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Current Understanding With Biomarkers in HCC

Panelists: Ghassan K. Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center; Richard S. Finn, MD, UCLA; Laura M. Kulik, MD, Northwestern University Feinberg School of Medicine; R. Kate Kelley, MD, University of California-San Francisco; Riad Salem, MD, Northwestern University Feinberg School of Medicine
Published: Tuesday, Mar 21, 2017



Transcript:

Ghassan K. Abou-Alfa, MD:
Patients come and you say, “I want to give sorafenib and, maybe very soon, regorafenib.” They’ll look at you and say, “Hey, Dr. Finn, I heard that you can now analyze my tumor and you can tell me exactly what I need at therapy.” What’s that story about precision medicine and individualized therapy, especially in HCC?

Richard S. Finn, MD: Well, HCC is a very heterogeneous disease, and it’s not one disease. We can speak of that in the context as we have in the clinical manifestations, that it’s liver disease and malignancy and therefore we need to individualize our approach based on their underlying liver function, their performance status, and their tumor characteristics. At the same time, you’re alluding to the molecular component. We know that in other cancers, perhaps the biggest impact has come from identifying individual molecular alterations and then targeting those alterations. In liver cancer, as we’ve spent the last several minutes discussing, the most successful agents have actually been multitargeted approaches because we lack a molecular driver. We are learning more, and the new generation of agents that are in development are trying to take a more biomarker-driven approach. There are platforms out there that give us molecular data, and then the challenge for us is: what do we do with that molecular data in HCC? It’s not like other diseases, where we find a certain molecular alteration and there are drugs readily available. However, I think in the future, that’s where we want to see HCC go; that we subsegment the disease based on a patient’s individual tumor characteristics. But as it stands now today for our patients, the sequence is based on the randomized phase III data we have, which is based on their clinical presentation and their course of treatments at the time we see them.

Ghassan K. Abou-Alfa, MD: This brings an important point that HCC is really a disease that’s caused by different risk factors that are very well-defined—among which are, of course, hepatitis C, hepatitis B, diabetes, and morbid obesity—and that lead to fatty liver disease, such as NASH (nonalcoholic steatohepatitis) and, of course, alcoholic steatohepatitis. I would like to go back to Laura one more time. Especially with the advent of the treatments for hepatitis C, there have been reports about the concern of recurrence of the cancer early. We just saw a recent report about that. In relation to that, what do we know about the interaction, if we know anything at all, between protease inhibitors and sorafenib?

Laura M. Kulik, MD: You’re right, there has been a concern. It’s causing a lot of challenges about when to treat patients when they have hepatitis C and HCC. There have been, first from Barcelona, patients who underwent resection or curative ablation and they had recurrence of their tumor, almost 30%. Shortly thereafter, there was another study that had almost the exact close-to-30% recurrence rate, so much higher than what we would expect. We normally see a 20% per year. This was at about 6 months, so it’s concerning, like why is that happening? Some have thought that with the interferon days, it would take 12 weeks to see the virus become negative. We’re seeing virus become negative within 1 week on these new medications. Is there some kind of immunosuppressive state that occurs when the virus is all of a sudden negative so quickly, which then could lead to fast reproduction of tumor cells that are still present? As far as your other question, it was regarding what?

Ghassan K. Abou-Alfa, MD: Sorafenib plus protease inhibitors.

Laura M. Kulik, MD: I have used both at the same time without having difficulties. I generally will talk with a specialty pharmacist because there are so many different drugs that are now available for hepatitis C and they’re not all exactly the same even though they’re similar classes. But I have had patients on hepatitis C treatment with sorafenib without increased toxicity.

Ghassan K. Abou-Alfa, MD: Nonetheless, it’s very important to know that these data do not exist. In other words, especially alluding to the concern about the recurrence, I think a clinical trial that will probably look into the combination of sorafenib plus protease inhibitors is still highly warranted, and definitely as an academic community, we’ll be very eager to see that one day.

Riad, back to you. On another level, have you looked at all or are there any data with regard to the local therapies and biomarkers that can tell us one way or the other what could be evolving there?

Riad Salem, MD: To my knowledge, there’s very little of this work today. It’s something, like you said, that we need to be working on, but it’s not something that’s very well developed right now.

Ghassan K. Abou-Alfa, MD: And I would say probably in systemic, it’s not necessarily highly defined either. Katie?

R. Kate Kelley, MD: Right. I think one of the challenges is that we often have very little tumor tissue to study in liver cancer because biopsy material is very scarce or patients may be diagnosed radiographically without a biopsy. And so, I think we’ve had less opportunity to study what markers in a tumor make a difference. In the SHARP trial that led to approval of sorafenib back in 2007, they looked at plasma biomarkers, trying to find potential markers of angiogenic activity that would be a predictive marker for a response to sorafenib. And nothing panned out as a significant predictor for benefit from sorafenib, though some plasma analytes, such as HGF, or hepatocyte growth factor, and KIT soluble levels, did seem to correlate with poor prognosis. I think it was strongly significant and nothing yet that has reached the clinic. Right now, we don’t have any tumor biomarkers for hepatocyte carcinoma that we use clinically, unlike most of our other solid tumors these days.

Ghassan K. Abou-Alfa, MD: Absolutely. This is something that we definitely aspire for. With regard to the biopsy question, I would say other than the research interest and definitely having the tissue so we can analyze it, there’s an important component here that, especially in the advanced setting, a biopsy is highly warranted. Because some of the HCC might really be misdiagnosed radiologically as a combination of, for example, HCC plus cholangiocarcinoma or even cholangiocarcinoma itself to that extent. So, I would say that the high-level data that have been shown in the screening setting and the early stage disease about radiologic evaluation, that doesn’t necessarily translate into the advanced disease where probably a biopsy is still highly warranted and probably recommended as well, as we just heard.

