JCO PO author Dr. Alicia Latham shares insights into her JCO PO article, “Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome.” Host Dr. Rafeh Naqash and Dr. Latham discuss microsatellite instability-high status as well as familial risk and testing. Click here to read the article!

TRANSCRIPT

Dr. Rafeh Naqash: Hello, and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology, and Assistant Professor at the OU Stephenson Cancer Center.

Today we are excited to be joined by Dr. Alicia Latham, Medical Director at the Memorial Sloan Kettering-CATCH, and the Assistant Attending Physician, General Internal Medicine and Clinical Genetics. Dr. Latham is also the author for our JCO Precision article titled "Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome."

At the time of this recording, our guest on this podcast had no disclosures.

Dr. Latham, thank you so much for joining us today, and welcome to our podcast.

Dr. Alicia Latham: Very happy to be here today. Thank you for inviting me.

Dr. Rafeh Naqash: For the sake of this podcast, we'll refer to each other using our first names if that's okay with you.

Dr. Alicia Latham: Sure.

Dr. Rafeh Naqash: So this is a very interesting, broad topic that I wanted to discuss with you, and hopefully, our listeners find it very interesting. It touches on a broad range of currently relevant precision medicine-related topics, which is mismatch repair deficiencies, colorectal cancers, and Lynch syndrome. Could you try to give us an understanding of what we know so far about colorectal cancers that are mismatched repair deficient as well as Lynch syndrome, which would be, hopefully, an interesting segue into your article?

Dr. Alicia Latham: Sure. In general, I think when speaking of mismatch repair deficiency in the setting of colorectal cancer, we know that the vast majority of the time it's somatically driven, not necessarily that there was an inherent genetic predisposition that drove it, and we've known that for quite some time. But the issue is that there's still about 15% of the time or so when you're looking at colon cancers, that a germline component is probably driving that mismatch repair deficiency, i.e. Lynch syndrome. And that became exceptionally relevant whenever universal screening for said tumors was occurring as a way to screen for Lynch syndrome. And even perhaps more importantly, with the usage and increasing usage of immune checkpoint blockade because we know that those cancers respond exquisitely well because of that driver. And in terms of our understanding, typically because patients with Lynch syndrome inherently have a defect in mismatch repair, their tumors, pan-cancer, which we published on previously in JCO, demonstrate mismatch repair deficiency or MSI high status, if that was contributed.

So really the point of looking at this was to take that initial work and kind of turn it on the flip side. And rather than assessing all tumors for MMRD status or MSI high status, to look at colorectal cancer tumors at our institution, find the underlying prevalence of Lynch syndrome, and then see how many presented with a mismatch repair proficient tumor and what that may or may not imply or mean for the patient clinically. That was really the whole point.

Dr. Rafeh Naqash: Excellent, thank you so much for the explanation. Now, I do remember when I was a fellow in my first-year fellowship, I would often get confused, and I think NGS was just becoming the thing of the day a couple of years back, especially for metastatic tumors. I would often get confused between MMR deficiency and MSI high. And for trainees who are going to start in a week or so into their fellowships, who hopefully will be listening to this, could you give us a simpler version of how you would explain to a new trainee what MMR deficiency versus MSI high is?

Dr. Alicia Latham: Sure. So we'll start with MMR deficiency. So IHC or immunohistochemical analysis has been around for a while. That's kind of your classic way of assessing for this. And really what that means is that when the tumor is stained for the mismatch repair proteins, they're found to be deficient, meaning that one or more of said proteins is not expressed in the tumor. So that's mismatch repair deficiency. Usually, the staining patterns have a very unique pattern to them, meaning that you'll typically see MLH1 and PMS2 absence go together, or MSH6 and MSH2 absence go together. They go hand in hand. I call it the “buddy system.”

