Inside the GENOME

Myriad Live - Let’s Talk Advancements in Lynch and Other Colon Cancer Predisposition Syndromes

May 24, 2021 Myriad Oncology Season 1 Episode 16
Inside the GENOME
Myriad Live - Let’s Talk Advancements in Lynch and Other Colon Cancer Predisposition Syndromes
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Inside the GENOME
Myriad Live - Let’s Talk Advancements in Lynch and Other Colon Cancer Predisposition Syndromes
May 24, 2021 Season 1 Episode 16
Myriad Oncology

Myriad Oncology Live episodes are recordings of an open-forum webinar hosted by Dr. Thomas Slavin. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, visit myriad-oncology.com/myriad-oncology-live for a list of dates, times, and subjects.

Show Notes Transcript

Myriad Oncology Live episodes are recordings of an open-forum webinar hosted by Dr. Thomas Slavin. The opinions and views expressed in this recording do not necessarily represent those of Myriad Genetics or its affiliates. To participate in a future recording, visit myriad-oncology.com/myriad-oncology-live for a list of dates, times, and subjects.

[music]

 

0:00:11.5 Thomas Slavin: Welcome. This episode of Inside the Genome is a recent recording at Myriad Oncology Live, a webinar hosted by me, Dr. Thomas Slavin, Senior Vice President of Medical Affairs at Myriad Oncology. The opinions and views expressed in this recording did not necessarily represent those of Myriad Genetics, or its affiliates. To participate in a future recording, please visit Myriad Oncology for a list of dates, times, and subjects. I look forward to exploring the world of genetics with you all.

 

0:00:40.3 TS: Hello everyone, welcome to Myriad Oncology Live. I'm Dr. Thomas Slavin, thank you for joining today. And this is our weekly webinar series, if this is your first time, looks like many people are repeat folks, but, yeah, if this is your first time, it's a live weekly webinar series and they're theme-based. A little housekeeping as always to start. Last week's was great. Yeah, Rob, Fitch, and Finch and Lauren Sferrazza, just did a fantastic job. We had just great discussion around LGBTQ issues in hereditary cancer specifically, and how it affects that community, how we can be more sensitive as providers, when working with that community and some of it was direct, some of it's even indirect, things like, how do you even have test requisitions and materials written. So yeah, a great discussion. Today we're talking about advancements in Lynch Syndrome and other colon cancer predisposition syndromes, and next week we're gonna get into HRD, so please join us for that one, that'll be a good discussion.

 

0:02:05.7 TS: And you see here, we'll come back to tumor germline later in the month, and then kind of getting a little lighter. I didn't build out all of July yet, but June is a little lighter, people start taking vacations here and there, and we had ASCO going on and a few other things, so June's a little on the light side. July, I'll build out once we kinda get into June or so. And if there's ever a topic that you really wanna have on discussion, please just let me know or Shelly know, and I see Shelly on, thanks. She will help with the chat, so if there's any questions, she can always... Feel free to unmute yourself but if you're not wanting to unmute, definitely send a chat to Shelly. And also, just to help everyone, we're recording, because we get a lot of requests just to have these available for people that can't unfortunately make these. We're... We still haven't put any of them up. We're talking through different ways to do it. We may just do it as like a general podcast-type format, just so there's some audio if anyone wants to go back through and listen to any of the really good topics.

 

0:03:20.9 TS: But we did start recording, so even last week's will be up at some point. And then, Shelly may also present a little bit, there was a recent paper that she was a co-author on, towards the end today, but without further ado, I'd like to present Dr. Eduardo Vilar-Sanchez, thank you for coming on today. So, Dr. Vilar-Sanchez is a medical oncologist at MD Anderson, and I've never met you in person, but we had a nice... We did at one of the CGA podcasts, based on some of your recent research, and then when I thought about this topic, I thought, jeez, yeah, you'd be perfect to bring on, because from that podcast, it was very clear that you're really plugged in to where prevention of colorectal and other cancers potentially are in Lynch syndrome, whether it's through chemoprevention or vaccine trials, things like that, so if you wanna unmute yourself and maybe tell the audience a little bit about what you do at MD Anderson, how maybe you got involved in all of this research, and what your current interests are, that'd be fantastic, kind kick off the discussion and anyone, feel free to ask questions throughout. We keep this as a very informal, flexible format.

 

0:04:48.4 Eduardo Vilar-Sanchez: Awesome. Well, thank you so much, TJ, for inviting me here today. I think this is a great format. So about me, about myself, so I am a medical oncologist by training, as you said very well in the introduction, I am originally from Spain, so I trained in medical oncology in Barcelona, at that time in Vall d'Hebron University Hospital. So I was one of the earlier trainees of Jose Baselga and Joseph Tabernero. And then, over... During residency and I had the opportunity obviously to be very exposed to the research, and particularly, my focus in that day was more colorectal cancer, but then became very interested on hereditary syndromes, familial cancers, and started to build up a translational research interest in the area. So then after...

