosed with intermediate to advanced-stage HCC, rapid advances in systemic therapy options are extending survival and reshaping the treatment landscape. However, considerable work is still needed, as currently these therapies are largely palliative and not curative. As explored in this issue, we are beginning to understand and utilize the realistic potential for the use of neo-adjuvant and adjuvant systemic therapy to consolidate the benefits of surgical resection in patients in settings where liver transplantation is not feasible, either for cultural or financial reasons. For example, the advent of combined monoclonal anti-angiogenic and anti-immune checkpoint therapy represents a major advance in therapy for patients with advanced HCC and portends the discovery of additional novel combinations that are already competitive with current standard catheter-based treatments for patients with intermediate-stage disease. There is a dire need for comprehensive efforts to educate providers and provide needed infrastructure for imaging, surgical treatment, and interventional radiology in low-resource settings, both for diagnosis and therapy of HCC and biliary tract cancers. Studies are still required in the area of dissemination and implementation science as it pertains to HCC, if we are to optimally achieve our goals of improving outcomes for patients with HCC across the globe.
Researchers studying hepatobiliary cancers have been making rapid progress in efforts to understand the fundamental biology of these cancers, improve the multi-omic subclassification of these tumors using genomic, proteomic, metabolomic and immune-based methods such as mass-cytometry, and catalyze the development of effective personalized treatments. It has become increasingly apparent over the past decade that the most powerful and meaningful cancer-focused studies are those that combine all of these approaches to provide a more complete assessment of these cancers. As stated recently in a Nature Outlook (2020) titled “Beyond the genome,” cancer investigators need to combine genomic analysis with strong cancer cell biology. As stated, “if we want to understand the function of a cancer cell the way to do this is looking at the proteins.” This would appear to make great sense, as the proteins themselves are perhaps the most influential actors in controlling tumor cell behavior and response to treatments. Due to the relative inaccessibility of the liver and advances in dynamic cross-sectional CT and MR imaging that allow accurate noninvasive diagnosis of HCCs, many practitioners had discontinued routine biopsy of intermediate and advanced-stage tumors, a crucial resource needed for phenotype–genotype prediction correlations critical for driving precision therapy in hepatobiliary cancers. In this regard, the discovery and targeting of key genetic alterations in intrahepatic cholangiocarcinoma, including isocitrate dehydrogenase (IDH) mutations and FGF receptor 2 fusions, has been an important advance and provides convincing justification to pursue these efforts. The intriguing observation from the Cancer Genome Atlas HCC project that a proportion of tumors that are histologically classified as HCC have genomic signatures consistent with intrahepatic cholangiocarcinoma and may bear IDH or other alterations characteristic of cholangiocarcinoma heightens the importance of efforts to normalize the use of tumor genomic profiling of HCCs. Liquid biopsy–based methods may be an important future technology that addresses this important gap, and we anticipate major advances in this next decade.
There has been a substantially increased rate in acquisition and clinical translation of scientific knowledge. This is leading to an increasing proliferation of treatment options, which also creates a corresponding challenge of developing more efficient clinical trial designs and paradigms to allow the identification and rapid deployment of the most effective new therapies for specific molecular subclasses of hepatobiliary cancers without compromising patient safety. Advances in the development of umbrella, basket, and adaptive clinical trial designs are being paired with an improved understanding of the most critical and meaningful clinical trial endpoints and response assessments for studies of hepatobiliary cancers at their different stages of presentation. These advances will allow us to make the most efficient use of improvements in our understanding of tumor development, progression, and metastasis, and the roles of neo-angiogenesis and the tumor microenvironment, including the immune microenvironment, in the design of precision therapy against hepatobiliary cancers.
We close with a call to action and an expression of hope. While we do not have all the tools we would wish for, we know enough already to make a major impact in surveillance, diagnosis, and treatment of the nearly 1 million people globally who are diagnosed annually with hepatobiliary cancers, an epidemic that is already with us, and to substantially reduce their burden of illness and death. We owe it to these patients to advocate for the needed resources, so as to make a difference now. We hope this compilation will provide a useful compendium of the state of the art in primary liver cancer research at the end of the decade, while concurrently providing a launching point for the next era of investigation and new advances in the field.