Mutational Complexity Reflects Treatment Challenges for Hepatocellular Carcinoma

Jane de Lartigue, PhD
Published: Monday, Dec 19, 2016
The growing incidence of primary liver cancer in the United States poses a great therapeutic challenge. Despite the plethora of new treatment options that have been tested, only a single targeted therapy is approved by the FDA for the treatment of the majority of patients who present with advanced-stage disease. Consequently, survival rates remain comparatively low.

Multiple phase III failures of promising drugs have led to the suggestion that a therapeutic plateau has been reached and that a vastly improved understanding of the molecular mechanisms of liver cancer will be necessary to drive new treatment paradigms.

Genome sequencing studies are helping to advance this goal but have highlighted key treatment challenges. In addition to the extensive heterogeneity both among and within tumors, differences in the underlying disease etiologies can significantly impact the types of potentially targetable events. Moving forward, these challenges need to be addressed in order to improve patient outcomes.

A Growing Problem

Primary liver cancer is not the most common type of cancer, but it does result in the second most common cause of cancer-related mortality worldwide, indicative of the significant treatment challenge posed by this malignancy. In recent years, the incidence of liver cancer has dramatically increased, particularly in the United States, and rates are expected to double again over the course of the next several decades.

Liver cancer typically manifests as hepatocellular carcinoma (HCC), arising from hepatocytes, which accounts for up to 85% of cases. The next most common form, intrahepatic cholangiocarcinoma (IHCC), is relatively rare in comparison; IHCC originates from the biliary tract epithelial cells in the bile duct or the liver.

The prognosis for most patients is poor, in large part due to a lack of effective surveillance techniques and limited treatment options for patients diagnosed with advanced-stage disease. Among the 30% to 40% of patients diagnosed at an early stage, surgical resection, liver transplantation, and ablative techniques offer a potentially curative option. The vast majority of patients, however, are not eligible for these treatments and advanced liver cancer is also notoriously chemo- and radioresistant, resulting in a 5-year overall survival (OS) rate of less than 10%.

The dearth of effective treatment options for these patients is not for lack of trying, but the highly complex nature of liver cancer is a major impediment to the development of new therapies. It almost always occurs against a background of underlying liver disease: liver cirrhosis is found in 80% to 90% of cases and is widely recognized as a key step in the pathogenesis of liver cancer.

Liver cancer has some of the most well-defined risk factors for any cancer. Although it is most commonly related to infection with the hepatitis B (HBV) and C viruses (HCV), other prevalent risk factors include alcohol consumption and obesity, both of which are growing concerns in developed countries in particular. The dominant risk factors vary according to geographic region and ethnic background, but all create an environment of chronic inflammation and liver damage that often leads to cirrhosis.

Ultimately, permanent damage to the hepatocytes prompts massive compensatory cell proliferation and regeneration, inducing genetic and epigenetic damage to the patient’s genome and fostering a highly carcinogenic environment. The process of hepatocarcinogenesis is a complex, multistep event that is still not fully understood, but several key signaling pathways have been closely linked to it.

Major Pathways Identified

The mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) pathways are the 2 major signaling cascades implicated in HCC development. It is also known to be a highly angiogenic tumor, with a dramatic alteration in arterial vascularity observed in many HCCs.

Thus, the MAPK and PI3K pathways, in addition to the major angiogenic pathways, have been the focus of targeted therapy development for HCC. So far, success has been limited to the multitargeted tyrosine kinase inhibitor sorafenib (Nexavar).

In the 2008 SHARP trial, sorafenib, which blocks components of both the MAPK pathway and VEGF and PDGF receptors that regulate angiogenesis, demonstrated improved OS of almost 3 months, with a manageable toxicity profile in patients with advanced-stage disease. Sorafenib has become standard of care for unresectable, nonablatable, advanced disease; however, in most cases, tumors begin to grow again after less than 6 months.

After multiple phase III failures, hopes are high that regorafenib (Stivarga) will soon join the list of approved therapies. The antiangiogenic multi-kinase inhibitor demonstrated efficacy as second-line therapy for HCC in the phase III RESORCE trial, in which median OS was 10.6 months with regorafenib plus best supportive care compared with 7.8 months for placebo plus best supportive care. This represented a 37% reduction in the risk of death (HR, 0.63; 95% CI, 0.50-0.79; P <.001).


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