Historical approach to the adjuvant treatment of localized colorectal cancer (CRC)

DR LOVE: Welcome to “Oncology Nursing Update: What Is Molecular Residual Disease Analysis and Why Is It Clinically Relevant in Colorectal Cancer?” This is medical oncologist Dr Neil Love.

I met with Dr Chris Lieu from the University of Colorado Cancer Center to provide an overview of circulating tumor DNA assessment and its potential prognostic and predictive abilities for patients with colorectal cancer.

To begin, I asked Dr Lieu to provide a historical overview of the approach to adjuvant treatment of colon cancer.

DR LIEU: When you think about the history of giving adjuvant therapy for colon cancer, it's really sad to say but nothing has really changed in the last 20 years. And when you think about Stage I colon cancers, that's very easy. We usually don't give any adjuvant chemotherapy in that setting because patients with Stage I colon cancers do really well. Stage II is a longer conversation with the patient because sometimes we give chemotherapy and sometimes we don't.

But I really want to talk about Stage III colon cancers because you're going to have many patients, including very young patients, that come in with Stage III colon cancer, which means that the cancer is not only developed in the colon, but it's also started to spread a little bit to the lymph nodes. And when we have spread of the cancer to the lymph nodes, we know that those patients likely have a chance to have metastases in the future. So what we're trying to do with chemotherapy is really just prevent somebody from having a recurrence of their colon cancer.

So this is the situation currently. If we take 10 patients with Stage III colon cancer, this is the current situation. We know that 5 of them are likely cured with surgery alone. We know that 2 or 3 of them are going to have recurrence whether we give them chemotherapy or not. And we also know that we're treating 10 patients with the same chemotherapy to essentially prevent recurrence in 2 or 3 of the 10 patients, which means that while we're saving some lives with chemotherapy, we're also treating roughly 7 to 8 patients needlessly with chemotherapy. This is the pure definition of a one-size-fits-all strategy.

DR LOVE: This occurs in all forms of adjuvant therapy, adjuvant therapy breast cancer, adjuvant therapy lung cancer that there are, when you do adjuvant therapy trying to prevent a recurrence, which in many cases, most cases is not going to be curable, you are going to be treating some people who were not destined to recur. Can you drill down a little bit, though, in terms of what Stage II is? And also what higher risk Stage II is? What Stage III is and higher risk, based on number of nodes? And roughly with these different stages what the risk is that they will develop recurrence, which again in many cases is not going to be curable.

DR LIEU: Absolutely. So when we think about Stage II colon cancer, this is the in-between. Because the data has never really been clear as to whether or not chemotherapy truly saves lives for Stage II colon cancer. And so we kind of divide currently Stage II based off of some features that we see under the microscope. So we consider high-risk Stage II to be any patient with a tumor that invades into other structures. We call that a T4 tumor. You can think about that as a very invasive cancer sometimes quite large.

We also look at some features under the microscope looking for something called lymphovascular invasion, also poor differentiation. And some of these features are really just looking at how aggressive a cancer looks under the microscope. And when we think about these high-risk features for Stage II, even then we're not entirely sure that adjuvant chemotherapy is going to prevent recurrence. And so just like we were talking about with Stage III colon cancer, we're giving all these patients with "high-risk" Stage II colon cancer without knowing whether it's truly going to benefit them.

But we obviously want to try and do everything that we can to prevent a recurrence from happening. But we know that if we give patients with Stage II colon cancer adjuvant chemotherapy, that the recurrence risk is around 20%. But obviously what we need is a tool that will better tell us, well, who should receive chemotherapy and who doesn't need it? Because it would be great to not offer chemotherapy to patients who aren't going to benefit from it.

DR LOVE: So for decades then patients have faced a situation where they're not really sure whether they're going to benefit or not even after the treatment often, unless they develop a recurrence. And one other element I want to bring out or want you to comment on before we get into what's new here is the patient perspective. And the fact that not everybody sees this the same way. Some people really hate the idea of getting adjuvant treatment, usually chemotherapy. Can you talk about the types of chemotherapy that are utilized? And how people tolerate it? And how you see people kind of how they feel about having going through this? How much of a difficulty is it?

DR LIEU: So I think our nurses more than anybody see a lot of these side effects even more so than the doctors. And where I've talked about the fact that there hasn't really been a big change in adjuvant chemotherapy, it's really been around the drugs. And so we usually use essentially 1 of 3 drugs that are FDA approved in the adjuvant setting. One is 5-fluorouracil, which everybody knows is this pump that somebody has to wear for 46 hours.

They also have the option to substitute that for a pill called capecitabine. And we oftentimes combine that with another drug called oxaliplatin. And we call these regimens FOLFOX or CAPOX and you'll hear this in the clinic that a patient will say or a doctor will say, oh, we're giving FOLFOX or we're giving CAPOX and that's what they mean in regards to these therapies. But these treatments aren't necessarily easy. FOLFOX is given over 2, every 2 weeks. It's given over 46 hours. So these patients actually have to wear a portable pump for 46 hours. Many of our nurses deal with these pumps.

And then the oxaliplatin also has a significant amount of fatigue associated with it. Also this weird side effect of having this cold sensitivity where if you touch something cold, you get this numbness and tingling at your fingertips, or if you drink cold liquids, you actually have this funny feeling in your throat. And what I usually tell patients, and this is not a regimen that takes off very much hair, but usually 3 to 4 days after chemotherapy, they're going to feel pretty tired and pretty run down.

DR LOVE: And so for patients who want information who are able to understand information, I mean, you might have a patient who's a medical oncologist who knows everything about this so it's very variable how much people know and want to know. How do you see people weighing the risks and benefits and whether or not they want to move forward with it? I don't know if I ever told you but quite a while ago, I think it was more than 10 years ago, this is the only time I ever did an oral presentation at a meeting.

