MD Anderson Cancer Center
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Lisa Garvin: Welcome to Cancer Newsline, a podcast series from the University of Texas, M.D. Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment and prevention, providing the latest information on reducing your family's cancer risk. I'm your host, Lisa Garvin. Today we have 2 guests in our studio: Dr. Anthony Lucci who is a professor of surgical oncology here at M.D. Anderson and Isabelle Bedrosian who is an associate professor of surgical oncology. Today our subject is an article that's going to be in the June issue of Lancet Oncology about circulating tumor cells and their role as a predictive tool in early stage cancer. First of all, Dr. Lucci, you're the PI on this study. Tell me -- let's just talk about circulating cancer cells just in general. What are they exactly?
Dr. Anthony Lucci: So the concept is that you can identify individual cells within the peripheral blood that likely break free from the primary tumor at some point and then spread through the circulation. And our idea was Number 1, "Could we identify these in a significant number of non-metastatic breast cancer patients." And then the second kind of hypothesis was, "If we found them, would they be significant?" So that's what we undertook to look for were these cells that float through the peripheral blood and I would just say that for the purposes of circulating tumor cells, you know there's many different ways to identify them. And we used what's kind of a standard automated technique but there's a lot of different ways you can find them in the blood.
Lisa Garvin: Now circulating tumor cells, they've already been used as a tool in metastatic breast cancer cases that have recurred. What made you make the leap to use it in earlier stage cancers?
Dr. Anthony Lucci: So if you look at patients with breast cancer, at least 25 percent of patients with negative lymph nodes will recur and have a distant spread of their cancer. And there's also patients with positive lymph nodes that never recur. So we though perhaps lymph nodes aren't going to tell the whole story about staging. So we looked to see could you find these cells in patients with non-metastatic disease and if so, would it be present in a significant number? If you're only going to find it in 1 or 2 percent, you know would it really be worth looking for? So I think the first question was, "Could you find it in a significant number of patients?"
Lisa Garvin: And in this study, you had about 300 women I believe enrolled in the study?
Dr. Anthony Lucci: Three hundred and two: correct.
Lisa Garvin: And give us some kind of baseline results from that cohort.
Dr. Anthony Lucci: So of the patients that were studied -- and I would say it's important to remember that all of these patients, the sample was drawn before they had any systemic chemotherapy before their operation so the tumor was still intact. We took the blood sample. We ran the sample. And any cell -- one or more cells was considered a positive result for the purpose of this study because we really don't know what the cut off or threshold is for non-metastatic patients. So we considered any cell to be a positive. So in using that criteria, we found that almost a quarter of the patients had 1 or more cells. And so looking further than that, when we found the cells we looked to see, "Are they significant?" And indeed, having 1 or more cells carried roughly a 4 times risk of the cancer either recurring or the patient dying from their disease as compared to those patients who had no cells. And what's also interesting, as the number of cells went up so did the hazard risk. So the hazard ratio -- so as you had more cells, your risk of having an event went up as well.
Lisa Garvin: So Dr. Bedrosian, how often is recurrence an issue with breast cancer survivors? I mean, is it kind of rare? Is it kind of common?
Dr. Isabelle Bedrosian: So it really depends on the stage of the disease. We know that's an important criteria that predicts for who is going to relapse. But we also know there's other features, even within stage. The growth factors on the cells, ER positivity, [inaudible] positivity: all of those are all relevant. So there's a variety of predictors and it's very hard to give a general answer as to what is the recurrence rate because it is so specific and pretty individualized. I do want to go back to a comment that Dr. Lucci said. You know, we do know that there is a reasonable number of women who look like they have a curable disease but yet they relapse. And many of these women are lymph node negative. And so it's always been a struggle to understand -- we had no evidence that this thing had spread outside the breast and yet here they are a few years down there with a relapse. Where are the cells that might be causing this relapse? And the findings from this study give us an idea that perhaps they're cells in the blood that are risk markers that we need to try to explore in women who otherwise based on classical criteria look like they're a very good prognosis.
Lisa Garvin: So circulating tumor cells, is this kind of a new kind of innovation or is this something that's been kind of built on with research over the years?
Dr. Anthony Lucci: Well actually the concept was described even in the 1800s. They had described the idea that cells could break free and travel in circulation. I think what's relatively new are reliable techniques for finding them and isolating them. That's the part that's really relatively new. And I think as far as studying them in any large number of patients that's what's new about this study is really to date in non-metastatic breast cancer there haven't been any large studies. And I think this is one of the largest studies and also one of the first in non-metastatic patients to show that you could not only find them in a significant number of people but they were also significant. Most of the other studies to date had been in patients with already known metastatic disease.
Lisa Garvin: Now circulating tumor cells, is this something that happens to every breast cancer patient?
Dr. Anthony Lucci: No, and in fact I think another important concept is that not all patients will have circulating tumor cells and even some patients that have them will not recur. It doesn't absolutely mean they will recur. It's likely again another kind of prognostic marker that gives you a better idea who's at risk and who is not. And I think that's the next difficult step is to figure out which patients really are going to have a recurrence and even to take that further: which cells are the ones that can really take hold and grow a metastasis and which ones will just die in the circulation and be you know either attacked by the immune system or don't make it? And that's something we don't know yet.
