Recent results from the GALAXY trial – Dr. Stacey Cohen (2024)

Manju George 0:00
I’m Dr Manju George, the Scientific Director at Paltown Development Foundation, the nonprofit that supports Colontown. Welcome to everyone. Today, we have Dr Stacey Cohen with us. She’s an Associate Professor at the Clinical Research Division at Fred Hutch. She’s also the Associate Professor in the Division of Oncology at UW. Welcome Dr Cohen. And if you haven’t watched Dr Cohen’s DocTalk from 2021, I would highly encourage everyone to watch that as a primer for this talk. So let’s get started.

Dr. Stacey Cohen 0:33
Sounds great! So thank you for inviting me. I’m super excited to talk a little bit more about circulating tumor DNA, or CtDNA. We’re going to focus on the GALAXY study, which has been around for a few years, but it had another major publication, and I jumped in a little bit to some background, just because I don’t expect everyone to watch my prior talk.But let’s go ahead and get started, and we’ll talk more about what we’ve learned and what we’re still learning. Oops, Sorry, I didn’t put my disclosures in yet. I forgot that part. But I want to note that I have done research with companies including Natera and Guardant as well as Tempus and Exact Sciences, all of whom who have platforms. But these research is not relevant to my talk today.

Speaker 1 1:19
So we’re going to review CtDNA, talk a little bit about GALAXY, and then just a couple slides on sort of how do we continue to use CtDNA in the future? So in terms of our overview, we know back from biology class, –this is recycling, but for my old talk, but I think an important background,– just that we know that within our cells, we have DNA that is turned into RNA, transcribed to RNA and then translated into protein. And then, on a bigger scale, we have the single cell that can turn into a malignant cell and become a tumor. And so as we think about sampling for cancer, we could do a tissue biopsy where we actually put a needle in or cut out a piece of the tumor and do analysis on that. And then we also have the ability to sample the blood, and that could be for proteins that we call biomarkers, or tumor markers, like CEA. And then also could be our so-called liquid biopsy. We’re actually looking for circulating tumor DNA fragments that are in the blood, and that’s the liquid biopsy. So what is CtDNA? We got to take a step back and say, What is cell free DNA, or cf DNA? We all have DNA in our blood, that is the byproduct of just cells breaking down. So even healthy individuals will have cell free DNA. In terms of using this as a test. It was first used for prenatal aneuploidy screening, so often called a cell free DNA test. And that’s for example, to look for chromosome changes like Trisomy 21 or Down syndrome. But when we think about CtDNA or circulating tumor DNA, we’re actually looking at the portion of cell free DNA that’s highly specific for cancer. And the reason why this is an interesting test is because we know that this is a very dynamic marker. It has a half life of less than two hours, meaning that it doesn’t stick around. It breaks down quickly in the blood. The levels are cancer burden dependent, so the higher the level, the more cancer might be in the body. But we also know that it’s not a perfect test, and there’s other things that it can increase both CtDNA or cell free DNA levels.

Dr. Stacey Cohen 3:22
So why do we even care about this? Well, anybody who’s had a tissue biopsy knows that it can be painful, it can be complicated to schedule or hard to get to. Maybe the actual location of the tumor is logistically difficult and it costs a lot of money. Blood tumor markers like CEA are good, but they don’t always detect our cancer recurrences. And theoretically, the sooner that you figure out that something’s going on, the sooner that you could start to treat it. So does that mean, perhaps that you could do surgery for metastasis, or maybe start chemotherapy earlier and fully treat a metastasis before it’s had the chance to grow up into a large tumor. So when we think about the spectrum of what we can do for CtDNA, it really goes through a lot of different clinical scenarios. It could be used as a screening test to even figure out if someone has cancer in the first place. We could be using this, though, that’s sort of what we’re seeing here in orange, where you’re trying to even detect there’s cancer going on. We could use it for what they call molecular profiling or prognostication, meaning actually detecting specific genetic changes like KRAS or BRAF, and you find that in the blood, and using that to help describe what type of treatment to do. Detection of residual disease, meaning you had surgery, you think the cancer is gone, and you’re trying to see if it truly is gone. Looking for response to therapy. So more of a longitudinal marker where you’re actually seeing how that looked over time. And then finally, what they call clonal evolution, which is basically saying that the genetic changes vary over time, and sometimes you want to look and say that levels went up or down. For example, we’ll use this after response to anti EGFR therapy like Cetuximab, and we might say, did the KRAS mutation come or go? Something like that.

