Colorectal Cancer Liver Metastasis

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepherd, a medical oncologist here at Cleveland Clinic, directing the Taussig Early Cancer Therapeutics Program and co-directing the Cleveland Clinic Sarcoma Program. Today I'm happy to be joined by Doctors Federico Aucejo, Director of the Liver Tumor Clinic, and Bassam Estfan, Co-Director of the Liver Tumor Program. They are here today to talk to us about circulating tumor DNA screening in colorectal cancer with liver metastases. So welcome to the podcast.

Bassam Estfan, MD: Thank you for having us.

Federico Aucejo, MD: Thank you, Dale. Thank you for having us.

Dale Shepard, MD, PhD: Absolutely. So tell us a little bit about what you do here. Bassam, we'll start with you.

Bassam Estfan, MD: So I'm a medical GI oncologist. I've been here at the clinic for about 20 years, maybe in different roles, but in my current role, as you mentioned earlier, I work with Dr. Aucejo very closely at the Liver Tumor Clinic. We also chair the liver tumor board. I'm a medical director for the inpatient solid services and also host a bunch of tumor boards, like the pancreatic and the liver tumor board specifically.

Dale Shepard, MD, PhD: So, overall, a busy guy.

Bassam Estfan, MD: So a busy guy, yeah. Yeah, we like to stay busy.

Dale Shepard, MD, PhD: Huh, all right, Federico, how about yourself? What do you do here at the clinic?

Federico Aucejo, MD: So I've been at the clinic for about 20 years now and I'm a liver surgeon. I perform advanced liver surgery for patients with liver malignancy and I also perform liver transplants. I spearhead the Liver Tumor Clinic and the Liver Cancer Program here at Main Campus, Cleveland Clinic.

Dale Shepard, MD, PhD: All right, excellent. So today we're going to talk about colon cancer liver metastases. We're going to get into a study you guys worked on related to circulating DNA, but let's just start really, really general. We're going to talk about liver metastases in colorectal cancer. Bassam, maybe start with you. Why is that important? Why is liver metastasis specifically important in patients with colon cancer?

Bassam Estfan, MD: So think about it this way, colon cancer is, number one, a very common cancer. It's probably the second most or third most common cancer in the United States, and globally it is the third perhaps leading cause of deaths of colon cancer. And most of these deaths are because of metastasis. Now, the majority of the diagnoses of colon cancer are in the earlier stages, Stage I, II, III. About 20, 25% will be diagnosed with metastatic disease from the get go.

Now, most of these cases where metastasis are present in the beginning, the majority of those will be liver dominant only. And not only that, but also about 20%, give or take, of those diagnosed with what's supposed to be a curable cancer, colon cancer, will develop later in life, usually within the first two to three years, metastasis or metastatic disease. And most of these also are going to be in the liver. So the liver also, and I'll [inaudible 00:03:35] Dr. Aucejo can talk a little bit more about that, is unique in a sense that, while it is a major organ where metastasis can happen from colon cancer, it's also a very relatively flexible organ that we can work with, unlike lung or peritoneum. But we can do stuff to the liver that can still keep the word cure and then discussion.

Dale Shepard, MD, PhD: All right, and some of those things we could do, of course, would involve surgery. And so Federico, let's turn to you and say, from a surgical standpoint, resections, and then also you mentioned transplants, something that's not necessarily as common at this point. But give us a little bit of an idea, just big picture, what we do from a surgical standpoint for this.

Federico Aucejo, MD: Yeah, so the main question we have to ask ourselves when we see these patients in clinic is if they have resectable disease, operable disease. And that's because surgery continues to be the mainstay therapy for these patients, obviously along with systemic therapies, but surgery can be curative. And essentially there are two ways we can approach these patients surgically, by resecting the tumor, meaning the patient keeps his own or her own native liver, or by transplantation, that is replacing the whole liver by a living donor or deceased donor liver graft. And in terms of survival, I mentioned this could be curable, but with resection, the overall five-year survival is estimated to be in the order of 30 to 60%, and in properly selected patients with transplantation, the five-year overall survival could be up to 60% or even higher. So that's why it is, like I said, very important to recognize which patients we can offer surgery, either upfront, or after techniques used for down staging the tumor to surgical potential approaches.