Lisa Garvin: And as far as circulating tumor cells, is it a blood test that confirms their presence?
Dr. Isabelle Bedrosian: Yeah, it is a blood test but this is not a standard assay so you couldn't just go to a lab and say, "Run me my circulating tumor cells." This is a pretty specialized research type of assay at this point and time. And it's really just done in the research setting. It's -- in the non-metastatic patients which is again what this study focused on, you can't just simply go and get this test done as routine practice. You know, I think this study just helps us learn more about biologically what's going on. And a lot of the women who had circulating tumor cells actually had lymph node negative disease. So now we have the opportunity to say, "Okay, we are able to take women who we think are at low risk, but further stratify the risk and identify the subset among them who have circulating tumor cells and are at increased risk compared to their compatriots in the study who had negative nodes and negative circulating tumor cells." But I think just Dr. Lucci said, that's not the end of the game. I mean it just is one more piece of information, one more refinement that will help us perhaps guide treatments down the road. But I think the other opportunity here with circulating tumor cells is to use them as a way to study biology. And I think there's efforts underway to look at these circulating tumor cells, look at the biology of the cells, what's going on in these cells, what are the markers of these cells that we might be able to target for treatment. So a lot of biology and target therapy may also come out of this type of research.
Lisa Garvin: And how do you work this into your clinical practice? I mean theoretically how would you test for ctcs and when would you do that?
Dr. Anthony Lucci: So that's really the big question and I think the answer is it's -- you know, I don't really think it's quite ready for the clinic use in all patients just yet. I know that sounds a little bit strange but I think the problem is, is that we know that the cells now - based on this data - are important. And you can find them and their significant but what we don't know is what to do clinically. In other words, how do we change treatment or add treatment or will that make a difference? That's the question we just don't know. So I think one of the problems -- actually a problem with a study like this is that then people say, "Why don't I have that blood test?" And the problem with that is that we may be able to do the blood test and provide information but we don't really know what to do with it yet. And I think that's the next step in all of this is how do we more forward and figure out who will benefit and who will not? And I think probably the best way to look at this is you take patients like estrogen receptor positive lymph node negative patients who traditionally are at a lower risk for recurrence and who may or may not benefit from chemotherapy. They may be able to simply take endocrine therapy and that's enough. We don't really know and I think tests like the Oncotype test which has been a useful tool and that group of patients can tell you, "Look this person would benefit from chemotherapy. This person may not." So what I think this study does is open up the window for bigger, larger multi center studies where you could power it to look at subsets and say, "What if we look at this low risk group? Will the cells help us decide if therapy is useful or going to be a benefit in this group?" And I think that's what it does is open up the window for that. It doesn't answer that question yet so I think that's the whole problem with a study like this is "Gosh, does everybody get the test?" And I would say, "No, I don't think it's ready for that." It's going to really require patience I think.
Lisa Garvin: What do you think this says about the future of the sentinel node lymph biopsy? I mean is that still a very efficient tool or perhaps maybe this -- a CTC test might replace a sentinel lymph node biopsy?
Dr. Anthony Lucci: No, I think sentinel node is a totally separate really concept. Sentinel node is excellent for staging the axilla and in many cases it actually provides local control because in many patients the sentinel node is the only positive node. So often times just by removing that node, you've provided local control for the axilla. I think the way these are intertwined these studies is that recently a large study has been completed by Acasod [phonetic] which showed that if you have patients with limited nodal disease, you don't always have to take out the rest of the lymph nodes. Their recurrence rate and their survival may not be much different. So in an era where we're starting to do less surgery and take out fewer - you know - lymph nodes, a test like this might be helpful to provide additional information, especially since in our study the ctcs didn't correlate with lymph nodes. So they may actually be complementary forms of information.
Lisa Garvin: And it sounds like that this may have applications to other cancers: specifically colorectal and prostate cancers.
Dr. Anthony Lucci: So the test -- the system we use - the Veridex cell search system is the one that we used for this study and it is approved for metastatic prostate and colorectal cancer. The problem is, is again I think -- I don't really know that we have enough data in any cancer system to say how it can be used in the clinic yet. I think that's the next step in all of these. I will tell you also here at M.D. Anderson we're looking at it in melanoma as well. We have a study in that as well because we feel that may be another group that could benefit from this information. And I think Dr. Bedrosian brought up a great point earlier that I would like to go back to about that really what this does is open up the window for biology and maybe thinking about, "Are there ways to even use the information from these cells to treat or target your therapy?" And I would just point out at ASCO this year we're presenting data to show that you can actually capture these cells and look at for instance HER-2 on the cells in the bloodstream. And in some patients you can find HER-2 amplified cells even when the primary tumor was negative. So I'm not saying every person should go and get - you know - Herceptin but I think it's an interesting idea that you could maybe look at find different markers than the primary tumor.