We did a study of people who had gone through adjuvant chemotherapy for colon cancer. And we patterned it after what had been done in breast cancer where they had showed that there were a bunch of patients who would go through chemotherapy for like a 1%, very minimal benefit. So we wanted to see well, what about colon? And what we saw was very interesting, which was that they were our cohort and we gave them graphs and we plotted out like you were saying, you have a 20% chance at recurrence and now it's going to go down to 15%. Would you want therapy? And, again, these people had adjuvant chemotherapy.

What we found was there were a significant number of patients, I think it was about a third, who would go through chemotherapy again for a 1% drop in recurrence rate. But there was also about 10% who would not go through chemotherapy even for an absolute benefit of 10%. Pretty big benefit. So a lot of heterogeneity. And one of the coolest things we saw was the same response of men and women. Because people used to say, oh women are more, they want more benefit and all, but we found that people see these trade-offs regardless of gender. And I'm curious how you see people who want to understand the numbers so to speak processing whether or not to move forward with it, again, before we had these new tests that came out that we're going to talk about.

DR LIEU: Absolutely. I think heterogeneity or in a heterogeneous patient population and viewpoints is exactly the right term. And really if you take a patient with Stage III colon cancer, if you ever get this question on the board's exam, it's a very easy answer. You just say, Stage III colon cancer, we're going to give you FOLFOX chemotherapy. But in reality, the conversation with the patients are so much more nuanced. There are going to be patients that come into the office and say, I don't care if it gives me 0.5% benefit, I want all the chemotherapy that you can give to me and there are going to be other patients that say, I don't care if you can cut my risk in half, I'm not going to ever receive chemotherapy. And then a lot of people fall in between.

And so how do we counsel patients? And I'm going to use Stage III colon cancer as a great example. And I literally give them these numbers. Out of 10 patients, 5 are going to be cured with surgery. We know that 2 or 3 are going to recur even with chemotherapy, but I can reduce your risk of having colorectal cancer return by about 20 to 25%. And a lot of times our patients will listen to those numbers and a lot of times they'll say, okay, I would like to reduce my risk by receiving this chemotherapy.

And the conversation even becomes more nuanced than that. Because when we talk about, should we give you 6 months of chemotherapy or 3 months of chemotherapy, we know that the difference in recurrence, absolute recurrence, is about 1 to 2% with the additional 3 months of chemotherapy. So it becomes a conversation of how many patients we need to treat to save one life or prevent one recurrence.

But we also have to have that conversation about well how many patients are we hurting with chemotherapy just to get that one recurrence that doesn't happen? And it's really, really important to have these conversations with our patients because we want them to go in eyes wide open saying, I'm receiving this chemotherapy, I'm accepting the toxicity and what is the potential benefit? And, like you said, we definitely need better tools than what we have had in the past.

DR LOVE: One of the things that I think people think about and that I think docs also think about is, what happens afterwards? So if you have a patient who was recommended to have chemotherapy, they decide not to and then they get a recurrence, do they have regret? If you have a patient who decides to get chemotherapy and they still get it in spite of the chemotherapy, they still get a recurrence. Then again, they may have regret that they even went through the chemo.

Breast cancer went through this about 20 years ago and then they came up with an assay, the Oncotype DX assay that helped a lot, really changed, dramatically reduced the number of people getting chemotherapy. And I'm kind of starting to get the feeling that that similar dynamic is happening right now in colorectal cancer. But again, we'll get into that in a second.

One other issue I wanted, a couple other issues sort of generic issues about adjuvant therapy I want to just bring up to you. One is you mentioned the peripheral neuropathy that's seen with oxaliplatin that's often given particularly in Stage III. What fraction of patients when they initially present already have peripheral neuropathy from diabetes or some other problem? And how much of that is a concern?

DR LIEU: It's a huge concern. We know that around 10 to 15% of our patients will come with some already preexisting neuropathy. That's not an insignificant amount of patients. I will tell you that I'm really, really stressed out about peripheral neuropathy because, and everybody listening to this knows this incredible rise in early onset colorectal cancer, if you give somebody debilitating peripheral neuropathy and they're 30 years old, and this is unfortunately becoming more and more common in our clinics, they're not living with that peripheral neuropathy for 10 or 20 years. I mean, it's possible that they're going to be living with severe peripheral neuropathy for 40 or 50 years.

And that is something that has completely changed in terms of a big paradigm shift of who we're treating in clinic and how these toxicities impact our patients. And so it really does do 2 things. Number 1 and if a patient with has preexisting neuropathy, we may not give oxaliplatin or we may start out at a dose reduction. In patients, particularly our younger patients, that start developing peripheral neuropathy during their treatment, it's going to get worse even after you stop the oxaliplatin. And so our providers and our nurses absolutely have to be asking about this every single visit so that we don't harm our patients because we want to save their lives without question, but we don't want to have them live where they can't walk or do things that they want to do.

Perspectives on earlier-onset colorectal cancer and potential drivers; management of oligometastatic disease

DR LOVE: So it's impossible to talk about colorectal cancer without at least mentioning the, which you just referred to, which is the increased incidence in younger people. I always like to touch base and see if there are any new theories about why we're seeing this whether it's related to diet or plastic particles or microbiome. Any pet theory you have or any new data out there?

DR LIEU: Yeah, I think, when you look at the amount of ultra-processed foods, there was recently a study from the Nurses' Health Study looking at a large number of nurses and looking at their intake of ultra-processed foods and their rate of developing colon polyps. And so as GI oncologists we've all become almost experts or now trying to become experts in the gut microbiome and I think a lot of focus has really focused on not only what we're putting into our body but the impact that the gut microbiome has on just everything, the immune system, inflammation. And certainly whenever you have inflammation in the gut and that type of cellular turnover, it's going to increase your chances of developing a mutation, a polyp and obviously eventually colorectal cancer. But there's just been a lot of focus on the gut microbiome, and I think that this is a big thing that's driving early onset colorectal cancer.