Dr. Stacey Cohen 5:12
So, let’s use all of that very quick background to think about what are the updates for GALAXY. So as I said, this data was recently published in Nature Medicine, a very, very good journal for medical literature. And this was sort of the update for the trial, which has previously also been published as well in its early form. So the GALAXY study is in the dashed line here. It’s part of an overall plan called CIRCULATE Japan. So they’re planning on doing over 5000 patients, with colon or rectal cancer who are planning to go to surgery. After their surgery, they do WES, Whole Exome Sequencing, so they do some genetic testing. But they’re also, which you can see with those blood files, following patients for up to two years, sampling them along the way and using that information just to figure out what happens to patients. There are two actual interventional trials, VEGA and ALTAIR. ALTAIR is actually, I think, supposed to read out sometime in 2025 so that’s pretty exciting. But these are trials where they actually use the results to treat patients differently. But for the moment, we’re just focusing on the GALAXY study, which is the observational portion.

Dr. Stacey Cohen 6:30
So I’m putting a lot of figures from the paper, and they have a lot of figures, so a lot of data to go through, so I’m trying just to do some of the highlights. But whenever you have an observational study, not all patients end up having the same outcomes. So for example, they had over 6000 patients, but then they took out different people for various reasons. One most notably that if they also were enrolled on a trial where they were given a specific treatment, they wanted to take those patients off study because they felt like that wasn’t a true representation of just what patients receive in response to their CtDNA alone. So that ended up with a little over 2000 patients who had post operative CtDNA, weren’t doing another study, etc. And then they looked at them sort of over time, and so I’ll highlight that in the time right after surgery, which we call the MRD window, they had about 2000 patients. And then if you looked at patients who they followed more longitudinally, they had a little bit less, more like 1800 patients.

Dr. Stacey Cohen 7:32
And then one last thing to show here, so about 16% were CtDNA positive in the MRD space. And that’s pretty typical for what we would expect for these types of studies. So this Sankey plot is, I think, just kind of helpful in looking at what happened to patients over time. And it just shows that there’s a lot of trends here, and we try to figure out what happens. They roughly break this down. What they’re showing here is that in red were patients who are positive, and in green, are patients who are negative. And when you see the lines criss cross, it could be because someone got chemotherapy, or someone later recurred, and so that’s sort of how this graph is read. But we can look at different things, like, well, what’s the impact of chemotherapy? Was that enough to convert someone from positive to negative and have a better outcome? Or, what about some patients who go to negative for a bit and then go back to positive, that would be called transient clearance. And how does that inform recurrences? And then the fact that some people still have occurrences even though they’re negative, and it’s about 5%. So this one picture kind of summarizes what we see for patients overall, notably the fact that, again, the majority of patients do not have a positive CtDNA test. But still, we see some crossover, and that’s really what we hope, is the impact for what you can do as a provider, which is to actually try and improve someone’s outcomes, depending on what happens and what types of treatments you use. Oh, and then one other point, which I just want to briefly bring up, which is everyone asked the questions, well, what if it’s a false positive? Is there any chance its just going to go away on its own? And in this large study, there was about 2% of patients who converted from positive to negative without any chemotherapy. They call that spontaneous clearance. So it does occur. It’s extremely rare, and two patients is not really enough to really adequately say the frequency, but it does tell us that it has occurred before, but I would never have a patient assume that it’s going to happen to them.

Dr. Stacey Cohen 9:34
So let’s look a little bit more at the patients, because the devil is always in the detail here, especially for an observational trial, because in an interventional trial, you decide criteria that are much more specific in advance and say they all have to fit into these boxes, and then from there, you treat patients accordingly, whereas an observational study, it’s often looser. So I like to highlight things like there’s a variety of different stages. Stage IV has a higher recurrence rate than stage I. So we expect to see differences there. 10% of patients had chemotherapy before surgery. I don’t know which patients, but my assumption is a lot of the stage IV patients, or who that’s going to refer to. And 42% had chemotherapy after surgery. So again, a little uncommon, because we would expect many of the stage III and stageIV patients, and some a stage II to have it. So a little low, perhaps in this study, And then the recurrence happened radiographically, meaning on scans, to 22% of patients. So this just gives us some rough idea about who actually was enrolled in the study.

