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Circulating Tumor DNA Analysis for Liquid Biopsies in Breast Cancer

Circulating Tumor DNA Analysis for Liquid Biopsies in Breast Cancer

Maximilian Diehn, MD, PhD

As part of our coverage of the annual San Antonio Breast Cancer Symposium being held December 8th to December 12th in San Antonio, Texas, we are speaking with Maximilian Diehn, assistant professor of radiation oncology at the Stanford School of Medicine in California and whose laboratory is developing genomics-based biomarkers to identify the presence of cancer cells for prognosis and predicting response to cancer therapies. Dr. Diehn’s talk on circulating tumor DNA analysis from liquid biopsies was on December 8th at the conference.

—Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: First, Dr. Diehn, could you talk about the concept of using patients’ blood samples to potentially diagnose cancer and monitor its development and responses to therapy?

Dr. Diehn: Sure. There is a burgeoning field in the area of what is sometimes called liquid biopsies which is the idea of sampling biological fluid, usually blood in order to access information about the tumor and particularly, molecular information. There are a variety of techniques that can do that. Some that have been studied heavily in the past include things such as protein biomarkers as well as circulating tumor cells where one looks for entire cells. And more recently, and this is what my laboratory focuses on, there has been interest in looking at circulating tumor DNA which refers to pieces of the cancer’s genome, the DNA and chromosomes that are floating in the blood of cancer patients. And these pieces of DNA represent potential biomarkers because one can interrogate them for the presence of mutations that are unique to the cancer and not found in any of the normal cells of the patient’s body, and in that way, circulating tumor DNA can be a very specific biomarker that can tell about the presence of the tumor cells and not of normal cells. Now there is a lot of excitement and ongoing work to develop clinical applications of this approach.

OncoTherapy Network: Where are we now as far as being able to detect circulating tumor DNA in a patient’s blood sample? How sensitive is this technique?

Dr. Diehn: We’ve come a long way in the last few years. So, the presence of circulating tumor DNA in the blood of cancer patients has been known in the field for decades, but only in the last few years have we had assays that are sensitive enough to detect the circulating tumor DNA.

One of the main challenges of circulating tumor DNA analysis is that the amount of DNA is very small. Every human being has some circulating DNA in their blood and for those of us that don’t have cancer, that DNA comes from the normal cells in our body that are dying on any given day. So, there is a small amount of DNA in every patient, but for cancer patients, on top of that normal DNA, there is a tiny amount of the cancer cell DNA and often this is present in much smaller amounts, much less than 1%, and often 0.1% or 0.01% of the DNA and so that presents the challenge that one needs very sensitive methods to detect it. Fortunately, in the last several years, a number of techniques have been developed that either use PCR, the polymerase chain reaction or something called next-generation sequencing, a method that allows very rapid and economical sequencing of DNA molecules.  And these methods allow us to detect circulating tumor DNA at 0.1% or less even for some of the methods. So now, just recently we have developed the techniques that allow us to do the experiments using  patients’ samples to see how low the levels of circulating tumor DNA get in patients who have small tumors or are being treated, and if that has clinical utility.

OncoTherapy Network: How do you envision this approach to be used for breast cancer patients? Are there any specific dynamics of circulating tumor DNA that are unique to breast cancer patients, for example?

Dr. Diehn: I think breast cancer is a great example of a tumor type for which circulating tumor DNA analysis is likely to be very useful. And, it is also an example of how circulating tumor DNA analysis can likely be used for many different kinds of applications.

So, summarizing it starting with patients with the most advanced disease to the patients with earlier stage disease, in patients with very advanced disease, these are generally patients with metastatic breast cancer, the levels of circulating tumor DNA are the highest of all breast cancer patients, so these are the easiest to study. And there, circulating tumor DNA analysis can be used to noninvasively detect what mutations a patient’s tumor has, without the need for surgery or biopsy, something we call noninvasive genotyping, meaning identifying the mutations present in a tumor in a noninvasive fashion. That could be very useful particularly in the setting of patients receiving targeted therapies such as hormonal therapies or some of the newer targeted agents where we know that resistance develops by the tumor acquiring additional mutations that make them no longer respond to the drug. And these mutations can be detected in the blood in a noninvasive fashion.

So, one can envision monitoring patients on such treatments while they are getting the drug to see if a resistance mutation pops up, and if it does, to consider switching therapy and that may have clinical benefits. That is in the most advanced patients. The other thing that one can do either in metastatic or locally advanced disease patients is one can imagine measuring circulating tumor DNA to track a response. So if a patient is getting chemotherapy, then one could draw blood before and during treatment and check the levels of circulating tumor DNA to see if the treatment is working, those levels should be dropping and if the treatment stops working, the levels should start rising. So, this could be a very sensitive and noninvasive way to track the response of a tumor in real time, that one can then envision building clinical trials based on changing therapies based on such biomarkers. And when we look at patients with earlier stage disease, patients who are treated with curative intent who have local disease and get surgery and/or radiotherapy to try to cure them, one potentially very exciting application is the potential detection of minimal residual disease at the completion of treatment.

So, the idea there is that we know a large fraction of breast cancer patients are cured by surgery, but of course, not everyone and some patients ultimately develop recurrence. And it would be great if we could identify the patients who are going to ultimately recur, right at the end of their surgery and right now we cannot, because those patients have no detectable disease on scans. But, if we had a way of detecting the minimal residual disease, then we might be able to identify these patients and there has been recent studies published suggesting that circulating tumor DNA can be used to do that.

So, one would draw blood after surgery and if there is still DNA present, then those patients are at higher risk for recurrence and would be candidates for clinical trials that could try to treat those patients more aggressively to see if we can cure a larger fraction of those patients. And then lastly, and maybe the holy grail of this whole approach, is to try to incorporate circulating tumor DNA into early detection of breast cancer, so for breast cancer screening. So, the idea there would be drawing blood in patients who are healthy and not interrogate those blood samples for the presence of breast cancer related mutations and if one finds those, to perform a work-up of trying to find the lesion and ideally finding it early where it can be cured. And that is the hardest of all the problems because those tumors are the smallest and have the smallest amount of circulating tumor DNA. And so it is unclear whether that will be technologically or biologically feasible, but there are some hints that it could be feasible and that is an area of active research.

So in summary, breast cancer is really an example of a tumor type to which circulating tumor DNA technology could be applied really in all phases of clinical treatment from early detection to the patients with the most advanced tumors, and what we need now are prospective trials that test where these technologies will be most useful.

OncoTherapy Network: Thank you so much for joining us today, Dr. Diehn.

Dr. Diehn: My pleasure.

 

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