CtDNA screening tests and the CIRCULATE-US trial: Dr. Lieu (2022)

Manju George 0:00
Hello Everyone, Welcome to DocTalks. I’m Dr Manju George, the Scientific Director of PALTOWN, the nonprofit that supports COLONTOWN. I organize DocTalks, which are Zoom video talks from expert clinicians from the field on topics that are relevant to colorectal cancer patients and caregivers. Today, we have Dr. Christopher Lieu with us. He’s the Associate Director of Clinical Research and the Co- Director of Gastrointestinal Medical Oncology at the Colorado Cancer Center. He’s also the Vice Chair of the NCI Colon Task Force. Very excited to have you with us, Dr. Lieu, and he’s going to tell us about CtDNA tests for cancer screening and about the CIRCULATE-US trial. Welcome.

Dr. Christopher Lieu 0:43
Thanks so much, Dr. George, and thank you so much for the opportunity to talk to you all today about circulating tumor DNA and an upcoming trial, or newly opened trial called CIRCULATE-US, where we’re trying to utilize this new technology to change the way we treat earlier stage colorectal cancer. So thanks for taking the time. These are my disclosures: I do want to mention that there is a contracting agreement between Natera and my institution, University of Colorado, and in regards to Natera, just mainly because they’re one of the companies that produce CtDNA assays.

Dr. Christopher Lieu 1:17
All right, so what are we going to talk about over the next 30 minutes? We’re going to go back. I know that you have already had great talks from Dr. Cohen and Dr. Kopetz in regards to circulating tumor DNA, and we’re going to build on that, but we’re going to take a little bit of a step back. I’m sure you’ve talked about circulating tumor DNA, or heard of it in terms of earlier stage, or even the utilization of this type of technology in later stage colorectal cancer. But what about screening and primary prevention of colorectal cancer? What we mean by that is essentially anybody who hasn’t ever been diagnosed with colorectal cancer, we want to prevent those cases. So where can blood based tests really make a difference? We’re going to talk about screening just in general initially, and we’re going to talk about screening rates within the United States, but we’re going to start then to talk about where CtDNA may be appropriate in primary prevention of any cancer. Of course, this includes colorectal cancer, and of course we want to follow up with a discussion about what CIRCULATE-US is in regards to the utilization of CtDNA for stage III colon cancer.

Dr. Christopher Lieu 2:24
So this is going to be a big background that everybody already knows about colorectal cancer, because this group that’s listening to this talk is, – you guys are really the experts, but it is good to go back to the basics and talk about, what is the landscape of the epidemiology to risk factors and screening for colorectal cancer. We know that this is the third most common cancer diagnosed in the United States, and the estimates for the number of colorectal cancer cases in 2022 are over 100,000 new cases of colon cancer and over 40,000 new cases of rectal cancers. So this is a tremendously big problem, and certainly something that this group knows a lot about. And of course, the risk factors for colorectal cancer include risk factors for a lot of cancers, including being overweight or obese, having physical inactivity. A little bit different than a lot of other cancers is this idea that a diet high in red meats, processed meats, or cooking meats at very high temperatures, is a risk factor for colorectal cancer. And of course, these are some foods that a lot of people like a lot. So if you eat barbecue, it is a risk factor for colorectal cancer. This isn’t an announcement to say, “don’t eat barbecue”. But of course, it does mean that we certainly want to limit how many processed meats, or red meats or high cooked or high temperature meats we eat on a daily basis.

Dr. Christopher Lieu 3:41
Smoking and alcohol use are significant risk factors for a lot of different cancers, but of course, we always worry about genetic risk and hereditary genes impacting our ability to develop a colorectal cancer. But this still is a vast minority of cases of colorectal cancer that have a genetic component to it. Familial Adenomatous Polyposis is only 1% of the population. Lynch Syndrome, which is the most common inherited cancer risk profile for colorectal cancer, is only 2 to 4%. So these are some really interesting charts in regards to the incidence of colorectal cancer by age. And so when you look at the population that’s 55 and older, you can see these dramatic decreases in the incidence of colorectal cancer. And this really speaks to the power of primary prevention. This idea that if you screen for colorectal cancer, if you get a colonoscopy and remove polyps, you can really reduce the incidence of colorectal cancer. That’s the big take home message. Of course, this group is also very familiar with the fact of the incidence in our younger population. So what you’re looking at here are graphs from 20 to 49 and you can see this inflection point in the 1980s and the 1990s where the rates of young onset colorectal cancer really started to increase, and then it increased year over year. Many of the people in this group and listening, and certainly the physicians and providers, would tell you that seeing young patients with colorectal cancer is really obviously still devastating, but it’s becoming, unfortunately, more common.