Dale Shepard, MD, PhD: And then I guess just from a procedural standpoint, where does ablation come in?

Federico Aucejo, MD: So ablation essentially is the treatment of tumors with microwave energy, delivered by a needle that is inserted into the tumor, guided by imaging, either ultrasound or CT scan. I could tell you that, in a general way, microwave ablation could be equivalent to resection. Resection is always superior in terms of effectiveness of the treatment, but microwave ablation can be equivalent to surgery when we treat lesions that are rather small, that is two to three centimeters. And when they are located deeply in the substance, in the parenchyma, of the liver because we need to try to preserve as much liver parenchyma as we can, because it's expected that the tumors will recur. And if that's the case, when that happens, we may want to perform more surgery. So we need to keep enough liver volume for the patient to obviously survive the operation.

So if we have a small lesion in the middle of the right lobe, we're not going to remove the whole right lobe to treat that lesion. In that case, if the lesion is small, I repeat this, I emphasize this, three centimeters or less, we could treat it with microwave ablation instead of resection.

Dale Shepard, MD, PhD: All right, we're going to talk about using circulating tumor DNA and how that might fit into managing patients with liver metastases. But maybe one last background topic would be, we're thinking about how we utilize circulating tumor DNA, what do we do now? What's the current state for managing these patients? So, Bassam?

Bassam Estfan, MD: So this is an evolving field. I think we have to say that upfront, and there are a lot of ongoing studies and studies are being reported. Majority of those are being done in the early stage colon cancer, and some of those are still not yet common practice, but that they are increasing. For instance, using tumor informed or tumor agnostic, and we can talk a little bit more about that, assays, with liquid biopsy or circulating tumor DNA, to check on what we call minimal residual disease, after resection of colon cancer, typically in Stage II and sometimes in Stage III. And there are different goals for that. First of all, sometimes it can influence treatments, whether to give more chemotherapy in the adjuvant or whether to give it at all. And also, influence whether we can spare some patients the troubles of chemotherapy if we know that these tests indicate a very low likelihood of recurrence.

So what we know about these tests is that they are very good in prognostication. So for instance, if we have a number of patients with a negative postoperative ctDNA test, whatever it is, and we have another group that has a positive ctDNA after surgery. And we know that those who have a positive ctDNA, specifically if they don't get treated with anything else, have a very high likelihood of the cancer recurrence. And sometimes we can discover that much earlier than what we can see on scans or by typical blood work. That's the current practice right now is primarily being utilized in the earlier stages, but it hasn't yet evolved into metastatic realm.

Dale Shepard, MD, PhD: And so currently, monitoring liver mets is primarily things like biomarkers, like CEA instead of DNA based, and scans.

Bassam Estfan, MD: And scans, absolutely.

Dale Shepard, MD, PhD: And so maybe the thought is, can we do something on a DNA level and maybe it'd be a little more sensitive and early. Federico, tell us a little bit about the study you guys put together.

Federico Aucejo, MD: Yeah, so the study looked at patients who were evaluated through the Liver Tumor Clinic, patients who were undergoing or already received liver resection or transplantation, and ctDNA was assessed. In some patients before the treatment only, and some patients after the treatment only, and in some patients before and after. And what we observed was that, and this goes in line with other early experiences that been published, is that the patients who had positive ctDNA, post surgical treatment, had higher risk of recurrence, as opposed to the patients who remain ctDNA negative.

What was truly compelling was to see that patients undergoing transplantation were able to clear positive ctDNA, because if you think about it, these are patients that present with very advanced disease. We're talking about metastatic Stage IV disease and with a large tumor burden affecting these patient's livers. So the fact that liver transplantation is able to remove tumor burden, and the molecular residual disease assessed by ctDNA, and in the setting of immunosuppression because these patients are going to be artificially immunosuppressed by medication so they don't reject the new organ. All that together is pretty impressive to see, to be able to observe the transplantation can clear ctDNA.

So this is essentially what we've seen, and like I said, it goes in line with a few other studies that have been published. I have to add that our group is proud to say that we were the first in the world to looked in, and of course this is very small number of patients, but we were the first in the world to looked into and publish the assessment of ctDNA in the liver transplant patient population.

Dale Shepard, MD, PhD: When we think about increased risk for recurrence with the elevated... Did those occur recurrences, were those in the liver or were those outside of the liver?