DR LOVE: I mean, given that even with this increase, what would you say the median age, what's the typical age of most patients you're seeing? I mean, you're different, you're in a tertiary center, you see more younger people, but in general in clinical practice, what's the typical age that you see people with colon cancer?

DR LIEU: Yeah, I mean, even in the traditional practice we used to say the average age was around 72. It's really dropped down now to 68 just because of this shift towards earlier onset colorectal cancer. Certainly at a big academic center, you're just going to see more and more younger patients. But even in community practices and rural practices, you're going to see younger and younger patients.

DR LOVE: So one final question before we get into what's new. We talked about recurrent disease, recurrent metastatic disease, for example. And I was saying that it seems like in general this is not curable. But can you just talk about there are people who have so-called oligometastatic disease. Can you explain what that is including in the liver and do some of these people get cured?

DR LIEU: Yeah, I think one of the major advances, beyond the drugs that we use in the metastatic setting, for patients that have metastatic or Stage IV colorectal cancer, is the ability to go after some of the metastases that develop. And so a patient that has 100 tumors in the lungs and liver and the peritoneum, that's considered to be Stage IV. A patient that has 1 tumor in the liver also considered to be Stage IV. And what we mean by oligometastatic disease is really just the ability to maybe take the 1 tumor that's in the liver and cut it out. And I think that's been really one of the major advances when you think about how aggressive our surgeons have become at cutting out some of these metastases if it's safe.

We've also looked at or seen the introduction of hepatic arterial infusion pumps where we're delivering chemotherapy directly into the liver. And there's data out of Europe and now additional areas of liver transplant, of taking the liver out and transplanting in a new liver. And we're starting to see overall survival benefit from that. And so this paradigm shift of saying, well, if it's Stage IV and there are only a handful of sites of disease or even 1 or 2, well those patients should likely be offered some type of intervention whether it's surgery, radiation or now, I mean, we're talking about transplant.

Overview of cell-free DNA (circulating tumor DNA [ctDNA]) and techniques for its measurement

DR LOVE: So let's put ourselves in the situation of a nurse in a clinic who's seeing a patient with colorectal cancer and sees that the patient had a Signatera™ assay, which is the type of assay we want to talk about today, a cell-free DNA MRD assay, and wants to know what it is and why we're doing it. So can you explain a little bit about what cell-free DNA is? What liquid biopsy is in particular with these new assays that are bespoke for this specific tumor and how it's done.

DR LIEU: Yeah, this is a rapidly evolving field and we've known about this idea of cell-free DNA for, I mean, now almost 80 years. But the technology has gotten to the point where we can actually capture this cell-free DNA and sequence it. And so, what is cell-free DNA? We know that our cells turn over all the time. We call this apoptosis. And when the cells turn over, they release multiple things into the bloodstream but one of them is actually fragments of DNA. And so we can draw your blood today and actually sequence out your genome, which is an amazing technology.

The other analogy that I use is if you take a look at pregnant moms, you can actually draw their blood and sequence out fetal DNA because the baby's DNA is actually circulating through the mom's bloodstream. And so that's a really really cool way of being able to look at the even the baby's DNA by drawing the mom's blood. In the same way, if a patient has a tumor, we know that that tumor releases fragments of DNA called circulating tumor DNA. And by drawing somebody's blood, you can actually detect the presence of circulating tumor DNA.

So this can actually give us 2 pieces of critical information. In patients with metastatic disease, you can actually draw their blood and sequence out the tumor. And we call this almost like a liquid biopsy. And that information can be critical sometimes in a metastatic setting for selecting targeted therapy or immunotherapy. But the second critical piece of information that we're getting from this test is either the presence or absence of circulating tumor DNA or what we call ctDNA. And why this is important, because you can probably tell with the conversation that we're having about adjuvant chemotherapy for colorectal cancer, is how much better would a test be if we could detect the molecular presence of cancer even if we can't see anything on a CT scan. And these ctDNA tests are starting to show us there is the presence or absence of circulating tumor DNA and the question is, well, can we start using some of that information?

Neil, you had also asked about the types of assays and so there are 2 main strategies for detecting circulating tumor DNA. One is to not use the tumor and just cast a wide net. We call this a tumor-uninformed or tumor-naïve assay. And really what you're doing is drawing the blood and just essentially looking for a lot of the changes whether it's a methylated DNA change or a mutation that cancers typically have and then you can say, oh, there's some altered DNA here. The nice thing about this is that it's pretty quick. You can usually get a result in a week and it's fast. I think the downside is that these assays are not quite as sensitive as tumor-informed ctDNA tests.

And so you had mentioned Signatera. Signatera is a great example of a tumor-informed ctDNA test where they take the original tumor, they sequence out all the alterations and they look specifically for that patient's tumors alterations. We call that a tumor-informed test. The nice thing about this is that it's a very, very sensitive assay because we know exactly what it is that we're looking for. The downside is that the initial test takes time, sometimes 3 to 4 weeks, to get a result back. And you can imagine there's a lot of anxiety in having to wait that long. But for what we're talking about, a lot of times we're using tumor-informed ctDNA assays.

Reliability and prognostic capability of ctDNA as a biomarker for clinical status in patients with localized colorectal cancer

DR LOVE: So I'm curious also, does the amount of cell-free DNA, if you do find it, correlate with the clinical status? If it goes up, is that from your mind, is it likely that means the tumor is growing? And how would you compare these types of assays to traditional tumor biomarkers? We use CEA in colorectal cancer, for example. How would you compare to that in terms of how it's — or PSA in prostate cancer is a good example of a very, very good tumor marker. How would you compare this to again a tumor marker like PSA or CEA in terms of what it is and how reliable it is?

