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Role of Molecular Testing in CRC Management

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Cathy Eng, MD, FACP, The University of Texas MD Anderson Cancer Center; John L. Marshall, MD, The Ruesch Center for the Cure of GI Cancers ; Michael A. Morse, MD, Duke Cancer Institute; Dale R. Shepard, MD, PhD, FACP, Taussig Cancer Institute, Cleveland Clinic
Published: Tuesday, Mar 20, 2018



Transcript: 

John L. Marshall, MD: Let’s talk a little bit about standard, ordinary, vanilla colon cancer patients who come into the office. And about genetic testing. Michael, what are your thoughts on required gene testing for metastatic colon cancer? What do you want to know?

Michael A. Morse, MD: I think we’d all agree that knowing about RAS, KRAS, and NRAS, and having the extended testing done, is important. I think that most people would agree that it’s worth checking BRAF mutational status as well. And MSI, of course, if it hasn’t been done.

John L. Marshall, MD: So, those are the key things that you’ve got to know, at some point?

Michael A. Morse, MD: I think you need to know those early on. The reality is, if you look, you would find out that your center may not be doing the extended testing. We found out that ours wasn’t doing the extended testing in house. We’re often sending it out anyway. We get these larger panels, as a matter of fact, because we want to know about the RAS status. We find out everything at the same time.

John L. Marshall, MD: I think this is one of the biggest challenges that we have in clinical practice. We all have electronic medical records. The results are coming from different shops. They’re scanned in, and it’s a bad copy. Everybody is reading different things. You find KRAS wild-type, or whatever, you think, “OK, I got it.” But isn’t the answer that you’ve got to check more?

Dale R. Shepard, MD, PhD, FACP: Yes. That happens a lot. There are simple logistical things. Like you said, testing comes in a variety of places. Where do you even find it, in the medical record, sometimes? This is a challenge.

John L. Marshall, MD: Yes. Then interpreting the results and having enough tissue to send out. It’s a really big deal for us, right now. I’m always impressed by how much they can get off of a biopsy from a colonoscopy.

Johanna C. Bendell, MD: They get a good grab, yes.

John L. Marshall, MD: Is anybody saying that this is not representative and that I need to biopsy the metastasis?

Cathy Eng, MD, FACP: I think it’s interesting, if you can, to biopsy the metastasis. Obviously, mutations change over time. Not all of them do, but it can happen.

John L. Marshall, MD: Do I need to though? If I’ve got a brand new diagnosis, I’ve got my sigmoid biopsy, and I’ve got a liver metastasis, can I do the profile on the primary?

Cathy Eng, MD, FACP: I think you can.

John L. Marshall, MD: Is everybody OK with that?

Johanna C. Bendell, MD: Yes.

Michael A. Morse, MD: If you have a small sample and you want to know MSI status, are you satisfied with what most people do—IHC testing? Or do you want to push for PCR testing as well?

John L. Marshall, MD: Our standard is that you start with the IHC. But we’re also doing a lot of these broad panels that give you the IHC. Plus, it comes back as a next-generation kind of analysis. So, it’s basically a fragment analysis. Others?

Johanna C. Bendell, MD: You know, we’ve seen that PCR and IHC, for the most part, are pretty concordant. So, I wouldn’t get a PCR if I’ve gotten an IHC. The next-generation sequencing, still learning how to use it. The sequencing can look at many more microsatellites than PCR can. So, could you get a broader perspective? So far, the word on the street is that next-generation sequencing is about as equivalent and is concordant with PCR. But it’s more convenient, if you’re going to order one of the next-generation panels anyway. Go ahead and get that, as part of it.

John L. Marshall, MD: Other practice patterns up in Cleveland?

Dale R. Shepard, MD, PhD, FACP: We pretty much do the same thing. Most of the time, we have next-generation sequencing that kind of gives you the slew of things that you need to know.

John L. Marshall, MD: For our doctors out there, you get that protein panel back. You get the IHC panel back. “Present, present, present, present.” The patient and everybody thinks, “Oh, they’ve got Lynch syndrome or something,” when, in fact, that’s normal. The language is terrible around this, and it is really confusing. Who gets MSI testing?

Cathy Eng, MD, FACP: Everybody.

Johanna C. Bendell, MD: Yes.

John L. Marshall, MD: Early, right? Even though the indications may be for later, for when therapy would play into that?

Johanna C. Bendell, MD: Yes.

Cathy Eng, MD, FACP: As mentioned earlier by Johanna, you never know if you have that patient in whom you’re detecting Lynch syndrome.

John L. Marshall, MD: Yes, and then finding those patients. Let’s say that the tumor comes back positive. There are a couple of proteins missing. Maybe the patient does not have a family history of cancer? This is a 72-year-old patient who is the first ever in the family to have cancer. What’s next? How do you handle that?