Dr. Christopher Lieu 5:13
Another way to look at this data is to look at colorectal cancer incidence rates by birth cohort, and you can again, see this inflection point that those born 1960 to 65 and then onwards. You can see this incidence increasing. Now I do have to tell you that early onset colorectal cancer is, of course, still rare, but if it increases by 2 or 3% every single year, then you can tell that even though it’s still a rare event, it’s becoming, unfortunately, more frequent. The United States is not the only country documenting an increase in early onset colorectal cancer, and those countries highlighted in red are showing similar trends. So this is a worldwide phenomenon, and not solely restricted to the United States. So the first take home point that everybody here already knows is that the incidence of colorectal cancer, particularly rectal cancer in young patients, is increasing. And this figure that you see here shows the duration of bleeding of having seen blood in the toilet before diagnosis, and this is stratified by the stage of diagnosis. When you look at older adults, the onset of bleeding to diagnosis of cancer is usually about 25 to 28 days. Here, if you look at some of the patients that were diagnosed with stage IV disease, on average, they were waiting over a year between the time that they had their initial symptoms and the time that they were actually diagnosed. And the longer that time takes, the more likely it is that you’re going to have advanced colorectal cancer, as opposed to an early stage colorectal cancer. So how do we prevent colorectal cancer? We don’t always talk a lot about screening as oncologists, because we’re usually taking care of patients after they’ve been diagnosed. But the problem with this is that there’s so many guidelines out there that it can be very confusing in terms of what patients should actually do. But of course, the American Cancer Society several years ago actually was very forward thinking and they actually decreased their age to start colorectal cancer screening from the age of 50 to 45 and I showed you the data as to why they wanted to change that. For people ages 76 to 85 the decision to be screened should be based on a lot of different factors, including how healthy that individual is. And the recommendation is that people over 85 should no longer get colorectal cancer screening.

Dr. Christopher Lieu 7:29
In terms of what tests that people offer, there’s stool-based tests and there’s visual tests. The stool-based tests include looking for blood in the stool, and that’s called a FIT Test or Fecal Immunochemical Test. We have this general fecal occult blood test, and there’s even a stool DNA test, which we’ll talk about. But of course, the gold standard is colonoscopy, because not only can you visually look at the colon, you can also remove polyps that may eventually turn into a cancer. There’s also CT imaging that’s available, and a flexible sigmoidoscopy looks at the first third of the colon, but cannot reach the last two thirds of the colon. The United States Preventative Services Task Force also has guidelines. This is our most conservative guideline group because their expectation for the level of evidence is quite high. So they really, really look at the data and say, well, the data doesn’t support certain screening, then they don’t recommend it. But if it does, then they do recommend it. Their Grade A recommendation is still for adults age 50 to 75, but the big update here in 2021 was a Grade B recommendation for 45 to 49 which means that these patients likely really should be screened. And, the more patients that get screened, the more we can prevent cancer. So your second take-home point: everybody should start screening at age 45 or 10 years before the youngest case in the immediate family. So if a first degree family member was diagnosed at the age of 40, then you would start screening at the age of 30. For patients 76 to 85: just consider the patient’s health. Then a colonoscopy is the gold standard, because it’s preventative and potentially treatable as well.

Dr. Christopher Lieu 9:10
Just a quick note from Dr. George that if you guys have any questions as the presentation comes in, feel free to put it into the chat. In all honesty, feel free to just unmute and ask the question even as I’m speaking. I’d love for this to be as interactive as possible. All right.

Manju George 9:26
Dr Lieu, then I have a question.

Dr. Christopher Lieu 9:28
Sure

Manju George 9:28
So my question is, what about polyps in the family, and how does that affect when you have to screen?

Dr. Christopher Lieu 9:36
So it really depends on the type of polyp. It’s such a great question, because I think that this really gets overlooked. If you have your typical tubular adenoma, and you get those things clipped off, and then the risk of having colorectal cancer, from a familial standpoint, is quite low. There are some times that patients have really, really advanced polyps, basically these polyps that have really high grade dysplasia and you can tell that in the next one or two years, you can tell that that patient is actually going to develop a colorectal cancer. And that’s why it’s actually so critically important to know that if you have a very advanced polyp that has significant malignant potential, we should treat those patients as if they already had a colon cancer. So, kind of complex. It’s certainly one of those things that when you get a colonoscopy, you get a polyp removed, it is good to ask, “Hey, was it a really benign polyp, or was this a really scary looking polyp?” And if it’s a scary looking polyp, then you go and tell your entire family. Great, great, great question!

Manju George 10:32
Okay, thank you.

