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Molecular Testing in 2019 for mCRC

Panelists: John Marshall, MD, Georgetown University; Cathy Eng, MD, Vanderbilt University; Tanios Bekaii-Saab, MD, Mayo Clinic; Dustin Deming, MD, University of Wisconsin; Michael Morse, MD, Duke Cancer Institute
Published: Wednesday, Jul 24, 2019



Transcript: 

John Marshall, MD: I want to shift our attention now to more advanced disease. Mike, I’m going to give you the lead on this. We mentioned already this idea that precision medicine is here to stay, and molecular profiling is appropriate. Tell us, in your stage IV colon cancer patients, what your strategy is, what you have to know, and what you like to know.

Michael Morse, MD: It’s clear that, at a minimum, we need to know KRAS, NRAS, BRAF mutational status and MSI [microsatellite instability]. If we could just get all patients to have that done, I think that would be very important, because clearly, it’s not done. We see people still come in who have had some KRAS testing and may not have had NRAS. BRAF is done occasionally. Maybe that will change with actual data for therapeutic options for those people. There are a lot of other mutations that could be present, but we’re not really acting on those in the first-line. We may subsequently. You could argue that alone is adequate, and that looking for the others later on is.....

John Marshall, MD: Your practice is to do that smaller panel first, and then maybe consider broader panels later?

Michael Morse, MD: Yes. A lot of this runs into the research agenda, where we have a lot of interest in circulating tumor DNA, and so on. People are getting analyzed for a larger panel, often. I would say the general practice for a patient who is not involved in research would just be that limited panel.

John Marshall, MD: I want to make 1 basic comment, which is that if I see a breast cancer patient, the first line of the HPI [history of the present illness] says, “Such-and-such year-old, ER [estrogen receptor], PR [progesterone receptor], HER2 [human epidermal growth factor receptor 2],” and no fellow would ever present a breast cancer case without starting there. On some level, we all need to do that in our world, where if it’s not in that first line—MSI, RAS, BRAF—that’s obviously missing. It’s not down in the thread. It’s not in some bad fax copy in the EMR [electronic medical record]. It’s right there, and that’s how you start talking about the patient.

Tanios Bekaii-Saab, MD: Let me make the case, though, for adding HER2 to that panel.

Cathy Eng, MD: I completely agree.

Tanios Bekaii-Saab, MD: I want to know that from day 1, along with everything you said, because HER2 will help with 2 things. It will help, certainly, as we understand a little bit more that these HER2-amplified tumors may have less benefit from EGFR [epidermal growth factor receptor] inhibitors, mostly from retrospective analyses. It also scientifically makes sense. HER2 is a driver of resistance to EGFR inhibition, they belong to the same family.

John Marshall, MD: I think a lot of people aren’t really aware of that.

Tanios Bekaii-Saab, MD: No.

John Marshall, MD: They’re starting an EGFR therapy in the absence of knowing about HER2, right?

Tanios Bekaii-Saab, MD: Yes.

John Marshall, MD: You really need to know that.

Tanios Bekaii-Saab, MD: I think you do. It enters into the equation. In fact, it makes your EGFR inhibitor work better, because you’re refining those who don’t, in some ways.

John Marshall, MD: Maybe the same is true for BRAF.

Tanios Bekaii-Saab, MD: Yes.

Cathy Eng, MD: The guidelines just got changed in regard to allowing you to consider utilizing Herceptin for your HER2-positive patient.

Michael Morse, MD: Yet, this is still a research question. There are randomized trials actually addressing this right now.

Cathy Eng, MD: There were impressive European data, and now we’re trying a different approach in the United States.

Tanios Bekaii-Saab, MD: Again, that helps you with planning for your patient for the clinical trial, as well. Rather than wait for 2 or 3 lines of therapy, you skip to second-line with a HER2 combination strategy, hopefully on a clinical trial.

Michael Morse, MD: What percentage of the time have you seen people switch from HER2 non-amplified to amplified after therapy, though?

Tanios Bekaii-Saab, MD: It’s unusual, but it happens.

Cathy Eng, MD: A very small percentage.

Dustin Deming, MD: The Italian data would say it’s up to 20% to 30%, but I think, in reality, it’s closer to 5%, maybe 10%.

Cathy Eng, MD: Absolutely. I think it’s closer to 5%.

Dustin Deming, MD: At least in my population.

John Marshall, MD: We don’t yet have a culture of rebiopsy or reanalysis, right? They do in breast cancer; they do in lung cancer. Should we, Mike?

Michael Morse, MD: Sorry to keep harping on circulating tumor DNA, but it’s certainly an interest of ours. That offers you the opportunity to rebiopsy, in effect. I agree with you. To put somebody through an additional liver biopsy is not desirable for many people. Maybe it’s not sound for us oncologists to recommend it to people, but we do know that there can be changes, particularly people treated with anti-EGFR therapy. Unusual mutations can arise—the rare RAS mutation in a subclonal fashion that didn’t exist before the therapy, binding site mutations in EGFR that can take months to resolve even after you stop the anti-EGFR therapy.

