Synopsis: Cancer biopsies traditionally require surgery to remove a piece of tumor. But doctors are increasingly able to find evidence of cancer in the blood, eliminating the need for surgery. Researchers hope to eventually be able to use these liquid biopsies for cancer screening and early diagnosis. Experts discuss.

Host: Reed Pence. Guests: Dr. Nicholas Papadopoulos, Professor of Oncology, Johns Hopkins University; Dr. Scott Kopetz, Associate Professor of Medical Oncology, University of Texas MD Anderson Cancer Center; Dr. Terry Friedlander, Assistant Clinical Professor of Medicine, University of California at San Francisco

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Liquid Biopsies

REED PENCE: Most of us are familiar with how a cancer biopsy works. Traditionally, it requires surgical removal of a piece of a tumor so pathologists can look at it under the microscope to determine if it’s cancer.

NICHOLAS PAPADOPOULOS: We take a piece of the cancer, and then we examine it. In the older days, they were looking at the structure of the cells, and trying to determine how advanced the cancer was, or if it was a cancer at all. Nowadays, also, we analyze the DNA of the cancer and other molecules.

PENCE: But Dr. Nicholas Papadopoulos, Professor of Oncology at Johns Hopkins University, says new tests hold the promise of eliminating surgery to find out if a patient has cancer, or if his cancer has recurred. Those tests, called liquid biopsies, look at the blood instead…because the blood contains plenty of evidence when cancer is present somewhere in the body.

PAPADOPOULOS: There are both cells from the cancer, those are called “circulating cancer cells,” and there is naked, as we call it, DNA, or small pieces of DNA that they derived from cancer cells, and that are floating in the bloodstream of an individual. Also, there are pieces of cells, so there are all sorts of different, as I call them, “materials” or “products” of cancer cells that are present in the bloodstream.

SCOTT KOPETZ: There’s two types of analyses that are typically done. One is looking for small, intact, circulating tumor cells in the blood, and the other is to actually look at fragments of the DNA that come from the cancer cells.

PENCE: That’s Dr. Scott Kopetz, Associate Professor of Medical Oncology at the MD Anderson Cancer Center in Houston.

KOPETZ: Both of these methodologies require, really, “needle in a haystack” precision, the ability to pick out very small cells or small fragments of DNA from the total circulating population that’s from the normal healthy tissues of the body. This has really, only been possible in recent years as these technologies have been developed. There are methodologies now that can use next generation sequencing, very rapid, precise methodologies that can be applied to really pick out that “needle in the haystack”, pick out that one or two fragments of DNA that are from the tumor in a tube or two of blood.

PAPADOPOULOS: So how do we know that one molecule is from a cancer cell and one molecule is not? Because they have some of the core mutations that are specific to cancer. That’s one of the markers, actually, that we use. So, there are specific changes that are present only in cancer cells. And that is when we analyze the DNA or other markers in the blood. when those changes are present in that sample, then that tells us that they came from the tumor.

PENCE: However, some of those mutations are shared between many kinds of cancer. One specific mutation is present in about half of all cancers. So, Papadopoulos says if a liquid biopsy flags one of those, the search is on.

PAPADOPOULOS: Once you see a mutation in the gene, if it’s not specific only to one type of cancer, then that just tells us that it is cancer, but it doesn’t tell us where the cancer is. So, it will require some follow up. You may require to follow up that with other tests, including, potentially having a body CT scan or whatever clues the mutation is going to give. For example, there are some mutations that can be cancer of the colon or of the stomach, so you can focus, potentially, in those areas.

PENCE: That’s one reason why the biggest use of liquid biopsies so far has been in patients who’ve already been treated for cancer. Doctors already know where the cancer might be, but they need to know quickly when it’s coming back.

PAPADOPOULOS: Monitoring how the treatment of the patient is working, that’s the first thing that, actually, this technology is being used, as we speak. In other words, to make it a little bit more specific, let’s say that the person has some lung cancer and we know that they have some mutation in this cancer. We treat him with the appropriate drug, and then every few months you can check the blood to see if this mutation is present. What happens initially usually goes away. That indicates that the person has responded to the therapy and the tumor cells are going away. And then you usually see if the tumor is going to come back.

PENCE: Liquid biopsies have already shown success at this: predicting the recurrence of cancer in patients who’d had colon cancer surgery. Another promising use of liquid biopsies is in selecting medications in cancer patients, according to Dr. Terry Friedlander, Assistant Clinical Professor of Medicine at the University of California at San Francisco.