Dr. Christopher Lieu 10:33
Absolutely! When you look at colorectal cancer screening across the country, there are disparities here. And actually, one of the questions I really wanted to ask the group was, well, what is the biggest predictor of getting colorectal cancer screening? You’ll find the answer as we go through the next several slides. But is it race and ethnicity? Is it income? Is it even geographic distribution? You can tell that your rate of colorectal cancer screening actually differs by by state. So if you’re living in Texas, for instance, then the rates are 62% which is obviously much lower than we want it to be. If you look into northeast: Rhode Island, Massachusetts, New Hampshire, Maine, they have 75 to 76% screening rates. And the goal here is, obviously would be 100% but in all honesty, even having 80% would be really, really, tremendously impactful, and you can see that there’s a difference across the entire country. Well, what about sex? So if you’re male or female, does that make a difference? In here, there’s a little bit of a difference between females and males, but for the most part, it’s relatively the same, and has stayed that way over time. What about age? It does make sense that as you get older, there’s increased use of screening. Maybe there are some other health factors, you’re seeing your doctor more frequently. But it is interesting that as you go from 50 to 64 and then from 65 to 70, there is a pretty significant jump in terms of who’s getting screened. What about race and ethnicity? It’s interesting because I thought that the disparity gap here would be wider. It’s not quite as bad as I thought there would be, but there is a disparity gap, and so even when you look at our Native American population and our Asian population, interestingly, those are some of lower rates of screening compared to some of the other groups that you’re seeing here. But for the most part, there isn’t a huge difference. But what I’ll tell you seems to be the biggest discrepancy, or disparity between colorectal cancer screening and groups is actually your insurance status. And I think that that’s actually one of the big take home points, is that if you’re insured, you’re going to get screened, and if you’re uninsured or underinsured, only half of those patients are actually getting screened. So it does tell you that a lot of these things, you can actually have an impact on. But it is interesting data.

Dr. Christopher Lieu 12:43
All right. Well, what about tumor DNA-based screening approaches for colorectal cancer? We’re here to talk about circulating tumor DNA, and we’re going to talk about — I see the question from Annie about right versus left sided primaries and screening methods. So that’s such a great, great question, and I’m actually going to answer that a little bit later over the course of the talk, because for these tumor DNA-based screening tests, you want to make sure that you can detect cancer on both sides. To go back to visual screening methods like flexible sigmoidoscopy and colonoscopy, if you have a left sided primary you should be able to see it on colonoscopy and flexible sigmoidoscopy, but because flex sigmoidoscopy only really looks at 1/3 of the colon, flex sigmoidoscopy is definitely going to miss the other two thirds, particularly the right side of primaries, because you’re just not looking. But of course, with even with colonoscopy, sometimes you can miss the right side of primaries because either the prep is not very good or, you know, because it’s just harder to get there, and sometimes you can’t even get the scope all the way that far. So the right side is a little bit harder in terms of detecting cancer even with colonoscopy, but colonoscopy is still the best bet to find it.

Dr. Christopher Lieu 13:55
All right, I do want to talk about the first ever DNA test approved for use for screening, and that is a stool-based DNA test. So we talk about circulating tumor DNA, but here we’re actually talking about stool DNA. And what you’re looking at here are the performance metrics between the stool DNA test and fecal immunochemical test, which is basically looking for blood in the stool. You can see across stages the multitarget DNA test does seem better for early stage stage I and II cancer, and then performs about as well for stage III and IV. That question about left versus right is shown on the right side of this graph, and so proximal cancer would be the right side and distal cancer will be on the left side, and then you can kind of see that this test does perform better than than the FIT test. What’s interesting about this is that you can actually even detect pre-cancerous lesions with the stool DNA test. Obviously it’s not as effective in patients with polyps versus cancer. But you can tell that there’s a certain amount of pre-cancerous lesions that the stool DNA test is actually picking up. All right, and that gets us to circulating tumor DNA.

Manju George 15:11
Dr. Lieu? I have a question. So basically, they’re looking for cells from the polyps that are shed into the stool. Is that what they’re looking at?

Dr. Christopher Lieu 15:20
So they’re looking at DNA shed from the polyps into the stool. You imagine that over the course of time, these polyps have some genetic alterations. We know that there’s some early events even like KRAS and RAS and BRAF mutations are kind of earlier events in the development of cancer. But you can actually detect some altered DNA, even in polyps, and you certainly can detect it when there’s a full blown colorectal cancer. So it is interesting that in some of the altered DNA, you can see in some of these higher grade polyps, particularly there’s high grade dysplasia. They are shedding altered DNA that can be picked up by these tests, which is kind of cool, right?

Manju George 16:03
Okay, thank you.

