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Chief of Breast Surgery at Cleveland Clinic Cancer Center, Julie Lang, MD, joins the Cancer Advances podcast to discuss liquid biopsies in breast cancer. Listen as Dr. Lang discusses how liquid biopsies have been used in the past and how she using them in a new study, funded in part by VeloSano. The study will use next generation sequencing to detect circulating tumor DNA in the blood samples, and to try to improve upon an existing assay based on biomarkers that may be secreted by different types of tumors, benign and malignant.

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Liquid Biopsy in Breast Cancer

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research in clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm you host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Julie Lang, Chief of Breast Surgery at Cleveland Clinic Cancer Center. She is here today to talk about liquid biopsies and breast cancer. Welcome, Julie.

Julie Lang, MD: Thank you.

Dale Shepard, MD, PhD: Maybe to start, give us a little bit of an idea of your role here at Cleveland Clinic.

Julie Lang, MD: I'm a breast surgeon and I see patients in collaboration with medical oncology, radiation oncology and plastic surgery. And in addition, I lead a research laboratory at the Lerner Research Institute, where we focus on circulating tumor cells and circulating tumor DNA.

Dale Shepard, MD, PhD: Excellent. Well, today we're going to talk about liquid biopsies and breast cancer. So, we have a wide range of people who may be listening in, so let's start basic. What is a liquid biopsy? And tell us a little bit about the background of liquid biopsies.

Julie Lang, MD: Yeah. Liquid biopsies are blood-based tests that look at circulating biomarkers or indicators in a laboratory test of features that might be going on with a cancer. So some examples of liquid biopsies would be circulating tumor DNA, which are fragments of DNA that are shed by primary or metastatic tumors into the blood circulation. And another example of liquid biopsy would be circulating tumor cells, which are whole cells that are shed by tumors into the circulation. There are other examples of liquid biopsies that are perhaps more exploratory. These are things like exosomes and things such as this.

Dale Shepard, MD, PhD: How did you get interested in liquid biopsies? As a surgeon, of course we always think about cutting and solid tissues and things like that. How'd you get interested in liquid biopsies?

Julie Lang, MD: Yeah, that's a great question. So it was an observation that was made many years ago that most breast cancers are systemic very early on. There was a theory by Dr. Bernie Fisher that breast cancers were all systemic at their inception, and so this is how studies came to include combination therapy with surgery, chemotherapy, and radiation therapy, as all these treatments have synergy when given in the right combinations. But if breast cancer is systemic early on, then investigators got interested in the idea of looking in the blood and looking for signs of cancer cells or fragments of cancer DNA in the blood. Indeed, these were able to be found and technologies have been developed that have improved upon the ability to detect this and to use these as measurements or indicators of tumor biology. So, I was part of a laboratory during my training, where we studied circulating tumor cells, and we were doing gene expression profiling, that is looking at the RNA level, to make assessments of tumor biology, and I helped to develop some of these techniques. I've continued in this line of research up until now.

Dale Shepard, MD, PhD: Excellent. So, tell us a little bit of about what are the things you can do with a liquid biopsy you might not be able to do with a core biopsy or a needle biopsy, and how would you maybe use one in a situation where you wouldn't use the other? Can you help us distinguish between the two?

Julie Lang, MD: Yeah, absolutely. So, there are several things that are unique about using liquid biopsies. First, when we think about treating a patient with metastatic breast cancer, the guidelines from the American Society of Clinical Oncology recommend pursuing a tissue biopsy for these patients, but many patients have lesions that may not be amenable to a safe biopsy for their metastatic breast cancer, so it's really very appealing to think about the use of a liquid biopsy to make some decisions for treatments for patients.

I will add that the current standard of care for breast cancer, we're not typically doing lots of these liquid biopsies, as is the case in many other solid tumors. In other areas of oncology, liquid biopsies have really caught on and then are used sometimes to make treatment decisions, but in breast cancer more so, it's driven by the metastatic tumor biology more often than not, and this is because we have lots of options for therapies for breast cancer, and these therapies can often be targeted based on the tumor biopsies, but when disease becomes resistance, so resistance develops, very often patients are not eager to have subsequent tissue biopsies because these are invasive. They might be in organs where there's a chance of bleeding or a chance of causing serious side effects. For example, a biopsy of a lung lesion, you can cause deflation of the lung and other such consequences. And then there are some sites that are truly not very amenable to biopsy. For example, brain lesions, bone lesions can be very problematic. The idea of a liquid biopsy becomes very appealing.
Liquid biopsies can also be used to look at the burden of disease if we're looking at the numbers of cells or the amount of circulated DNA that's present. You can use this as a surrogate for treatment response, and then you can predict the mutational burden that's present in some tumors in order to use this information to make some treatment decisions.