TERRY FRIEDLANDER: Currently when we treat people with cancer, we tend to use a “one size fits all” approach. We have, maybe, one or two drugs we use in the first line. If those fail, we’d go to a second line regimen or third line regimen. But, there’s not really tailoring of our treatment to an individual patient at the individual patient level. And the reason we don’t do that is because we don’t know, in most people, what the specific mutations or genetic changes are in that person’s cancer that would make them sensitive or resistant to a specific drug. So, understanding more about the individual person’s cancer can help us pick which agent is going to best work for that patient.

PENCE: Studies are beginning to support using liquid biopsies to veto some therapies. For example, a recent study in the New England Journal of Medicine on prostate cancer.

FRIEDLANDER: They used circulating tumor cell. They look for a specific genetic mutation in circulating tumor cell that told the clinician that the patient was going to be resistant to hormone therapy. And if these patients had that mutation and they got hormone therapy, it didn’t work. And that was exciting for researching for the clinic because it really says that we can start identifying patients who are appropriate for certain therapies, or who are not appropriate for certain therapies. And then we can really start tailoring our treatment to an individual patient’s cancer instead of using this “one size fits all” approach.

PENCE: Doctors can also monitor recurrent cancer very closely. Surgery for a tissue biopsy isn’t something that can reasonably be done once a week, but doctors can perform a liquid biopsy as often as they’d like. Kopetz says they’ve also found other pluses that tissue biopsies don’t have.

KOPETZ: There are advantages to, also, getting a complete picture of all of the different areas in the body, which we can get with the liquid biopsy. We do know in some settings that there are important differences in the behavior of the cancer at different sites. It’s what we call “tumor heterogeneity,” the idea that not all the cancer is behaving similarly. When we take a biopsy, we’re getting just one piece of the tissue and it doesn’t always reflect the entirety of the cancer.

FRIEDLANDER: We sort of think of tissue as the gold standard for understanding what’s going on in a tumor. So, somebody has colon cancer that metastasizes to the liver, we get a biopsy of that liver in the tumor then we’re able to see genetic tests on that, and we’re very confident that what we see in those tests are essentially, really what’s going on in the cancer. There’ve been a few studies recently that show that cancer is not homogenous, that different tumors in different sites in the body will have different mutations. And it’s almost like a tree, an evolutionary tree, where there’s some common mutations that all the cancer cells share, but as they start to branch out to different parts of the body, you can start to see different mutations in each branch and then within each smaller branch and etc.

PENCE: However, it’s in cancer screening that many doctors think liquid biopsies will eventually make a major difference. Some cancers, such as ovarian and pancreatic cancer, are almost never detected until their often-fatal later stages. Liquid biopsies could change that. However, reliability would have to be proven, and without more specific markers, doctors might have to go on a search to find where the cancer is in the body.

FRIEDLANDER: The challenge with using this technology for screening is that you can’t always be sure that when you find something that it’s truly there. And that’s a problem called a “false positive,” so you can imagine that if somebody who is feeling healthy and who went to their doctor for a checkup had this test and the test was considered positive, that patient would then have to undergo CT scans, or maybe MRIs to look for the cancer. It’s not clear that you’re always going to be able to find that cancer. If the cancer is very early it may be very hard to locate that cancer, so you sort of raise the spectrum of patients getting lots of radiologic tests, maybe lots of biopsies, that aren’t necessary. That said, you can imagine that catching the cancer early is better than waiting for it to appear.

PENCE: It’s possible, then, that the tests might be too sensitive. Kopetz says some early tumors that would never be a threat could light up the results.

KOPETZ: Early cancers, or even pre-cancerous lesions, do secrete some of these circulating markers that can be detected, although, they are at lower levels. So, the technology is not quite ready to have this move forward into the clinic immediately, but I think that we’re getting closer, and it may be the very near future that some of these technologies become available. There’s a concern as our sensitivity increases, with any screening task, that we’re making sure that the cancers we’re detecting are really clinically relevant cancers, meaning these are cancers that would cause problems had we not detected them.

PENCE: However, it’s likely that those hurdles will be overcome. Eventually, liquid biopsies will likely become standard tests. But now, they’re extremely new, and doctors aren’t sure where or when they’ll reach their potential.

KOPETZ: It is a completely new mode of testing. It provides a new snapshot into the complexities of cancer that we have not been able to incorporate before. Some of the biggest advances in the liquid biopsies are using them immediately to assess response of chemotherapy, success of surgeries. And these are all being done in the research setting, but the results have been very promising, and we are seeing this as a new frontier, a new avenue for interrogating the behavior of cancer. The potential to repeatedly assess the state of the cancer many times over the course of the patient’s disease is a remarkable insight that clinicians have not had before.

PENCE: You can find out more about all our guests on our website, You can also find archives of our shows there, as well as on iTunes and Stitcher. I’m Reed Pence.


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