Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline

Dr. Praveen Vikas, Dr. Tyler Johnson, and Dr. Russell Broaddus present the ASCO endorsement of the Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer. They discuss key evidence-based recommendations, focusing on the appropriate modality of testing (immunohistochemistry, polymerase chain reaction, or next generation sequencing) across multiple cancer types. Additionally, they cover the ASCO endorsement process, points of emphasis raised by the ASCO expert panel, and implications for clinicians and patients. Read the full guideline endorsement, Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline at www.asco.org/molecular-testing-and-biomarkers-guidelines.   TRANSCRIPT Brittany Harvey: Hello, and welcome, to the ASCO Guidelines podcast; one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Praveen Vikas from the University of Iowa, Dr. Tyler Johnson from Stanford University, and Dr. Russell Broaddus from the University of North Carolina; authors on, 'Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline'. Thank you for being here, Dr. Vikas, Dr. Johnson, and Dr. Broaddus. Dr. Praveen Vikas: Sure. Dr. Tyler Johnson: Thanks for having us. Dr. Russell Broaddus: Thank you. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline product. The full conflict of interest information for this guideline endorsement panel is available online with the publication of the guideline endorsement in the Journal of Clinical Oncology. To start, Dr. Vikas, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Praveen Vikas: I don't. Brittany Harvey: And Dr. Johnson, do you have any relevant disclosures that are directly related to this guideline? Dr. Tyler Johnson: I do not. Brittany Harvey: And finally, Dr. Broaddus, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Russell Broaddus: I do not. Brittany Harvey: Great. Thank you all for providing that information. So, starting us off on the content of this endorsement, Dr. Vikas, what is the scope of this guideline endorsement? Dr. Praveen Vikas: So, as you can see from the topic and headline, the guideline endorsement was focused on mismatch repair and microsatellite instability testing for immune checkpoint inhibitor therapy, and this is basically an endorsement by ASCO, of a guideline that was developed jointly by CAP, and others. Brittany Harvey: Great. And then you just mentioned that this is an endorsement of the guideline developed by CAP and other organizations. Can you provide us an overview of how this guideline endorsement process works? Dr. Praveen Vikas: ASCO definitely takes great pride in endorsing some of the guidelines that are relevant to our cancer community, and of course, mismatch repair and microsatellite instability testing has been one of those areas where there is a lack of clear guidance. So, when we were approached from CAP about endorsing this guideline, we definitely realized that there's not much published from most of our oncology community, so we were very excited about looking into this guideline and endorsing it. So, this was very much for a topic that we thought is very useful and very timely. Brittany Harvey: And that's great to hear. So then, Dr. Broaddus, as an author both on the guideline endorsement and as a member of the original guideline panel, what are the key recommendations of the CAP guideline? Dr. Russell Broaddus: So, there are six key recommendations from the College of American Pathologists guideline that ASCO recently endorsed. I like to think of the first four as being bundled together because they're interrelated - we dealt with these by cancer type for the first four. So, for colorectal cancer, there's by far the most published evidence on this type of testing, and the evidence-based guideline found that really did not matter so much whether you used immunohistochemistry, or PCR-based microsatellite instability analysis, or next-generation sequencing-based analysis to detect mismatch repair or microsatellite instability. The three different techniques are almost interchangeable in their metrics. Similarly, for gastroesophageal adenocarcinoma and small intestinal adenocarcinoma, immunohistochemistry and PCR-based MSI are very, very similar. There's not quite enough published evidence to equate next-generation sequencing. There were one or two very, very good papers with limited number of patients. The guideline committee felt like if there was maybe one or two more published papers in this space, that for gastroesophageal adenocarcinoma and small bowel adenocarcinoma, it would be similar to colorectal adenocarcinoma, whereas the three techniques were nearly interchangeable. After that, unfortunately, the published evidence really drops off in both quantity and quality for almost all other cancer types. So, endometrial cancer, there's quite a bit of literature. Most of it really points to the immunohistochemistry outperforms PCR-based MSI analysis and PCR-based next-generation sequencing analysis. Most likely, that's because these PCR-based approaches nearly always are optimized to detect mismatch repair defects in colorectal cancer, or other GI types of cancer. And there's actually very good published evidence that this detection of mismatch repair can be cancer-type specific. So, the