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Progress in CRC Precision Medicine

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Cathy Eng, MD, FACP, The University of Texas MD Anderson Cancer Center; John L. Marshall, MD, The Ruesch Center for the Cure of GI Cancers ; Michael A. Morse, MD, Duke Cancer Institute; Dale R. Shepard, MD, PhD, FACP, Taussig Cancer Institute, Cleveland Clinic
Published: Monday, May 07, 2018



Transcript: 

John L. Marshall, MD: I want to talk about one more emerging area—precision medicine. Immunotherapy and precision medicine are 2 big things. Cathy, if all of these patients have a good performance status and there’s tissue available, should we be doing broad profiling?

Cathy Eng, MD, FACP: I definitely think so.

John L. Marshall, MD: Should the government pay for it? Should Medicare pay for it?

Cathy Eng, MD, FACP: For a metastatic patient, if it’s not been done previously, I definitely think so. We need to look at other options.

John L. Marshall, MD: There’s all of this fight about whether it is research or standard of care. We all order CHEM-20s, and a lot of that is kind of just fiddling and seeing…

Cathy Eng, MD, FACP: We’re looking for targetable mutations. That’s the only way you’re going to identify them. We have to take the information that we have, if it’s available. If it’s not available, we really need to pursue it. Otherwise, we have very few treatment options for patients, especially since so many of the new drugs are very, very specific.

John L. Marshall, MD: Yes. We’re really in this interesting space, where companies are doing molecular profiling. Even our own shops are doing this. Yet, they’re doing it without making any money. They’re hoping that this will become standard and appropriate. Can everybody vote? Should it be done? Is it worth getting back? What do you think?

Johanna C. Bendell, MD: Well, I think it’s the raw data, also. That’s something that we can go back and learn from. If we can start to create these data sets of broad-based molecular profiling, over broad populations, maybe we can start to pull something out as we start to learn something more about how these patients may respond to new drugs that are coming out? The other big issue, and you’ve mentioned it and have done some very good work with it, is longitudinal biopsies. How are these cancers changing over time? Certainly, we’re seeing more targetable genes that are starting to appear as mutations later on in the course of the cancer, across multiple different tumor types.

John L. Marshall, MD: And we’re seeing mixed responses. EGFR therapy, everything is responding with that. And, all of a sudden, there’s your RAS mutation. The more that we’re doing all of this, the more that we’re recognizing that it’s not static. Are we where our lung cancer colleagues are? We know about molecular profiling, repeat biopsies, options, basket studies, and these kinds of things. We have TAPUR. We have MATCH. Now, COLOMATE is emerging. Is this becoming a new way of doing things?

Michael A. Morse, MD: I’d like to believe that it is. Unfortunately, this isn’t lung cancer. There aren’t quite as many driver mutations that are detectable. And although you occasionally get very unusual ones that you wouldn’t expect, where do we go with those? If we don’t have basket trials, we’re very limited in how we can target them.

John L. Marshall, MD: It’s becoming a very important way to go forward, even though it might not be the majority of patients. Does anybody have a new, favorite target? We talked about HER2. We’ve talked about some of the new immuno markers. We know about MSI. We’ve mentioned PD-L1. What about tumor mutation burden?

Johanna C. Bendell, MD: The thought is that the more mutations the tumor has, the more weirdo proteins it makes for the immune system to recognize. And so, people in multiple different tumor types who have a higher tumor mutational burden, like MSI-high colon cancer, tend to respond better to immunotherapies. Now, is that the end-all, be-all for deciding who is going to respond? No. But it would suggest that the patient population may be more likely to respond. There are some rarer scenarios. For instance, in colon cancer, there are some rare BRCA mutations that might result in increased tumor mutational burden. Should we be looking at those folks? Cathy wrote an article on the polymerase epsilon as well. That could be associated with a potential response to immunotherapy. So, now we have to dig down deeper to see what else we can find and pull out.