DR LIEU: Yeah, when you think about CEA for colorectal cancer I think many listening to this understand that CEA is a tool that we use but it's not perfect. Sometimes patients have a ton of metastatic disease and their CEA is normal. And I actually have plenty of patients that are in surveillance for colorectal cancer and they have slightly elevated CEAs but they have no evidence of disease, and this goes on for years.

And so just like any test, ctDNA is certainly not perfect, but we believe it is way more sensitive and specific to colorectal cancer. And I think a lot of this is because it's not just a protein that is present in the body like CEA. We know that ctDNA, if it's present, we know that there's the presence of cancer there. And if the ctDNA is negative, that's where it's not particularly perfect, right? We know that ctDNA can miss. And so you had asked the question, well, what about the absolute number? And so we know that a higher number probably suggests that there's a higher burden of disease.

But just as you mentioned, we're looking at trends. And so if I see a ctDNA increase, I'm getting even more worried, much like we do with CEA, that cancer is getting worse. Simultaneously, if we have a ctDNA that's positive and let's just say it drops down to 0 and remains at 0, then I'm feeling really good about not only how that patient is going to do, because I think the data is pretty clear that those patients seem to do very well, but I do start to wonder, well, is the disease just gone?

And I think the other point to this is that these single data points I think are very, very important and they're great to get, but really what we're talking about is serial testing, so getting testing over time, and seeing those trends where ctDNA either gets better, gets worse or in some cases just remains negative. We know that that's very, very predictive of how our patients are going to do.

DR LOVE: So let's go back to the situation we just talked about. The patient has presented with colorectal cancer, has had primary surgery. We've looked at it pathologically, it's Stage II or Stage III, I guess it could be Stage I as well. And we have the ways of trying to predict if they're going to recur or not, hopefully trying to figure out whether or not they have the potential to benefit from adjuvant treatment. What do we know about these types of assays and particularly these tumor-informed assays in terms of their predictive capabilities? How accurate are they in predicting whether or not a patient's going to relapse or not?

DR LIEU: Yeah, and I will tell you for ctDNA this is without question the most prognostic test we have ever seen in this disease. And I think this is going to be true in multiple diseases as well. But when you look at the patients that are serially negative for ctDNA, I mean, the recurrence risk there is in the single digits when they're negative and they stay negative. At the same time, when a patient is positive, we know that the recurrence risk of those patients is extraordinarily high. Almost universally, at some point, you're going to see something on a CT scan. And there are a lot of studies looking into this.

But when somebody turns positive, the lead time is around 6 to 8 months before you see some disease on a CT scan. And so that window of time when somebody is ctCNA positive is your chance as a provider to intervene on that patient and potentially prevent recurrence. But I will say it again, this is without question the most prognostic test that we've ever seen. What the future clinical trials will hopefully tell us is whether or not this can be predictive of the benefit of chemotherapy or if we can use this test to not give chemotherapy. And so there's a lot of research that's ongoing right now and will happen in the future so that we know how to use these tests better.

DR LOVE: So it's interesting when you ask people about these types of assays across oncology, not just in GI oncology, you get different responses to this. A lot of people say, well, we need data in a randomized clinical trial to prove that it actually makes a difference about whether you treat or you don't treat. And that makes a lot of sense but on the other hand, I don't know that we had that great of similar data for the other prognostic markers that we talk about when we just go on risk and if they're higher risk, we think they'll benefit a little bit more.

ctDNA assessment and treatment decision-making for patients with Stage II colon cancer

DR LOVE: Let's talk a little bit about how you think about a patient with Stage II and how a cell-free DNA assay affects your decision-making.

DR LIEU: Yeah, Stage II is the perfect example of how we can use the currently available data with a test that we have now have a lot of knowledge about to make a clinical decision. And so with ctDNA, you're right, we need way more prospective randomized clinical trials to really tell us what the impact of these tests are. You can still use this information to guide patient treatment decision-making even with what we have so far. So Stage II is a great example. We had talked about Stage II as a scenario where sometimes we use chemotherapy, sometimes we don't. We don't really totally know what the benefit is, but we say, oh, you're kind of "high risk" so we're going to offer you chemotherapy.

Let's take a patient with low-risk, Stage II colon cancer. That means that the tumor doesn't look very aggressive under a microscope, they seem like their recurrence risk is quite low. We traditionally don't offer chemotherapy for that patient. Let's say we get a ctDNA test for a patient with low-risk, Stage II colon cancer. Our paradigm is to not give chemotherapy. We get that test back and it's positive. In other words, there's a presence of ctDNA from the test that was drawn.

And I would ask the audience, in that situation, who listening to this would want chemotherapy and who would just say, oh, it's okay and we're just then going to ignore it? I would say a vast majority of the people listening to this would say, in that situation, I want chemotherapy. Why? Because we know that if you can clear that ctDNA, and that is a sustained clearance, that those patients have a very low recurrence risk.

At the same time, if you have a ctDNA positive test and it remains positive, we know that in 6 to 8 months you're likely going to have something show up on a CT scan. And I think that that's just a really great clinical example of how we can use a test. Who in that scenario wouldn't want chemotherapy? And I think that's where I've used that in my clinic and my patients have universally said, yes, I'm going to use chemotherapy. Simultaneously when it's negative and I wasn't going to give you chemotherapy anyway, it just makes them feel even better about not receiving chemotherapy.

DR LOVE: It's interesting, I'm actually just working with the program you did not too long ago where we gave you cases to discuss with the faculty in a meeting at the ASCO GI meeting in San Francisco. And we had one of the cases is exactly what you described, a low-risk patient with Stage II who had a positive ctDNA. And I remember when you turned to the faculty and said, what would you do, they kind of squirmed around in their seat a little bit because it was so unconventional, but they just they went back and forth and finally they just said, yeah, I'd definitely offer chemotherapy. I mean, the patient can refuse it as well, but maybe you recommend it. So what about Stage III?

