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An Update on Molecular Testing in Colorectal Cancer

Panelists:John L. Marshall, MD, Georgetown University Hospital;Tanios Bekaii-Saab, MD, Mayo Clinic;Cathy Eng, MD, FACP, MD Anderson Cancer Center;Daniel G. Haller, MD,FACP,FRCP, University of Pennsylvania;Tara E. Seery, MD, UC Irvine
Published: Monday, Jul 11, 2016



Transcript:

John L. Marshall, MD:
Hello, and thank you for joining us today for this OncLive Peer Exchange Panel Discussion on the topic of advanced colorectal cancer. Research and treatment advances have continued to move colorectal cancer treatment closer to a precision-medicine model, and more patients are surviving long enough to require later lines of therapy. Today I’m joined by really fabulous people. Our panel of experts will discuss the role of molecular testing, frontline treatment options, and sequencing decisions that are rapidly altering clinical practice.

My name is Dr. John Marshall. I’m a professor and chief of the Division of Hematology and Oncology at Georgetown University Hospital and the director of the Ruesch Center for the Cure of Gastrointestinal Cancer. I’m joined today by fabulous folks, as I said before. Way on my left is Dr. Tanios Bekaii-Saab, the co-leader for the GI Cancer Program at the Mayo Clinic. Next to him is Dr. Cathy Eng, associate director for the MD Anderson Cancer Center of Houston, Texas. Next on this side, Dr. Daniel Haller, professor of medicine at the Abramson Cancer Center at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia. And next to me is Dr. Tara Seery, who’s [an] associate professor of medicine at UC Irvine Health Chao Family Comprehensive Cancer Center at the University of California in Irvine, Orange County. Thanks everybody for joining us. Thank you, guys, for joining us. Let’s dig in; there’s a lot of ground to cover.

Cathy, I’m going to pick on you first. Nowadays, we are doing molecular testing for almost all kinds of cancer. It seems every year the story changes. What should we be testing today? Give us the update. What’s your standard? What’s the standard at your center for new patient metastatic colon cancer? What are you testing?

Cathy Eng, MD: For every patient that comes through that’s newly diagnosed, we definitely test them for not only KRAS, but extended RAS analysis, including NRAS and HRAS.

John L. Marshall, MD: What if I already have a KRAS in the bank and it’s wild-type? What do I do then?

Cathy Eng, MD: You need to do an extended RAS panel analysis.

John L. Marshall, MD: I’ve got to send it again? What if I have no tissue left?

Cathy Eng, MD: I would definitely do a new biopsy. You’ll identify, at least, an additional 13% to 16% of extended RAS mutations that could impact your treatment, despite being KRAS wild-type.

John L. Marshall, MD: Okay, so I’ve got to do RAS?

Cathy Eng, MD: You’ve got to do RAS. You should also do BRAF because it’s a poor prognostic indicator, and there are good clinical trials for the BRAF patient population. We do test all of our patients for microsatellite instability nowadays.

John L. Marshall, MD: Right from the beginning as a frontline, all patients—85-year-olds and 25-year-olds—you’re going to test MSI (microsatellite instability)?

Cathy Eng, MD: It’s part of our panel.

John L. Marshall, MD: We’ll talk a little bit about why that’s an important part. Does anybody differ? Any other testing that you’re doing routinely, Dan? RAS, BRAF, or MSI?

Daniel G. Haller, MD: We get the same panel as Cathy, and although BRAF doesn’t direct your therapy, it certainly directs prognosis. In my heart and in my head, I have differing ideas about how you impart that to patients, where they’re reading about 33-month median survivals. But that patient with the BRAF mutation probably has a survival of a year or a little bit more.

John L. Marshall, MD: Do you tell them that?

Daniel G. Haller, MD: I actually do share it with them in the best way possible, as we always do with poor prognostic situations. I think it’s fair, and it’s good to tell them that. And it really impacts worrying about fourth-line therapy because they don’t get there.

John L. Marshall, MD: And how are you doing this? Is this your internal panel at your big cancer center?

Cathy Eng, MD: It is our internal panel that we’re running. It actually also includes HER2/neu.

John L. Marshall, MD: Do you use HER2 on everybody right from the beginning?

Cathy Eng, MD: It’s currently part of our up-front panel. But I think that’s really important, because you’re going to see it in a clinical trial.

John L. Marshall, MD: Any role, Tanios, for broader molecular testing other than these key elements that we’ve laid out right now?

Tanios Bekaii-Saab, MD: Other than the ones that were mentioned, I don’t think that there is a need to expand it any further, at least when we’re thinking about our first line or two of treatment. Beyond that, I think it may become relevant, especially when we have more of these targeted trials. But from the get-go, I think RAS, BRAF, and MSI definitely—plus or minus HER2—will probably be your best bet.