Dr. Stacey Cohen 10:37
So just to give an update on what do we think CtDNA is most established for? It’s most established as a survival biomarker, meaning patients who are negative do better than patients who are positive. And this has been shown over and over in different studies, just as a marker on its own. That is not enough to say that we should check CtDNA, because we need to know that if we have the result and we change management because of it, then you get better outcomes, that’s when we start to actually use it in clinical practice. But at least in this point, we can say it has been shown to be a marker of prognosis. So if you’re not familiar with looking at these curves, they are called Kaplan Meier curves, you’ll see that everybody starts at 100% kind of in the upper area, [Manju. Can you see my mouse by the way? Yes. Okay, great. Okay, I’m not talking to myself]. So we started at 100% and then if someone has an event, then the number drops down. So on the left we have disease free survival, and on the right we have overall survival. So on the left, the number drops down, if the disease recurs or someone passes away. On the right, it’s just about life and death. If someone dies, then the number ticks down. So what you’re going to see here is that you’re going to have more recurrences than you are going to have deaths from cancer, but you see marked differences between the patients who are negative and positive. And so that says to us, that’s a prognostic endpoint. And this is based on the MRD time point. MRD stands for minimal residual disease, or molecular residual disease, but specifically, this is done about one month after surgery and before anyone had any chemotherapy. When you look at the surveillance time point, so after all the chemotherapy is done, at least six months after. Then, you’re going to see again, patients who are negative do better than patients who are positive, and still here you see marked differences. Now the patients here that are positive are doing worse, and that makes sense, because you didn’t have that opportunity of doing the chemotherapy right away, maybe clearing whatever cancer was left over when it was micro metastatic. Now you’re actually having real recurrences. So again, suggesting a prognostic marker.

Dr. Stacey Cohen 12:53
So as we look at some of the newer data from this GALAXY update, again, they have one of these graphs just kind of show where everyone goes. But I want to point out the fact that now we’re looking at patients who actually had radiographic recurrence, and comparing those to patients who didn’t have recurrence. And so broken out on the right in these rainbow colors, is looking at the site of recurrence. And I want to highlight a couple things, the liver turns out to be something that we know to be a high shedding site. And what I mean by that is that if someone has a liver metastasis, they’re more likely to shed CtDNA, have detectable CtDNA than some other sites. So what you’ll see is that you look at the orange and light orange, that patients who have a recurrence are more likely to have CtDNA positivity, so 95% here, whereas when you look at low shedding sites like lung and peritoneum, you’re seeing lower frequencies. And so we know this from multiple studies as well, saying that these are notorious sites that either have lower cancer burden, so they don’t shed as much, or just doesn’t get into the bloodstream in the same way, like if it’s in the peritoneum. And so this remains an interesting finding for us to know, because if someone has radiographic recurrence, but the CtDNA is negative, we still need to believe our scans, because we know that it doesn’t 100% tell us what’s going on. On the other hand, let’s say the CtDNA was positive and there was, like an indeterminate finding in the liver, we might be more likely to say, I actually think that’s a tumor there, because we’re finding the CtDNA to be positive. So you can sort of use it in both directions.

Dr. Stacey Cohen 14:36
Now after when we look among the recurrences, CtDNA remains prognostic. So this is of patients who recurred, patientswho were negative still did better than patients who are positive. And when you look at this bar chart here on the right, looking just even in the MRD time point, this is the proportion of patients who end up being able to do a curative intent surgery, patients who are negative were more likely to go through despite now being stage IV or always being stage IV, but having a recurrence, they’re able to go through a surgery, of trying to have curative intent even after that recurrence. And so what that says to me is that it’s not the test that’s actually guiding management, but we know that when patients have a smaller burden of disease, so fewer tumors or smaller tumors and more clustered in one area, we’re able to do more aggressive interventions. So again, this is more prognostic than predictive, but it sort of supports this idea that you know when someone is negative, you anticipate that they’re going to have a better outcome.

Dr. Stacey Cohen 15:44
So interestingly, they show data by different molecular subtypes. So we know that there is sort of different types of colorectal cancer. It is not one disease. It is multiple diseases arising from one organ, and we can define that by what we call driver mutations. And they looked at these specific mutations, because these are genetic changes in the tumor for which we have drugs. And so what we see is that cancers that notoriously do well, like MSI high, which is a marker for being able to use immunotherapy, seems to have the best outcomes, where some of the other ones in the RAS RAF pathway, like ERBB2 and KRAS, G12C, don’t do as well. Now the interesting one is BRAF, because BRAF is notoriously a poor prognostic marker. But the tricky part for interpreting here is that BRAF sometimes goes hand in hand with MSI, and those patients tend to do better. So in a graph that I didn’t show they basically broke it down and said, Look, recurrences didn’t happen that often when you looked at BRAF overall. But if you broke it out, and I’m sorry, don’t mean recurrences, I mean, disease free survival. But when you look at just the BRAF mutant cases who were MSS or micro satellite stable, then they had much worse outcomes. So sort of what we would expect. But again, this is an observational study. This is interesting information, but what do we do about it? Did these patients receive immunotherapy or Encorafenib or, Adagrasib, we don’t know, and we don’t know that because this trial was done in Japan. We don’t know if they had access to the same types of targeted therapies that we do, and in the same combinations or the same order. So survival is partly driven by what therapies you receive. And so it all becomes kind of muddy as you look at this. So I think really, my takeaway from this again, is that this supports what we already knew about these molecular markers, but doesn’t really help us treat patients here.