John L. Marshall, MD: I don’t think there’s a right answer, but I’d like to hear your opinion. In the high tumor mutational burden patient, is it that there are a lot of mutations or neoantigens that somehow stimulate the immune response? Or, if you have a lot of them, is it that you’re more likely to have the individual ones that are causing the stimulation? What do you think? It’s a vote. It’s a bet. Who knows what the right answer is?

Michael A. Morse, MD: Not all mutations lead to neoepitopes. They have to be able to fit within the HLA (human leukocyte antigen) molecule of that particular patient. In fact, a lot of the mutations don’t. So, even in clinical trials, when we think that we’re vaccinating against those mutations, we’re really not achieving anything. It’s going to be very individualized. As precision medicine enters immunotherapy, this is why we are trying to identify the neoepitopes in a particular person’s tumor and create a vaccine or some other immune strategy that targets it to become more important.

John L. Marshall, MD: Yes.

Johanna C. Bendell, MD: And those studies are going. They’re moving.

John L. Marshall, MD: Dale, let’s talk about liquid biopsies. A lot of our people are getting them. People are knocking on our door and are saying that we should be doing this. What are your thoughts on that versus tissue-based biopsy?

Dale R. Shepard, MD, PhD, FACP: I think it’s early. We don’t know with certainty what that’s going to yield. I think that this is one of my peeves with a lot of our trials. We do a lot of biopsies and we gain some information. Particularly, in early phase trials, we oftentimes show 400% inhibition of whatever we want to show, but we have no responses. And so, if we can develop biopsy systems, or liquid biopsies, and we can do that with less problems for the patients, perfect.

John L. Marshall, MD: I think the COLOMATE study is being designed in a way that does both liquid and tissue-based biopsies. So, that will really be the first database for this. It will be very interesting. So, using them as the standard approach, is anybody doing a liquid biopsy instead of a tissue-based biopsy to determine some of these things?

Cathy Eng, MD, FACP: No, not at this time.

Johanna C. Bendell, MD: Not yet.

Cathy Eng, MD, FACP: In all honesty, we also are concerned about payment for liquid biopsies, unless it’s part of a clinical trial. That’s another area of concern.

Transcript Edited for Clarity 

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Transcript: 

John L. Marshall, MD: I want to talk about one more emerging area—precision medicine. Immunotherapy and precision medicine are 2 big things. Cathy, if all of these patients have a good performance status and there’s tissue available, should we be doing broad profiling?

Cathy Eng, MD, FACP: I definitely think so.

John L. Marshall, MD: Should the government pay for it? Should Medicare pay for it?

Cathy Eng, MD, FACP: For a metastatic patient, if it’s not been done previously, I definitely think so. We need to look at other options.

John L. Marshall, MD: There’s all of this fight about whether it is research or standard of care. We all order CHEM-20s, and a lot of that is kind of just fiddling and seeing…

Cathy Eng, MD, FACP: We’re looking for targetable mutations. That’s the only way you’re going to identify them. We have to take the information that we have, if it’s available. If it’s not available, we really need to pursue it. Otherwise, we have very few treatment options for patients, especially since so many of the new drugs are very, very specific.

John L. Marshall, MD: Yes. We’re really in this interesting space, where companies are doing molecular profiling. Even our own shops are doing this. Yet, they’re doing it without making any money. They’re hoping that this will become standard and appropriate. Can everybody vote? Should it be done? Is it worth getting back? What do you think?

Johanna C. Bendell, MD: Well, I think it’s the raw data, also. That’s something that we can go back and learn from. If we can start to create these data sets of broad-based molecular profiling, over broad populations, maybe we can start to pull something out as we start to learn something more about how these patients may respond to new drugs that are coming out? The other big issue, and you’ve mentioned it and have done some very good work with it, is longitudinal biopsies. How are these cancers changing over time? Certainly, we’re seeing more targetable genes that are starting to appear as mutations later on in the course of the cancer, across multiple different tumor types.