John L. Marshall, MD: Any differences at Irvine that might influence practice for others?

Tara E. Seery, MD: No, but there is one thing to remember. If your center’s not doing the extended RAS and you need to send it out, a lot of companies will do that. A lot of them will also check MSI, but it’s a separate test. You have to make sure that you specify that you want that also.

John L. Marshall, MD: Let me pick on you a little bit. Why do I need MSI?

Tara E. Seery, MD: In the past, we used to just do MSI for stage 2 cancers to see if they would benefit from the 5-FU or not. But now, in stage 4, when we realized they’re MSI-high, they’ll benefit from a checkpoint inhibitor. What everyone is talking about are checkpoint inhibitors, and this is the little fraction of the patients that will benefit from it. So, it’s definitely worth checking right now.

John L. Marshall, MD: Everybody, all colon cancer patients stage 1 through 4 are doing MSI? How are you testing MSI?

Cathy Eng, MD: Everybody gets MSI testing by IHC (immunohistochemistry) originally. That captures about 90% of your patient population. And then if we have a high suspicion, we’ll do the additional PCR (polymerase chain reaction) testing.

John L. Marshall, MD: This is so hard and complicated that in our little conference room, we actually have, up on the wall, how to interpret MSI testing because there are four proteins and one’s missing. It’s maybe not a big deal; it depends. Does anybody have a simple solution for MSI interpretation, or does everybody have a little thing on your phone? Do you have it memorized?

Cathy Eng, MD: I look at the report by our pathologist.

Daniel G. Haller, MD: I call Stan Hamilton.

John L. Marshall, MD: Well, that’s right. The pathology report is confusing, too, right?

Cathy Eng, MD: It is very, very complicated.

John L. Marshall, MD: And so everybody thinks they have it, but, in fact, that means the protein’s there and normal, right?

Cathy Eng, MD: Yes, MSI stable.

John L. Marshall, MD: So, you’re MSI stable when it’s in that setting, right?

Daniel G. Haller, MD: I’m an editor at ASCO University. We put molecular oncology tumor boards in place in January of last year for this very reason. Doctors order these tests that come back with multiple results, but they don’t know how they’re done, how they’re interpreted, and which ones are actually actionable. I think with MSI the issue is that it’s actionable. What will the FDA require to actually approve the drugs? Will it turn into breast cancer with a response rate, or is it going to be overall survival?

Transcript Edited for Clarity

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Transcript:

John L. Marshall, MD:
Hello, and thank you for joining us today for this OncLive Peer Exchange Panel Discussion on the topic of advanced colorectal cancer. Research and treatment advances have continued to move colorectal cancer treatment closer to a precision-medicine model, and more patients are surviving long enough to require later lines of therapy. Today I’m joined by really fabulous people. Our panel of experts will discuss the role of molecular testing, frontline treatment options, and sequencing decisions that are rapidly altering clinical practice.

My name is Dr. John Marshall. I’m a professor and chief of the Division of Hematology and Oncology at Georgetown University Hospital and the director of the Ruesch Center for the Cure of Gastrointestinal Cancer. I’m joined today by fabulous folks, as I said before. Way on my left is Dr. Tanios Bekaii-Saab, the co-leader for the GI Cancer Program at the Mayo Clinic. Next to him is Dr. Cathy Eng, associate director for the MD Anderson Cancer Center of Houston, Texas. Next on this side, Dr. Daniel Haller, professor of medicine at the Abramson Cancer Center at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia. And next to me is Dr. Tara Seery, who’s [an] associate professor of medicine at UC Irvine Health Chao Family Comprehensive Cancer Center at the University of California in Irvine, Orange County. Thanks everybody for joining us. Thank you, guys, for joining us. Let’s dig in; there’s a lot of ground to cover.

Cathy, I’m going to pick on you first. Nowadays, we are doing molecular testing for almost all kinds of cancer. It seems every year the story changes. What should we be testing today? Give us the update. What’s your standard? What’s the standard at your center for new patient metastatic colon cancer? What are you testing?

Cathy Eng, MD: For every patient that comes through that’s newly diagnosed, we definitely test them for not only KRAS, but extended RAS analysis, including NRAS and HRAS.

John L. Marshall, MD: What if I already have a KRAS in the bank and it’s wild-type? What do I do then?

Cathy Eng, MD: You need to do an extended RAS panel analysis.

John L. Marshall, MD: I’ve got to send it again? What if I have no tissue left?