Johanna C. Bendell, MD: We look at BRAF mutational status. We know that if you have a BRAF mutation, this is likely a sporadic mutation. It’s not germline. It’s not Lynch syndrome. If you are BRAF wild-type and have this, then it’s probably Lynch syndrome. Now, one of the big questions that’s come up is, is that enough evidence to say that the patient has Lynch syndrome? Or do you have to send off one of those tests to really confirm it? That’s an area of controversy.

John L. Marshall, MD: Do you germline test, or not, in that patient?

Michael A. Morse, MD: In that patient, we would send them to a hereditary counselor. They would usually get testing. But keep in mind that this is not always paid for by insurance, unfortunately. So, people may bear the cost.

John L. Marshall, MD: This is getting better, but you’re right. They have to fight for it, depending on the insurer. What is the frequency of MSI-high patients in metastatic disease?

Cathy Eng, MD, FACP: It is very low—less than 5%.

John L. Marshall, MD: Yes, so low that we are not expecting it. Some data that we’ve looked at says that the further around the colon you get, the less likely. In rectal cases, it’s less than 1%, for example. The reason that matters to me is, if you don’t have it yet and you needed to get tissue, would it be worth the payout for that very low percentage of finding it? Maybe it’s worth it, maybe it’s not. We can talk about that. Let’s talk about other genes. We’ve talked about RAS. We talked about MSI. Are there other genes that you’d want to know about? Other molecular expression?

Cathy Eng, MD, FACP: You already mentioned BRAF.

John L. Marshall, MD: Why do I care about BRAF?

Johanna C. Bendell, MD: There is a worse prognosis, potentially. There are clinical trials available for those patients.

John L. Marshall, MD: But say that I have a BRAF-mutated tumor. I’m not eligible for the trial. What are you going to do for me?

Johanna C. Bendell, MD: For first-line treatment, there’s some data that suggest that FOLFOXIRI and bevacizumab is the way to go—for these patients with BRAF mutations. If you can’t get into a clinical trial, there’s a lot of debate going on, depending on how your tumor is behaving, as to whether or not you might think about using something off-label, in terms of the targeted therapies. But, it is really about trying to get those patients to study.

John L. Marshall, MD: Scott Kopetz’s data in combination with that BRAF patient is pretty compelling.

Cathy Eng, MD, FACP: Yes, the phase II data is nice. There’s a big phase III trial, though, that’s ongoing—the BEACON study.

John L. Marshall, MD: It’s going to take a while to accrue. So, I think it will be a challenge in today’s environment. Scott’s was very positive. It is kind of the Wild West, too, in getting access to drugs. You call up and they say, “Fine.” It’s really fascinating. How about BRAF studies?

Dale R. Shepard, MD, PhD, FACP: We don’t currently have any, in terms of clinical trials. But we certainly try to get patients to the right place.

Transcript Edited for Clarity 

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Transcript: 

John L. Marshall, MD: Let’s talk a little bit about standard, ordinary, vanilla colon cancer patients who come into the office. And about genetic testing. Michael, what are your thoughts on required gene testing for metastatic colon cancer? What do you want to know?

Michael A. Morse, MD: I think we’d all agree that knowing about RAS, KRAS, and NRAS, and having the extended testing done, is important. I think that most people would agree that it’s worth checking BRAF mutational status as well. And MSI, of course, if it hasn’t been done.

John L. Marshall, MD: So, those are the key things that you’ve got to know, at some point?

Michael A. Morse, MD: I think you need to know those early on. The reality is, if you look, you would find out that your center may not be doing the extended testing. We found out that ours wasn’t doing the extended testing in house. We’re often sending it out anyway. We get these larger panels, as a matter of fact, because we want to know about the RAS status. We find out everything at the same time.

John L. Marshall, MD: I think this is one of the biggest challenges that we have in clinical practice. We all have electronic medical records. The results are coming from different shops. They’re scanned in, and it’s a bad copy. Everybody is reading different things. You find KRAS wild-type, or whatever, you think, “OK, I got it.” But isn’t the answer that you’ve got to check more?

Dale R. Shepard, MD, PhD, FACP: Yes. That happens a lot. There are simple logistical things. Like you said, testing comes in a variety of places. Where do you even find it, in the medical record, sometimes? This is a challenge.

John L. Marshall, MD: Yes. Then interpreting the results and having enough tissue to send out. It’s a really big deal for us, right now. I’m always impressed by how much they can get off of a biopsy from a colonoscopy.

Johanna C. Bendell, MD: They get a good grab, yes.

John L. Marshall, MD: Is anybody saying that this is not representative and that I need to biopsy the metastasis?

Cathy Eng, MD, FACP: I think it’s interesting, if you can, to biopsy the metastasis. Obviously, mutations change over time. Not all of them do, but it can happen.

John L. Marshall, MD: Do I need to though? If I’ve got a brand new diagnosis, I’ve got my sigmoid biopsy, and I’ve got a liver metastasis, can I do the profile on the primary?

Cathy Eng, MD, FACP: I think you can.

John L. Marshall, MD: Is everybody OK with that?

Johanna C. Bendell, MD: Yes.