Well, I should also mention in terms of Stage II, I guess there have been clinical trials or at least 1 clinical trial that actually randomized patients between getting this information and deciding with the information versus not getting it. And my basic take on it was that the patients did just as well in terms of recurrence but a lot less of them got chemo.

DR LIEU: Yeah, there was a study called the DYNAMIC-II study that showed, that really exactly divided up patients between getting the ctDNA test and making an informed decision or just what we call standard management. What we know is that the outcomes were completely similar, which is good because a lot of the patients did very, very well. It was just that half the chemotherapy was given. So 30% in the standard of care arm, 15% in the ctDNA arm and they both did the same. So you basically got the same outcomes by using half the chemotherapy. And listen, as a provider, anytime we don't have to give chemotherapy, that's absolutely a win. And so I think that really is a very telling study in Stage II colon cancer.

DR LOVE: And again, we saw the same thing happen 20 years ago in breast cancer. At that point, every patient who had a tumor that was 1 cm or over got chemo. And when Oncotype came along and showed, oh here 50% of them are not going to benefit, boom chemotherapy dropped. I mean, maybe people don't realize that now when they see all these people in the clinic, but much less use of chemotherapy.

So let's talk also about high-risk Stage II. You mentioned it’s like a T4 where it's invading other structures, but also node-positive Stage III. And I can tell you that as soon as this data came out the first thing oncologists were asking me was, what about my 75-year-old person who really doesn't want to get chemo, they've got diabetes, hypertension, all this other stuff and they have 1 positive node and the guidelines say chemo but what about using a cell-free DNA assay like Signatera in a patient like that? And even though I don't know if it's exactly blessed by the guidelines at this point, I see a lot of people doing that and I'm curious how you approach that right now.

DR LIEU: Yeah, and so you can probably tell from the tenor of our conversation that I'm really a lot more comfortable using ctDNA for what we call escalation decisions. I wasn't going to give chemotherapy, now I'm going to give chemotherapy. I actually do feel very comfortable about that in Stage II even Stage III. I feel less comfortable regarding de-escalation strategies because I don't want to hurt patients, right? And that's where we probably do need these clinical trials to read out so we can know that we can safely use this test to say, okay, well, you don't need chemotherapy.

Now having said that, the reality is that our patients come in from all walks of life and we had talked about the heterogeneity of the patients that we see. And there are patients that are going to come in and say, I absolutely want chemotherapy, I don't care what you say. And then there are patients that say, I really, really don't want chemotherapy. And so the practice part of this and the art of medicine is really in a patient that says, listen, I really don't want chemotherapy, is there anything that I can do to inform my decision? Well ctDNA testing may help in that situation. Because if a patient says, if I get this test back and it's positive, I'm getting chemotherapy or if the test comes back negative, it just supports my decision that I didn't want chemotherapy. This is allowing our patients to be involved with their care, to make informed decisions that's best for them.

And, Neil, you had mentioned this. I think this is a great thing to ask our patients. And that is, listen, if we go back to this moment in time and if there's a recurrence in the future, will you regret this moment? And I actually say that to my patients all the time because I really want them to look forward and say, if there's something bad that happens, will we look back at this pivotal moment in this conversation and say, ah, I have so much regret. Because I think that really should help our patients inform some of their decision-making. But this is where ctDNA has maybe helped my patients. And I think it's critical to go in with a plan. If we do this test, will it change what you decide to do? If the answer is no, there's no use in getting the test. If we get the test and it is going to change what you want to do, I think it's worth getting.

DR LOVE: And again that principle was reflected with the use of Oncotype. People would say, okay, we're going to send this but if it's low, are you still okay not getting chemo? If they go, “No, I want to get the chemo,” as you say, don't do it.

Potential incorporation of ctDNA assays into the management of metastatic colorectal cancer or microsatellite instability-high disease

DR LOVE: A couple other questions and then I want to get into your cases. One, what about these types of assays in metastatic disease, either to monitor like a tumor biomarker in terms of how people are, whether they're getting better or not? Or maybe in a situation like you talked about before where you're going to remove or give radiation therapy to a localized met to see whether it comes back. Do we have any data in the metastatic setting? And do you think it's rational to think about it in the metastatic setting?

DR LIEU: Yeah, I think in metastatic disease we think about the traditional we give 2 months of treatment and then we're going to get a CT scan. Sometimes the ctDNA trends, they may help, they may not help, but a lot of times we're honestly just following the CT scan. Sometimes our patients are actually asking for it and I don't mind sending it because, again, it's another data point, but it doesn't necessarily change what I'm going to do.

I will tell you that we've talked a lot about microsatellite-stable colorectal cancer, this is 96% of our patients with metastatic colorectal cancer. In microsatellite-stable disease, we don't use immunotherapy. But in the 4% of patients with metastatic colorectal cancer that are MSI-high or deficient in mismatch repair, we don't start with chemotherapy. We start with immunotherapy and the results have really been great. We know that ctDNA can actually be helpful in that situation because we know when ctDNA drops down that they're likely responding to immunotherapy.

The second thing that's come up is that sometimes patients have these dramatic responses to immunotherapy, but we can still see masses on a CT scan. And I've actually taken some of these patients to surgery, MSI-high who've received immunotherapy, and they've just taken out scar tissue, which means that what we've been measuring as tumor is just dead tissue or scar tissue. ctDNA may actually be helpful for that because if you see this kind of mass that isn't changing and it maybe looks like tumor, maybe it looks like scar tissue, but the ctDNA remains completely negative, that might be a telling sign.

But I have taken patients for oligometastatic, MSI-high colorectal cancer to take out what remains of their tumor and they've literally taken out just nothing. And so there are some situations in metastatic disease where ctDNA may help guide some of your decision-making.