Dr. Stacey Cohen 15:44
Okay, so now we’re going to talk about what happens over time. So we referred to the idea that you could check more than one time for your CtDNA and use that to inform outcomes. So again, on the left, we have disease free survival, and on the right we have overall survival. And this is looking at patients who are MRD positive, and whether they converted to negative or not by three months. So patients who went from positive to negative, they call that clearance, did better than patients who stayed positive. And again, we’ve seen this in other studies, but it makes sense. So if you have a patient where you’re detecting microscopic amounts of cancer, and you can, so called, get rid of it with your chemotherapy given after surgery, you expect that those patients are going to do better, have less recurrences. On the other hand, you can see that being positive in the beginning still mattered. That blue line is not all the way up at that 95% like it was before, they still saw a number of recurrences in those patients. So what we know from that is being negative upfront is a really good thing. It is great if you can clear your CtDNA, that’s definitely a step in the right direction. But by no means is that sort of make up for the fact that it was positive before. And then they also looked at six months. Because again, sometimes people have transient clearance, it goes negative, and then it goes back to positive. And so six months is sort of a better time point, because again, if you’ve really stayed with clearance at six months, you see that the levels bumped up a little bit in the clearance group, that they did a little bit better. So this just shows the fact that the results over time can matter as well. So how do you put this all together? So when you look on the left for CtDNA positive patients, patients who cleared did the best. Transient clearance was better, at least they had some response to chemotherapy versus no clearance, but still, patients who converted back to positive, basically all of them eventually went on to have a cancer recurrence.

Dr. Stacey Cohen 19:49
But I think it’s also interesting as we look for the timing of that. So when you look at the patients who were CtDNA negative, and then how when they actually had molecular recurrence, meaning they turned to positive. So this would be you were negative, you had your chemo or not, and you’re in your surveillance time period, and then all of a sudden you got a positive test. When did that test occur in relation to surgery? The longer that it was, the better patients did. So patients who had a whole year did better than patients who had less than a year, whether it was six to 12 months or less than six months. And there’s not that many patients in these groupings, we have to kind of take it with a grain of salt, but that kind of goes with what we expect again. Because a slower growing tumor tends to have better outcomes than a fast growing tumor. But it really kind of puts some numbers and pictures to this idea, and shows that maybe CtDNA can help us understand when that’s going to happen. So the stage IV group, I think, is of high interest, because we know that those are patients that recur frequently. This is again, these are patients who had stage IV who were taken to surgery with the idea of curative intent. But we know that even, let’s say, liver surgery, there’s at least a 50-50, recurrence risk. And that this could include other patients of higher risk areas. And so this is, to me, a really good group to look at CtDNA in, because we expect a lot of events, or a lot of times that people have recurrences, so we can really learn from it. So what I thought was interesting is, again, we said that 10% of patients in the study had prior chemotherapy. We don’t exactly know which ones, those were which stages. But if you looked at patients who had pre operative chemotherapy and then had their surgery, in patients who were positive for their CtDNA after MRD positive, giving chemotherapy after surgery did not really help them all that much. And again, there’s not that many patients so there was some benefit. Probably not that we would still give the chemotherapy honestly, but it just shows you that it helped a little bit, it didn’t help a lot. Whereas, when we look at patients who did not have prior chemotherapy, they went straight into surgery, and then they were MRD positive after. Here, the chemotherapy had greater benefit. And so again, as we interpret the GALAXY study overall, we have to recognize that heterogeneity and the fact that as you interpret benefit from chemo after surgery, for example, it is super important to understand what therapies they’ve had before, because it really influences how you look at those outcomes.

Dr. Stacey Cohen 22:30
So now this is a slightly different group. These are patients who were negative after surgery. They were still stage four, and we’re looking at whether or not they had prior chemo. If the patient was MRD negative, you can see here that again, there was a benefit, though minimal. The curves are much closer together, and that benefit amount was pretty similar, whether or not they had prior chemotherapy or did not have prior chemotherapy. And so again, what this suggests overall is that these patients who are MRD negative are likely to do better. But again, you’ll also note that the curves are much lower than in the early stage. So despite this, we are still seeing a high frequency of recurrences. So that’s you can see, like on the bar chart here, that almost 50% of patients on the observation arm, and about whatever that is, 35% on the adjuvant therapy arm still had a recurrence. And so this just gives us pause to say, Well, what do you do? Because you have the option of giving chemo, at least that’s an intervention you can do. But maybe the chemo that we’re using is not actually helping that much. Maybe we need to change the type of chemotherapy or do something differently, because we’re still seeing a decent number of occurrences, enough that, as an oncologist, I want to intervene. I want to make that better. But the things that I have, the tools at my hands here, are not the ones that we want to use. But step back, what was the chemo? We just grouped it all and called it adjuvant chemotherapy or ACT, we don’t know. I mean, we can go back, and they presented some of that in the earlier table, but we don’t know of these specific patients, did they get aggressive chemo, or, sort of not aggressive chemotherapy? Did they get things that we consider standard or non standard? So, GALAXY is still interesting and thought provoking, but you have to sort of take every conclusion with the grain of salt that comes with where it came from.