Transcript Edited for Clarity

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Transcript:

Ghassan K. Abou-Alfa, MD:
Patients come and you say, “I want to give sorafenib and, maybe very soon, regorafenib.” They’ll look at you and say, “Hey, Dr. Finn, I heard that you can now analyze my tumor and you can tell me exactly what I need at therapy.” What’s that story about precision medicine and individualized therapy, especially in HCC?

Richard S. Finn, MD: Well, HCC is a very heterogeneous disease, and it’s not one disease. We can speak of that in the context as we have in the clinical manifestations, that it’s liver disease and malignancy and therefore we need to individualize our approach based on their underlying liver function, their performance status, and their tumor characteristics. At the same time, you’re alluding to the molecular component. We know that in other cancers, perhaps the biggest impact has come from identifying individual molecular alterations and then targeting those alterations. In liver cancer, as we’ve spent the last several minutes discussing, the most successful agents have actually been multitargeted approaches because we lack a molecular driver. We are learning more, and the new generation of agents that are in development are trying to take a more biomarker-driven approach. There are platforms out there that give us molecular data, and then the challenge for us is: what do we do with that molecular data in HCC? It’s not like other diseases, where we find a certain molecular alteration and there are drugs readily available. However, I think in the future, that’s where we want to see HCC go; that we subsegment the disease based on a patient’s individual tumor characteristics. But as it stands now today for our patients, the sequence is based on the randomized phase III data we have, which is based on their clinical presentation and their course of treatments at the time we see them.

Ghassan K. Abou-Alfa, MD: This brings an important point that HCC is really a disease that’s caused by different risk factors that are very well-defined—among which are, of course, hepatitis C, hepatitis B, diabetes, and morbid obesity—and that lead to fatty liver disease, such as NASH (nonalcoholic steatohepatitis) and, of course, alcoholic steatohepatitis. I would like to go back to Laura one more time. Especially with the advent of the treatments for hepatitis C, there have been reports about the concern of recurrence of the cancer early. We just saw a recent report about that. In relation to that, what do we know about the interaction, if we know anything at all, between protease inhibitors and sorafenib?

Laura M. Kulik, MD: You’re right, there has been a concern. It’s causing a lot of challenges about when to treat patients when they have hepatitis C and HCC. There have been, first from Barcelona, patients who underwent resection or curative ablation and they had recurrence of their tumor, almost 30%. Shortly thereafter, there was another study that had almost the exact close-to-30% recurrence rate, so much higher than what we would expect. We normally see a 20% per year. This was at about 6 months, so it’s concerning, like why is that happening? Some have thought that with the interferon days, it would take 12 weeks to see the virus become negative. We’re seeing virus become negative within 1 week on these new medications. Is there some kind of immunosuppressive state that occurs when the virus is all of a sudden negative so quickly, which then could lead to fast reproduction of tumor cells that are still present? As far as your other question, it was regarding what?

Ghassan K. Abou-Alfa, MD: Sorafenib plus protease inhibitors.

Laura M. Kulik, MD: I have used both at the same time without having difficulties. I generally will talk with a specialty pharmacist because there are so many different drugs that are now available for hepatitis C and they’re not all exactly the same even though they’re similar classes. But I have had patients on hepatitis C treatment with sorafenib without increased toxicity.

Ghassan K. Abou-Alfa, MD: Nonetheless, it’s very important to know that these data do not exist. In other words, especially alluding to the concern about the recurrence, I think a clinical trial that will probably look into the combination of sorafenib plus protease inhibitors is still highly warranted, and definitely as an academic community, we’ll be very eager to see that one day.

Riad, back to you. On another level, have you looked at all or are there any data with regard to the local therapies and biomarkers that can tell us one way or the other what could be evolving there?

Riad Salem, MD: To my knowledge, there’s very little of this work today. It’s something, like you said, that we need to be working on, but it’s not something that’s very well developed right now.

Ghassan K. Abou-Alfa, MD: And I would say probably in systemic, it’s not necessarily highly defined either. Katie?

R. Kate Kelley, MD: Right. I think one of the challenges is that we often have very little tumor tissue to study in liver cancer because biopsy material is very scarce or patients may be diagnosed radiographically without a biopsy. And so, I think we’ve had less opportunity to study what markers in a tumor make a difference. In the SHARP trial that led to approval of sorafenib back in 2007, they looked at plasma biomarkers, trying to find potential markers of angiogenic activity that would be a predictive marker for a response to sorafenib. And nothing panned out as a significant predictor for benefit from sorafenib, though some plasma analytes, such as HGF, or hepatocyte growth factor, and KIT soluble levels, did seem to correlate with poor prognosis. I think it was strongly significant and nothing yet that has reached the clinic. Right now, we don’t have any tumor biomarkers for hepatocyte carcinoma that we use clinically, unlike most of our other solid tumors these days.

Ghassan K. Abou-Alfa, MD: Absolutely. This is something that we definitely aspire for. With regard to the biopsy question, I would say other than the research interest and definitely having the tissue so we can analyze it, there’s an important component here that, especially in the advanced setting, a biopsy is highly warranted. Because some of the HCC might really be misdiagnosed radiologically as a combination of, for example, HCC plus cholangiocarcinoma or even cholangiocarcinoma itself to that extent. So, I would say that the high-level data that have been shown in the screening setting and the early stage disease about radiologic evaluation, that doesn’t necessarily translate into the advanced disease where probably a biopsy is still highly warranted and probably recommended as well, as we just heard.

Transcript Edited for Clarity
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