DR LOVE: And I think we should point out that really it was just this summer at the ASCO meeting in June for the first time and this was a plenary presentation, one of the top presentations at the big ASCO meeting, there was a randomized adjuvant trial, finally, we've been looking for this for a long time, looking at immunotherapy in the adjuvant setting. We knew it worked with MSI-high disease in the metastatic setting. But the interesting thing about this trial was it combined immunotherapy atezolizumab with chemotherapy and bevacizumab and people, and it was very positive as everybody expected. The people got immunotherapy because we know the people with MSI disease they respond really well, maybe even some of them are cured. So big, big benefit but they also were getting chemo.

And again all the docs are asking me, do we really need to give the chemo? How are you thinking that through? You've got an 85-year-old who's MSI-high? And would you ever, would cell-free DNA be helpful in trying to make a decision? For example, let's say they were Stage III, but they were cell-free DNA negative, would you be okay maybe just trying immunotherapy?

DR LIEU: Absolutely. We had talked about the art of medicine and so we know what the guidelines are going to say. They're going to say in the adjuvant setting for Stage III MSI-high give FOLFOX plus atezolizumab. But the reality is that there's going to be a lot of variation in practice. There are going to be some patients that just aren't eligible to receive FOLFOX. Would you give immunotherapy alone? Could you give, could you drop the chemotherapy early? Because in the trial they gave 6 months of chemotherapy and that's a lot of chemotherapy. And so certainly this is another instance where ctDNA can be used as a tool. Should it be the sole decisionmaker? I don't think so.

But in patients that have negative ctDNA, they're on FOLFOX/atezolizumab, they aren't tolerating the chemotherapy well, you might feel a lot more comfortable as a provider dropping the chemotherapy, continuing atezolizumab and then following the ctDNA.

Available clinical data with ctDNA assessment in localized rectal cancer

DR LOVE: What about these types of assays in localized rectal cancer? So we've used TNT, total neoadjuvant therapy. Can you explain what that is? But also in the, again small number of people with MSI-high, we've seen a lot of trials use immunotherapy alone not even go to surgery in many of these patients. They seem to almost all respond. Again, do you think cell-free DNA, has cell-free DNA been studied in the rectal cancer setting? And do you think it makes sense to look at it in that setting?

DR LIEU: Yeah, and so, the neoadjuvant space for rectal cancer has changed dramatically. It used to be a very simple answer like 10, 15 years ago. Give chemoradiation, take them to surgery and then give them chemotherapy afterwards. The paradigm shift for rectal cancer has been to provide all the treatment up-front. Many times, centers are starting with chemoradiation followed by chemotherapy and in a percentage of patients, they're going to have what we call a complete clinical response where the tumor is just not visible.

And so we have started now for patients with locally advanced rectal cancer in about 25 to 30% of patients doing what we call a watch and wait strategy. We're not offering them surgery. How great would it be if patients with locally advanced rectal cancer didn't have to get a lifelong ostomy because they didn't get surgery. That would be — and we've seen that, right? In our patients now, we have global experience with this kind of total neoadjuvant therapy and watch and wait strategy. But ctDNA assay may help us understand, well, who have we truly cured with chemoradiation and chemotherapy and they don't need to go to surgery. And so we would love to get more and more data there.

I will tell you that the data in microsatellite-stable, locally advanced rectal cancer is kind of plus/minus. It's somewhat predictive, but we still need bigger numbers and more data. The data with MSI-high rectal cancer where we use immunotherapy, and this is the story that made The New York Times about giving dostarlimab for locally advanced rectal cancer, we know that from the Sloan-Kettering experience, and the outcomes have been great. We actually know that and have published data looking at ctDNA in that setting. It seems to be a lot more predictive. And so this is a field that's evolving rapidly, but we do need some more data in the locally advanced rectal space.

Current practice patterns with ctDNA assays for patients with localized colorectal cancer

DR LOVE: So I want to finish out talking about some of the cases from your practice, but first this one other question. As I mentioned, we just, over the last couple of weeks, did a survey of 20 investigators, people like yourself who specialize in particular interest in GI and colorectal cancer, gave a bunch of situations and questions about this whole topic we're talking about today. And over the years when new things come out, as a CME group, we're seeing this all over oncology, typically a new paper comes out and first you see the reaction of the experts, the investigators. They're very close to it. They understand it. And sometimes a paper will come out and everybody will switch right away. Then you see the community over the next few months, they start switching. And sometimes there's more of a heterogeneous response also.

We just actually had 4 posters at the San Antonio Breast Cancer meeting. They were all in surveys that we did. And a lot of the questions, the key clinical questions you see differences in responses. I'm curious what you see when you look out to, first of all your colleagues who specialize in research in this area. You just made a very convincing argument particularly with Stage II, to me, to utilize this strategy. I think anybody listening this would say, okay, yeah. But do you see everybody doing this or you think there's maybe some people are not quite on board?

DR LIEU: I think it's an incredibly, maybe the key word for this is just heterogeneous. But I think the differences in practice patterns is humongous regarding ctDNA. And I think it's really because of 3 issues. Number 1, some of it is regarding the availability of the testing, of people having the ability to order it or not. Number 2 is the guidelines. Because there's no prospective randomized data, there aren't clear guidelines for the use of ctDNA. And number 3 is actually the patients. So we have patients that are asking for it and providers either being willing to order it or not willing to order it.

And so I think that that's led to really a wide range of how this test is being used. The most common situation that I get called about is a patient wanted Signatera testing or ctDNA testing, they have a positive result, they've completed their adjuvant therapy and the provider is left with I don't know what to do right now because I've already given them the adjuvant therapy, I know that the ctDNA test is a very prognostic test and so I'm worried that I'm going to see metastatic disease in the coming months. What do I do? And, of course, there really isn't a great answer right now besides obviously trying to enroll these patients on the clinical trials.

DR LOVE: And I guess you can't really justify using out of trial therapy in a situation like this, I don't think. But again, when you look at this, to me the most convincing use is a Stage II. I'm not saying it doesn't make sense in Stage III or beyond. But do you think that most or almost all clinical investigators are using this assay in Stage II or you find some people are not?