Dr. Stacey Cohen 24:28
Okay, so where does that lead us now, what did we actually learn from GALAXY? We learned again, I would say we knew this, but I think this reiterates is that CtDNA is a marker of poor prognosis, meaning poor survival outcomes. Patients who are CtDNA positive don’t do as well as patients who are negative. We see that CtDNA negativity is a potential marker of less benefit to post operative or adjuvant chemotherapy, though, again, we don’t know which regimens, and we’ve known from other studies that that really makes a big difference. We know that spontaneous clearance going from positive to negative without any treatment is rare, so maybe at most 2% but we are not going to ever assume in an individual patient that this is likely to happen. Instead, we assume that a positive patient is more likely to recur. So as we look at patients who are defined by their actionable, or what we call druggable genetic changes. So this was BRAF and MSI. CtDNA positivity was still associated with worse outcome, but again, we have no idea if they got any of those therapies. So to break it up in these groups doesn’t really matter unless you know that they got those treatments. And when we look over time as we evaluate changes in their ctDNA, like, were they positive? Were they negative? Did they clear or not? The timing of that, the sustainability of that, that is associated with outcomes. So I think we can see some definite trends here which go back to prognosis. But all of this alone is not enough to change our guidelines, because all of this is observational. It’s heterogeneous. There’s a lot of different factors, and when you see trends, we really need to break it down and look at how are decisions made based on the results. Because we can’t promise that if I go into practice and I see a patient with a result that I’m making the same choices as the people that had in the study. So therefore, I don’t really know if what we’re doing even replicates this data. And so because of that, you need a more clear kind of decision tree for how to interpret results to make it practice changing.

Dr. Stacey Cohen 26:34
So we need trials to prove efficacy. This is one trial. So this is also called CIRCULATE, but this is CIRCULATE North America. And so this is a study in stage III colon cancer, where all patients are recommended to have chemotherapy, typically, but they’re actually triaging patients based on their ctDNA status. If it’s positive, we’re deciding between a standard regimen, which is CAPOX or FOLFOX versus an escalated regimen, which is FOLFOXIRI, also called FOLFIRINOX. Whereas, if it’s negative, and we think they have a low risk group, we’re actually randomizing patients to standard therapy or just observation, so not giving chemotherapy, which is extremely, I would say, controversial and cutting edge. And so and then if they stay negative, great, and if they turn positive, they get to flip over to the other arm. So I encourage anybody who has the ability to go on such a study, I think that it both has the ability to help you as a patient and also help patients at large, because really, all four arms, I think, make justifiable sense with the data that we have.

Dr. Stacey Cohen 27:38
So where are we at today? This test can be ordered by your physician. You can then get into all of the details. Which test, how do you use it? When do you use it? Why do you use it? They all have their pros and cons. There’s multiple tests that are done. We in GALAXY, we were talking about a tumor informed assay. There’s also tumor naive and that’s a whole other topic that we would need to go over. But just know that there’s a lot of different types, and you can’t necessarily borrow data from one study to the next. It remains unclear how treatment decisions should be changed based on CtDNA results for MRD, so therefore it is not part of our guidelines. And if you look at our national guidelines, and this gets updated every year, so this is technically 2024 language which will continue to be changed, but they basically say it’s an emerging prognostic marker, but it’s insufficient evidence to recommend routine use outside of a trial. And they don’t recommend scaling back on treatment based on the CtDNA results. So what you and a provider might decide to do on your own is your own prerogative, but as it comes from the National Guidelines Committee, it’s not recommended that patients necessarily even receive these tests because of all of the sort of up in the air questions. So you can talk to your provider if you are interested, if you’re a patient, if you’re a caregiver and you want to learn more, I would say, talk to your provider about what this test is. Does it make sense for you and when? But just know we’re really still learning how to use the results, and so everybody’s going to have their own take on things, myself included, but I hope that this will help really improve cancer treatment in the future And I think that’s all I have.

