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The Complexities of Hepatocellular Carcinoma

Insights From: Richard S. Finn, MD, Geffen School of Medicine;Arndt Vogel, MD, Hannover Medical School
Published: Monday, Oct 31, 2016


Transcript:

Arndt Vogel, MD:
I think, in the last years, we really have made a lot of progress in our understanding of the molecular biology of HCC. Specifically, with the help of next-generation sequencing, we were able to identify a lot of mutations we can frequently observe in hepatocellular carcinoma. However, these findings have so far not really translated into a targeted therapy or successful clinical trials in HCC because there are a couple of problems.

First of all, we have really significant intratumoral heterogeneity, which means we do not have one single driver mutation that would be important for all tumors. And, also, if you look at the genomic alteration we can find in HCC, there are some mutations—for example, mutations in p53—which we can find quite often. If they occur in patients with a hepatitis B underlying liver disease, with viral hepatitis B infection, it can have prognostic impacts with poor prognostic markers. It’s not in patients who do not have hepatitis B infections, which means specific mutations can have specific or different meanings in the context of the underlying liver disease. And the other problem we have, that we also see within one patient, is different tumors. So, we have intratumoral heterogeneity, which makes it also a little bit more complex. We have improved our understanding in the molecular landscape of hepatocellular carcinomas. We have identified early mutations, like mutations in the TERT (telomerase reverse transcriptase) promoter. We know what the most frequent mutations in beta-catenin are (for example, p53). But, so far, we were not able to use this to really improve our treatments we have at the moment.

I think we really have to distinguish different groups of patients we see in our daily clinical lives. So, some patients have really early disease, which means they have one single nodule. They are candidates for liver transplantation, for example. Then, we have patients with intermediate-stage disease. That means they have more tumor nodules, larger tumor nodules. And we have patients with advanced disease, which means they have vascular invasion, for example, or extrahepatic metastases. And for all these different states—early, intermediate, and advanced—we have different treatment options.

And another point, which is really important in the treatment of HCC, is that these patients do not have one disease; they have at least two diseases. They have the underlying liver disease, which means they have chronic infection, for example. They might have liver cirrhosis, which also might impact the treatment we can use in our patients. And most studies that we have were done in patients with very good liver function, which also makes it very difficult. Is the treatment of HCC very individualized? I think it is. It was always because it has to be, specifically because we have two diseases: the chronic liver disease and the tumor. Both need to be acknowledged and balanced, and we have to find for every patient the best possible treatment, which depends on both.

Richard Finn, MD: Hepatocellular carcinoma, or liver cancer, is a very complex disease. Unlike a lot of malignancies that we treat, it almost always, 90% of the time, occurs in the presence of underlying liver disease, some degree of cirrhosis. The most common causes being hepatitis C, hepatitis B, alcohol use, and now, increasingly, the metabolic syndrome and nonalcoholic steatohepatitis. Because of these two diseases, there’s a competing risk for outcomes, both outcomes from liver disease and outcomes from a malignancy. And, therefore, its approach really requires, what we term, a “multidisciplinary team. “

The only way to cure the disease is really with a surgical approach, which means resection or transplant. For disease confined to the liver, interventional radiology plays a very key role with procedures like radiofrequency ablation or chemoembolization. Hepatology is often involved because of the underlying liver disease and complications that arise from that. And then people like myself, medical oncologists, help triage patients through the system, as far as appropriate care for their given stage, as well as managing, generally, patients who have advanced disease who need systemic treatment.

Transcript Edited for Clarity
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Transcript:

Arndt Vogel, MD:
I think, in the last years, we really have made a lot of progress in our understanding of the molecular biology of HCC. Specifically, with the help of next-generation sequencing, we were able to identify a lot of mutations we can frequently observe in hepatocellular carcinoma. However, these findings have so far not really translated into a targeted therapy or successful clinical trials in HCC because there are a couple of problems.

First of all, we have really significant intratumoral heterogeneity, which means we do not have one single driver mutation that would be important for all tumors. And, also, if you look at the genomic alteration we can find in HCC, there are some mutations—for example, mutations in p53—which we can find quite often. If they occur in patients with a hepatitis B underlying liver disease, with viral hepatitis B infection, it can have prognostic impacts with poor prognostic markers. It’s not in patients who do not have hepatitis B infections, which means specific mutations can have specific or different meanings in the context of the underlying liver disease. And the other problem we have, that we also see within one patient, is different tumors. So, we have intratumoral heterogeneity, which makes it also a little bit more complex. We have improved our understanding in the molecular landscape of hepatocellular carcinomas. We have identified early mutations, like mutations in the TERT (telomerase reverse transcriptase) promoter. We know what the most frequent mutations in beta-catenin are (for example, p53). But, so far, we were not able to use this to really improve our treatments we have at the moment.

I think we really have to distinguish different groups of patients we see in our daily clinical lives. So, some patients have really early disease, which means they have one single nodule. They are candidates for liver transplantation, for example. Then, we have patients with intermediate-stage disease. That means they have more tumor nodules, larger tumor nodules. And we have patients with advanced disease, which means they have vascular invasion, for example, or extrahepatic metastases. And for all these different states—early, intermediate, and advanced—we have different treatment options.

And another point, which is really important in the treatment of HCC, is that these patients do not have one disease; they have at least two diseases. They have the underlying liver disease, which means they have chronic infection, for example. They might have liver cirrhosis, which also might impact the treatment we can use in our patients. And most studies that we have were done in patients with very good liver function, which also makes it very difficult. Is the treatment of HCC very individualized? I think it is. It was always because it has to be, specifically because we have two diseases: the chronic liver disease and the tumor. Both need to be acknowledged and balanced, and we have to find for every patient the best possible treatment, which depends on both.

Richard Finn, MD: Hepatocellular carcinoma, or liver cancer, is a very complex disease. Unlike a lot of malignancies that we treat, it almost always, 90% of the time, occurs in the presence of underlying liver disease, some degree of cirrhosis. The most common causes being hepatitis C, hepatitis B, alcohol use, and now, increasingly, the metabolic syndrome and nonalcoholic steatohepatitis. Because of these two diseases, there’s a competing risk for outcomes, both outcomes from liver disease and outcomes from a malignancy. And, therefore, its approach really requires, what we term, a “multidisciplinary team. “

The only way to cure the disease is really with a surgical approach, which means resection or transplant. For disease confined to the liver, interventional radiology plays a very key role with procedures like radiofrequency ablation or chemoembolization. Hepatology is often involved because of the underlying liver disease and complications that arise from that. And then people like myself, medical oncologists, help triage patients through the system, as far as appropriate care for their given stage, as well as managing, generally, patients who have advanced disease who need systemic treatment.

Transcript Edited for Clarity
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