John L. Marshall, MD: And we’re seeing mixed responses. EGFR therapy, everything is responding with that. And, all of a sudden, there’s your RAS mutation. The more that we’re doing all of this, the more that we’re recognizing that it’s not static. Are we where our lung cancer colleagues are? We know about molecular profiling, repeat biopsies, options, basket studies, and these kinds of things. We have TAPUR. We have MATCH. Now, COLOMATE is emerging. Is this becoming a new way of doing things?

Michael A. Morse, MD: I’d like to believe that it is. Unfortunately, this isn’t lung cancer. There aren’t quite as many driver mutations that are detectable. And although you occasionally get very unusual ones that you wouldn’t expect, where do we go with those? If we don’t have basket trials, we’re very limited in how we can target them.

John L. Marshall, MD: It’s becoming a very important way to go forward, even though it might not be the majority of patients. Does anybody have a new, favorite target? We talked about HER2. We’ve talked about some of the new immuno markers. We know about MSI. We’ve mentioned PD-L1. What about tumor mutation burden?

Johanna C. Bendell, MD: The thought is that the more mutations the tumor has, the more weirdo proteins it makes for the immune system to recognize. And so, people in multiple different tumor types who have a higher tumor mutational burden, like MSI-high colon cancer, tend to respond better to immunotherapies. Now, is that the end-all, be-all for deciding who is going to respond? No. But it would suggest that the patient population may be more likely to respond. There are some rarer scenarios. For instance, in colon cancer, there are some rare BRCA mutations that might result in increased tumor mutational burden. Should we be looking at those folks? Cathy wrote an article on the polymerase epsilon as well. That could be associated with a potential response to immunotherapy. So, now we have to dig down deeper to see what else we can find and pull out.

John L. Marshall, MD: I don’t think there’s a right answer, but I’d like to hear your opinion. In the high tumor mutational burden patient, is it that there are a lot of mutations or neoantigens that somehow stimulate the immune response? Or, if you have a lot of them, is it that you’re more likely to have the individual ones that are causing the stimulation? What do you think? It’s a vote. It’s a bet. Who knows what the right answer is?

Michael A. Morse, MD: Not all mutations lead to neoepitopes. They have to be able to fit within the HLA (human leukocyte antigen) molecule of that particular patient. In fact, a lot of the mutations don’t. So, even in clinical trials, when we think that we’re vaccinating against those mutations, we’re really not achieving anything. It’s going to be very individualized. As precision medicine enters immunotherapy, this is why we are trying to identify the neoepitopes in a particular person’s tumor and create a vaccine or some other immune strategy that targets it to become more important.

John L. Marshall, MD: Yes.

Johanna C. Bendell, MD: And those studies are going. They’re moving.

John L. Marshall, MD: Dale, let’s talk about liquid biopsies. A lot of our people are getting them. People are knocking on our door and are saying that we should be doing this. What are your thoughts on that versus tissue-based biopsy?

Dale R. Shepard, MD, PhD, FACP: I think it’s early. We don’t know with certainty what that’s going to yield. I think that this is one of my peeves with a lot of our trials. We do a lot of biopsies and we gain some information. Particularly, in early phase trials, we oftentimes show 400% inhibition of whatever we want to show, but we have no responses. And so, if we can develop biopsy systems, or liquid biopsies, and we can do that with less problems for the patients, perfect.

John L. Marshall, MD: I think the COLOMATE study is being designed in a way that does both liquid and tissue-based biopsies. So, that will really be the first database for this. It will be very interesting. So, using them as the standard approach, is anybody doing a liquid biopsy instead of a tissue-based biopsy to determine some of these things?

Cathy Eng, MD, FACP: No, not at this time.

Johanna C. Bendell, MD: Not yet.

Cathy Eng, MD, FACP: In all honesty, we also are concerned about payment for liquid biopsies, unless it’s part of a clinical trial. That’s another area of concern.

Transcript Edited for Clarity 
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