Lisa Garvin: And would this also help you understand more about circulating tumor cells in and of themselves? Why some tumors throw off cells and why some don't? Or is that too big of a...
Dr. Isabelle Bedrosian: Yeah that's -- I think that's a very large and broad question. I think that this work sets the ground to investigate whether or not additional treatment of women that have ctcs is going to make a difference. So you know, again I think Dr. Lucci brought this up, we're not doing this test as standard of care because we have not answered whether or not identifying ctcs -- we know that they're not good prognosis, but we also don't know that treating these women with more aggressive chemo for example is going to change anything. So I think the first step is to demonstrate, "Yes, you have a bad prognosis but if we give you treatment, we can improve that prognosis." We have to demonstrate that I think before we can come full circle and say, "It's important to test you for ctcs because there's something we can do about it to change what's ultimately going to happen." And I think the second thing that this sort of study sets the stage for is again trying to identify what is different about the circulating tumor cells compared to the primary tumor. Tumors evolve in their biology as they go from early stage to [inaudible] metastasis to distant metastasis. And there's going to be differences between the primary tumor and then the disease that's outside of the breast in the lymph nodes. And for a long time we've always tried -- we've struggled because we've tried to explain everything that goes on with a tumor based on the biopsy that was done on the tumor in the breast. And that's been a limited approach because again tumors evolve and change constantly. So being able to access tumor at a site away from the breast to help learn about what is driving the tumor now in the bloodstream is going to be I think important to help us develop more smart treatments and hopefully more effective treatments as well.
Lisa Garvin: And Dr. Lucci, was this a Phase 2 or a Phase 3 trial?
Dr. Anthony Lucci: No, there was no comparison with any you know drug or anything to determine if it was more [inaudible]. I think -- you know, before I forget I want to go back to something that Dr. Bedrosian said which is you know, this idea of finding these cells, this is like the first step. And I think the next idea is, "What do you do with them?" And I just want to again go back to the point: I think it's not a standard of care test yet. And I just would hope that you know, it's hard because we know we can find the information but what do we do with it? And I would just hate for you know -- it's difficult because now people may say, "But I want that test." I think what we need to do is see, "Does adding therapies or changing or do different therapies get rid of them?" And I would just throw in a little bit of information that's not in this study but we also have collected samples from patients who have completed their chemotherapy and indeed you can find cells in a significant number of people: even after their chemotherapy. And we've done a kind of a concomitant study looking at disseminated tumor cells in the bone marrow. And we actually have published a study showing that if the cells are still present after chemotherapy, it predicts a worse outcome: significantly worse outcome. And that's been shown from Europe as well. So I think there's evidence already to show that maybe chemotherapy or some chemotherapies don't always get rid of these cells. And so we may have to think of a different approach. And she brought that point up and I didn't want it to go by simply because I think that's a really important point. People may say, "But if I have these, maybe I need more additional chemotherapy." But we don't know if that's the right thing to do. We don't know.
Dr. Isabelle Bedrosian: Yeah, I think we need to develop clinical trials not based on this study to take these women and put them in trials of additional therapies: hopefully targeted therapies if we can identify appropriate targets in the ctcs versus women who don't get this therapy. So a true randomized clinical trial and only with that type of study can we say, "You have the ctcs. These are the drugs that we need to give you that will make a difference. It will work. It will help improve your prognosis." But short of that I think it would be irresponsible for us to just order ctcs on everybody and not be able to do much with that information.
Lisa Garvin: And even though we may be a few years away from the clinic, this is kind of exciting news because really recurrence is kind of a mystery more or less. I mean we can't really say, "You're going to recur. You're not going to recur. You're going to recur as distant metastases, blah blah blah." So this is a step in the right direction at least in that realm.
Dr. Anthony Lucci: Well absolutely. I think the important point of all of this is that we just didn't have enough information in the non-metastatic setting to say whether or not these cells were really important. And I think this is one of the largest and one of the first studies to say, "Yes, you can find them and yes they are." And so it just opens up a whole new area. Really the hard part about this is you would love to have such a test that you knew what to do with it. And I think the problem is we're just not at the stage where we know what to do with the results. Even if we find them, we could give the information but then do we change the therapy? Do we add therapy? We just don't know. And I think that's the hard part.
Dr. Isabelle Bedrosian: I think this is very exciting information. I think it really opens a door to exploring a lot of avenues in the area of breast cancer recurrence and hopefully exploiting some of the information that we get along the way as well. You know? So we now have an opportunity to refine our ability to identify women who are at increased risk of occurrence and hopefully we will design the clinical trials that exploit targeted pathways for example that might help you know, improve the outcomes that we know are more concerning in these group of women. So again, I think an avenue to explore and hopefully exploit the biology of these ctcs and hopefully improve patient related outcomes.
Lisa Garvin: Well and it's an exciting first step and your work is cut out for you for the next few years. Thank you both for being with us today. If you have questions about anything you've heard today on Cancer Newsline, contact Ask M.D. Anderson at 1-877-mda-6789 or online at www.mdanderson.org/ask. Thank you for listening to this episode of Cancer Newsline. Tune in for the next podcast in our series.
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