Manju George 29:16
Okay, thank you so much. This was very helpful. So what I would suggest is, like, if we can go back to that rainbow slide, I think that’s the one that, because we have in COLONTOWN a lot of patients using CtDNA. And there are questions about some of what they saw in this study. They see radiographic recurrence, but they don’t see a CtDNA positivity, whereas there are other people who have something show up on CtDNA, but can’t find anything on the scans. So if you can, it’d be nice to explain this figure a little bit more to say that there is that margin, right, in both ways.

Dr. Stacey Cohen 30:01
yeah, so I think Manju, I think that’s great. So, as we interpret these results, I think I always tell folks, as I’m talking about, how to use it, that I didn’t say it yesterday, but I should, which is that this augments what we know. This is not meant to replace current clinical management, though, I can think of many instances of clear metastasis on scans with a negative CT DNA or a clear positive CT DNA result, where we haven’t been able to find it on scans. And in this study and in other studies, they’ve shown that CT DNA about half the time, you’re going to find it right away. If you have a positive result and you do a scan, you’re going to find that area that’s a recurrence. And so you take care of whatever that needs. The other half of the time you don’t find it. And it’s a median, or 50-50 mark of about five and a half months before you actually see something on scans. So that is a time, of course, increased anxiety. But what that allows us to do is to actually maybe increase the frequency of scans. Maybe you were getting once a year scans, and so now we’re going to start to do every three months, or when we get a positive CT DNA result, and maybe your CT was negative. Well, we know that the liver is a high shedding site. We know that the liver may be better imaged with a multi phase CT or multi phase MRI, which is not the standard protocol when you just do your like surveillance scan, that’s not a multi phase scan. And so it may prompt you or your provider to ask about, do you need to do additional imaging of the liver to try and understand. And that’s something that I’ll do. They don’t often get PET scans unless there’s an indeterminate finding. But I use the results in both directions. If there’s an indeterminate finding in a negative CT DNA, I’m going to be a little bit more reassured. If there’s an indeterminate finding in a positive CT DNA, I’m going to think something’s more likely there. And if there’s a positive CT DNA without a source, I might dig a little deeper. But again, what we’re trying to show here is, I’m going to really focus on this sort of any time after surgery, because I think that’s what’s more important here. But generally speaking, the liver metastases seem to show up with a positive CT DNA at the same time that you’re able to find it on scans. When in green, here we have lymph nodes. That’s okay. Lung is a big area where we may not see a positive CT DNA, and a common pattern for lung metastases is tiny lung nodules. So they’re both small, so they’re not going to shed as much, and lung just doesn’t seem to get to the bloodstream in the same amount. So it’s not just this particular assay. It’s been shown in multiple studies. But look here. I mean, only 54% had a positive CT DNA where they had clear imaging findings of metastasis. And so that really gives us pause to say we need to be aware that if there’s a new lung nodule, that’s out of the blue, six millimeters, that’s a tricky one. We can’t biopsy it. We can’t do a PET. If the ctDNA is negative, obviously we’re happy, but that doesn’t take away the fact that something was seen on scans. And so I would probably, in that scenario, if they hadn’t had previous lung nodules, just follow it again with a scan in three months and see did it grow? But it at least allows us to kind of hone in a little bit more. So I would just say, just be aware that this test is not replaced what we’ve learned about oncology. It augments it, and in some ways it enhances it. In some ways it makes it more confusing.

Speaker 2 33:36
Okay,thank you very much for that. So there are some questions in chat.

Dr. Stacey Cohen 33:40
Oh, okay, I can’t see that. Let me turn over here.

Speaker 2 33:44
So in this question, it says For slide by molecular subtypes, this was for all people with positive CT DNA?

Dr. Stacey Cohen 33:52
Let me just go there to this. So, yes, this was looking at all people. So the way you can tell that is if you look at the number at risk here, this is whatever that adds up to being, let’s say, like, 1500 patients. So this is not just positive CT DNA on the right here, they have the frequency of MRD positivity or positive CT DNA afterwards. And looking that at different groups had different frequencies. And then, as I said, BRAF is a little bit off. And then, as you actually interpret this curve right here, you’re looking at disease free survival as defined just by their molecular subgroup, without their CT DNA being considered. And so this, the graph on the left, is just saying that we know that certain subgroups do differently, some do better, some do worse, and then they were trying to show with the MRD positivity that we can kind of reflect that, but cancers that tend to recur more also had a higher frequency of CT DNA positivity.

Speaker 2 34:54
Thank you very much. The next question is, is there any data on stage for non surgical patients who become. CT DNA negative, that is chemo cleared disease.