John Marshall, MD: With our targeted therapy, I’m seeing more mixed responses where a lot of the disease is under control, but 1 lesion is growing, and I’m tempted to biopsy that lesion to see if there.....

Dustin Deming, MD: Radiate it.

John Marshall, MD: And radiate it, right? Keep your systemic therapy going. Play whack-a-mole.

Cathy Eng, MD: I agree.

John Marshall, MD: Everybody in on that?

Tanios Bekaii-Saab, MD: I think that’s an important aspect of what we do. When we’re thinking about a biopsy versus a liquid biopsy, if there’s only 1 tumor that’s acting badly, that would be a good target. If the patient has 10 lesions and they’re all acting badly, which one do you biopsy? This is where, actually, I would favor the liquid biopsy piece.

John Marshall, MD: Tony, when are you doing your analysis? Is this right from the beginning? Are you starting, then waiting, and then getting another?

Tanios Bekaii-Saab, MD: The moment I’m meeting the patient, I want everything. That doesn’t mean I would recommend that to be done on a wide basis for every patient in the community. I’d say, get at least the ones we’ve already discussed—the RAS, RAF, MSI and HER2, maybe even the NTRK fusion, as well, so you’re informed if you ever find it.

John Marshall, MD: Big institutions do their own assays, right?

Michael Morse, MD: We have it available, but we send a lot out.

John Marshall, MD: Are you basically partnering with somebody when you do this? Are you doing broad profiling?

Cathy Eng, MD: At The University of Texas MD Anderson Cancer Center, we were doing it ourselves, but I know at other institutions, they are sending it out.

Tanios Bekaii-Saab, MD: We have our own, but we send it, and one of the primary reasons is challenges with reimbursement issues. Our own costs quite a bit of money. We’re trying to figure out a way to cut it down for the patient. The companies that are doing it, before we ever even thought about it, have become quite privy to how to deal with the reimbursement issues. That actually is one of the limiting factors of not running with just our own.

John Marshall, MD: Yes, we’ve got 3 main tissue-based companies that are out there. We’ve got 1 major liquid biopsy, but there are others.

Tanios Bekaii-Saab, MD: There are others.

John Marshall, MD: You have strategic partnerships. They’re not all created equally. They’re different. They do different things, and it changes day to day.

Transcript Edited for Clarity

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Transcript: 

John Marshall, MD: I want to shift our attention now to more advanced disease. Mike, I’m going to give you the lead on this. We mentioned already this idea that precision medicine is here to stay, and molecular profiling is appropriate. Tell us, in your stage IV colon cancer patients, what your strategy is, what you have to know, and what you like to know.

Michael Morse, MD: It’s clear that, at a minimum, we need to know KRAS, NRAS, BRAF mutational status and MSI [microsatellite instability]. If we could just get all patients to have that done, I think that would be very important, because clearly, it’s not done. We see people still come in who have had some KRAS testing and may not have had NRAS. BRAF is done occasionally. Maybe that will change with actual data for therapeutic options for those people. There are a lot of other mutations that could be present, but we’re not really acting on those in the first-line. We may subsequently. You could argue that alone is adequate, and that looking for the others later on is.....

John Marshall, MD: Your practice is to do that smaller panel first, and then maybe consider broader panels later?

Michael Morse, MD: Yes. A lot of this runs into the research agenda, where we have a lot of interest in circulating tumor DNA, and so on. People are getting analyzed for a larger panel, often. I would say the general practice for a patient who is not involved in research would just be that limited panel.

John Marshall, MD: I want to make 1 basic comment, which is that if I see a breast cancer patient, the first line of the HPI [history of the present illness] says, “Such-and-such year-old, ER [estrogen receptor], PR [progesterone receptor], HER2 [human epidermal growth factor receptor 2],” and no fellow would ever present a breast cancer case without starting there. On some level, we all need to do that in our world, where if it’s not in that first line—MSI, RAS, BRAF—that’s obviously missing. It’s not down in the thread. It’s not in some bad fax copy in the EMR [electronic medical record]. It’s right there, and that’s how you start talking about the patient.

Tanios Bekaii-Saab, MD: Let me make the case, though, for adding HER2 to that panel.

Cathy Eng, MD: I completely agree.

Tanios Bekaii-Saab, MD: I want to know that from day 1, along with everything you said, because HER2 will help with 2 things. It will help, certainly, as we understand a little bit more that these HER2-amplified tumors may have less benefit from EGFR [epidermal growth factor receptor] inhibitors, mostly from retrospective analyses. It also scientifically makes sense. HER2 is a driver of resistance to EGFR inhibition, they belong to the same family.