Dale Shepard, MD, PhD: Excellent. Tell me a little bit about the work you're doing to incorporate this into diagnosis and guiding biopsies more on the front end.

Julie Lang, MD: Yeah, so I'm very interested in building a project here at Cleveland Clinic where we look at patients that have abnormal mammograms and look at circulating tumor DNA with a deep sequencing technology to see if we're able to determine which patients with abnormal mammograms may actually have something going on that can't be definitively assessed by the mammogram. So we're working on this in collaboration with industry and just getting started on that effort.

Dale Shepard, MD, PhD: And so I guess the question at hand is someone that has an abnormality on a mammogram, how often does that person necessarily have a biopsy that shows cancers? Is this what we're trying to minimize, the sort of unknown unnecessary procedures?

Julie Lang, MD: Yeah, that's a great point, Dale. So, when a woman is recommended for a tissue biopsy after an abnormal mammogram, only 20% of patients actually have an invasive breast cancer. So the idea is could we make things better by using this liquid biopsy approach to do a very sensitive sequencing where we look for fragments of DNA that might able to lead to diagnosis by showing all the different types of breast cancer that can be screened from this particular approach and be able to improve upon that sensitivity of the mammogram to make a better treatment assessment with the liquid biopsy? For example, should the are be excised? Should the area be followed?

What we would like to do is first develop this liquid biopsy blood test, because the current liquid biopsy technologies that exist from industry, they fall short right now in capturing what we call the heterogeneity of breast cancer. The heterogeneity means there are multiple different subtypes of breast cancer. So there's probably at least 10 different kinds of breast cancer that's present, and we are looking for these different mutations that are present as reflected by the different subtypes of breast cancer. And when focusing on these different mutations that can occur, there's actually quite a large number of possible mutations. And in non-metastatic breast cancer, the incidence of any one type of DNA mutation is less than 10% of the patients with breast cancer, so it really requires looking for very small numbers of these DNA molecules. We're interested in using this high tech approach of deep sequencing to try to improve how we diagnose breast cancer patients with liquid biopsies.

Dale Shepard, MD, PhD: So, do we have any promising results at this point or are we still looking for ideal targets?

Julie Lang, MD: We're still looking for ideal targets right now, but I have an industry collaborator that has developed a prototype of a test, and what we hope to do is to collaborate with them, and to consent patients on a study where we get some tissue biopsies after biopsies were done showing cancer and biopsies are done showing the benign disease, and we can use a statistical modeling technique called bootstrapping. We look at all the possible permutations of benign and malignant findings and the circulating tumor DNA and improve upon an existing liquid biopsy approach in order to arrive at a better test that might be able to be useful in the clinic.

Dale Shepard, MD, PhD: So this is utilizing circulating tumor DNA, not necessarily circulating tumor cells themselves?

Julie Lang, MD: Yes. The project for diagnostics would be with circulating tumor DNA since it's more likely that they would be able to find the mutational heterogeneity with circulating tumor DNA. It turns out with circulating tumor cells that not all cancer patients have detectable circulating tumor cells, and when you do capture the circulating tumor cells, one would have to really do a lot of deep sequencing in that those modalities would be more exploratory than studying this in circulating tumor DNA. There would be analytic problems associated with trying to do that with circulating tumor cells, so circulating tumor DNA, I think, would be preferable to try to do a study in combination with radiology to improve upon diagnostic accuracy.

Dale Shepard, MD, PhD: So that seems pretty promising because it seems like not only in breast, but prostate, some other areas, it seemed like there was a lot of interest in circulating tumor cells themselves and some correlations, but it never really hit clinical practice and seemed a little cumbersome for routine use. So sounds like this might be a good step forward.

Julie Lang, MD: Yeah. Yeah. I think that there's utility for both circulating tumor cells and circulating tumor DNA, but they're tools that require the right question, and so circulating tumor cells, there's currently just one FDA-approved test, and it's a cell search test, and that has been shown to be prognostic. It's a great prognostic biomarker, but it's more limited in terms of being a predictive biomarker or predicting exactly what therapy may benefit patients. I've been part of a study with a different company, Angle Parsortix, and they have an FDA application pending regarding their liquid biopsy technology for circulating tumor cells. This particular technology allows the capture of the circulating tumor cells, and clinicians and pathologists can use this for whatever downstream technique that they wish to do.

So, I think new generations of circulating tumor cell assays are coming before the us FDA, and so it's very exciting and it remains to be seen how disease might be utilized in the clinic. Currently, many clinical trials incorporate circulating tumor DNA because one could focus on a particular genomic event that might be linked to sensitivity to a therapy, and so there's been a lot of promise in that regard and across a domain of different solid tumors.