Dr. Christopher Lieu 16:04
Absolutely. I know that you’ve had lectures from Dr. Cohen and Dr. Kopetz in regards to what gets leaked into the bloodstream. When you have a tumor that’s in place, sometimes tumors can shed actual tumor cells that you can pick up and even sequence. They release these things called exosomes into the bloodstream, but when tumors undergo cell lysis, or cell death, they do shed cell-free DNA into the bloodstream. Now the way I always describe this to my patients is that if you have somebody who’s pregnant and you draw their blood, obviously a majority of what you see in the mom’s blood is their own cell-free DNA. These are just cells, normal cells that are just turning over, and there’s release ofDNA into the bloodstream, which gets metabolized by your body fairly quickly. And so that represents a majority of the DNA that floats around in the bloodstream. But a portion of that would be fetal DNA. So you can actually sequence out the baby’s DNA, the DNA from the baby that’s being circulating around the mom, that also gets metabolized very, very quickly. Well, the same thing happens with tumors. So in our patients that have a tumor, a majority of the circulating tumor cell-free DNA in the body is that person’s normal DNA, but there’s a fraction of that that can be circulating tumor DNA, or CtDNA, which can then be sequenced and detected. And that’s really the basis of a lot of the technology that we’re looking at.

Dr. Christopher Lieu 17:39
And certainly, circulating DNA has its advantages. It’s stable – you can actually do mutational testing on it. There are established biomarkers, and it’s a short half life. Why is that important? It’s because a lot of times we get information from tissue, and that just represents one point in time. What’s circulating in the body is happening right at that moment.It gives you this real-time look of what’s happening in the body at that moment. And there’s the potential to do even further genomic characterization from the fragments of DNA that are released into the bloodstream. But of course, the disadvantages are the ones that are critically important, especially when we’re talking about screening for cancer. So not all tumors appear to shed detectable CtDNA. We worry, if a tumor is too small and is not releasing at least enough detectable circulating tumor DNA to capture in the blood, then you may, at that point, not be able to detect CtDNA, even though a patient does actually have cancer. The methodologies for analysis are really complex and expensive andthis idea that you have to filter out a lot of noise. And so part of this is that that noise can even be that as patients age, they develop these mutations that exist usually in their white cells, in their bloodstream, that are not harmful at all and are not precursors for cancer. They’re just these altered mutations that are benign. But we call this clonal hematopoiesis of indeterminate potential, or we call it CHIP for short. And that is that sometimes, as we age, we develop these mutations that exist in some of our cells that are completely benign and have nothing to do with cancer. Well, what if we detect those mutations and say, “Oh, you have cancer”. That would be obviously a real problem. So your take home point, only a fraction of cell-free DNA is circulating tumor DNA, but CtDNA may provide a real time look at what is happening in the body.

Dr. Christopher Lieu 19:33
And so there’s a couple of points as we kind of go into this idea of utilizing a test to detect cancer for the first time. One of the things that people ask is, “Well, why don’t we just use CEA?”. CEA is a blood test, and a protein that we look for in patients with colorectal cancer. And sometimes we can trend CEA to determine if a cancer is getting better or getting worse. But a CtDNA is better than CEA. What you’re looking at here is CtDNA versus CEA positivity in different stages of cancer. What I want to show you is that, particularly in earlier stage colorectal cancer, CtDNA definitely outperforms CEA. You can see that with CtDNA being on the left and CEA being on the right. You can see that CEA isnegative in a lot of patients that actually have cancer, whereas when you look at CtDNA for stage II and stage III colorectal cancer in particular, it’s almost never negative. Which means that when it’s positive, there’s definitely cancer there.

Dr. Christopher Lieu 20:41
I want to talk about two tests that are currently under investigation. One is colorectal cancer specific, and one is just looking for cancer, period. There are companies that are certainly developing both of these right now. So this is a multimodal circulating tumor DNA test looking at the primary detection of colorectal cancer. This is called a LUNAR-2 assay. Essentially what both of these tests are doing is they are looking at something called DNA methylation. And aberrant methylation signals in tumor, versus benign tissues, are different. Therefore, if you see this methylated DNA, you might be able to detect cancer earlier. And this is the test case: There were 434 cases, 271 controls, and this is the distribution by age in the controls and in colorectal cancer. Really what I want to show you is essentially this slide. What you’re seeing here is the overall sensitivity for this assay for patients with colorectal cancer or without colorectal cancer. You can tell that the overall sensitivity is unbelievably high: 91%. In the age cohort 45 to 84 which is traditionally the group that we’re looking at to detect colorectal cancer, it’s 90%. You’re seeing this high sensitivity across stages: stage I and II, stage III. Specificity is this idea that if you detect cancer and if the test is positive and you do have cancer, what is the accuracy there? And it’s 94%. So the key here is that again, across stages, it’s a really, really highly sensitive test. That’s what you want in any good screening test. Then this question of left sided versus right sided, it’s actually detecting cancers pretty well, maybe even slightly better on the right side versus the left side. And then transverse, there are not as many cases. There are only 17 cases of colorectal cancer, but it was 82% sensitive in that case. So a really, really interesting test, and I think this is really interesting early data. What they did was, – the company, Guardant – has a trial where they enrolled 12,750 patients to detect colorectal cancer, and we’re hoping to get data in the middle of this year. We’ll find out what the performance of this LUNAR-2 blood test is in the individuals that would normally be screened for colorectal cancer, and we’re going to see how good of a test this is. But can you imagine, drawing a blood test to screen for colorectal cancer, as opposed to potentially either putting in for a stool sample or undergoing a flexible sigmoidoscopy or a full on colonoscopy. So, very, very interesting, and we’ll see what the data is as they as they come out later this year.