Cathy Eng, MD: I would definitely do a new biopsy. You’ll identify, at least, an additional 13% to 16% of extended RAS mutations that could impact your treatment, despite being KRAS wild-type.

John L. Marshall, MD: Okay, so I’ve got to do RAS?

Cathy Eng, MD: You’ve got to do RAS. You should also do BRAF because it’s a poor prognostic indicator, and there are good clinical trials for the BRAF patient population. We do test all of our patients for microsatellite instability nowadays.

John L. Marshall, MD: Right from the beginning as a frontline, all patients—85-year-olds and 25-year-olds—you’re going to test MSI (microsatellite instability)?

Cathy Eng, MD: It’s part of our panel.

John L. Marshall, MD: We’ll talk a little bit about why that’s an important part. Does anybody differ? Any other testing that you’re doing routinely, Dan? RAS, BRAF, or MSI?

Daniel G. Haller, MD: We get the same panel as Cathy, and although BRAF doesn’t direct your therapy, it certainly directs prognosis. In my heart and in my head, I have differing ideas about how you impart that to patients, where they’re reading about 33-month median survivals. But that patient with the BRAF mutation probably has a survival of a year or a little bit more.

John L. Marshall, MD: Do you tell them that?

Daniel G. Haller, MD: I actually do share it with them in the best way possible, as we always do with poor prognostic situations. I think it’s fair, and it’s good to tell them that. And it really impacts worrying about fourth-line therapy because they don’t get there.

John L. Marshall, MD: And how are you doing this? Is this your internal panel at your big cancer center?

Cathy Eng, MD: It is our internal panel that we’re running. It actually also includes HER2/neu.

John L. Marshall, MD: Do you use HER2 on everybody right from the beginning?

Cathy Eng, MD: It’s currently part of our up-front panel. But I think that’s really important, because you’re going to see it in a clinical trial.

John L. Marshall, MD: Any role, Tanios, for broader molecular testing other than these key elements that we’ve laid out right now?

Tanios Bekaii-Saab, MD: Other than the ones that were mentioned, I don’t think that there is a need to expand it any further, at least when we’re thinking about our first line or two of treatment. Beyond that, I think it may become relevant, especially when we have more of these targeted trials. But from the get-go, I think RAS, BRAF, and MSI definitely—plus or minus HER2—will probably be your best bet.

John L. Marshall, MD: Any differences at Irvine that might influence practice for others?

Tara E. Seery, MD: No, but there is one thing to remember. If your center’s not doing the extended RAS and you need to send it out, a lot of companies will do that. A lot of them will also check MSI, but it’s a separate test. You have to make sure that you specify that you want that also.

John L. Marshall, MD: Let me pick on you a little bit. Why do I need MSI?

Tara E. Seery, MD: In the past, we used to just do MSI for stage 2 cancers to see if they would benefit from the 5-FU or not. But now, in stage 4, when we realized they’re MSI-high, they’ll benefit from a checkpoint inhibitor. What everyone is talking about are checkpoint inhibitors, and this is the little fraction of the patients that will benefit from it. So, it’s definitely worth checking right now.

John L. Marshall, MD: Everybody, all colon cancer patients stage 1 through 4 are doing MSI? How are you testing MSI?

Cathy Eng, MD: Everybody gets MSI testing by IHC (immunohistochemistry) originally. That captures about 90% of your patient population. And then if we have a high suspicion, we’ll do the additional PCR (polymerase chain reaction) testing.

John L. Marshall, MD: This is so hard and complicated that in our little conference room, we actually have, up on the wall, how to interpret MSI testing because there are four proteins and one’s missing. It’s maybe not a big deal; it depends. Does anybody have a simple solution for MSI interpretation, or does everybody have a little thing on your phone? Do you have it memorized?

Cathy Eng, MD: I look at the report by our pathologist.

Daniel G. Haller, MD: I call Stan Hamilton.

John L. Marshall, MD: Well, that’s right. The pathology report is confusing, too, right?

Cathy Eng, MD: It is very, very complicated.

John L. Marshall, MD: And so everybody thinks they have it, but, in fact, that means the protein’s there and normal, right?

Cathy Eng, MD: Yes, MSI stable.

John L. Marshall, MD: So, you’re MSI stable when it’s in that setting, right?

Daniel G. Haller, MD: I’m an editor at ASCO University. We put molecular oncology tumor boards in place in January of last year for this very reason. Doctors order these tests that come back with multiple results, but they don’t know how they’re done, how they’re interpreted, and which ones are actually actionable. I think with MSI the issue is that it’s actionable. What will the FDA require to actually approve the drugs? Will it turn into breast cancer with a response rate, or is it going to be overall survival?

Transcript Edited for Clarity
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