Michael A. Morse, MD: If you have a small sample and you want to know MSI status, are you satisfied with what most people do—IHC testing? Or do you want to push for PCR testing as well?

John L. Marshall, MD: Our standard is that you start with the IHC. But we’re also doing a lot of these broad panels that give you the IHC. Plus, it comes back as a next-generation kind of analysis. So, it’s basically a fragment analysis. Others?

Johanna C. Bendell, MD: You know, we’ve seen that PCR and IHC, for the most part, are pretty concordant. So, I wouldn’t get a PCR if I’ve gotten an IHC. The next-generation sequencing, still learning how to use it. The sequencing can look at many more microsatellites than PCR can. So, could you get a broader perspective? So far, the word on the street is that next-generation sequencing is about as equivalent and is concordant with PCR. But it’s more convenient, if you’re going to order one of the next-generation panels anyway. Go ahead and get that, as part of it.

John L. Marshall, MD: Other practice patterns up in Cleveland?

Dale R. Shepard, MD, PhD, FACP: We pretty much do the same thing. Most of the time, we have next-generation sequencing that kind of gives you the slew of things that you need to know.

John L. Marshall, MD: For our doctors out there, you get that protein panel back. You get the IHC panel back. “Present, present, present, present.” The patient and everybody thinks, “Oh, they’ve got Lynch syndrome or something,” when, in fact, that’s normal. The language is terrible around this, and it is really confusing. Who gets MSI testing?

Cathy Eng, MD, FACP: Everybody.

Johanna C. Bendell, MD: Yes.

John L. Marshall, MD: Early, right? Even though the indications may be for later, for when therapy would play into that?

Johanna C. Bendell, MD: Yes.

Cathy Eng, MD, FACP: As mentioned earlier by Johanna, you never know if you have that patient in whom you’re detecting Lynch syndrome.

John L. Marshall, MD: Yes, and then finding those patients. Let’s say that the tumor comes back positive. There are a couple of proteins missing. Maybe the patient does not have a family history of cancer? This is a 72-year-old patient who is the first ever in the family to have cancer. What’s next? How do you handle that?

Johanna C. Bendell, MD: We look at BRAF mutational status. We know that if you have a BRAF mutation, this is likely a sporadic mutation. It’s not germline. It’s not Lynch syndrome. If you are BRAF wild-type and have this, then it’s probably Lynch syndrome. Now, one of the big questions that’s come up is, is that enough evidence to say that the patient has Lynch syndrome? Or do you have to send off one of those tests to really confirm it? That’s an area of controversy.

John L. Marshall, MD: Do you germline test, or not, in that patient?

Michael A. Morse, MD: In that patient, we would send them to a hereditary counselor. They would usually get testing. But keep in mind that this is not always paid for by insurance, unfortunately. So, people may bear the cost.

John L. Marshall, MD: This is getting better, but you’re right. They have to fight for it, depending on the insurer. What is the frequency of MSI-high patients in metastatic disease?

Cathy Eng, MD, FACP: It is very low—less than 5%.

John L. Marshall, MD: Yes, so low that we are not expecting it. Some data that we’ve looked at says that the further around the colon you get, the less likely. In rectal cases, it’s less than 1%, for example. The reason that matters to me is, if you don’t have it yet and you needed to get tissue, would it be worth the payout for that very low percentage of finding it? Maybe it’s worth it, maybe it’s not. We can talk about that. Let’s talk about other genes. We’ve talked about RAS. We talked about MSI. Are there other genes that you’d want to know about? Other molecular expression?

Cathy Eng, MD, FACP: You already mentioned BRAF.

John L. Marshall, MD: Why do I care about BRAF?

Johanna C. Bendell, MD: There is a worse prognosis, potentially. There are clinical trials available for those patients.

John L. Marshall, MD: But say that I have a BRAF-mutated tumor. I’m not eligible for the trial. What are you going to do for me?

Johanna C. Bendell, MD: For first-line treatment, there’s some data that suggest that FOLFOXIRI and bevacizumab is the way to go—for these patients with BRAF mutations. If you can’t get into a clinical trial, there’s a lot of debate going on, depending on how your tumor is behaving, as to whether or not you might think about using something off-label, in terms of the targeted therapies. But, it is really about trying to get those patients to study.

John L. Marshall, MD: Scott Kopetz’s data in combination with that BRAF patient is pretty compelling.

Cathy Eng, MD, FACP: Yes, the phase II data is nice. There’s a big phase III trial, though, that’s ongoing—the BEACON study.

John L. Marshall, MD: It’s going to take a while to accrue. So, I think it will be a challenge in today’s environment. Scott’s was very positive. It is kind of the Wild West, too, in getting access to drugs. You call up and they say, “Fine.” It’s really fascinating. How about BRAF studies?

Dale R. Shepard, MD, PhD, FACP: We don’t currently have any, in terms of clinical trials. But we certainly try to get patients to the right place.

Transcript Edited for Clarity 
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