Dr. Christopher Lieu 23:39
All right. So we talked about colorectal cancer. I just want to briefly touch on a multi-cancer early detection test, and this idea that can you utilize the same technology that we were just talking about, but look for all cancers. So imagine a blood test to be able to detect any cancer, and obviously, hopefully at an early stage. We had talked a little bit about this before, but this focus on DNA methylation. The idea is to have a low false positive rate, and we call that “high specificity”. And this idea that if you have a lot of coverage over these methylated regions, not only would you be able to detect cancer, but if different cancer sites have a unique methylation pattern, then you could at least tell somebody, “Well, you may have cancer. We have no idea where it’s coming from”. You might be able to point people towards, “Well, this fingerprint is more suggestive of lung cancer or pancreas cancer or colorectal cancer”. And that’s what this really complex figure basically shows you, is that you can draw somebody’s blood, look at the DNA methylation, and then what they’re really trying to figure out is that, is there a tissue specific methylation fingerprint where a specific methylation pattern might tell somebody, well, we really need to look for lung cancer or liver cancer or colorectal cancer. Because, you can imagine as a primary care provider, if you just get this test back that says, “Oh, we think you have cancer”. That’s not only incredibly anxiety inducing from the patient’s standpoint, it’s also incredibly anxiety inducing from the physician’s standpoint, because then, what do you do? Do you do a colonoscopy? Do you do a full body CT scan? So you can see some risk involved with these tests as well.

Dr. Christopher Lieu 25:29
This is a 15,000 participant study at 142 sites, and essentially what they had was a discovery group and a validation group. Essentially they wanted to see if the test could potentially work in a smaller group of patients, and then look at a bigger group of patients. These patients, some of them had cancer, some of them didn’t have cancer. What this test shows you is two take-home messages. Number one, the sensitivity is not great. It’s 51.5% which means in patients that had cancer, sometimes the test was positive, sometimes the test was negative. The other take home point is that it was a highly specific test, which means that in patients that didn’t have cancer, if the test was negative, they really didn’t have cancer. And there are very, very few false positives, in other words, where the test was positive, but they did not have cancer. So it meant that basically, the test was negative. There’s an incredibly high chance that they didn’t have cancer, and that’s obviously a good thing, but the sensitivity rates across diseases, range very, very differently. So you can clearly tell on the left side of this graph that this test is not a great test for prostate cancer. 11% sensitivity. That is definitely not ready for prime time.

Dr. Christopher Lieu 26:48
Well, what about colorectal cancer? Here the sensitivity is quite good, 82%. And then if you go into liver cancer or even carcinoma of unknown primary, there the sensitivity is 93 to 94% so it’s a big spread. So I would say the data is very promising towards the right side of this graph. Very not promising on the left side of this graph. And I think the main question that you have to ask is, well, will the technology get better? Can we get all of these sensitivity rates really, really high? So again, this is colorectal cancer sensitivity looking at stage I through stage IV. It’s clear that as you go higher in stage that the ability of this test to detect cancer goes up significantly. It always seems like these tests have a harder time with stage I, but the moment you get to stage II and III and IV, it gets actually quite good. I wanted to show you that detection of other GI malignancies. There’s really one take home message, and that is, for all these GI malignancies, it doesn’t do great for stage I, but as you get further into the stages, it does quite a good job of being able to pick up the detection of cancer. But again, the main question that you want to answer is, can this test save lives? We’ll say, additional studies are needed. I think you’re going to see this technology really change the way healthcare is delivered in the future. Right now the question is, is it ready for prime time? And I would say we don’t really know the answer to that quite yet. All right.

Manju George 28:19
Dr. Lieu, I had a question. So, Exact Sciences had a large trial. Is that more like a multi-cancer, or is it more like the Guardant Health?

Dr. Christopher Lieu 28:29
Yeah, so Colvera is really focused predominantly on CRC, although I know that they have data on other cancers as well. It’s interesting, because a lot of these tests that I’m showing you are casting this really, really wide net. Colvera is very interesting in the sense that they’re really looking at two genes. But they found that those two genes really do a great job of predicting for colorectal cancer. So, a little bit different, but dissimilar technology.

Manju George 28:54
Okay, thank you.