Dr. Stacey Cohen 35:05
I mean, not within this trial that I saw. Yes, it’s been looked at in other studies. The strongest data is probably with immunotherapy, where it seems to be an actual usable marker that if the CT DNA clears on immunotherapy, that that is a very good prognostic sign. I would say in your average patient who’s receiving chemotherapy, I don’t really follow the CT DNA all that much, because we know that you can get false negatives on chemotherapy, and so it’s hard to use the marker. And I also would say that some tests give a quantitative measurement, like 10 or 20 or 300 whatever it is. And so you can kind of follow that, but it’s variable. I mean, I’ve had patients who’ve gone anywhere between, like I had this one patient was like, 0.4 and 1.9 and we hadn’t done anything differently. We were just checking it, along with some scans along the way. And so it wasn’t necessarily trending up or down. I think it just shows that there’s a sampling error when you’re testing these blood vials, and so I don’t use it as much on chemotherapy.

Speaker 2 36:10
Okay. Thank you very much. The next question is, with stage three rectal having done TNT treatment with the low CEA marker, would that mean CT DNA isn’t appropriate as a diagnostic for recurrence.

Dr. Stacey Cohen 36:25
So I think that’s really great question. It’s not really addressed in this trial because they were so focused on the post operative setting, whereas rectal cancer, it’s all about the management in the neoadjuvant or pre surgical setting. I think data is emerging, and I can speak to some of the data that I helped present at prior meetings. But when CT DNA is found to be positive, at least in one study after someone, let’s say, had their chemo, chemo radiation, and they were ready for surgery, and you check a CT DNA, if it’s positive then, they were more likely to still have had a local cancer that was visible, as opposed to a distant cancer or metastasis. So we are thinking about, how could we use this for patients where we’re trying to decide about non operative management, because those are patients where you’re saying, like, I think the cancer is gone, so if you then detect CT DNA, well, hey, that cancer is not gone, but the question then remained of, is it not gone and it’s still in the rectum? You should do the rectal surgery, or is it not gone and it’s already spread somewhere else? So you should leave the rectum intact and maybe start on chemo. And so I think we’re still learning that, but at least in one series, it seemed to be more local, which I think is helpful for us making decisions. But really it’s very early days to figure out how to use it.

Speaker 2 37:42
Okay. Thank you very much. So another question that I have is like, for example, in COLONTOWN, people will post their Signatera results. And somebody has like, the MTM per ml as 1 or 2, and another will have something like 40. And then the question is how do you compare these values? Does it mean that the person with the value of 40 is having much more tumor than the one with the one or 1.5, if you can provide some guidance on how you answer this question, that would be great.

Dr. Stacey Cohen 38:18
Yeah, so we definitely see that it’s related to cancer burden. So the higher the number, the more cancer there is in the body. Which could be one large tumor, it could be multiple smaller tumors. It just means that overall, there’s sort of more cancer in the body, and we may see a higher amount, let’s say, from that liver metastasis, than from lung. I’ve seendefinitely numbers like that, where it seemed like everything was responding, but just one liver met was growing, then we saw quite a high number. So I also think that, just like there’s a variability in CEA, there’s going to be variabilities in CT DNA. And so we see differences in different patients. But like many things, the trends probably matter more than theabsolute value, because I have seen very different scans and ctDNA results where if you had to match up what you thought would go with which it doesn’t always make sense. So I would say, as you look at someone else’s number, negative is great. That’s what everyone hopes for. But as you look at positive results, one test doesn’t tell you as much as if you can list all your results. And then also at the same time as your results, well, did you have treatments during that time? Because were you on chemo? So when negative and then positive, or were you off of treatment,it’s gotten off. I mean, these things all matter as you interpret things.

Speaker 2 39:41
Okay. Thank you very much. So next question is, are there minimal residual disease trials that you find for patients to consider?

Dr. Stacey Cohen 39:51
Yeah. I mean, I think there’s a lot of studies, like there was the one the CIRCULATE trial that I showed I think is a great study for stage III, because that’s really getting at our first use of chemotherapy after surgery. There are trials looking at vaccines for patients who are positive after they’ve received chemotherapy. There’s trials looking at additional chemotherapy for patients who remain positive, and even targeted therapy in that setting. And then there’s even novel therapies. And so I would say if you’re found to be positive after surgery and you have the option for chemotherapy, I typically give chemotherapy at that time.You could choose to go on a trial if it’s an option for you, but I realize a clinical trial is not either an option or logistically feasible for every patient. So that’s when you would might think about going on or not going on. But you know, as you think about these second layer studies for additional therapies that aren’t currently approved, I mean, I think if you have the ability to go on a study, they’re very interesting, but they’re all kind of sporadic, and we really don’t know if that’s going to make a difference, like I have anecdotes of patients that it helps, but that’s very minimal data, and I think we need the bigger studies to really answer the questions.

