Liquid Biopsies in Lung Cancer

Benjamin P. Levy, MD

Today we are speaking with Benjamin P. Levy, MD, assistant professor of medicine, hematology, and medical oncology at the Icahn School of Medicine at Mount Sinai in New York, where Dr. Levy is medical director of thoracic medical oncology. Dr. Levy spoke at the New York Lung Cancer Symposium last month on how to use liquid biopsies to make treatment decisions for lung cancer patients.

  -Interviewed by Anna Azvolinsky 

Cancer Network: So, first, Dr. Levy, could you define what a liquid biopsy is? How does this assay work?

Dr. Levy: Liquid biopsies are potentially a new way to perform genetic interrogation on patients with advanced-stage lung cancer. I think we know that the gold standard currently for diagnosing and for molecular interrogation for lung cancer patients is with tissue biopsies obtained surgically or by fine-needle aspiration or core biopsies. But these procedures for tissue acquisition have many challenges and hurdles, and that dovetails nicely into the integration of liquid biopsies for lung cancer. Liquid biopsies are minimally invasive blood tests that can capture information from the blood-circulating tumor DNA or cell-free DNA, which is DNA that is shed from the tumor as a product of apoptosis and necrosis, which we know are two processes very relevant in cancer growth and progression. Many of these platforms are able to isolate cell-free DNA, and then perform the analysis, and you can pick up genetic alterations and rearrangements the same way that you can pick them up in tissue-so EGFR mutations or T790M mutations-and with more current technologies you can pick up other mutations and do a full panel.

There are different platforms out there that exist for liquid biopsies, and there is a new platform being developed almost every week. Perhaps the most common platforms being exploited in research and used in the clinic are droplet polymerase chain reaction (PCR) and next-generation sequencing platforms. There are multiple platforms out there that incorporate these types of technologies. I think we also have to keep in mind that there is also now an approved liquid biopsy test for both EGFR mutations and T790M mutations-the COBAS test, which is a PCR test. So the bottom line is they’re a minimally invasive way to not only diagnose lung cancer, but to perform molecular interrogation of advanced-stage lung cancer patients, which is going to, I think, change the diagnostic algorithm and paradigm for our patients moving forward.

Cancer Network: How do you see this assay being used for lung cancer patients and how is this different from the way tissue biopsies are used?

Dr. Levy: I think we are still learning how to best use these assays. As they are still being used and evaluated in clinical trials, we are just starting to learn and understand how to use them in clinical practice. The bottom line is, we are taking the same technologies that we use for tissue, and applying them to liquid. The difference is that these platforms are very sensitive and can detect very low levels of circulating tumor DNA in the blood.

I think there are multiple places for lung cancer patients that this may have utility, both for patients who develop resistance to first- or second-generation tyrosine kinase inhibitors (TKIs) and patients with EGFR mutations who go on to have tumor progression. There is a place for plasma or liquid in this space and potentially for treatment-naive patients as well.

I think that it’s important to understand the differences between the utility of what we call plasma genotyping and that of tissue biopsies. Liquid biopsies really don’t share the same challenges as tissue biopsies. I think we know that there are many hurdles and challenges to tissue biopsies-tumor heterogeneity, turn around times for the results, the percentage of patients who will not have enough tissue from their procedure to get the molecular testing done. And for all of those reasons, these types of assays are really moving up the chain quickly to be used in clinical practice.

In the end, the results we are trying to get from liquid biopsies are what we get from tissue biopsies. We are trying to understand the genetic interrogation of the tumor so that we can make really good treatment decisions. There is a lot we still need to learn about these. I think we have fairly good data that the ability to obtain genetic information of a tumor with liquid biopsies or plasma genotyping is fairly reliable. And when you do one of these tests, it’s a fairly accurate molecular proxy of the tumor biology, which is encouraging. Using these tests to make treatment decisions is, I think, how we are going to really implement this technology for our lung cancer patients.

Cancer Network: Are clinicians already using these assays to make treatment decisions? And how do you see liquid biopsies being used in lung cancer in the near future?

Dr. Levy: I think the routine use of these is just starting to happen. And I see really two broad spaces where liquid biopsies are beginning to be used in the clinic. The first space is probably the resistant setting. So patients on an EGFR TKI who have EGFR-mutant lung cancer. Unfortunately, what we know about these therapies is that while they work well at the beginning, progression is universal. And what we now know is that when that progression happens, up to two-thirds of the EGFR-mutant patients will have a second site mutation called T790M. I think plasma genotyping, liquid biopsies kind of made a splash in lung cancer due to their ability to identify T790M. So, the first space that I see this taking hold for lung cancer patients is identifying T790M. In patients who are on a first-generation TKI who experience clinical progression, at that time it’s worthwhile doing a plasma test specifically to identify the T790M mutation.

What we know is that if a patient has a T790M mutation identified in the blood, their chances of responding to a T790M-directed therapy are just as high as if the mutation was identified in the tissue, so if you have T790M mutation in the blood, that is an accurate molecular surrogate and can be used to make treatment decisions. And that is nice, because before the plasma tests were being used routinely patients had to go get another biopsy. So that first space is the resistant setting specifically for EGFR-mutated lung cancer who develop radiographic or clinical progression on a TKI.

The second setting where things are just starting to happen is in the treatment-naive setting-patients who are stage IV who have had a biopsy and maybe that biopsy did not yield the information we needed, or didn’t have enough tissue available to perform all of the molecular testing. This is where I am starting to see plasma genotyping being used more routinely. And we have some preliminary data that these types of tests, in the event where the tissue did not yield enough material for genetic testing, can be supplemental and help drive treatment decisions. The tissue was done and was insufficient, and we can identify genetic alterations in the blood. I have done this in my own practice where the biopsy confirms lung adenocarcinoma, but there is not enough tissue left over to do the relevant genetic testing that we need to do. In this case I will order a liquid biopsy, and many times we have identified relevant genetic alterations that can help drive treatment decisions. I have had two patients where instead of doing a re-biopsy, we interrogated the molecular analysis by doing a blood test and found an EGFR mutation that allowed us to give this patient a TKI. So two broad spaces where this is starting to take hold. In the treatment-naive setting this is not just for EGFR mutations, we are also finding ALK rearrangements in the blood that are relevant. This is so new and evolving so quickly that we’ll have to see how this pans out in the next 6 months to a year.

Cancer Network: Thank you so much for joining us today, Dr. Levy.

Dr. Levy: Thank you so much.