Evolving Approaches for HCC in the Molecular Medicine Era - Episode 3

Testing for Targetable Mutations in Hepatocellular Carcinoma

November 5, 2020
Targeted Oncology

Richard S. Finn, MD: In liver cancer, we now stratify based on clinical characteristics—tumor burden and liver function. And obviously, patients will have their greatest survival, as Catherine alluded to, if they have well-preserved liver function. And so, it’s important that we triage patients appropriately to the correct treatment at the right time.

Someone might start with intermediate disease, liver confined disease, no vascular invasion. They may get locoregional treatment, and then they might progress and become advanced. I always emphasize that patients can have advanced liver cancer and still have tumors confined just in the liver, right? They might have a tumor that’s invading the vasculature, or what we call macrovascular invasion. Or, they might get locoregional treatment, as you alluded to, and recur very quickly. Or, they receive repeated locoregional treatments to their tumor, and every time they get another scan there’s still residual disease, and they have some resistance. Those would be patients who would be candidates for medical treatment.

As we have more medical treatments, systemic treatments, I think we need to reconsider the limits of locoregional therapy. But still, when we talk about cancer medicine today, we talk a lot about molecular profiling. We talk about cancer genomics. We talk about PD-1/PD-L1.

Michael, I know you’ve always had some laboratory interests as well as clinical interests. Has this personalized approach impacted liver cancer? What do you see the treatment landscape including when you see a patient? Is it still a one-size-fits all approach, so to speak?

Michael A. Morse, MD, FACP, MHS: Well, outside of AFP, we don’t really have a biomarker that we use. We use immunotherapies regardless of PD-L1 status, for example.

Obviously, there are molecular differences in HCC [hepatocellular carcinoma] cases. There’s recent work that’s been done with circulating tumor DNA that demonstrates that there are at least 2 separate groups—there are probably more—that have certain molecular aberrations. Most of those molecular aberrations are not truly actionable, unfortunately, and in regard to those few that do occur that are considered actionable in other malignancies, we don’t really know how to target them in hepatocellular carcinoma.

I do think it’s a start. We have the tools to be able to look at molecular changes, whether it’s by circulating tumor DNA or biopsying the tumor. I think as we do this more and more in clinical practice, we’ll find some subgroups that might be treated differently. But right now, the simple answer is that we treat everybody fairly similarly. AFP is the 1 marker we have for 1 particular drug.

Richard S. Finn, MD: Yes. Some of you have said, “Well, you don’t biopsy people with liver cancer.” Maybe that set us back a little bit? Although there are some alterations that occur with various frequency, many of them are not actionable. There has been some interest in the FGF19 amplification and targeting fibroblast growth factor receptor 4, which is its known target for FGF19.

The landscape and the treatment of liver cancer is changing so fast. I think we haven’t seen where some of these niche indications will go. For example, c-Met was looked at a while ago, and there are some mixed signals about c-Met expression versus amplification being a predictive marker for response to targeted therapies against the HGF axis.

Catherine, do you biopsy all of your patients with advanced liver cancer?

Catherine Frenette, MD: It’s interesting how the field has moved. And you’re right, Rich. I think it might have set us back a little bit. Years ago, we used to biopsy patients. Then, we really got away from doing so because we didn’t have markers that were useful. You’d see a few complications and get a little bit anxious about biopsying people when you’re not going to do anything different with the information, necessarily.

I think that now with where the field is moving, we are going to. We are getting to a point where we may have some useful analyses.

I have started biopsying more patients. I definitely agree, now with the move of all of the studies requiring biopsies again, that it’s important to look for these targetable mutations and try to identify how to group patients into categories for treatments that may actually work for them.

Michael A. Morse, MD, FACP, MHS: If I could take a slightly different tack? We’re actually really excited about circulating tumor DNA analyses at our institutions. We’re building them into many studies now.

A recent article in Clinical Cancer Research looked at more than 200 patients. Almost 90% of the patients had some molecular aberration detectable. They weren’t always actionable, but I think this says that hepatocellular carcinomas typically do release DNA into the circulation. And as I think we get more comfortable with circulating tumor DNA in other cancers—lung cancer, for example, would be a prime example—I think that could carry over into HCC, where we’ve been so reluctant to biopsy for fear of causing complications.

And once we accept circulating tumor DNA as giving results that are as good, if not better than the biopsy, I think we can really argue that most patients should be given the chance. Every once in a while you do find an amplification. We don’t know exactly what that means in HCC, but it allows patients to be put into basket trials so we can learn whether they’ll respond to these targeted therapies.

Richard S. Finn, MD: Right. NTRK occurs in a single-digit number of cases, but there are some instances. I’m sorry, Catherine, you had a comment?

Catherine Frenette, MD: I was going to say that I agree that circulating tumor DNA is incredibly interesting. It may end up being more accurate in HCC than a biopsy. These tumors can be so heterogeneous. I’ve seen 1 tumor have 3 different types of tumor within it, all could be releasing their circulating tumor DNA. That could give us a lot more information than a single needle biopsy, potentially. I do think this is exciting.

Richard S. Finn, MD: Yes. I think the true impact will come, hopefully, in the near future.

Transcript edited for clarity.