Microsatellite instability - before defining what that means, I think it's important to explain what microsatellites themselves are. And so when I talk to trainees, I say microsatellites are just little repeat sequences throughout our genome that are kind of little “bookmarks.” And our mismatch repair system finds those little repeat sequences to try to look for errors, spelling errors. That's the spell checker of the mismatch repair. And so it scans, finds a bookmark, reads to see if there's a mismatch. If there is, it corrects it and then goes to the next one, and so on and so forth.

Over time, if those mismatches aren't repaired, then you may see a discrepancy in the now cancerous tissue versus the normal. And that is what's called microsatellite instability, meaning that the tumor, the variance in those repeat sequences is different in the tumor versus the normal tissue. They typically have a concordance rate of greater than 90%.

Dr. Rafeh Naqash: So basically, in your practice, do you often do, and I know you've touched upon some of the overlapping incidences in your paper, but do you, in your practice, do MSI testing using NGS and IHC testing on all patients that need to be tested?

Dr. Alicia Latham: So it depends on how they get to us. By the time patients have gotten to genetics, usually at MSK because we have this institutional protocol, MSK-IMPACT, these patients are offered paired NGS sequencing, so tumor-normal sequencing, and they can either consent to just somatic profiling, or somatic and germline. And so by the time we see them, our NGS profile uses MSIsensor for categorization of the MSI status. So they usually have that.

But if there's any discordance or surprising feature, say the patient comes in, their tumor is MSS but the patient has a known MLH1 germline mutation and the family history looks striking for Lynch syndrome, that's suspicious. So we'll do an orthogonal method to look at the tumor, usually starting with IHC to see if it's mismatch repair deficient because that's very easy to do. And then we can also have an additional analysis that's in the process of going through clinical validation called MiMSI, which is essentially an algorithm that has been trained as a machine learning tool on the original impact data and MSIsensor that has a higher clinical validity in tumors that have low tumor content. So MSIsensor is known to have a bit of a flaw in that in tumors with less than 10% of tumor content in the sample, that it may be artificially low. So that's why we also look at that too. So we typically do, if we're suspicious, we'll do an additional method.

Dr. Rafeh Naqash: Interesting. Now, going to this interesting work that you published in JCO PO, it seems the premise is more or less around understanding what percentage of patients with Lynch syndrome have mismatch repair proficient colorectal cancers that could be driven by other sporadic changes, genomic changes, or whatever factors that could be, perhaps, leading to tumorigenesis. So was that how you started this project? Or were you trying to answer a different question but understood that this could be a very clinically relevant or meaningful question also?

Dr. Alicia Latham: Honestly, how this came about was we had our first patient come in with- had known Lynch Syndrome and had a proficient tumor. And what brought up the question about it as to why it was clinically relevant is one, they were considering immunotherapy, and the oncologist was like, “Do I or do I not do this?” And then the second question is: well, what does this necessarily mean for the family? If this tumor is truly mismatch repair proficient, does that mean that the Lynch syndrome caused it, and so, therefore, someone that tests negative, or deficient, someone who tested negative for the Lynch syndrome, may be off the hook for screening? Or if it's truly proficient, does that family member now have a familial risk for colon cancer and should perhaps consider increased screening? So those were the clinical questions that came up in that case.

And because of that case, that was like, well, how many times does this really happen? Has anybody published on this yet? And we didn't see anything at the time, and we had this large impact data cohort. So we decided to dive a little bit deeper and see what we can find. It is rare, but it happens.

Dr. Rafeh Naqash: You bring this very interesting point that some of the very clinically relevant projects or research, it stems from a unique clinical patient scenario where you saw an individual, you tried to understand why, and you took it to the next step. In fact, I do drug development, Phase 1 clinical trials, and I have an individual with a history of Lynch syndrome and germline positive with osteosarcoma but mismatch repair proficient. And before reading this paper, I've come across some other data. In the Phase I setting when you don't have a target, your next best option is to go for immunotherapy--novel immunotherapy-based approaches. And in this individual, I was debating whether an immunotherapy approach would be reasonable or not. But based on the data and then looking at your paper, I am less convinced that with a mismatch repair proficient tumor, because in the standard care setting, obviously, immune checkpoint inhibitors have an indication for tumor MSI high, not germline. So these are rare, but when they happen, it does bring into question, like you said, implications for the family, whether or not immunotherapy is a relevant option in those individuals. So, very, very important to understand this.