Federico Aucejo, MD: That's a great question. Some patients recur in the liver, some patients recur outside of the liver. Some patients recurred only through one lesion. Some patients recur through multiple lesions. And that is very important because it changes the outcome of a patient because it changes the way you can treat these patients. If there is a unifocal recurrence, you most likely be able to address it, either by surgery, or radiation, or ablation. But if the patient presents with multifocal recurrence, you may just only be able to put the patient back on palliative systemic therapy and clearly the outcomes are different. The problem is that we don't know how the recurrence is going to be. We know that a large number of these patients, I'm talking about after transplantation, they're expected to recur, but we know that not all of them will recur. We don't know who will, who won't and we do not know how the recurrence will be.

Dale Shepard, MD, PhD: All right. You've done something, some procedure, you've taken out tumor. Now, Bassam, you get circulating tumor DNA. There's still DNA there. Is the thought that this might drive decisions on use of adjuvant therapies based on whether there's still some residual disease based on DNA?

Bassam Estfan, MD: That would be the main goal here, is how do we use the information that we get into one of two things, either treatment or the next one will be how do we monitor? Maybe I'll talk a little bit more about the monitoring first because it is a little bit different than when we're talking about early stage colon cancer. Most people who undergo transplantation or who undergo resection, or ablation, any other procedure to the liver for metastatic disease, we are already intensely monitoring those with the typical stuff, which is CEA, labs and also sectional imaging, MRIs or CT scans. And so we're already doing that every three months, maybe for the first couple of years.

So how do we incorporate the ctDNA with that? Do we do it every time we're doing it and what do we do with that information? For instance, if the ctDNA is negative and everything else is negative, well, that's an easy approach, right? But what if everything else is negative and the ctDNA is positive? What does that mean and let's say that we are now a year out of surgery? Well, we know one thing, that oftentimes positive ctDNA can detect cancers a little earlier than what we can see on imaging, because we need to have a cancer of a certain volume or certain size to be seen on imaging [inaudible 00:15:09] the millions and billions of cells.

So it may lead us into one of two approaches, either well, we do scans a little bit even more closer than originally intended, or the other thing which should be a subject of future studies or research, well, do we try and use other modalities for treatment earlier than when we detect the actual cancer? For instance, if there was a conversion, specifically if there was a conversion from a negative to a positive test, can we, at that time, use chemotherapy based on that test alone, even if you don't see anything? And then follow the ctDNA to know how effective our treatments are. So that's one aspect.

The other aspect's maybe in the immediate aftermath of surgery, most of these people are not going to have surgery as a first step. They've already been through some chemotherapy and now they have a resection or the transplant. And if we have a ctDNA test that is positive, then that, if possible, will lead us to think more closely about using adjuvant therapies. Because think about most of the studies that were done in the perioperative chemotherapy for liver dissections, the majority of those have no survival advantage, but they have a recurrence-free advantage or disease-free advantage. So maybe this ctDNA would be a way to be able to better select those people who could benefit from having perioperative chemotherapy as opposed to having a negative test, and maybe we can just monitor those.

Dale Shepard, MD, PhD: Tell us a little bit about the changes in DNA that were seen, or differences in DNA, preoperatively, postoperatively, in terms of tumor mutational burden. There were some differences in terms of high tumor mutational burden, preoperatively, lower burden afterward.

Federico Aucejo, MD: Yeah, so we observed that the TMB, or tumor mutational burden, decrease after surgery. The main specific mutations obviously remain the same, and this is something that may happen as we follow longer time, these patients, that can be changes in the mutational profile of these patients, right? So the ctDNA could help us to pick better therapies that are out there, either in the market already or through trials, if the mutational profile of the tumor changes. But overall, what we observe is either completely clearance of the ctDNA or a decrease in the tumor mutational burden after surgery.

Dale Shepard, MD, PhD: And there were differences in tumor mutational burden based on response to previous chemotherapy. Is that correct?

Bassam Estfan, MD: Yeah, I believe so. And of interest, it seemed to be that those who had a higher tumor mutation burden score, compared to those who had no response or maybe let's say decreased response to cytotoxic chemotherapy, had a higher tumor mutation burden than those who had the response. And maybe that has to do with the fact that those patients with higher tumor mutation burden should be more responsive to immunotherapy, for instance. So it definitely has an impact on how we can navigate treatment for these patients.

