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The Future of MRD Assessment in CRC

Insights From: Axel Grothey, MD, West Cancer Center, University of Tennessee; John Marshall, MD, Ruesch Center for the Cure of Gastrointestinal Cancers
Published: Wednesday, Feb 26, 2020



Transcript: 

Axel Grothey, MD: The assessment of immune therapy responses on cancer is always a little bit tainted by the idea of, when do we see responses? Is there pseudoprogression, for instance—kind of an imaging phenomenon due to the inflammatory infiltration of lymphocytes into the cancer? And so, having early assessment of responses using circulating markers like ctDNA [circulating tumor DNA] would be very helpful, in particular to identify early on whether we see a response, and to distinguish between pseudoprogression and real progression. We have actually seen data presented at ASCO [the American Society of Clinical Oncology 2019 annual meeting] that revealed that ctDNA levels can actually be highly predictive of response to immunotherapy in various, different cancers. This was still an early group of patients—not more than 70 patients were tested—but it was very interesting that these patients actually showed a drop in their ctDNA, which predicted response to immunotherapy.

John Marshall, MD: We need to figure out how best to use this. One way, of course, is to do very tightly designed randomized studies and the like, and those are being done. I actually like the BESPOKE trial. It’s more of a registry, really, because it lets us, in certain scenarios, collect data on large numbers of patients with real-world evidence and incorporates this kind of test to see, what did the physician do? Also, what did the patient receive? How did they turn out? And I think by collecting this kind of data over the next couple of years, we will truly advance this field. BESPOKE is not really anything terribly fancy. It’s mostly a registry study, but it’s going to be very important and informing on the use of ctDNA in daily practice.

Let’s say this is really starting to click and work. Not only are we talking about yes/no on therapy, but I think maybe even more importantly it becomes the way we follow patients after their diagnosis. Right now in colon cancer, for example, you have your surgery. You might get your chemotherapy, and then you have a very nervous 5 years while you’re being monitored with CEA [carcinoembryonic antigen] and CT [computed tomography] scans to know whether you’re cured. That’s a big deal.

What this test might do is replace all of that. Instead of going to get CTs and all of this, you get this blood test every now and then. What we’re hoping is that when it does show up, or if it does show up, you see it earlier than we saw it before. This may give us new opportunities for a therapeutic intervention.

At the same time, we will see more patients with a positive circulating tumor DNA but whose scans are negative. And so, we’ve created this new controversy about, what are we going to do with those people? Do we jump right in with chemotherapy? Do we wait and see what happens? We know it’s going to regrow. We don’t know yet what to do. And so, it’ll be great to start to study that patient who relapses just with a ctDNA, but not by traditional measures of a CT scan, and determine how best to intervene.

Let’s think about 1 more scenario where you could use a test like this. So I’ve given a treatment, whatever it is. It could be a checkpoint inhibitor, it could be a chemotherapy. It doesn’t matter. I’ve started the treatment. Today, what I do is I give that treatment for 8, maybe 12 weeks. I expose the patient to that therapy for a long period. Adverse effects, cost. I then do a scan to see if the cancer got better or not.

What if I had a test that after 2 weeks of treatment, if the ctDNA levels fell, it’s a very strong indicator that the treatment’s working? If the ctDNA is rising, it’s a pretty strong indicator that it’s not. So what we may end up doing is having an early readout using this kind of analysis to see if we’re having a clinical benefit, and continuing therapies that are working and avoiding therapies that are not.

Axel Grothey, MD: In a community setting like the kind of hybrid model that I work in—West Cancer Center is, by definition, a community setting and is linked to the University of Tennessee—MRD [minimal residual disease] testing can be operationalized. We have actually started doing it, and my challenge right now is more in trying to find ways to communicate results to patients, because that’s not trivial. What does a positive ctDNA test mean, when normally you would say without treatment the patient has a 100% risk of eventually being diagnosed with metastatic disease?

The challenge is one that I and a lot of people have to wrap our heads around. I also believe that physicians need to be educated about the prognostic value, treatment consequences, and again, communication strategies with patients, as well as the sensitivity and specificity of tests. It’s a new era. It’s a new way to identify, in making treatment decisions for patients, patients at high risk of recurrence. So there is a lot of let’s say educational need that we still have. I believe that we need to include patient advocates to really identify the best communication strategies with patients that community oncologists and oncologists, in general, would be facing.

