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ONCAlert | Upfront Therapy for mRCC

Case 3: NGS Testing in Patients With CRC

Targeted Oncology
Published Online:1:32 PM, Wed November 21, 2018

Michael Morse, MD: In summary, this is a case of a patient with KRAS-mutated metastatic colon cancer who had progressed on first-line FOLFOX [folinic acid, fluorouracil, and oxaliplatin] plus bevacizumab [Avastin], then proceeded to second-line FOLFIRI [folinic acid, fluorouracil, and irinotecan] plus bevacizumab, and is now in the third-line setting and has the options of 2 different oral agents.

Shubham Pant, MD: Thank you for the case discussion, Mike. Greg, we saw this interesting thing about NGS testing. When do you normally get the NGS testing for colorectal cancer [CRC] from your oncologist?

Michael Morse, MD: It really depends. We’ve been doing a lot of Foundation Medicine, the commercial NGS testing, for a while. I think the oncologists in our area are fairly comfortable with that test. So we do a lot, typically when the patients either aren’t responding, have refractory disease, or maybe don’t have MSI [microsatellite instability]–high disease or some other potentially targetable mutation through your normal frontline types of therapies.

Shubham Pant, MD: What’s the difference between IHC [immunohistochemistry], PCR [polymerase chain reaction], and NGS testing, or expanded NGS testing?

Gregory Riedlinger, MD, PhD: Specifically, in colon cancer, usually when they’re talking about immunohistochemistry, they’re doing immunohistochemistry specifically for the mismatch repair [MMR] proteins. It’s just an antibody-based test that looks for the protein expression of MLH1, MSH2, MSH6, and PMS2, which are typically the 4 most frequently mismatch repair–altered genes. And then, a PCR is just polymerase chain reaction. Traditionally, that had looked more at single genes—potentially what people were doing for ROS testing, initially.

And then, there is something which people usually refer to as next-generation sequencing. Some people don’t like that. They prefer the term “massively parallel sequencing.” It’s essentially millions, or even billions, of PCR reactions that are occurring simultaneously on a chip. It allows you to interrogate many gene regions and, potentially, multiple patient samples all in the same reaction.

Shubham Pant, MD: There has been a lot of discussion in the gastrointestinal world about liquid biopsy in the ctDNA [circulating tumor DNA]. What are your thoughts about testing from the tumor versus ctDNA?

Gregory Riedlinger, MD, PhD: MD Anderson Cancer Center has kind of been the pioneer in non–small cell lung cancer. Traditionally, I think people are most comfortable, at least up front, with doing some type of tissue-based test to identify the mutation. Obviously like in non–small cell lung cancer, where there are certain resistant mutations and it can be a bit more difficult to get a second biopsy, I think we’ve seen a lot more of the plasma circulating tumor DNA. You’re looking for those specific mutations. We’ve seen certain instances for which a tissue biopsy isn’t feasible. In those cases, liquid biopsy has been used as an alternative.

Shubham Pant, MD: Rich, I’ll come to you. This is a great clinical question. We talked about this before. A new patient comes in. You have a biopsy. Are you sending it for all NGS at that time, just an NGS panel, or do you test for what we talked about before: BRAF, MSI, and expanded RAS?

Richard Kim, MD: In my practice, we may have a lack of tissue, right? The tissue is always an issue. When you see the patient, you have tissue. If you send a test for BRAF and a test for RAS, MMR, you’re using all the tissue up. Let’s say they progress after first-line therapy. You’re out of tissue. Then you have to do another biopsy or track some tissue down from outside of the hospital.

In our practice, we like to get everything at once. We have an internal panel of 200 assay mutations. You could send to Foundation Medicine, where they have 400-assay panels as well. I like to do everything up front for the reasons that we talked about: to test for RAS or BRAF. It could also test for MSI status as well. And there are other subtle-like fusions out there that don’t commonly occur in colon cancer, such as TRK, RET, or ALK, which we see in about 1% or less of patients. The nice thing, even though it’s very rare, is that they are targetable, actionable fusions. There are drugs out there, on a trial basis, that you can get off label. Some are approved for TRK fusions. The response rate can be as high as 75%. They are durable. This could be life saving for certain patients.