Dr. Christopher Lieu 28:55
Absolutely. I’ll just wrap up on this with the last five minutes, because, well, we talked about primary prevention of colorectal cancer. We talked about screening. Well, what about in patients that do have colorectal cancer? What happens to CtDNA in those patients, either postoperatively after surgery, but even during adjuvant chemotherapy? What happens to CtDNA? Does it go up? Does it go down? Does it become detectable? Does it become undetectable? We call that CtDNA kinetics. I just want to show you data from the Japanese group. This is their GALAXY study where they’re utilizing CtDNA, and it’s really interesting data. What this shows you is that postoperatively all the way to 12 weeks, if you’re negative and stay negative, you’re going to do great. That’s the black line. And what you’re looking at here is disease-free survival. Basically, nobody’s recurring, right? So that’s good. Interestingly, if you’re CtDNA positive post operatively, and then you turn negative, that’s almost as good as just being negative from the get-go. So that’s interesting. If you’re CtDNA positive postoperatively, you’re freaking out. – I’m worried, you’re worried. But if you turn negative, then your prognosis is quite good. If you’re negative and then turn positive, then there’s a pretty high rate of recurrence. And if you’re positive and stay positive, these are the patients that here, you’re looking at almost 70 to 80% of those patients recurring even within one year’s time.

Dr. Christopher Lieu 30:25
And I do want to show you that adjuvant chemotherapy can clear CtDNA. Interestingly, there is a 10% clearance rate by doing nothing and it makes you wonder what’s going on in those patients. Are those patients just clearing it due to their immune system? But interestingly, there is a significant rate of patients that even if they’re CtDNA positive, they receive adjuvant chemotherapy, they can clear it. We also know that if in patients that are CtDNA positive and they receive adjuvant chemotherapy, that they do better. And so that’s what you’re seeing in stage II, stage III and stage IV. That if there’s CtDNA postoperatively, and they receive chemotherapy, that their recurrence rates are significantly less. So the real question that everybody in this group wants to answer is, are the findings of this test, which is very, very cool, but is it actionable? Because that’s how we’re going to save lives.

Dr. Christopher Lieu 31:20
So what do we know so far? If CtDNA is positive, the recurrence risk is extremely high. That makes sense. If we detect tumor DNA in the bloodstream, it means cancer is there, and it means that at some point it’s going to show up on a CT scan. If CtDNA can be cleared, in other words, with adjuvant therapy, then disease-free survival is significantly improved, and we know that adjuvant chemotherapy can clear CtDNA. And we also know that if CtDNA is not detected, and it’s not detected over multiple time points, we also know that those patients are going to do incredibly well. This is the overall problem with stage III colorectal cancer, and that is that we’re treating 10 patients with with stage III colorectal cancer to save 2 to 3. I’m going to go through that. Why is that? In 10 patients that have stage III colorectal cancer, 5 of them are essentially cured with surgery. They never needed chemotherapy. In other words, they’re getting treatment even though they never needed treatment because they were cured. There are 2 or 3 that get treated with adjuvant chemotherapy who relapse anyway, which means that we didn’t help them with adjuvant chemotherapy. They were going to have recurrence whether we gave them chemotherapy or not. So we almost gave them chemotherapy needlessly. So essentially, we treat 10 patients to save 2 to 3, which means that we basically treat 7 to 8 patients needlessly with chemotherapy, either because they’re going to be cured or because they’re going to recur regardless.

Dr. Christopher Lieu 32:45
The idea is, maybe CT DNA can tell us who we don’t need to treat, and maybe we can tell with CtDNA who needs to be treated even more aggressively. I want to highlight this study, because this study is now open to enrollment and it’s going to be open up across the entirety of the United States. Essentially the way this trial is designed is that if you have stage III colon cancer and you have no CtDNA detected post operatively, you are then randomized to receive standard of care chemotherapy, which is what we normally do, or surveillance without chemotherapy, with serial CtDNA checks. If you’re negative CtDNA and stay negative, you never get chemotherapy. But if you’re negative, and then turn positive, at that point, you get chemotherapy. You get randomized to either receive standard of care chemotherapy or an escalation of chemotherapy, where we try a three-drug regimen versus a two-drug regimen. We do this because we’re worried that our patients have a poor prognosis when CtDNA is detected. Postoperatively, if you are CtDNA detected from the get-go, you undergo that randomization: either the standard of care chemo, or this triplet combination which represents an escalation of chemotherapy.

Dr. Christopher Lieu 34:00
And so the real question is, is CtDNA ready for prime time? I would say, in terms of identifying alterations in the bloodstream, that it is ready for prime time. But what we’re really trying to answer is, this bottom one. In terms of the detection of minimal residual disease, this presence of cancer, even though we can’t see it on a CT scan. The answer is possibly. Is it ready for prime time? It’s clear that CtDNA can detect cancer, but are the results actionable? And so the idea being, we know that this is an incredibly prognostic tool. It can tell us whether somebody’s going to recur or not, and we know that getting serial testing helps, but will it alter clinical practice? What happens if you get a positive result? Do you increase surveillance? We don’t know the answer to that. Will these tests save lives? So in other words, will a clinical trial like CIRCULATE-US end up showing good data in terms of well, can we use this test to determine who should and shouldn’t get chemotherapy? Can we use this test to determine who needs more chemotherapy? I’m hopeful that we’ll get the answer to that as time goes on.