Speaker 2 41:11
Okay, thank you. If a person has a set of negative tests, do you think three would be a fairly high certainty of no ctDNA in blood. If you had a patient with three negative tests, would you wait six or 12 months before another one?

Dr. Stacey Cohen 41:29
So I pretty much check patients through two years if I’m going to check them, regardless of their results. Obviously, if they turn positive and they’re found to be stage IV, we might stop testing if it doesn’t make sense anymore, but if someone is negative, I usually follow it with every visit through the two year mark, once you know certain their surveillance is about every three months, because there’s that potential for lead time. Even if someone’s negative at the two year mark, it kind of makes me reassured that perhaps they’re not going to spend the next three years with a recurrence. But I don’t usually check beyond that, and I say that recurrences are extremely rare after two years of surveillance anyway, so I don’t know that it’s really adding much at that point in the absence of other changes on scans or blood tests or anything else– symptoms to suggest something. So I pretty much just check it along with the visits that I’m having for patients anyway, through the two years, and then I stop. But yes, absolutely I’m I’m super excited when my patients get negative test results, especially if they get lots of them,

Speaker 2 42:34
Okay. And then the other question would be, what about the use of ctDNA testing, or CTDNA MRD testing for patients who have been on immunotherapy? Because for some people, they might still see something on scans, and their ctDNA is negative, like in in those situations, how to interpret those results?

Dr. Stacey Cohen 42:57
Yeah, so I think that a negative CT DNA, especially if you had one before you could show that it converted to negative. Ithink would be very reassuring. We know that in manyy cancers, [sorry, Manju do you hear my dog barking in the background]?

Speaker 3 43:14
No ..

Dr. Stacey Cohen 43:14
Okay, good, okay, she’s she’s done with me having conversations today. So in patients who have MSI cancer, sometimesthey’ll still have, especially with immunotherapy, they’ll still have residual findings on scans. And so having a negative CT DNA has been tossed around as an idea that if you’re thinking of stopping immunotherapy, that may be something that would be supportive. So someone turned to negative, and they’d been on for certain period of time and their scans were stable. Maybe you choose to actually stop the immunotherapy, and you could just trend their CT DNA as a marker. So in immunotherapy, specifically, there’s extra data that it may be helpful.

Speaker 2 43:55
Okay, okay, I think almost the last question would be, we’ve had some patients in COLONTOWN, where they had a positive CT DNA after adjuvant chemo. It’s, you know, for stage III patients, and then nothing could be found in scans. And then it turned out later that they were having a peritoneal mets, Or, in your practice, do you do something differentif a patient has a positive CT DNA and you can’t find it anywhere?

Dr. Stacey Cohen 44:27
I guess the most aggressive thing that you could do would be a diagnostic laparoscopy, which is basically asking a surgeon to put a camera in the belly and see if they can see anything. Peritoneal disease is really tricky, because it is hard to see on scans. It is notoriously difficult, whether you use CT, MRI or PET, and I haven’t done that in a patient unless they’ve had symptoms, like, if someone had CT DNA positivity and they had bloating, or distention of their belly or a lot of bowel issues, maybe that would really start to raise our suspicion. But I haven’t done it just for CtDNApositivity alone and negative scans. So I will say, in my experience, we’ve usually seen something. Maybe it hasn’t come right away, maybe it’s taken six months, but we usually see something on scan such that I haven’t been left for months and months waiting to figure out what’s going on.

Speaker 2 45:27
Okay, okay, thank you for that. I mean, the reason I ask is, like, for example, with the peritoneal mets. You know, getting a patient to surgery is only useful and curative if they have not too much disease, right?

Dr. Stacey Cohen 45:41
Yeah, okay, right. And I think that’s the tricky thing. That may be one of those situations where, if you see, like a little something, and they’re calling it, you know, post operative change, you might say, Look, maybe this isn’t post operative changes. Maybe this is actually disease in the belly. And I’ve definitely had situations like so I think it can help you before you might have realized it otherwise.

Speaker 2 46:04
Okay. Could you explain how MSI patients are slower to recur? I have seen that MSI patients are also less likely to have a recurrence.

Dr. Stacey Cohen 46:13
Yeah. So I don’t as I mean that the time to when they have recurrence is longer. It just means that when you look at the whole group over time, there’s going to be fewer recurrences in the MSI high patients.

Speaker 2 46:26
Okay, I think that’s it. And I’m going to give you your 10 minutes back since you said you have another meeting. Thank you so much. And a recording of this video will be edited and posted on COLONTOWN University for people who want to watch it later. Thank you all for attending! Thank you very much.

Dr. Stacey Cohen 46:46
This was very My pleasure, Thanks, everybody. Bye.