 

0:05:58.4 TS: I saw you did a fellowship, yeah, in Michigan, right? 

 

0:06:02.7 EV: Well, yeah, so then after that is when I decided, after my residency, decided to spend some time to do a peer postdoc fellowship. And so, then I moved to Ann Arbor, Michigan, where I was initially doing just research in the laboratory of Steve Grover, who many of you may know, somebody that has been working as well in hereditary cancers for a long time, and continues doing so, right now at City of Hope. And then after that, Steve was the one that put the bug on whether or not should I consider to stay permanently and then develop more of my career in the United States, and then I had to subsequently retrain in hematology and oncology at the University of Michigan, so overall, I stayed in Ann Arbor for almost five years between my research time and my clinical fellowship time. And then I moved to MD Anderson Cancer Center in Houston. That was January of 2012 and basically, recruited by Powel Brown and Ernie Hawk for the Department of Clinical Cancer Prevention in MD Anderson where I have stayed since, and so this was my first faculty position. [chuckle] So in MD Anderson, the Department of Clinical Cancer Prevention is a very heterogeneous group of individuals where we have basically one branch that runs our Cancer Prevention Clinic and we basically do a screening and prevention for breast cancers, colon cancers, melanoma and whatnot. So part of the department are clinicians that are basically practicing full-time in prevention issues.

 

0:08:06.0 EV: Then, there is a part of the department that basically are PhD scientists that run research labs that are interested on understanding molecular carcinogenesis, in general, but early initiations, the first steps that lead to the transformation of normal tissues into pre-malignancies. And then, there is a group of us that are MBPhDs, physicists and scientists that we do both, so in my case, I continue practicing as a medical oncologist in MD Anderson one day a week and, basically, my clinic has evolved. So I continue seeing patients with colorectal cancer and where I provide care from the medical oncologist standpoint but then, I am also a faculty in the genetics program and I do see patients with hereditary syndromes, same basically, what we would do in a clinical cancer genetics clinic, recommend and work very closely with the talented group of genetic counselors that we have and discuss issues with genetic testing and then, obviously, balance after that.

 

0:09:19.0 EV: My specific focus, obviously, is more towards GI. There are other groups that do more breast, but basically pancreas, colorectal, stomach is most of what I see and then, obviously, within the community in MD Anderson then, naturally, many patients that run into, unfortunately, diagnosis of cancer within the context of hereditary syndromes also come to me and I take care specifically of them. And then the rest of the time is basically running my research firm that right now is a little bit spread all over the place. So I have a lab where I have a group with lab researchers, PhD researchers, and again, we are interested on understanding molecular carcinogenesis from the very initiation point. We have mouse models, but always use...

 

0:10:20.3 TS: So just in hereditary cancer or just in general? 

 

0:10:23.0 EV: No, yeah, yeah. So that was hereditary there, we use hereditary cancers as...

 

0:10:27.9 TS: As a model, yeah.

 

0:10:29.0 EV: As our model, right? Particularly, FAP and Lynch syndrome. I think there are, historically, they have been exceptional models to understand and sporadic carcinogenesis, what I will say more chromosomal instability carcinogenesis and then, mismatch of repetitive phase in carcinogenesis. And then, obviously, they serve as a model but at the same time, help us to identify targets...

 

0:10:50.5 TS: Yeah, of all this, yeah.

 

0:10:54.1 EV: And then, we push that into another of my hats, which is basically implement clinical trials. And in that regard, we have a very nice collaboration with the Division of Cancer Prevention in the National Cancer Institute, and we are the half of one of the, so called, consortia to develop early phase chemoprevention and immunoprevention clinical trial. So that's where, for example, the work that we published recently with Naproxen was generated and...

 

0:11:26.4 TS: Yeah, and we'll dig into that in a little bit 'cause I... Yeah, I think so.

 

0:11:29.0 EV: Yeah. And then the other thing is, there is another part which is more in silico system biology where from the get go, we were very interested on using next generation sequencing and understand better what is the genomic landscape of normal at-risk tissue and pre-malignancy. It's kind of funny because when I started to do this back in 2012, people thought that we were a little bit crazy like, "Okay, you're going to sequence somatic mutations in normal tissue, but you're going to find nothing there." And that was the feedback that I was getting all the time and I was like, "Well, no, these tissues are at risk, so they should be accumulating mutations."

 

0:12:14.3 TS: You're ahead of your time. [chuckle]

 

0:12:16.5 EV: Well, I mean, I don't wanted to... Also, I don't wanted to over sell the entire process. I think we always approach these issues from a naive standpoint and then we realize how complex it is, but I think, we, at least, we took the chance and again, naively, but I think we were right and obviously, there has been a lot of subsequent research, not only by us, but by many others that basically have been hammering on the same issue, that there is already somatic genomic variation that you can identify in normal tissues but then, obviously, working on pre-malignancy and we have a very, very good biobank of samples that we have been collecting over the years from our amazing Lynch syndrome patients, families, and also as well, FAP and other genetic syndromes, and I'm sure everybody here is very, pretty well aware. So, that's what I have been doing for the past nine years and so far, it has been a really, pretty good ride and enjoying it basically every day.

