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Microsatellite Instability Status in Colorectal Cancer

Insights From: Charles S. Fuchs, MD, Harvard Medical School; Daniel G. Haller, MD, FACP, FRCP, Perelman School of Medicine; Richard Kim, MD, University of South Florida College of Medicine
Published: Monday, Apr 25, 2016


Transcript:

Richard Kim, MD:
Mismatch repair deficiency is something that I do test on most of the patients. We know that in stage II patients, mismatch repair deficiency is a predictive marker as well as a prognostic marker. If you have a patient with stage II disease, we test them to see if they benefit from the chemotherapy 5-FU. In stage II patients, we definitely test for them. In stage IV patients, we test for them as well, because right now, based on some of the data presented at ASCO last year, mismatch repair deficiency can be a predictive marker to checkpoint inhibitors or immunotherapy drugs. Therefore, currently, there are many phase I or phase II studies going on looking at colon cancer with mismatch repair deficiency that could potentially get this drug. Even in stage IV patients, I do test for it. Predictive value of mismatch repair deficiency in stage IV is unclear.

Now, the complicated part is stage III patients. In stage III patients, the prognostic value of mismatch repair is mixed. There's some data that support that it is a prognostic marker, but then last year, the data presented with the PEACOCK study tells us that MMR may not be a prognostic marker in stage III patients. Also, in stage III patients, typical adjuvant chemotherapy that we give is FOLFOX therapy. And there’s data from the French study, the NSABP C-07/C-08 study, that tells us that the benefit of oxaliplatin is independent of mismatch repair status. Therefore, I think in stage III patients, I feel comfortable giving FOLFOX therapy as an adjuvant therapy in patients who are mismatch repair deficient. Having said that, if you’re planning to give just the 5-FU alone in stage III patients, I would still test for mismatch repair. And if they’re mismatch-repair deficient, I probably would not offer them 5-FU alone because of the lack of response that we’ve seen in stage II patients.

Daniel G. Haller, MD, FACP, FRCP: You use PCR for MSI, and you use IHC to look for deficient mismatch repair; 95% of the time it’s the same thing. And the reality is, are you testing for use in selecting for adjuvant therapy, or are you looking for people with Lynch syndrome?

My answer always is, go to the expert. One of my jobs is to be the editor and chief of ASCO University, which is the online continuing education program for ASCO. And we now have something called the Molecular Oncology Tumor Boards. The reason we did this is that many people don’t know what to order, and then they don’t know what to do with the results of the studies that they get back. Now many companies, and I won’t name them, will send back a report that you can actually read and understand where the data are interpreted. But many do not. And so doctors don’t know what to order, and then they don’t know what to do with the answers that they finally get.

So for MSI testing, the methodology is not important. What’s important, whether it’s PCR or IHC, is whether you’re looking to screen a patient for Lynch syndrome by testing their tumors, or whether you’re using it to predict, or prognose, in stage II colon cancer. For Genomic Health’s Oncotype DX and a number of ColoPrint and other predictive assays, they use the word “predictive” somewhat misleadingly. They predict recurrence pretty well, but that’s really prognosis; it’s not predicting the outcome of treatment for recurrence. For example, with Oncotype DX, if MSI is performed by their technology—and they use PCR—if the MSI is high, they don’t go on to do the recurrent score because these stage II patients have such good outcomes that chemotherapy is not likely to be effective.

It’s also done based on data from the NSABP C-O7 trial, for patients with early stage IIIA or IIIB disease, to see whether or not these people can benefit. It might better be treated with single-agent 5-FU therapy or with oxaliplatin. There are no studies to show that when you do recurrent score and then you randomize patients, based on the score, to different treatments, that you get better outcomes or different outcomes. In fact, for recurrent scores when the Mayo Clinic group did their study in stage II disease, what they found was when doctors made a decision about whether they were going to treat with adjuvant therapy and were then given the recurrent score, 45% of the time they changed their minds about treatment.

That’s an important factor, they changed their minds. It didn’t say what happened to the patients when that change was made. But what interested me the most is, what did people decide to do? And more often than not, they decided not to use adjuvant therapy. The cost of the test, in that case, was much less than the cost of chemotherapy, especially if they were going to use oxaliplatin. So they didn’t use treatment at all, or they decided not to use oxaliplatin in patients that they otherwise would have considered high-risk.

The technology for how MSI or dMMR is done is not as important for the doctor as it is for the doctor to talk to the pathologist and tell them what they’re looking for and why they want to use it.