Dr. Christopher Lieu 35:11
So I know that’s a lot of information in a short amount of time, but happy to – , I know Manju, you had to step aside for a little bit, but wanted to see if you guys had any questions? I see Julie has a question, can you talk a little bit little more about patient selection in CIRCULATE for stage II? Yep. So, I was trying to keep it a little bit simpler, but Julie’s asking a really, really great question, and that is the trial enrolls lower risk stage III, so if you don’t have a ton of lymph nodes involved. But there is this thing called high risk stage III, if the tumor is aggressively moving into other organs, or if a lot of lymph nodes are involved. There is also high risk stage II, where there are features of the tumor that are really concerning for the clinicians, and that’s usually related to how angry it looks under a microscope, or that tumor is actually invading into other organs. You can actually enroll into CIRCULATE if you get outside testing and that test is positive for CtDNA. You can actually enroll into the CtDNA-positive arm. We just want to give those patients the ability to have a chance of getting more aggressive chemotherapy. So if you’re high risk stage II colon cancer, or high risk stage III colon cancer, you don’t traditionally enroll into CIRCULATE, but if you have outside testing that you got as standard of care and you’re positive, then you can enroll. Annie’s asking, “The trial is only in this location in NRG?” Yes. So essentially my hope is that it’ll be open at more than 400 sites across the country. This is a collaborative effort between all the cooperative groups, which includes NRG, so this trial should, honestly, it should really be open within, my hope is 30 miles from every patient, but the reality of it is that it should be open in every state and in most, if not all, major cities.

Julie Clauer 37:13
So in terms of, you know, we have a lot of patients that come into COLONTOWN who would qualify for CIRCULATE-US, but they’re not necessarily looking at clinical trials at that point, because, they’re not high stage. They’re just recently diagnosed. Can you talk about what that conversation could be in terms of, how do they talk to their doctor, about, “Hey, I heard about this trial. What is it? Is it interesting?” Because the timing is, they might be post-surgery, but pre-adjuvant chemo, and so that’s good timing. So talk a little bit more about that, just because it seems like a quick turnaround has to happen, but it’s not necessarily people that are poised to have that quick conversation.

Dr. Christopher Lieu 37:58
So yeah, I think the timing of this is the most challenging part of the trial, and that is this idea that, if most people get seen by medical oncologists, usually a decent amount of weeks after their surgery. Capturing these patients early and getting CtDNA testing so it can inform which arm of this trial you go on is critically important. And so, I think where COLONTOWN and PALTOWN have been amazing is number one, it’s a resource. People are told they have colon cancer, and obviously, understandably, they’re freaking out. So I think the information that’s provided on COLONTOWN University is absolutely incredible. And then honestly, the earlier you can have the conversation, the better. So even before surgery, asking about it, “Is it available? Can I talk to somebody about it?” would be huge, because then everybody knows as soon as surgery is done, that they’re going to start thinking about the study, and they’ll know whether or not it’s even available at their site, or if there’s a practice closer, or within close proximity that they can enroll in. And so I think, honestly, COLONTOWN will find patients way before medical oncologists will. I think just getting the word out would be really cool, because I think, – but it’s a tough conversation, because people are just now getting introduced to this technology, and then they’re talking about clinical trials, and it’s a complex clinical trial. So having that information available and even people to talk to, I think, makes all the difference in the world for our patients but, can also help with a clinical trial accrual.

Julie Clauer 39:41
So let’s say it is available at their location. Would they connect then to the PI, or would they have CtDNA done before?

Dr. Christopher Lieu 39:54
Yeah, so I honestly would connect either through ClinicalTrials.gov, which would show the sites. Honestly, the easiest way to find clinical trials, and this is just in general, is to really ask the doctors in that area to see if, –because if they don’t have CIRCULATE open, I’m sure that they’ll actually know who does. But then also contacting the PI even like Dr. Dasari or myself, is always, I think, easy, because we’ll happily direct people to the right place.

Julie Clauer 40:26
Great, thanks.

Dr. Christopher Lieu 40:29
And then, can either a Signatera or Reveal test qualify for high risk stage II? It’ll need to be a Signatera test.