So could you tell me, and the listeners also, walk us through the data set that you looked at? What was the denominator and how did you end up with the sample size that helped you understand this topic?

Dr. Alicia Latham: Sure. So we first started with just looking at our overall MSK IMPACT cohort at the time that had undergone germline or analysis of their DNA. And so that was over, at the time, 17,000 cases. Then looking at those, we wanted to understand and assess the underlying Lynch syndrome prevalence of all of those cases. So overall, it was 17,617 pan-cancer patients. And we found, of those, about a 1.5% prevalence of Lynch syndrome pan-cancer. And then of those we assessed, of those patients with known Lynch syndrome, how many had at least one colorectal tumor that underwent that NGS profiling, and that came out to about 36% or 86 cases.

Of course, because Lynch syndrome is known to have synchronous and metachronous tumors, there were a few patients that had more than one colorectal cancer assessed, so it actually ended up being 99 pooled tumors. So then you're looking at 99 pooled tumors there of those Lynch syndrome cohorts, of which about roughly 10% were found to be mismatch repair proficient, and they were also MSS or microsatellite stable by MSIsensor. So that was how we broke it down.

Dr. Rafeh Naqash: Interesting. Now, looking through your manuscript, I understood that you identified some unique differences between the mismatch repair proficient Lynch syndrome-positive individuals and mismatch repair deficient individuals in the cohort. What were some of the highlights of the different clinical characteristics that could be clinically meaningful?

Dr. Alicia Latham: Sure. So I think one of the most important things, at least from a genetics perspective, was we did find an enrichment among the mismatch repair proficient group of those having either an MSH6 or PMS2 germline variant. And that's notable because those are known to be kind of our lower-risk genes. And in fact, oftentimes patients and families don't meet typical clinical criteria for genetic testing in those families. So PMS2 is probably the most obvious case of that where the families don't really look suggestive of classic Lynch syndrome. That was significant even in a small cohort, so it was 89% of patients with mismatch repair proficient tumors had MSH6 or PMS2 mutations.

The other, while it didn't quite achieve statistical significance simply because it was a small cohort, the age of onset was different. So mismatch repair proficient, they were a little bit older. Our median age of onset was 58 in that group and then the mismatch repair deficient group median age was 43%. So I think if we had a larger sample size that would achieve statistical significance there.

The other important caveat was just kind of when they presented, what stage did they present at. So, unfortunately, we did see a higher prevalence of patients presenting with metastatic disease in our mismatch repair proficient group. And that makes sense because if these are patients that are typically with Lynch syndrome, that is perhaps a milder phenotype if you will, maybe they weren't identified early enough because the family histories weren't suggestive. So they weren't undergoing high-intensity surveillance compared to those that were in the mismatch repair deficient group that had the higher risk genes. And likely their family histories met clinical criteria for Lynch syndrome.

Dr. Rafeh Naqash: Thank you so much. Now, the number that stands out in your manuscript is 10%--with individuals that had Lynch Syndrome and having mismatch repair proficient colorectal cancers. In your tumor boards that you perhaps participate in with GI, medical oncology, or other multidisciplinary tumor boards, do you try to discuss some of this early on so that implementation and uptake of whether it's NGS or germline testing is high right from the get-go? Do you try in your tumor boards to suggest to the treatment team that they should have perhaps germline testing also before they see you or at least have ordered it by the time they see you and also a full NGS panel? Or is that something that's just routinely done at your cancer center?