recommendation is to use immunohistochemistry for endometrial cancer. Fourth recommendation for all other cancer types not encompassed by those first three recommendations, the committee recommends to choose a laboratory-based approach to detect mismatch repair or microsatellite instability defects, but there is no good published evidence to suggest which is the best approach. And again, like with endometrial cancer, there's evidence that the PCR-based approaches, which are usually optimized for colorectal cancer and GI-type cancers, may not be sufficient to work well with cancer types outside of the GI tract. So, almost by default, the recommendation is to choose immunohistochemistry. Fifth recommendation: Many people tend to equate microsatellite instability and high tumor mutation burden. For sure, in colorectal cancer and other GI tract cancers, these two entities, there is substantial overlap. But for cancer types outside of the GI tract, you can easily have a tumor that has a mismatch repair defect, or high levels of microsatellite instability and not have high tumor mutation burdens. So, the recommendation is to not equate those two entities. And finally, last recommendation is that for all of us to remember that these defects in DNA mismatch repair or microsatellite instability, are also hallmarks of hereditary cancer syndrome - Lynch syndrome, and that if you identify unexpectedly that a patient with an advanced cancer has one of these defects and DNA mismatch repair, to consider the possibility of Lynch syndrome, and to alert the appropriate care team, for those patients’ family members can be screened as well. Brittany Harvey: Understood. Thank you for reviewing those evidence-based recommendations made by the CAP panel, and then endorsed by the ASCO panel. So, were there any additional points of discussion or emphasis raised by the ASCO endorsement panel? Dr. Russell Broaddus: Yes. And very appropriately, I believe. One-- and this is purely because of the issue of scope, and not to minimize the importance of these issues. One issue that the CAP guideline did not address was the important issue of pre-analytic variables and how they can impact diagnostic testing. A second issue, again, not considered by the CAP evidence-based guideline group, because of just tremendous scope problems, is how do these tests - immunohistochemistry, PCR-based MSI analysis, PCR-based next-generation sequencing analysis - how do we incorporate their use with PD-L1 immunohistochemistry, for example? Liquid biopsies, as a second example. Should we have a staged approach in assessing tumors with all these different testing modalities? And frankly, the answer is, we don't know right now. I think this represents an excellent area where oncologists and pathologists can actually work to provide the evidence in some specific cancer types on whether multiple modalities provide benefit compared to just one modality. Brittany Harvey: Definitely, those are key points perhaps for future research, and I appreciate you explaining what was in and out of scope of this guideline. So then following that, Dr. Johnson, in your view, what is the importance of this guideline endorsement, and how will it affect ASCO members? Dr. Tyler Johnson: I think to understand the importance of this particular endorsement, it's helpful to zoom the lens out to 30,000 feet for a minute. Pretty much, all oncologists, I think remember 10 or 12 years ago, the types of drugs that we now commonly use for immunotherapy, burst onto the scene with the treatment of melanoma. And those trials were quite remarkable because previous to that, not only did we not have a cure for metastatic melanoma, we hardly had a treatment for metastatic melanoma. We had really almost nothing to offer those patients. And then there was this, initially a small and then a larger, and then a much larger series of patients, who we now know with 10 or 12 years of follow up, that many patients who were treated with immunotherapy, who had metastatic melanoma were actually cured. Not just treated but cured. So, in the decade or so since then, there has been this understandable and appropriate stampede of trying to figure out, "Okay, how do we use similar drugs in all of the other many metastatic tumor types?" And I think to generalize a lot, and to make overly simple a very complicated picture, what has emerged from that is that unfortunately for many metastatic solid tumors, immunotherapy just doesn't do much. It's essentially inert, as best we can tell clinically. But there is a small percentage of patients, exactly what percentage depends on the tumor type and the genetic analysis as we're talking about here, but there's a small percentage, maybe 10-20% of patients, who derive this unbelievable benefit from immunotherapy in metastatic solid tumors, to the point that some of those patients, including in other solid tumors, not just melanoma, appear to be functionally cured by the administration of immunotherapy. And so, the question of course that has resulted from that, is if eight or nine patients are going to get no benefit and maybe even harm from administration of immunotherapy, but one or two patients out of 10 is going to get this really remarkable benefit, it would be so great if we could be much more