Dale Shepard, MD, PhD: You were talking about different technologies and platforms and things. Are there any current gaps in technology that are sort of limiting this field or is it really more just a matter of capturing the data, making the correlations and moving forward from that point? Are there technical things we need to overcome to make this a success?

Julie Lang, MD: I think there are still technical challenges. One that comes to mind for me is that not all DNA mutations are expressed. Only about half of DNA mutations are expressed. This is sort of a conundrum in oncology as we try to move toward incorporating genomics, is that we can identify targets. The targets may or may not be a drugable target, and then are these targets clinically actionable and did the clinicians actually act upon them? So I think studies that integrate RNA and DNA in terms of the endpoints will be really useful as we try to see, did that DNA mutation have a bad function that had consequences or not?

I think also for liquid biopsy, it's really a big signal to noise problem. So if you're looking for rare molecules of DNA, then you might be able to find it, or you might not be able to sequence it using the circulating tumor DNA approach. And it could just be because of signal to noise. There also are some instances where there could be false positives. There's something called clonal hematopoiesis, where DNA from background leukocytes could be overrepresented that gives a false positive test result. So while the field is really very exciting, we have to be cautious not to embrace the technologies too early, before they're fully proven.

Dale Shepard, MD, PhD: So certainly biomarkers play a big role in following along and checking for recurrence in some settings and monitoring treatment response, and you mentioned that previously, about maybe monitoring treatment response. Is there a thought that this might play a big role in kind of routine surveillance and even determining when to get imaging, for instance? We talked about maybe correlating who needs a biopsy, but what about correlation with imaging and minimizing procedures on that side?

Julie Lang, MD: Yeah. There's a lot of folks that are interested in this and there have been studies going on, for example, a company called Grail, looking at hand cancer diagnostics and being able to diagnose breast cancer or other malignancies using liquid biopsy. And so these types of approaches work well for some malignancies and don't work as well for others. And so it turns out breast cancer is a very heterogeneous disease. This is where improvements are really needed. So I see this as an opportunity for clinicians and scientists to work together to try to improve upon liquid biopsy approaches. Definitely this is a worthy goal.

Dale Shepard, MD, PhD: So when you think about, this is all very cool science and the potential is great. We always think about how the end users perceive it. If we're proposing that you take a mammogram and you do a test and you go, "Well, you need a biopsy but you don't," do you anticipate there might be some hesitancy on the part of either providers or patients to not just go ahead and get the biopsy?

Julie Lang, MD: Oh, I absolutely do. I think that this will have to be very careful, stepwise, work in progress to be able to show that there's diagnostic accuracy, that we're not forgoing biopsies that may actually show that there's something that requires a treatment. There are other biomarker tests. There are certain protein-based tests that are available. There's sort of Eliza-based technologies and these have as yet caught on. So I think that this has to be done very carefully, controlling for all the different possible types of breast cancer and patients have to be given choices so that if they just wish to pursue a surgical excision instead, that's a very valid approach and would be very reasonable. But other patients, if they're told that maybe they get a mammogram and they're told there's an abnormality and they should be called back to the mammography unit in six months' time for a repeat assessment, it might be compelling to use a liquid biopsy for some of these patients to see, should we take action at this time, rather than waiting a full six months?

Dale Shepard, MD, PhD: So this is certainly an interesting area. What would you say is your greatest frustration with the field and what do you think is the greatest hope?

Julie Lang, MD: My greatest frustration for the field is that liquid biopsy has really been around for quite some time, and although there's lots of great technologies, very few of them are applicable for use in the clinic. So I would like to see future studies be very translational, where they're asking clinically relevant questions that are important to address things, problems that we're actually facing in the clinic on a day-to-day basis, rather than studying the wings of the butterfly in order to make a better mouse trap for circulating tumor cells or circulating tumor DNA. So the actionability of this, I think will be easier to parse out when the study design is well designed. And then, I think the great hope for this would be that we might be able to improve on the lives of some patients by not overtreating and not undertreating patients and being able to deliver precision oncology treatments based on getting high-quality information from a blood test rather than an invasive procedure.

Dale Shepard, MD, PhD: Well, Julie, I appreciate your insight. It sounds like this really is something that can be a game changer in how we treat patients. I appreciate you being with us today.

Julie Lang, MD: Thanks so much, Dale. I've enjoyed it.

Dale Shepard, MD, PhD: To make a direct online referral to Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled.

This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud or wherever you listen to podcasts. And don't forget, you can access real-time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.

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