Richard Kim, MD: The MSI status is very important in stage II disease. We know that we base our adjuvant treatment decisions on MSI status in stage II disease. If you have MSI-high or mismatch repair–deficiency in stage IIA disease, we typically do not offer patients adjuvant chemotherapy; we go with observation. That’s a well-known fact, and every community oncologist should follow that. Having said that, stage IV disease is an area where it’s a work-in-progress. We do test for patients with MSI status in stage IV disease to put the patient on a clinical trial, knowing that there’s a lot of data telling us that immune checkpoint inhibitors work on patients with MSI-high status or a mismatch repair deficiency. Therefore, it is still important in patients with stage IV disease—where you’re giving the patients other cytotoxic biologic chemotherapy—to know the MSI status, knowing that if the patient is MSI-high or mismatch-repair deficient, you could offer a patient a trial that uses checkpoint inhibitors.

Charles S. Fuchs, MD: For a long time, we’ve known that microsatellite-unstable or MSI-high tumors are a different subset of colon cancer. Principally, patients with MSI-high colon cancer have a better survival. And, moreover, it’s been part of the paradigm of making decisions on adjuvant therapy, such that with stage II colon cancer, if you have an MSI-high tumor, you might be less likely to give any adjuvant therapy. More recently, and in an exciting manner, what we’ve learned is that when microsatellite instability of MSI-high occurs in metastatic patients, that predicts response to a PD-1 or PD-L1 antibody, so-called immunotherapy. Now, admittedly, the prevalence of MSI-high tumors in stage IV is low: it may only be about 4% of patients with metastatic disease having that subset of MSI-high, but it’s very clear that those are the patients that are responding to these really important drugs. And we learned from a paper in the New England Journal of Medicine, in 2015, that we’re seeing response rates in the range of 60% with a PD-1 antibody administered to a patient with an MSI-high colon cancer. That’s a really exciting result.

As a consequence, we know we should be getting MSI testing on all patients. If you have stage IV disease and you have an MSI-high tumor, you should get into one of these studies—and there are many of them now looking at a PD-1 or PD-L1 antibody. Now, the one question you might ask: what do you do if you find an MSI-high patient, stage IV, and you don’t have a trial, you don’t have access to one? Should you give one of these antibodies that are now approved to a patient outside of a clinical trial? And I have seen that happen. I’ve seen people give compassionate-use pembrolizumab or nivolumab, both of which are approved, to patients outside of a clinical trial with an MSI-high patient. Now, they’ve probably gone to the payer and gotten approval, and you need to do that. But it’s an interesting area, and the results are exciting. We need more studies, but what we’ve seen so far is really compelling.

Transcript Edited for Clarity
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Transcript:

Richard Kim, MD:
Mismatch repair deficiency is something that I do test on most of the patients. We know that in stage II patients, mismatch repair deficiency is a predictive marker as well as a prognostic marker. If you have a patient with stage II disease, we test them to see if they benefit from the chemotherapy 5-FU. In stage II patients, we definitely test for them. In stage IV patients, we test for them as well, because right now, based on some of the data presented at ASCO last year, mismatch repair deficiency can be a predictive marker to checkpoint inhibitors or immunotherapy drugs. Therefore, currently, there are many phase I or phase II studies going on looking at colon cancer with mismatch repair deficiency that could potentially get this drug. Even in stage IV patients, I do test for it. Predictive value of mismatch repair deficiency in stage IV is unclear.

Now, the complicated part is stage III patients. In stage III patients, the prognostic value of mismatch repair is mixed. There's some data that support that it is a prognostic marker, but then last year, the data presented with the PEACOCK study tells us that MMR may not be a prognostic marker in stage III patients. Also, in stage III patients, typical adjuvant chemotherapy that we give is FOLFOX therapy. And there’s data from the French study, the NSABP C-07/C-08 study, that tells us that the benefit of oxaliplatin is independent of mismatch repair status. Therefore, I think in stage III patients, I feel comfortable giving FOLFOX therapy as an adjuvant therapy in patients who are mismatch repair deficient. Having said that, if you’re planning to give just the 5-FU alone in stage III patients, I would still test for mismatch repair. And if they’re mismatch-repair deficient, I probably would not offer them 5-FU alone because of the lack of response that we’ve seen in stage II patients.

Daniel G. Haller, MD, FACP, FRCP: You use PCR for MSI, and you use IHC to look for deficient mismatch repair; 95% of the time it’s the same thing. And the reality is, are you testing for use in selecting for adjuvant therapy, or are you looking for people with Lynch syndrome?

My answer always is, go to the expert. One of my jobs is to be the editor and chief of ASCO University, which is the online continuing education program for ASCO. And we now have something called the Molecular Oncology Tumor Boards. The reason we did this is that many people don’t know what to order, and then they don’t know what to do with the results of the studies that they get back. Now many companies, and I won’t name them, will send back a report that you can actually read and understand where the data are interpreted. But many do not. And so doctors don’t know what to order, and then they don’t know what to do with the answers that they finally get.