Dr. Alicia Latham: It's routinely done at MSK. We are fortunate because of the MSK IMPACT protocol that they are routinely done. Having said that, if there is any sort of question, like I said before, oftentimes we'll talk to the oncologist about doing an orthogonal method just to verify. We also have patients that come from outside and maybe they've already had some sort of initial screening and so they wouldn't necessarily be candidates with insurance criteria, etc., for additional assessment. So we have to get a little bit creative in terms of our workup and how we can help those patients as well. But yes, we typically do. If you're suspicious, yes, we do recommend it.

Dr. Rafeh Naqash: Excellent. And I know, I think, with more and more precision oncology coming up, I was speaking with a few other clinical geneticist experts at ASCO, I think incorporating individuals with clinical genomics and genetics expertise like yourself, incorporating those individuals into tumor boards, not just molecular tumor boards, but the multidisciplinary tumor boards early on, I think, could make an impact as far as testing is concerned and as far as identifying some of these things early on is concerned.

Now I would like to ask you an interesting, provocative question that you necessarily haven't addressed in the paper, but it is nevertheless interesting. So when you found or you mentioned that some of these genes have different penetrants or some are higher risk in the MSI group, the mismatch repair deficient genes, or when you think about DNA damage response, you think about neoantigens, which goes into the context of immune checkpoint inhibitors. Has there been any data or what would you think from a perspective of whether a certain gene has a higher neo antigen burden associated with it, meaning a higher number of antigens that are necessarily something that the immune system thinks that they're foreign, which helps immune checkpoint inhibitors to work? So do you think there is a difference from a neoantigen perspective in these genes suggesting that a certain tumor with a PMS deficiency versus another tumor with an MSH6 deficiency have different responses or outcomes to immune checkpoint therapy?

Dr. Alicia Latham: My gut tells me perhaps. We know that when you're looking at different tumors for their MSI status or their MMR status, that MSH6, for example, mutation carriers, seem to have lower levels of that. So even just looking at our MSIsensor scores in general, they tend to be lower for MSH6 mutation carriers. So to me that signal, if it's not as pronounced, you would think that perhaps that's also there. And I think other groups have looked at that, that you're seeing that. As far as clinical response, I don't know if you're, in terms of comparing tumor to tumor, if they have the same profile, I would suspect that the response would be similar. Of course, if there's something varied, then I think that whichever profile has that higher tumor mutation burden or those neoantigens would respond better.

But I think at least as a non-oncologist, as a geneticist, and someone who's very interested in prevention, I think it's something that is incredibly important for the vaccine trials that are going on to understand and making sure that patients that we are recruiting to these trials have PMS2 and MSH6 associated Lynch syndrome, that we're not just focusing on those that we know have higher tumor mutation burden or MSI status because those are the patients we want to make sure that we're including in designing those and targeting the appropriate antigens for those trials because that is very important work that I know colleagues at other institutions are working on diligently.

Dr. Rafeh Naqash: I think those are very interesting thoughts and perhaps somebody in the near future will address some of these interesting concepts.

One of the things that I didn't see in the paper that we are discussing today is what were the potential somatic, tumor somatic, events in the mismatch repair proficient colorectal cancers in the 10% that you identified that could have led to their tumor genesis. Did you look into that? Is there any subsequent work that is going on in that space?

Dr. Alicia Latham: Yeah, we are looking at it subsequently, we didn’t for the content of this paper. We were really focused on the MSI and mismatch repair proficiency. But yes, there was actually a study that is assessing this - really more of a pan-cancer study. We started here and one of my colleagues at MSK is working on looking at this pan-cancer and trying to understand these orthogonal methods, the tumor somatic drivers. They actually presented this abstract at ASCO this year. So trying to understand what actually did drive this. And is that something in terms of treatment that we need to be very much aware of? And I think the answer is ‘yes.’ So more to come on.

Dr. Rafeh Naqash: That's excellent. So hopefully, we'll see something in that space from your group in the coming months.