Therefore, in my practice, I like to get everything up front. I have a battle plan, whether you have a TRK fusion or not. If you have TRK fusion, there is a therapy to possibly use in the second-line setting. If you have a BRAF mutation, you don’t want to do that. So, in my practice I like to do everything up front, if possible.

Shubham Pant, MD: Rare is rare, right? In the community practice, when they’re doing it, these tests are always expensive versus doing an IHC and testing for a couple of genes. Let’s say the performance status goes down in these patients and you cannot use this testing. What would you recommend? What is your practice? Would you do everything up front or would you say, “Hey, I’m going to test for these 4? And then, after my first or second line of therapy, if the performance status is good and they look good clinically, that’s the time I would come in and maybe do an NGS. I don’t test in the beginning, and the patients don’t get it because their disease is uncontrollable.”

Michael Morse, MD: The theme, today, has been that this is personalized. Not every patient should get complete NGS testing up front. It’s not going to be appropriate for a lot of people. However, there are some subtleties. Physicians should know what’s actually being tested. A good example is with KRAS. I always assumed that when you sent that test off we were getting exon 2, 3, and 4. In reality, we weren’t. We were getting exon 2, predominantly. And so, for us to get all of the possible mutations, it actually involves getting next-generation sequencing. For that reason alone, we find it valuable to do it up front.

It also gives you a baseline. Most of these mutations are not going to go away. They’ll presumably be there later on. It then allows you to use a liquid biopsy, as you pointed out, subsequently. If somebody is being treated with, for example, anti-EGFR therapy, we have sometimes seen mutations develop that render the therapy no longer effective. The only way you can realistically follow for that is with a liquid biopsy. And so, I think knowing what the mutational status is up front does allow you to plan for later. If you find there is HER2 amplification, you know that’s going to be an option.

The mantra in gastrointestinal oncology has been this continuum of care and being able to sort of anticipate what therapies you’re going to have available for the person over time. Having all of the information available up front allows you to really do the continuum of care in the best possible way.

Transcript edited for clarity.

Michael Morse, MD: In summary, this is a case of a patient with KRAS-mutated metastatic colon cancer who had progressed on first-line FOLFOX [folinic acid, fluorouracil, and oxaliplatin] plus bevacizumab [Avastin], then proceeded to second-line FOLFIRI [folinic acid, fluorouracil, and irinotecan] plus bevacizumab, and is now in the third-line setting and has the options of 2 different oral agents.

Shubham Pant, MD: Thank you for the case discussion, Mike. Greg, we saw this interesting thing about NGS testing. When do you normally get the NGS testing for colorectal cancer [CRC] from your oncologist?

Michael Morse, MD: It really depends. We’ve been doing a lot of Foundation Medicine, the commercial NGS testing, for a while. I think the oncologists in our area are fairly comfortable with that test. So we do a lot, typically when the patients either aren’t responding, have refractory disease, or maybe don’t have MSI [microsatellite instability]–high disease or some other potentially targetable mutation through your normal frontline types of therapies.

Shubham Pant, MD: What’s the difference between IHC [immunohistochemistry], PCR [polymerase chain reaction], and NGS testing, or expanded NGS testing?

Gregory Riedlinger, MD, PhD: Specifically, in colon cancer, usually when they’re talking about immunohistochemistry, they’re doing immunohistochemistry specifically for the mismatch repair [MMR] proteins. It’s just an antibody-based test that looks for the protein expression of MLH1, MSH2, MSH6, and PMS2, which are typically the 4 most frequently mismatch repair–altered genes. And then, a PCR is just polymerase chain reaction. Traditionally, that had looked more at single genes—potentially what people were doing for ROS testing, initially.

And then, there is something which people usually refer to as next-generation sequencing. Some people don’t like that. They prefer the term “massively parallel sequencing.” It’s essentially millions, or even billions, of PCR reactions that are occurring simultaneously on a chip. It allows you to interrogate many gene regions and, potentially, multiple patient samples all in the same reaction.