DR LIEU: I think that it's a conversation — these conversations have only gotten longer, which also impacts the clinic, right? Is that these conversations regarding Stage II colon cancer have already been somewhat long because we talk about risks/benefits of chemotherapy and the fact that there isn't great data. When you throw ctDNA into that mix, you're going to increase your conversation by about 20 to 30 minutes in some instances. I would say that if patients are up for it I'm seeing it more and more offered. Certainly in our clinic, they're being offered in the Stage II setting ctDNA and we're giving them right of refusal.

DR LOVE: So, but, again, let's say we were to take 20 prominent GI investigators, people who are on guideline committees, and say, are you using ctDNA in making clinical decisions outside of a trial, for example, in Stage II, do you think that pretty much all of them will say yes, or do you think there'd be a significant minority who would say no?

DR LIEU: I would say a majority of providers, and I guess you're going to tell us when we look at our survey results, but I do think a majority of providers, particularly for low-risk, Stage II colon cancer are offering patients ctDNA testing.

DR LOVE: No, I mean, I think that's what we found, but I think, I was surprised it wasn't almost unanimous.

Case: A woman in her early 40s with resected lower risk Stage III colon cancer requests ctDNA testing

DR LOVE: Alright, let's get into your cases here. We'll start out with this 41-year-old woman. Can you just talk a little bit about what happened with her?

DR LIEU: Yeah, and trying to give these as real life as they get and these are honestly real patients that have requested ctDNA testing and this is a patient with what we call lower risk Stage III colon cancer because there are not very many nodes, in this case just 1 node, that was positive for colon cancer. And so this patient had a colonoscopy. She was young. Developed or found to have a sigmoid colon tumor, no metastatic disease. And the resection did show that it was a T3N1 Stage III colon cancer and this just means that there's just 1 lymph node that was positive. This patient wanted ctDNA testing. We got it a couple weeks after surgery and the testing was negative.

And so my question to the group is, well, for this patient, what would you recommend? And the guidelines in this situation really say to give chemotherapy. And here I actually would still, even though the ctDNA was negative, offer the patient 3 months of either FOLFOX or CAPOX chemotherapy. But, of course, this is also shared decision-making with a patient knowing that with the initial ctDNA test that's negative, she's not only low risk Stage III, but she's just low risk in general.

DR LOVE: And I don't know whether she actually asked you for any numbers. And also maybe what her background was and how interested she was in numbers or she was just like, tell me what to do. But what actually happened?

DR LIEU: Yeah, so even though the test was negative, she did want 3 months of chemotherapy. We tell people with the initial test being negative obviously we get better results when we serially test. So if she's negative and continues to be negative, we know her recurrence risk is extraordinarily low into single digits. But we also know that just with 1 test, her recurrence risk still remains around 10%.

DR LOVE: So again, she's another example of a younger patient, 41 years old. I'm curious, in general, do you find younger patients more pro treatment than older patients?

DR LIEU: Yeah, absolutely. I mean, I think understandably our younger patients have an incredible amount of anxiety particularly when they develop colorectal cancer at an age where they shouldn't even be screened and 41 is a great example of that. I think that understanding that we are not only trying to save 10 or 15 years of life, that we're trying to save, in many cases, 30 to 40 years of life, they're going to do everything to grab every single percentage point of reduced recurrence risk possible.

And I think that that's why a lot of our younger patients are motivated to receive chemotherapy, but, and again, our nurses know this better than anybody else, the side effects and the long-term side effects is something that we should always keep in mind. Because, again, these patients are taking care of young kids and they're in school and they have early careers and they really need to be able to function well afterwards.

DR LOVE: So what's this patient's current status? Has she already been treated?

DR LIEU: She's already been treated, serially ctDNA negative and is doing great.

DR LOVE: And how did she tolerate the treatment just out of curiosity? Was she working and was she able to work?

DR LIEU: Yeah, and I find that many of our patients are able to work. There are always a handful of patients that have minimal side effects to chemotherapy. Those are always fun because they're working completely full-time. But I think the biggest decision point for providers is really 3 versus 6 months of chemotherapy. And for lower risk, I never offer 6 months, I always offer 3 months.

But for higher-risk disease, we have to have a big conversation about, well, what is the benefit of an additional 3 months of chemotherapy, which in some cases may be as low as 1 to 2% of recurrence-free survival. And this is the discussion that you're talking about with breast cancer where some patients are like, I'm going to take every single one of those percentage points so give me the 6 months of chemotherapy, I don't care what the side effects are. And then there are other patients that are going to say, 1 to 2%, I'm done, right? And so this is where that conversation happens particularly at the 3-month mark.

DR LOVE: Did this woman have any neuropathy or any significant problems like that?

DR LIEU: Yeah, so at 3 months, that's usually where our patients start to have some longer lasting peripheral neuropathy. This patient actually did pretty well. I will tell you that again how you need to counsel patients is that the peripheral neuropathy will worsen even after we stop chemotherapy. So and the drug here is oxaliplatin. And so, again, it's something that our patients should be aware of and I always want nurses, providers and patients to overcommunicate on this issue and that way we're not going to end up harming our patients with the chemotherapy.

Case: A man in his early 50s with Stage IIIB colon cancer wants to avoid adjuvant chemotherapy

DR LOVE: Alright, how about this 51-year-old man? Again, another younger patient. Sometimes I ask people to present cases and they're all under age 50. It's amazing. I guess because you guys see it — you're seeing more of this even than people in the community. But anyhow 51 years old.

DR LIEU: Yeah, we run a colon cancer colorectal cancer multidisciplinary clinic and sometimes nobody's seen under the age of 40 or over the age of 40 and so it's just it's wild and obviously —

DR LOVE: Scary.