Julie Clauer 40:37
I have an unrelated question, but it drives me nuts. So now we have a lot of awesome tools that are using blood tests, like, you can get your biomarkers from a liquid biopsy, you have CtDNA to detect whether you have cancer, whether you have MRD, but it gets really confusing in terms of what to call these tests if you don’t call them by the brand name. So it’s like trying to explain to a patient like, “Oh, no that’s a liquid biopsy, but it’s a different liquid biopsy than the one…”. So is there an easy terminology of what to call these different tests? Because you say a CtDNA test, and some doctors still don’t necessarily differentiate between the different tests. So anything that can help on that end, because it gets super confusing.

Dr. Christopher Lieu 41:25
Absolutely, I think we’re all learning this new terminology, right? And I would say whenever you’re talking about: ‘is there cancer or not’, we should just call those MRD tests or minimal residual disease tests, that’s probably the easiest way. And if we’re looking for mutations in patients with stage IV cancer, we’re just basically looking for – we wouldn’t call those MRD tests or minimal residual disease tests, we would call them, I think maybe the easiest way to describe it is almost like a liquid biopsy to look for mutations. That’s essentially what you’re doing. And so I think the easiest way to kind of think about is, hey, if it’s trying to determine whether cancer is present or not, MRD is probably the way to go. And then the question, is this for rectal? Well, so CIRCULATE-US is only for colon cancer. Rectal cancer is a little bit tough, because a lot of times patients are getting a lot of therapy even before surgery. In fact, they’re getting almost all their adjuvant therapy before surgery. So this study is only for colon cancer, but these assays can be used for rectal cancer as well as colon cancer. And then Annie mentioned that for those over 70 with a high immunoscore. Yeah. The question is, is it only CtDNA? Could it be a combination of immunoscore and CtDNA? And I would love to see those collaborations in the future, because it may not just be “it’s one test to rule them all”. Maybe it’s a combination of different factors to help us make these determinations. But we’re starting with CtDNA, and then we’ll have to look how immunoscore may be added to this to help our decision making.

Julie Clauer 43:03
In terms of sensitivity. So we know this sensitivity is really high for for MRD tests, but there seems to be some things that tend to be more questionable, right? So lung mets, or maybe, the location of mets, if you’re stage IV. And I know we’re not necessarily talking about it in terms of stage IV, but a lot of patients are doing it or age or things like that. So is there any kind of good understanding of where, within colorectal cancer, how the sensitivity changes by either location of tumors or age or other facors?

Dr. Christopher Lieu 43:39
Yeah, we had talked about the age and the fact that sometimes patients have mutations that don’t have anything to do with cancer, so that can be a confounder that we have to be very careful about. But then, this idea that maybe we’re missing small lung metastases or peritoneal metastases, where they’re in the lining of the abdomen, I think that’s what keeps us up at night, right? And this idea that, are we going to miss patients that may benefit from chemotherapy? Are we just going to miss patients period that have cancer and we just can’t detect it? I think we mitigate some of that by having serial testing. Testing that’s done over the course of time. And so if patients are negative and they stay negative, that’s good. If they’re negative and they turn positive, that’s what we worry about. But I think that therein lies the risk. We want these tests to be perfect, but no test ever is. And so the question being, is it good enough? And that’s what we’re trying to answer. And then the testing is on site. I think for the study, they’ll get collected by the teams, and then they’ll be sent off, but oftentimes, these companies do offer at home blood draws.

Julie Clauer 43:42
It is very compelling, for patients from a trial perspective, and is in terms of cost. All those testing costs would be covered as part of the trial.

Dr. Christopher Lieu 45:00
That’s correct. Great question, Julie, that’s correct.

Manju George 45:04
This is about CHIP. So a test such as Signatera, you don’t have to worry about CHIP, right?

Dr. Christopher Lieu 45:11
Yeah, because it’s a personalized assay, and this idea of testing it, getting a personalized assay developed off of that really does help us with a sensitivity. It really does.

Manju George 45:26
Okay, thank you.

Dr. Christopher Lieu 45:28
Guys, thank you so much for taking the time. These are phenomenal questions and you guys are way more informed than even some of our practitioners. It is so fun to talk to you guys, and you guys are asking all the right questions, and really appreciate your interest in this, and hopefully patients will enroll, and they’ll find it interesting. The hope is that we’re going to change the way we treat stage III colon cancer. That is the hope. But at the least, at the very least, we’re going to learn a lot, and we’ll do better, and we’ll be better. So thank you guys. Really appreciate it.

Manju George 46:03
I want to say that we will have the CIRCULATE-US as a feature trial in COLONTOWN University, and our hope is that patients in COLONTOWN are, in general CRC caregivers and the patients in the public will be able to access it and find more information. The video of this talk will also be linked there, so we are hoping that this will be a great educational resource for everyone involved. Dr Lieu, thank you so much for your time, this is excellent.

Dr. Christopher Lieu 46:32
Thank you everybody. Have a wonderful day.

Manju George 46:35
Thanks everyone for attending. Take care.

Dr. Christopher Lieu 46:38
Bye bye.

Manju George 46:38
Bye