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Clinical Applications for NSCLC Liquid Biopsy

Insights From: Geoffrey R. Oxnard, MD, Harvard Medical School; Sandip Patel, MD, UC San Diego Moores Cancer Center
Published Online: Tuesday, Sep 12, 2017



Transcript:

Sandip Patel, MD: There are a variety of liquid biopsy tests currently available for clinical use in cancer. The first are CTC-based sequencing methods, for which circulating tumor cells are isolated in those specific tumors that are sequenced. There are also next-generation sequencing methods for plasma-based DNA that’s shed by the cancer. These are the cell-free DNA approaches. Depending on the clinical question being asked, there may be strengths and weaknesses in testing for a specific type of liquid biopsy. Traditionally, in my practice at diagnosis, I’m looking for a broad panel to cover all the NCCN recommended genomic aberrations, as well as some others that may be amenable to targeted therapy. And so, for my own clinical use, I tend to use a cell-free DNA panel, often a next-generation sequencing cell-free DNA panel, to get the broadest experience—to capture the broadest number of genes that may be clinically relevant for my patient.

Many of our patients who are diagnosed with a driver mutation for their non–small cell lung cancer—EGFR, ALK, and ROS1, but also other types of driver mutations, such as BRAF, HER2, MET exon 14—can develop resistance to targeted therapies. And, often, that resistance relates to changes that happen in that specific gene. And so, for EGFR, that’s often T790M or sometimes C797S. In the doubly resistant setting for ALK, there are various mutations, including L1196M and others that may confer sensitivity or resistance to a variety of different targeted agents that are currently available. And so, at progression, for a patient’s targeted therapy, we know which specific gene we have to look at. Whether a similar NGS approach or a more specific CTC approach is required depends on the clinical context of the particular patient, but oftentimes we’ll use the same assay that we used at diagnosis to make sure we have consistency in results and to check the preferential changes and percentages in cell-free DNA that could occur over time.

Geoffrey R. Oxnard, MD: The first setting where I send a liquid biopsy is when there’s time pressure. The patient presents who I need EGFR genotyping on, and the tissue is at the pathologist. They aren’t done yet, they’re working on it, but I want an EGFR result today. And so, we have launched at our own center a rapid EGFR test where I can send a piece of specimen of blood and get an answer back in a couple of days that tells me, in a patient who’s shedding, I can find EGFR mutations. In some of my patients, that allows me to start targeted therapy quickly without waiting for the tumor result. In a patient with cancer-related symptoms, in a patient with brain metastases where I’m trying to avoid brain radiation, this is a rapid approach that gets me an answer quickly and gets me to a treatment option.

Here’s a second patient. Their cancer is aggressive; they’re symptomatic. They need treatment today. What do I do to make genomics a backup plan down the line? I send a liquid biopsy panel that’s going to take a few weeks, and perhaps and I start chemotherapy. And a few weeks down the line, I know how they’re doing on chemotherapy. If chemotherapy isn’t working, I’ve got that panel test back to tell me what me what my backup plans are for the second line.

For another patient, they have progressive cancer and tissue is inadequate. I am sending them for radiation for a couple of weeks. I send a panel-based liquid biopsy, and that will get back in time for me to plan systemic therapy. But I’m always thinking about the turnaround time of my diagnostic test that allows me to get a genotype for an un-genotyped patient when tissue is not an option.

The second broad setting where I’m using liquid biopsies is at resistance. We now have a drug, osimertinib, that is only approved for resistance mutation T790M. And if I want to use this drug, I need to figure out, in a patient with an EGFR mutation and resistance, what is the type of resistance they have? I talk about a biopsy, the patient doesn’t want a biopsy, so I try a liquid biopsy first. If the liquid biopsy finds T790M, that allows me to go down the targeted therapy route. If the liquid biopsy is negative, I go back to the patient and I say, “We need that tumor biopsy to get us to an answer and to create targeted therapy options, like osimertinib, as an alternative to chemotherapy.” And so, the 2 main categories for using liquid biopsies are the un-genotyped patient, where you need to find their genotype, or the patient with resistance where you need to figure out the characteristics of their resistance.