Dale Shepard, MD, PhD: So is there a possibility that this might suggest maybe a way to differentiate patients who would benefit from maybe even preoperative chemo, versus trying to see if there's a benefit to preoperative immunotherapy, prior to doing resection? Is that maybe a potential?

Bassam Estfan, MD: There may be a potential for that, and that definitely is something worth researching, either in smaller or larger clinical trials.

Dale Shepard, MD, PhD: I realize this is all very early, in terms of information here. What are the next steps? Where are we going from here?

Federico Aucejo, MD: Well, we'll continue increasing the volume of this practice of our experience. So hopefully we can join that with other ongoing similar efforts, within the US and other parts of the world, so we can see if we can confirm these early observations and we'll see what it takes us. I think that likely ctDNA will be assessed before and after resection as a standard practice at some point in time. It may, again, guide us to pick the most effective targeted therapy that is out there in the market, like I said, or through trials. And it may help us also adjust the surveillance protocols on these patients. Those who remain negative after treatment, we may space out more the scans and lab work. Those ones who are persistent ctDNA positive, we might want to have a more strict surveillance with these modalities. So definitely I think this is a new technology that has arrived to stay, and I think that it's going to help patients' survival overall.

Dale Shepard, MD, PhD: Bassam, anything else you'd like to see come out of this?

Bassam Estfan, MD: Well, I think the opportunities are vast, and what I'd like to see come out of this is be able to know more what tests are the proper tests to use, because we talk about ctDNA but that's just a big umbrella. We have ctDNA, that is more like an NGS-type ctDNA, which is similar to the one that was used in the study Dr. Aucejo spearheaded. There are ctDNA that are more tumor based, either tumor informed or tumor agnostic, but they're looking at is there evidence of cancer? You're not necessarily looking at the mutations themself, but looking at something that is quantitative. Is it positive or negative, in the sense of tumor agnostic ctDNA, or is it variable? And do we see an increase or the decrease, like in the tumor informed ctDNA? So what is the best test that we should use in this situation, or should it be maybe a combination of two and then we increase the sensitivity and specificity of these tests? So that is one thing that we need to understand, specifically in the setting of metastatic colon cancer.

We talked earlier about ablation, you mentioned ablations and stuff like that. We should also try to look at these, outside of resection and transplant, and see how we can employ that in other liver directed therapy, whether it's ablation, microwave ablation, and also the timing of that. We're using something destructive, we can expect some release of cellular component, and so we need to understand where the timing of doing these tests will be best, so we don't have any false positives. Or even using it with some of the more novel approaches to destruction of liver metastases, like histotripsy for instance, which is a new technology that we have here at the Cleveland Clinic nowadays. Do we use it with other stuff like radioembolization or hepatic artery infusion? So there is a lot of room here. And also to me, I like to see how we can use it better to guide treatment, and using the dynamics of the ctDNA, how does it change over time to know when to treat and also who are the people who could be spared treatment?

Dale Shepard, MD, PhD: And again, just to make sure everyone's aware, that might be listening, these tests that we're talking about, the circulating tumor DNA, this is a blood test, right? And so when we talk about serial monitoring, this isn't going in and doing biopsies repeatedly. This is a simple blood draw, right?

Bassam Estfan, MD: This is a simple blood draw and the turnaround time for those are usually faster than tissue that we send for next-generation sequencing, usually maybe an average of 10 days or so, you can get the results back. So it is a simple blood draw, which could be done with any planned blood draw a patient might be going for.

Federico Aucejo, MD: And I just want to add that some of these platforms also offer their own people going to the patient's house for the phlebotomy, and so that increases the chances of the patient getting the test -

Dale Shepard, MD, PhD: So, seems really it can be a pretty simple test.

Federico Aucejo, MD: It's pretty practical, yes, pretty feasible.

Dale Shepard, MD, PhD: Excellent. Well, it's a serious problem, the liver metastases in colorectal cancer. It sounds like you guys are doing great work from the surgical side, from medical oncology side, trying to figure out what's best for each individual patient, how we monitor them and provide them the best care. Appreciate your insights.

Bassam Estfan, MD: Thank you for having us.

Federico Aucejo, MD: Thank you for having us, Dale. Thanks.

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