John Marshall, MD: I think a lot of people aren’t really aware of that.

Tanios Bekaii-Saab, MD: No.

John Marshall, MD: They’re starting an EGFR therapy in the absence of knowing about HER2, right?

Tanios Bekaii-Saab, MD: Yes.

John Marshall, MD: You really need to know that.

Tanios Bekaii-Saab, MD: I think you do. It enters into the equation. In fact, it makes your EGFR inhibitor work better, because you’re refining those who don’t, in some ways.

John Marshall, MD: Maybe the same is true for BRAF.

Tanios Bekaii-Saab, MD: Yes.

Cathy Eng, MD: The guidelines just got changed in regard to allowing you to consider utilizing Herceptin for your HER2-positive patient.

Michael Morse, MD: Yet, this is still a research question. There are randomized trials actually addressing this right now.

Cathy Eng, MD: There were impressive European data, and now we’re trying a different approach in the United States.

Tanios Bekaii-Saab, MD: Again, that helps you with planning for your patient for the clinical trial, as well. Rather than wait for 2 or 3 lines of therapy, you skip to second-line with a HER2 combination strategy, hopefully on a clinical trial.

Michael Morse, MD: What percentage of the time have you seen people switch from HER2 non-amplified to amplified after therapy, though?

Tanios Bekaii-Saab, MD: It’s unusual, but it happens.

Cathy Eng, MD: A very small percentage.

Dustin Deming, MD: The Italian data would say it’s up to 20% to 30%, but I think, in reality, it’s closer to 5%, maybe 10%.

Cathy Eng, MD: Absolutely. I think it’s closer to 5%.

Dustin Deming, MD: At least in my population.

John Marshall, MD: We don’t yet have a culture of rebiopsy or reanalysis, right? They do in breast cancer; they do in lung cancer. Should we, Mike?

Michael Morse, MD: Sorry to keep harping on circulating tumor DNA, but it’s certainly an interest of ours. That offers you the opportunity to rebiopsy, in effect. I agree with you. To put somebody through an additional liver biopsy is not desirable for many people. Maybe it’s not sound for us oncologists to recommend it to people, but we do know that there can be changes, particularly people treated with anti-EGFR therapy. Unusual mutations can arise—the rare RAS mutation in a subclonal fashion that didn’t exist before the therapy, binding site mutations in EGFR that can take months to resolve even after you stop the anti-EGFR therapy.

John Marshall, MD: With our targeted therapy, I’m seeing more mixed responses where a lot of the disease is under control, but 1 lesion is growing, and I’m tempted to biopsy that lesion to see if there.....

Dustin Deming, MD: Radiate it.

John Marshall, MD: And radiate it, right? Keep your systemic therapy going. Play whack-a-mole.

Cathy Eng, MD: I agree.

John Marshall, MD: Everybody in on that?

Tanios Bekaii-Saab, MD: I think that’s an important aspect of what we do. When we’re thinking about a biopsy versus a liquid biopsy, if there’s only 1 tumor that’s acting badly, that would be a good target. If the patient has 10 lesions and they’re all acting badly, which one do you biopsy? This is where, actually, I would favor the liquid biopsy piece.

John Marshall, MD: Tony, when are you doing your analysis? Is this right from the beginning? Are you starting, then waiting, and then getting another?

Tanios Bekaii-Saab, MD: The moment I’m meeting the patient, I want everything. That doesn’t mean I would recommend that to be done on a wide basis for every patient in the community. I’d say, get at least the ones we’ve already discussed—the RAS, RAF, MSI and HER2, maybe even the NTRK fusion, as well, so you’re informed if you ever find it.

John Marshall, MD: Big institutions do their own assays, right?

Michael Morse, MD: We have it available, but we send a lot out.

John Marshall, MD: Are you basically partnering with somebody when you do this? Are you doing broad profiling?

Cathy Eng, MD: At The University of Texas MD Anderson Cancer Center, we were doing it ourselves, but I know at other institutions, they are sending it out.

Tanios Bekaii-Saab, MD: We have our own, but we send it, and one of the primary reasons is challenges with reimbursement issues. Our own costs quite a bit of money. We’re trying to figure out a way to cut it down for the patient. The companies that are doing it, before we ever even thought about it, have become quite privy to how to deal with the reimbursement issues. That actually is one of the limiting factors of not running with just our own.

John Marshall, MD: Yes, we’ve got 3 main tissue-based companies that are out there. We’ve got 1 major liquid biopsy, but there are others.

Tanios Bekaii-Saab, MD: There are others.

John Marshall, MD: You have strategic partnerships. They’re not all created equally. They’re different. They do different things, and it changes day to day.

Transcript Edited for Clarity
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