Another question you touched upon earlier is the implications for familial testing. So if an individual, for the sake of our listeners, if an individual comes to my clinic tomorrow with a mismatch repair proficient tumor but with a Lynch syndrome history, something similar to that I described earlier for my patient with sarcoma, what would the counseling be from a geneticist standpoint for the family? How would you explain the risk? How would you explain the tumor in that individual and then testing for the family members?

Dr. Alicia Latham: So regardless of what the tumor demonstrated, I think it would be important, if this is a known Lynch syndrome patient, explaining to close family members that they have a risk of having this, a first-degree family member’s 50% chance of sharing the mutation. And that's important regardless of what the tumor shows. Where I think it's more of the nuance is explaining to particularly those patient family members that test negative for Lynch syndrome. For example, in colon cancer, we say that if you have a first-degree relative with colon cancer, that, regardless of the looks like familial colon cancer without a genetic explanation, that you start colonoscopies a little sooner and you do them more frequently. So rather than 45, you start at around age 40, rather than every ten years, you repeat every five. Of course, if polyps appear, that's altered.

And so because we don't quite know if a mismatch repair colon cancer was really driven by that germline, say PMS2 mutation, could this in fact be a sporadic colon cancer that's incidental to the PMS2 mutation? Therefore, that family member that tests negative may be at an elevated risk of colon cancer and may want to consider doing colonoscopies a little sooner and a little more frequently. Having said that, I think that it's a very important conversation to have with the family members to make sure that they are very clear on that. But I think that there's a lot of work that needs to be done to understand - is it truly the case? Is there any role at all? What can we use as far as understanding kind of a different pathway for certain mutation carriers like MSH6 and PMS2? Is there something else that we're missing? So for now, I counsel my patients that I would recommend, even if you test negative, to screen a little bit earlier and a little more frequently until we understand this a little better.

Dr. Rafeh Naqash: Thank you so much for that explanation. And this was a very interesting opportunity for me to help take a deeper dive into this paper, hopefully for our listeners as well. Now, a few questions about yourself, Alicia. So we like to know a little bit about the individual or individuals behind the work. So tell us a little bit about your training and your current interests and also what advice you have for early pre-investigators in the space of precision medicine, the way it's developing right now.

Dr. Alicia Latham: Sure. My training is a little bit unique, so I'm not a medical oncologist by training. I knew that I wanted to be on the prevention side, not necessarily the treatment side because when I was in medical school what was available was chemotherapy. And that wasn't for me. I didn't want to do that. And so I trained in family medicine and then completed a fellowship in medical genetics with a focus on cancer. And my clinical focus is really taking care of patients with a genetic predisposition, so at-risk patients. In that regard, I serve as Medical Director for our program at MSK called MSK CATCH, which is really for patients that have a germline susceptibility of cancer, but they want to be followed and managed at Sloan. So that's my clinical focus.

And then my research is really looking at germline predisposition, primarily Lynch syndrome, to try to understand what do we know and more importantly, what don't we know about this pan-cancer syndrome and how can we help these patients and families. Many of my studies have looked at that from understanding descriptively Lynch syndrome among different types of cancer, like small bowel cancer or the MSI status pan-cancer paper. But importantly, where we're going in the future and where I am going in the future is looking at where can we go to early detection in these patients and really increase screening because right now, the only proven effective screening for Lynch syndrome is colonoscopy, and yet it's a pan-cancer syndrome. So we have a lot of work to do.

Dr. Rafeh Naqash: Thank you so much. It was really awesome to talk to you today. And thanks for explaining some of the interesting concepts around MSI-high colorectal cancers and Lynch syndromes. Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcast.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Guest Biography: Dr. Alicia Latham is Medical Director at Memorial Sloan Kettering-CATCH and Assistant Attending Physician, General Internal Medicine and Clinical Genetics

COIs: none

MMR-P Colorectal Cancer in Lynch Syndrome

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