DR LIEU: Scary, yeah. It certainly will impact you as a nurse and a physician. But this is a 51-year-old again within the screening age for patients. T3N1 disease, sigmoid mass again, 1 out of 16 lymph nodes. So really similar to our 41-year-old. But this patient really just did not want chemotherapy. And it's funny, it depends on where you live and what your population is like. And there's some populations where I think they're just all for chemotherapy and there are others, particularly in rural areas, where they really don't want anything to do with chemotherapy. And so again, it's a lot of difference in how patients approach their disease and what their thoughts are about chemotherapy.

Patient does not want adjuvant chemotherapy. He wants to opt for ctDNA testing. And again for this particular patient, we got a ctDNA test because again that conversation has to be had before you order the test. If we get this test and it's positive, will that influence your decision to then receive chemotherapy? And he said, yes, if I get this test and it's positive, I will absolutely get chemotherapy. And it wasn't only that it was just like, listen, if it's negative and then it turns positive, I'm going to get chemotherapy at that time. And so I said, okay, this is, we know that there's no data here to drive this discussion. I know you don't want chemotherapy, but you're telling me that you're going to change what you're going to do based off of the test? Let's get the test.

It was negative and then the patient, it just reinforced his decision that he wasn't going to get chemotherapy. He has also serially been negative and then at this time we're just doing surveillance for him and he never received chemotherapy. But that was in line with his goals.

DR LOVE: How long has it been now? Well, I see 2022. So several years.

DR LIEU: Yes. So we got away with it. Again, I would love to be able to point to randomized clinical data from clinical trials to be able to show you that this is exactly what we're supposed to do, but that was not that — we don't have that yet.

DR LOVE: Yeah, this thinking, this discussion is going on every day in the general medical oncology clinic. Every day.

DR LIEU: Very complicated. Very, very complicated.

Case: A man in his early 60s with Stage IV colon cancer receives a positive postoperative ctDNA assessment result

DR LOVE: Alright. Metastatic disease, 63-year-old man.

DR LIEU: Yeah, and so this is a case that I — and this is as real world as it gets and it shows you that we, a lot of times we'll get this test back and we really don't know what to do. But it really did influence this patient and his course. So this patient underwent, had Stage III colon cancer, underwent surgery in 2022 and got, he got 6 months of chemotherapy even though a lot of times we're only offering 3 months of chemotherapy for these patients. But he, before I saw him, got 6 months. And that was in 2023.

Now he had been following his Signatera test and what's amazing is that you can actually follow him from 2022 all the way up to 2025 and it was negative that entire time. And so he had actually continued Signatera testing for a long time and then June 23, 2025 the ctDNA turned positive to 0.12, which is a low level. Now this is where ctDNA actually influenced what we did, right? Because at that time, several years out from resection, you're just getting a CT scan annually. So with a ctDNA test that was positive, we got a CT scan and a PET scan. We usually don't get PET scans in the surveillance stage for colorectal cancer. And sure enough, there was a right upper lobe nodule that lit up on a PET scan and was concerning for malignancy. And so in September, the patient received a right upper lobe lobectomy, mediastinal lymph node dissection. The patient actually had the tumor removed and had a lymph node dissection and one of the lymph nodes was positive.

And when we rechecked the Signatera a month later, it had dropped some to 0.09, but was still positive, which is concerning to us. And so the question then to the group and to the patient and for me was, okay, we have resected Stage IV colorectal cancer, ctDNA testing helped us maybe identify that earlier, but it remains positive postoperatively. So what would you do in this situation? Would you offer adjuvant chemotherapy or not?

DR LOVE: So I guess another scenario that could happen was the cell-free DNA went down to 0 and hopefully he was cured. It doesn't sound like that was the situation here. What's his current status?

DR LIEU: So the patient ended up opting for additional 3 months of chemotherapy. Again, what's interesting about chemotherapy in the perioperative space where we're doing this oligometastatic surgery and getting rid of all the visible disease, is that we actually don't know that chemotherapy saves lives in this situation. When you look at all these trials, there always seems to be a disease-free survival benefit with chemotherapy but no difference in overall survival. And that's provided a lot of pause in the field of in these patients where we cut out the metastatic disease, should we be offering them chemotherapy?

And so this is another area where because the clinical data isn't very clear, ctDNA is starting to fill some of that gap. Again, do we know that chemotherapy is going to save my patient's life? We don't know that but based off the available data we are worried that there's some additional disease there that we cannot see and the Signatera is positive or ctDNA test is positive. So here the patient did opt for additional 3 months of FOLFOX. Currently the ctDNA is still around like 0.03, right? It's incredibly low but there's been no evidence of recurrence and we've been scanning pretty aggressively every 3 months.

DR LOVE: So final question. I'm just curious whether or not this technology is being utilized in clinical trials of new approaches. We were talking about MSI-high disease, that's kind of a new approach, but also new agents. We're trying to find new therapies, immune-based therapies, et cetera. Do you see ctDNA measurements being incorporated into clinical trials?

DR LIEU: Absolutely, and, in fact, I believe that every patient that has completed their adjuvant therapy and remains ctDNA positive really should be offered a clinical trial if possible. There's been a lot of interest of immune-based agents in this setting. And the question is, could MRNA vaccine, could immunotherapy, could a different kind of chemotherapy even impact this group of patients that are ctDNA positive but have no evidence of disease? And I actually am really, really excited about the possibility of immunotherapy, particularly the personalized cancer vaccines in this space. We know that immunotherapy has a tendency to work better before these tumors become really bulky. And so I'm very excited about what the future holds.

This represents an incredibly high-risk population and if we can prevent recurrences in these patients, that would be a huge advance in our field and just make a tremendous difference to our patients.

DR LOVE: This concludes our program. Conflict of interest statements for the faculty can be found in the program notes. And keep in mind that the use of agents and treatments that are not approved may be discussed in this program, so check out the package insert for more.

Special thanks to Dr Lieu, and thank you for listening. This is Dr Neil Love for Oncology Nursing Update.