Shubham Pant, MD: There has been a lot of discussion in the gastrointestinal world about liquid biopsy in the ctDNA [circulating tumor DNA]. What are your thoughts about testing from the tumor versus ctDNA?

Gregory Riedlinger, MD, PhD: MD Anderson Cancer Center has kind of been the pioneer in non–small cell lung cancer. Traditionally, I think people are most comfortable, at least up front, with doing some type of tissue-based test to identify the mutation. Obviously like in non–small cell lung cancer, where there are certain resistant mutations and it can be a bit more difficult to get a second biopsy, I think we’ve seen a lot more of the plasma circulating tumor DNA. You’re looking for those specific mutations. We’ve seen certain instances for which a tissue biopsy isn’t feasible. In those cases, liquid biopsy has been used as an alternative.

Shubham Pant, MD: Rich, I’ll come to you. This is a great clinical question. We talked about this before. A new patient comes in. You have a biopsy. Are you sending it for all NGS at that time, just an NGS panel, or do you test for what we talked about before: BRAF, MSI, and expanded RAS?

Richard Kim, MD: In my practice, we may have a lack of tissue, right? The tissue is always an issue. When you see the patient, you have tissue. If you send a test for BRAF and a test for RAS, MMR, you’re using all the tissue up. Let’s say they progress after first-line therapy. You’re out of tissue. Then you have to do another biopsy or track some tissue down from outside of the hospital.

In our practice, we like to get everything at once. We have an internal panel of 200 assay mutations. You could send to Foundation Medicine, where they have 400-assay panels as well. I like to do everything up front for the reasons that we talked about: to test for RAS or BRAF. It could also test for MSI status as well. And there are other subtle-like fusions out there that don’t commonly occur in colon cancer, such as TRK, RET, or ALK, which we see in about 1% or less of patients. The nice thing, even though it’s very rare, is that they are targetable, actionable fusions. There are drugs out there, on a trial basis, that you can get off label. Some are approved for TRK fusions. The response rate can be as high as 75%. They are durable. This could be life saving for certain patients.

Therefore, in my practice, I like to get everything up front. I have a battle plan, whether you have a TRK fusion or not. If you have TRK fusion, there is a therapy to possibly use in the second-line setting. If you have a BRAF mutation, you don’t want to do that. So, in my practice I like to do everything up front, if possible.

Shubham Pant, MD: Rare is rare, right? In the community practice, when they’re doing it, these tests are always expensive versus doing an IHC and testing for a couple of genes. Let’s say the performance status goes down in these patients and you cannot use this testing. What would you recommend? What is your practice? Would you do everything up front or would you say, “Hey, I’m going to test for these 4? And then, after my first or second line of therapy, if the performance status is good and they look good clinically, that’s the time I would come in and maybe do an NGS. I don’t test in the beginning, and the patients don’t get it because their disease is uncontrollable.”

Michael Morse, MD: The theme, today, has been that this is personalized. Not every patient should get complete NGS testing up front. It’s not going to be appropriate for a lot of people. However, there are some subtleties. Physicians should know what’s actually being tested. A good example is with KRAS. I always assumed that when you sent that test off we were getting exon 2, 3, and 4. In reality, we weren’t. We were getting exon 2, predominantly. And so, for us to get all of the possible mutations, it actually involves getting next-generation sequencing. For that reason alone, we find it valuable to do it up front.

It also gives you a baseline. Most of these mutations are not going to go away. They’ll presumably be there later on. It then allows you to use a liquid biopsy, as you pointed out, subsequently. If somebody is being treated with, for example, anti-EGFR therapy, we have sometimes seen mutations develop that render the therapy no longer effective. The only way you can realistically follow for that is with a liquid biopsy. And so, I think knowing what the mutational status is up front does allow you to plan for later. If you find there is HER2 amplification, you know that’s going to be an option.

The mantra in gastrointestinal oncology has been this continuum of care and being able to sort of anticipate what therapies you’re going to have available for the person over time. Having all of the information available up front allows you to really do the continuum of care in the best possible way.

Transcript edited for clarity.
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