So for MSI testing, the methodology is not important. What’s important, whether it’s PCR or IHC, is whether you’re looking to screen a patient for Lynch syndrome by testing their tumors, or whether you’re using it to predict, or prognose, in stage II colon cancer. For Genomic Health’s Oncotype DX and a number of ColoPrint and other predictive assays, they use the word “predictive” somewhat misleadingly. They predict recurrence pretty well, but that’s really prognosis; it’s not predicting the outcome of treatment for recurrence. For example, with Oncotype DX, if MSI is performed by their technology—and they use PCR—if the MSI is high, they don’t go on to do the recurrent score because these stage II patients have such good outcomes that chemotherapy is not likely to be effective.

It’s also done based on data from the NSABP C-O7 trial, for patients with early stage IIIA or IIIB disease, to see whether or not these people can benefit. It might better be treated with single-agent 5-FU therapy or with oxaliplatin. There are no studies to show that when you do recurrent score and then you randomize patients, based on the score, to different treatments, that you get better outcomes or different outcomes. In fact, for recurrent scores when the Mayo Clinic group did their study in stage II disease, what they found was when doctors made a decision about whether they were going to treat with adjuvant therapy and were then given the recurrent score, 45% of the time they changed their minds about treatment.

That’s an important factor, they changed their minds. It didn’t say what happened to the patients when that change was made. But what interested me the most is, what did people decide to do? And more often than not, they decided not to use adjuvant therapy. The cost of the test, in that case, was much less than the cost of chemotherapy, especially if they were going to use oxaliplatin. So they didn’t use treatment at all, or they decided not to use oxaliplatin in patients that they otherwise would have considered high-risk.

The technology for how MSI or dMMR is done is not as important for the doctor as it is for the doctor to talk to the pathologist and tell them what they’re looking for and why they want to use it.

Richard Kim, MD: The MSI status is very important in stage II disease. We know that we base our adjuvant treatment decisions on MSI status in stage II disease. If you have MSI-high or mismatch repair–deficiency in stage IIA disease, we typically do not offer patients adjuvant chemotherapy; we go with observation. That’s a well-known fact, and every community oncologist should follow that. Having said that, stage IV disease is an area where it’s a work-in-progress. We do test for patients with MSI status in stage IV disease to put the patient on a clinical trial, knowing that there’s a lot of data telling us that immune checkpoint inhibitors work on patients with MSI-high status or a mismatch repair deficiency. Therefore, it is still important in patients with stage IV disease—where you’re giving the patients other cytotoxic biologic chemotherapy—to know the MSI status, knowing that if the patient is MSI-high or mismatch-repair deficient, you could offer a patient a trial that uses checkpoint inhibitors.

Charles S. Fuchs, MD: For a long time, we’ve known that microsatellite-unstable or MSI-high tumors are a different subset of colon cancer. Principally, patients with MSI-high colon cancer have a better survival. And, moreover, it’s been part of the paradigm of making decisions on adjuvant therapy, such that with stage II colon cancer, if you have an MSI-high tumor, you might be less likely to give any adjuvant therapy. More recently, and in an exciting manner, what we’ve learned is that when microsatellite instability of MSI-high occurs in metastatic patients, that predicts response to a PD-1 or PD-L1 antibody, so-called immunotherapy. Now, admittedly, the prevalence of MSI-high tumors in stage IV is low: it may only be about 4% of patients with metastatic disease having that subset of MSI-high, but it’s very clear that those are the patients that are responding to these really important drugs. And we learned from a paper in the New England Journal of Medicine, in 2015, that we’re seeing response rates in the range of 60% with a PD-1 antibody administered to a patient with an MSI-high colon cancer. That’s a really exciting result.

As a consequence, we know we should be getting MSI testing on all patients. If you have stage IV disease and you have an MSI-high tumor, you should get into one of these studies—and there are many of them now looking at a PD-1 or PD-L1 antibody. Now, the one question you might ask: what do you do if you find an MSI-high patient, stage IV, and you don’t have a trial, you don’t have access to one? Should you give one of these antibodies that are now approved to a patient outside of a clinical trial? And I have seen that happen. I’ve seen people give compassionate-use pembrolizumab or nivolumab, both of which are approved, to patients outside of a clinical trial with an MSI-high patient. Now, they’ve probably gone to the payer and gotten approval, and you need to do that. But it’s an interesting area, and the results are exciting. We need more studies, but what we’ve seen so far is really compelling.

Transcript Edited for Clarity
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