Molecular Residual Disease (MRD) Testing in Colorectal Cancer (CRC): Surveillance Setting (Round 3)
Video Transcript
Dr Jason Zell: Okay. So, there's a great potential. So, I showed you the pelican beak curves. Those are for people who converted here. I mean, we want to identify people here before they have clinical disease. I mean, are we able to intervene and change this course? That's really what this is about. But that makes this a game changer, in my opinion, because we never had this before. We just waited. And then, all of a sudden, tumors pop up and it's whack-a-mole or whatever, right? At that point, you do what you can. So, the theoretical advantages are basically the same, but they're going towards personalized approach. And I had the idea too about escalating and also deescalating therapy and imaging and surveillance during this period. I have just a couple studies to show here. This was the first, and I will say it's the most provocative. So, this study by Reinert in 2019 showed that in every case of recurrence, ctDNA predicted in advance of CT scan. So, you can see this is a timeline. So, ctDNA occurs earlier, ctDNA positivity by a mean of 8.7 months. In a study since then, the average might be six, seven months, somewhere in there. So, I mean, that's a very valuable thing. And you can say, so what? Well, they prove that there were actionable mutations in 82% of these samples. So, that does suggest we could target these. That alone, I think makes it a game changer without the next trial to show which is the right drug, which is where we're headed. These are two studies. INTERCEPT is a prospective cohort study at MD Anderson where they have 1,100 patients. They're using this to identify patients who relapse on—I should say molecular relapse—and then target those for individual clinical trials. We have a trial at UC Irvine doing the same thing with a much smaller cohort. The ALTAIR trial you'll hear about. This is a trial of the molecular relapses in the GALAXY study. And I think it's a very interesting study, and I want to just focus on it for one second. So, overall, 243 patients, status post resection, who developed MRD-positive ctDNA by the Signatera-based assay. Their DFS was 9.3 months versus 5.5 months. And it was not significant, P is .10. And then, among resected stage IV, it was highly significant at .012, 10 months versus four months. So, what does this show you? I mean, my statistician mentor always taught me, look at the effect size. I think the study is underpowered. I looked at their methods. They proposed to show basically a four-month difference, which they found, but the placebo rate is different than what they projected. So, I don't know, this study is not going to answer that question. But I think the data are significant and impactful, still hard to ignore, just looking at the raw data and definitely among stage IV. So, I would say, lastly, we got to talk about financial toxicity, something I talk about whenever I talk about this topic, and health care disparities. This remains a big issue. I mean, just antinausea meds, it can cost multiple thousands of dollars. These are $4,000 to $5,000 a test. So, it's something we need to talk about. I am concerned about health care disparities, people not having access to this. They're now CMS approved. That's a huge hurdle, right? Insurers usually follow CMS. So, that's excellent news. And I just want to note, there is a very interesting health affair study on screening, circulating—or cell-free DNA—which showed that uptake of these blood-based tests is the same among Blacks, Whites, and Hispanics. It’s about 94%. So, really, you could argue there's potential to overcome some race, ethnic disparities by using these tests. Thank you.
Dr Namrata (Neena) Vijayvergia: Thank you, Dr Zell. So, we're going to talk about the surveillance setting and if we think ctDNA should be—this basically means that once you've treated, should we do it every three months for the patients up to two years? That's how CMS has approved it at this point in time. So, in this surveillance setting, the problems that, you know, you can see this is—we're trying to identify and prevent these patients from becoming, you know, overt cancers again. The biggest problem is the lack of effective therapies, right? ALTAIR is an example of that, like, do we have a game-changing therapy that can actually make a significant difference in these patients' lives if we actually identify that MRD? The other issue is, are we just doing a lead time bias, right? We're just identifying—is it, is MRD positivity in colon cancer a separate entity or just early identification of metastatic disease, which should be just treated as metastatic disease. We don't know that yet. And then, finally is, there's false negatives. And we can talk about ctDNA shedding rates, and if we can trust ctDNA by itself in that setting. So, the ALTAIR trial, we just talked about what it was, right? So, basically, they used—trifluridine/tipiracil was the drug of intervention that was used if you were ctDNA positive but you don't have any evidence of metastatic disease. This is a very effective and an approved agent in patients with metastatic disease. And they were trying to just move it up the ladder, right? Is it—and what they found was, it really didn't change outcomes, at least whatever be the reason, in the patients who had—in all, so one, two, three or one, two, four patients. In the resected stage IV patients, there was an improvement in the survival, in the disease-free survival. But you see the difference, like four or five months? That's sort of the difference we see, a little less in the metastatic setting when I use trifluridine/tipiracil based on the phase three data that we use at third-line right now. So, are we just moving it from the third line and putting it even before frontline therapy? We don't—you know, that begs the question, giving the patient the side effects, I might as well just use it when they actually develop disease. Unless I develop a drug or an agent which is actually going to cure some of these patients, which we don't have yet. So, I really think that this study showed that there's, at this point in time, trying to treat a ctDNA-positive patient before radiological recurrence is not a good idea.
Off-camera question: Do you wish that they had done TAS with BEV rather than TAS as a single agent?
Dr Namrata (Neena) Vijayvergia: No, I actually would probably want some novel agent. I don't think bringing a drug from the metastatic setting and moving it up altogether makes any sense. You know, bevacizumab has very little role in the adjuvant setting, too. But I think we just need better drugs in that setting. The next point is about the false negative. This is the ctDNA shedding rate. So, if patient—this is from the BESPOKE trial updated data. What they found was the rate of shedding of ctDNA from different sites. The lowest one I want to talk about, right, local recurrence, really very poor shedding. Patients with peritoneal, not as good. Lung is only 75%, too. So, a lot of the ctDNA-negative patients recur in these areas, and a lot of these are actually targetable, right? We can actually cure these patients via resection of a lung mass. So, just basing it on ctDNA is really—so we need to improve our tests so we can get these areas evaluated, too. And then, talking about the cost, the same idea, right? Yes, it is approved. But it still comes from our pockets, right? It's $3,000 to $5,000 a test. I know we had earlier talked about, you know, lymph node ratios and LVI. These are no cost. We already get these results anyways from our surgery because they do the surgery. These are an extra added test every three months, like, not just one time in the adjuvant. We're talking about every three months for two years. That's a lot of burden. And you don't want a patient—you know, this message that I just read on American Cancer Society. Patients pleading that now they're stuck with a bill of some sort from some company. So, there are prospective studies, as we know. There's actually a very cool study happening in Canada, I think, the IMPROVE-IT, which is trying to study—and they're basically checking out if you do ctDNA and you actually find a tumor that you can still treat with a curative intent. So, again, a therapy that actually makes difference. And if checking ctDNA early improves it, we're going to find out. And there are novel therapies, right? There's ctDNA-positive patients. People are—RAS-targeted vaccine therapies. There's immunomodulatory vaccines that are being studied in this setting. Once we get those results and if they're promising, I would totally do it. But until then, I'm not going to. That’s it. Thank you.
This is a non-CME activity. The views and opinions expressed by the presenter(s) do not necessarily reflect the views and opinions of the Oncology Learning Network, HMP Global, or its employees and affiliates.