Transcript Edited for Clarity
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Transcript: 

Axel Grothey, MD: The assessment of immune therapy responses on cancer is always a little bit tainted by the idea of, when do we see responses? Is there pseudoprogression, for instance—kind of an imaging phenomenon due to the inflammatory infiltration of lymphocytes into the cancer? And so, having early assessment of responses using circulating markers like ctDNA [circulating tumor DNA] would be very helpful, in particular to identify early on whether we see a response, and to distinguish between pseudoprogression and real progression. We have actually seen data presented at ASCO [the American Society of Clinical Oncology 2019 annual meeting] that revealed that ctDNA levels can actually be highly predictive of response to immunotherapy in various, different cancers. This was still an early group of patients—not more than 70 patients were tested—but it was very interesting that these patients actually showed a drop in their ctDNA, which predicted response to immunotherapy.

John Marshall, MD: We need to figure out how best to use this. One way, of course, is to do very tightly designed randomized studies and the like, and those are being done. I actually like the BESPOKE trial. It’s more of a registry, really, because it lets us, in certain scenarios, collect data on large numbers of patients with real-world evidence and incorporates this kind of test to see, what did the physician do? Also, what did the patient receive? How did they turn out? And I think by collecting this kind of data over the next couple of years, we will truly advance this field. BESPOKE is not really anything terribly fancy. It’s mostly a registry study, but it’s going to be very important and informing on the use of ctDNA in daily practice.

Let’s say this is really starting to click and work. Not only are we talking about yes/no on therapy, but I think maybe even more importantly it becomes the way we follow patients after their diagnosis. Right now in colon cancer, for example, you have your surgery. You might get your chemotherapy, and then you have a very nervous 5 years while you’re being monitored with CEA [carcinoembryonic antigen] and CT [computed tomography] scans to know whether you’re cured. That’s a big deal.

What this test might do is replace all of that. Instead of going to get CTs and all of this, you get this blood test every now and then. What we’re hoping is that when it does show up, or if it does show up, you see it earlier than we saw it before. This may give us new opportunities for a therapeutic intervention.

At the same time, we will see more patients with a positive circulating tumor DNA but whose scans are negative. And so, we’ve created this new controversy about, what are we going to do with those people? Do we jump right in with chemotherapy? Do we wait and see what happens? We know it’s going to regrow. We don’t know yet what to do. And so, it’ll be great to start to study that patient who relapses just with a ctDNA, but not by traditional measures of a CT scan, and determine how best to intervene.

Let’s think about 1 more scenario where you could use a test like this. So I’ve given a treatment, whatever it is. It could be a checkpoint inhibitor, it could be a chemotherapy. It doesn’t matter. I’ve started the treatment. Today, what I do is I give that treatment for 8, maybe 12 weeks. I expose the patient to that therapy for a long period. Adverse effects, cost. I then do a scan to see if the cancer got better or not.

What if I had a test that after 2 weeks of treatment, if the ctDNA levels fell, it’s a very strong indicator that the treatment’s working? If the ctDNA is rising, it’s a pretty strong indicator that it’s not. So what we may end up doing is having an early readout using this kind of analysis to see if we’re having a clinical benefit, and continuing therapies that are working and avoiding therapies that are not.

Axel Grothey, MD: In a community setting like the kind of hybrid model that I work in—West Cancer Center is, by definition, a community setting and is linked to the University of Tennessee—MRD [minimal residual disease] testing can be operationalized. We have actually started doing it, and my challenge right now is more in trying to find ways to communicate results to patients, because that’s not trivial. What does a positive ctDNA test mean, when normally you would say without treatment the patient has a 100% risk of eventually being diagnosed with metastatic disease?

The challenge is one that I and a lot of people have to wrap our heads around. I also believe that physicians need to be educated about the prognostic value, treatment consequences, and again, communication strategies with patients, as well as the sensitivity and specificity of tests. It’s a new era. It’s a new way to identify, in making treatment decisions for patients, patients at high risk of recurrence. So there is a lot of let’s say educational need that we still have. I believe that we need to include patient advocates to really identify the best communication strategies with patients that community oncologists and oncologists, in general, would be facing.

Transcript Edited for Clarity
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