MSI Testing Utility Evolves in Gastrointestinal Cancers, Expert Says

Myriam Chalabi, MD

Microsatellite instability (MSI) testing has become an important tool in colorectal cancer (CRC) and is demonstrating its utility in the management and treatment of patients with other gastrointestinal (GI) cancers as well now. Although rarer in other GI cancers than in CRC, MSI status could help guide treatment for these patients, particularly when therapeutic options are limited.

Just a decade ago, MSI testing, as well as testing for mismatch repair deficiency (dMMR), has been used in patients with CRC to determine whether a patient or a family member was at risk for Lynch syndrome, but due to the rising increase in using immunotherapy in CRC, MSI and dMMR have become more important tools in the field to guide treatment selection.

In June 2020, the FDA granted approval to the immune checkpoint inhibitor pembrolizumab (Keytruda) monotherapy for the frontline treatment of patients with either unresectable or metastatic MSI-high or dMMR CRC. This approval has generated excitement for the role of immunotherapy in MSI tumors, but more research is needed to refine its role in GI cancers.

In an interview Targeted Oncology, Myriam Chalabi, MD, a medical oncologist at the Netherlands Cancer Institute, discussed the utility of MSI testing in GI cancers and highlights the current role of immunotherapy for these patient populations.

TARGETED ONCOLOGY: Describe how MSI plays into diagnostics in GI cancers. How has this evolved over the years?

Chalabi: If we look back more than 10 years ago, testing for MSI or dMMR was mainly important to find out which patients had Lynch syndrome and were developing tumors based on Lynch syndrome because that entails more diagnostics. Also, for the family, it has importance, so that's what we thought it was important for 10 years ago. In the last couple of years, especially with immunotherapy arising, it became much more important too in the therapeutic sense, for the patients with metastatic disease of MSI tumors of any kind, basically, but we know that MSI tumors are most common in GI cancers, mainly CRCs. However, we now have a treatment that is very highly effective in MSI tumors in the metastatic disease setting, so that's why it has become so important to test for MSI, and whenever possible to treat patients with immunotherapy when they have metastatic disease.

Of course, all studies start with metastatic disease, and then we move up. In the neoadjuvant setting, more and more studies are being done with MSI tumors, and it has become important for us here in the Netherlands to test for MSI, especially in the larger MSI tumors and larger colorectal tumors, prior to surgery and prior to induction treatments, because we know that MSI tumors respond very well to neoadjuvant immunotherapy as well. We have trials going on for that, so that makes it important to test for also in the non-metastatic setting.

TARGETED ONCOLOGY: How do you currently test for MSI? Are there any notable differences between testing methods?

Chalabi: It's probably different for countries I think, so in the Netherlands, we prefer testing for MMR proteins, which is the easiest and also the cheapest method to do that. It's done by experienced pathologists, and it should be just as good as polymerase chain reaction (PCR) testing. When there is doubt, then you should add the PCR testing to that, so that is the method that is preferred here.

PCR is also a good method to test for MSI, so when we're testing with MMR proteins, we're talking about dMMR tumors because of the type of test we're doing. Those are the MSI tumors, and vice versa. When you're testing with a PCR, that's when you're testing for MSI, and if those tumors are MSI, then they should be dMMR as well. They are complimentary, so usually, you only need 1 of either them, but in some cases where the results are not as clear, then those 2 tests can be very complementary to each other. With the upcoming of next-generation sequencing and genome sequencing, those are also methods to test for MSI, but that's something that we don't have the means to do that for every single patient. If we did and if that was going to become standard of care in the near future, then that would also be a very good method to test for MSI.

TARGETED ONCOLOGY: Are there are any advantages with a method that specifically tests for function versus a more indirect method?

Chalabi: I don't think there is. I cannot think of a reason why 1 would be better than the other. As far as I know, we don't have data on which would be better than the other. I think when you're testing for dMMR, what you need is pathologists who are experienced with that, so some GI pathologists who know what they should be looking for and what the patterns could be when you're staining for MMR proteins because there are many different patterns. It can be difficult to interpret, and if the pathologist knows what to look for, then it's much easier to give an interpretation than when it's something you do very little. I think experience is more important than the test itself because of the data we have now that the different methods seem to be very similar, both sensitivity-wise and specificity-wise.

TARGETED ONCOLOGY: How do you apply the results of these testing on a more clinical level?

Chalabi: MSI is 1 of the things that I use every single day in my patient population because that gives me a direction in where I should be looking for to treat my patients. If we start with the patients who have non-metastatic disease, so those are patients with MSI tumors, especially those patients who need induction treatment prior to surgery, so for the large tumors, those are the patients I would preferably treat within trials with neoadjuvant immunotherapy. We have such a trial going on, so these patients are referred and also [referred] from the rest of the country to us. Patients we get here. We discuss this trial with them more preferably than chemotherapy, which would be the standard induction treatment.

Because of the results we've seen in this patient population with neoadjuvant immunotherapy in the NICHE trial for patients with metastatic disease, in the United States, immunotherapy is a standard of care now for patients with MSI tumors and metastatic disease as first-, second-, and third-line treatment. I believe now that also has been approved for the first-line treatment of MSI patients, but that is not the case in Netherlands, so if we want to treat a patient with an MSI metastatic colorectal tumor, we need to treat them within clinical studies. When we know that a patient has an MSI tumor, then we will go and look for those clinical studies to treat patients, and usually we have studies such as now for patients in all lines of treatment. That tells us how we should be treating our patients or what the preferred method of treatment would be, so MSI is very important. I think we should have MSI testing for all patients with CRC and especially for patients with metastatic disease before we decide on what treatment to give.

TARGETED ONCOLOGY: In terms of germline testing, could you touch on the importance of testing for reliable biomarkers in GI cancers?

Chalabi: I think that there are a couple of things that we need to know about GI cancers before starting a treatment or during treatment, so I think MSI is 1 of them. The BRAF mutation is another, as well as the RASmutations, KRAS and NRAS. Those are 3 tests that all patients with metastatic disease have to have, and we need to know what the results are. Then you can think about a couple of other targets, especially because we have targeted treatments or treatments for them, such as fusion genes. Those are all specific aberrations or mutations that we could look in to, only there is no standard of care for those, so I think it would be important, especially if you have the means in your country of treating patients, for example, within HER2 amplification or to treat them with HER2 targeted treatment, then that would be a reason to test. If you don't have that, you could think about whether that should be a priority, but I think that BRAF, RAS, and MSI are the most important to have.

TARGETED ONCOLOGY: What would you say would be your take home message regarding the state of MSI in GI cancers?

Chalabi: Most important is to test. We need to test patients, all patients with CRC, but I'm [for testing in] patients with other GI cancers and other tumor types, especially when there are no other treatment options available. The chances of having an MSI tumor are small in other tumor types, but when you do have a patient with an MSI tumor, then the impact of treatment with immunotherapy can be huge. That would be my main take home message, to consider MSI testing. This is a very exciting field, also from a patient perspective too, so even though it's 1% to 2% in other tumor types, we have to test everybody when you don't have other good treatment options, and in GI cancers, I hope that more and more studies will come for MSI tumors in GI cancers, not only in the metastatic disease but also in the neoadjuvant setting. We're seeing that in gastric cancer patients with MSI tumors also do much better on immunotherapy than chemotherapy, only these are always the small patient populations within huge studies, so very few studies are mainly focused on MSI tumors. This makes it difficult to draw real conclusions from studies, but I think that going towards immunotherapy should be standard of care for all MSI tumors. I hope that people will test more.