specific in knowing which patients are going to derive benefit, and which patients are not going to derive any benefit and may even be harmed. And I think that that's the context within which we have to understand this guideline endorsement, is that this is getting us one step further to knowing which patients are likely to get benefit from immunotherapy in metastatic solid tumors. And the really nice thing, as Russell pointed out, is that one kind of shorthand takeaway from this is that it is almost never wrong to look at the question with immunohistochemistry. And that's a great answer, because it is also almost always the most readily available test. And so, if you have a patient who has a metastatic solid tumor and you order immunohistochemistry to look for microsatellite instability, that's almost regardless of the tumor type, it's probably going to give you a reliable answer. And if it shows that they're microsatellite unstable, then that means that that patient, regardless of the tumor type, really probably should get immunotherapy upfront or very close to upfront. And then there are more nuances sort of beyond that. But I think that's really the take home message, that this gives us one powerful tool for discerning who is likely to get benefit from these therapies. Brittany Harvey: Absolutely. That's a key thought that you just mentioned, that this is about delivering personalized medicine to individual patients. So then, you've already touched on this a bit in your last answer, but finally, to wrap us up, how will these recommendations impact patients with cancer being considered for immune checkpoint inhibitor therapy? Dr. Tyler Johnson: I think that many clinical oncologists have the experience that when you sit down to talk to a patient who has newly diagnosed metastatic cancer, what their treatment is going to be, almost all of them have heard about immunotherapy somewhere; in the newspaper, or from friends, or in a cancer support group or whatever. So, most of them want to know what part, if any, immunotherapy is going to play in the care of their cancer right upfront. And I think this gets us one step closer to being able to answer that question. Now, the one thing that-- and Russell touched on this a little bit, but I think it's just important to highlight, this gives us an important way to predict people who are going to respond, but that does not necessarily mean that people who this does not identify as likely responders are therefore not going to respond. And that gets into a much more complicated question that depending on the tumor type, you may have to look at PD-L1 expression, or other things. So, it's just to say that this is not a comprehensive, definitive answer, but it is one important part of the answer. I don't know if Russell or Praveen wants to add any more thoughts about that, but that's kind of how I would contextualize this. Dr. Russell Broaddus: I think where there's a lot of opportunity here for us to start developing the evidence on the utility or not, of such staged approaches that if-- say like, immunohistochemistry does not reveal a mismatch repair defect, should we, for some of these cancer types where we don't routinely assess PD-L1, should we next do PD-L1 immunohistochemistry? And if that doesn't show overexpression, should we next try next-generation sequencing approach? Because sometimes those don't overlap with immunohistochemistry. So, I think there's a lot of room for us to provide this evidence. Dr. Praveen Vikas: Yeah. And one point I would like to add, we had a lot of discussion among our ASCO endorsement panel, was that by recommending IHC or PCR over NGS in certain cancer, there would be scenarios where NGS will be needed, because NGS would tell us a lot more, like HER2 amplifications, and that was our point of discussion. We wanted to make sure that we send that message that even in cases where IHC and PCR is being done, that we may still have additional need for NGS testing. Dr. Tyler Johnson: Yeah. Thank you, Praveen, for that. I should qualify, just to make sure that it's clear, that when I said that IHC is a good go-to, I only meant in terms of testing for this specific thing. Part of the problem with next gen sequencing is that it often takes 4-6 weeks, and so I think the practical approach is, you should send the next-generation sequencing, but in the meantime, you can do the IHC to have an answer to that particular question, and usually in one or two days, depending on the lab, and then the next gen sequencing can come back whenever it comes back, and then you can use that for directing later lines of therapy. Brittany Harvey: Excellent. Well, I've really enjoyed this discussion today, and I want to thank you all for your work on this guideline endorsement, and thank you for your time today, Dr. Vikas, Dr. Johnson and Dr. Broaddus. Dr. Praveen Vikas: Thanks so much, Brittany. Dr. Russell Broaddus: Thank you. Dr. Tyler Johnson: Appreciate the time. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to: www.asco.org/molecular-testing-and-biomarkers-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App store or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode. The purpose of this podcast is to educate and to inform. 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