Transcript Edited for Clarity 
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Transcript:

Sandip Patel, MD: There are a variety of liquid biopsy tests currently available for clinical use in cancer. The first are CTC-based sequencing methods, for which circulating tumor cells are isolated in those specific tumors that are sequenced. There are also next-generation sequencing methods for plasma-based DNA that’s shed by the cancer. These are the cell-free DNA approaches. Depending on the clinical question being asked, there may be strengths and weaknesses in testing for a specific type of liquid biopsy. Traditionally, in my practice at diagnosis, I’m looking for a broad panel to cover all the NCCN recommended genomic aberrations, as well as some others that may be amenable to targeted therapy. And so, for my own clinical use, I tend to use a cell-free DNA panel, often a next-generation sequencing cell-free DNA panel, to get the broadest experience—to capture the broadest number of genes that may be clinically relevant for my patient.

Many of our patients who are diagnosed with a driver mutation for their non–small cell lung cancer—EGFR, ALK, and ROS1, but also other types of driver mutations, such as BRAF, HER2, MET exon 14—can develop resistance to targeted therapies. And, often, that resistance relates to changes that happen in that specific gene. And so, for EGFR, that’s often T790M or sometimes C797S. In the doubly resistant setting for ALK, there are various mutations, including L1196M and others that may confer sensitivity or resistance to a variety of different targeted agents that are currently available. And so, at progression, for a patient’s targeted therapy, we know which specific gene we have to look at. Whether a similar NGS approach or a more specific CTC approach is required depends on the clinical context of the particular patient, but oftentimes we’ll use the same assay that we used at diagnosis to make sure we have consistency in results and to check the preferential changes and percentages in cell-free DNA that could occur over time.

Geoffrey R. Oxnard, MD: The first setting where I send a liquid biopsy is when there’s time pressure. The patient presents who I need EGFR genotyping on, and the tissue is at the pathologist. They aren’t done yet, they’re working on it, but I want an EGFR result today. And so, we have launched at our own center a rapid EGFR test where I can send a piece of specimen of blood and get an answer back in a couple of days that tells me, in a patient who’s shedding, I can find EGFR mutations. In some of my patients, that allows me to start targeted therapy quickly without waiting for the tumor result. In a patient with cancer-related symptoms, in a patient with brain metastases where I’m trying to avoid brain radiation, this is a rapid approach that gets me an answer quickly and gets me to a treatment option.

Here’s a second patient. Their cancer is aggressive; they’re symptomatic. They need treatment today. What do I do to make genomics a backup plan down the line? I send a liquid biopsy panel that’s going to take a few weeks, and perhaps and I start chemotherapy. And a few weeks down the line, I know how they’re doing on chemotherapy. If chemotherapy isn’t working, I’ve got that panel test back to tell me what me what my backup plans are for the second line.

For another patient, they have progressive cancer and tissue is inadequate. I am sending them for radiation for a couple of weeks. I send a panel-based liquid biopsy, and that will get back in time for me to plan systemic therapy. But I’m always thinking about the turnaround time of my diagnostic test that allows me to get a genotype for an un-genotyped patient when tissue is not an option.

The second broad setting where I’m using liquid biopsies is at resistance. We now have a drug, osimertinib, that is only approved for resistance mutation T790M. And if I want to use this drug, I need to figure out, in a patient with an EGFR mutation and resistance, what is the type of resistance they have? I talk about a biopsy, the patient doesn’t want a biopsy, so I try a liquid biopsy first. If the liquid biopsy finds T790M, that allows me to go down the targeted therapy route. If the liquid biopsy is negative, I go back to the patient and I say, “We need that tumor biopsy to get us to an answer and to create targeted therapy options, like osimertinib, as an alternative to chemotherapy.” And so, the 2 main categories for using liquid biopsies are the un-genotyped patient, where you need to find their genotype, or the patient with resistance where you need to figure out the characteristics of their resistance.

Transcript Edited for Clarity 
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