 

0:13:38.0 TS: Yeah, that's great. You're definitely a full-plate kind of person, it sounds. [chuckle] How many days of clinic are you doing a week? 

 

0:13:46.8 EV: One day, one day. One day.

 

0:13:47.9 TS: Oh, okay, yeah. So you just kind of alternate between hereditary and...

 

0:13:57.2 EV: My clinic schedule is kind of funny, my PA probably has issues some times reconciling what we are saying, but it's basically intercalated, it's seemingly integrated basically, and we have our genetic patients and our oncology patients, through the day, so it's quite interesting, now, obviously with COVID, things have evolved in a very interesting way, but... So part of the clinic is virtual, part of the clinic is in-person. Obviously, initial stages of genetic testing and all of that is more virtual. I have to say that we don't do much in-person, the in-person visits that happened with the high-risk population are when they have been diagnosed and we need to discuss balance and things like that, or, yeah.

 

0:14:55.8 TS: Yeah, yeah. Great, so getting back to the chemoprevention, yes, you just had a really nice publication in Gut that came out in March looking at Naproxen. The title is Naproxen chemoprevention Promotes Immune Activation in Lynch Syndrome Colon Mucosa. Let me... I'm gonna put the link in the chat actually so people have it 'cause it's a very nice article. And that's what we spoke about on the CGA podcast, which I thought was really interesting and, yeah, I think, from my perspective, I was on the NCCN Genetic/Familial High Risk Committee, we've been talking about aspirin for some time. It's still, at the moment, off the top of my head, it's now written in as it could be a potential chemopreventative, but I think it says something like the dosing is not quite worked out or something like that or new trials are going on and, yeah, I just was wondering your perspective, and...

 

0:15:56.3 EV: Well.

 

0:15:57.2 TS: Yeah, and where all this is going.

 

0:16:00.7 EV: Yeah, I am kind of surprised, obviously, I am a medical oncologist by training, and so treatment is how we are trained, so we are trained to treat people and obviously, I went through the process of transforming myself into a prevention person. My boss, Powel Brown, defined it as, that they have induced a mutation on me, so I have mutated from a medical oncologist into a prevention oncologist. My bias obviously is the words intervention, I would say, and treat, so I feel comfortable. To me, it's a little bit shocking that we are not adopting this much more in the field. Yeah, I understand, all the theoretical... Not concerns, but all the theoretical arguments behind that too. Yes, it's a high dose of aspirin, but in reality, the paper is quite clear on the benefit. You can argue...

 

0:17:11.3 TS: This is the John Burn study.

 

0:17:14.1 EV: Yeah. But you can argue it's a high dose, sure, but don't we have enough epidemiology and research on one side, which you can argue that it's observational, but large studies demonstrating that aspirin, at whatever dose you use it, it's chemopreventive for many cancers. And then at the same time, we have prospective cardiovascular intervention trials. Now, yes, chemoprevention endpoints were not primary endpoints, but it's a wide, fairly structured research that you can trust. Now, a purist would come and say, "But the trial was not designed in that way. All that I'm saying is, we have an intervention that has been proven by multiple ways to be efficacious, and we know well the agent, we know well the side effects, we know what population to treat and get, or even apply. I don't know. Now you ask me, do you treat... Do you recommend 600 milligrams of aspirin to your Lynch syndrome patients? The answer is no, I don't. I personally don't and I don't have any problem, and I'm saying what I do, I do recommend that they take 300 milligrams. Where did I pull that dose...

 

0:18:35.0 TS: 325, you mean? 

 

0:18:35.8 EV: 300 or around 300.

 

0:18:38.9 TS: Yeah, 'cause 325 is what you can get in the US, yeah.

 

0:18:43.0 EV: Yeah, 325. I try to say 300 because then my European colleagues then don't reconcile to those.

 

0:18:51.2 TS: For those that don't know, we may just do a side on that because, so in that trial, it was looking at 600 milligrams is the primary dose, but we really can't... In the US, we do 325 tablets, so to get to 600, you'd have to... You're really going to 650, so it's been actually a point of a problem but there's probably not a huge difference between 600 and 650 at the end of the day. [chuckle]

 

0:19:21.9 EV: I think we are talking about minimal comparison but yeah, so 325 is what I would recommend that they do. Now, once I take into consideration, I look into the age, obviously. Probably my recommendation is less strong when patients are already 60 or older, and where is the reasoning for that, because obviously, in terms of life expectancy and the potential benefit over time, obviously, this goes into carcinogenesis, so you have to treat way ahead of time to then see a potential benefit in the future, right? 

 

0:20:07.0 TS: Interesting, okay, I hadn't really though of that.

 

0:20:09.2 EV: Well, if you think about it...

 

0:20:10.6 TS: Yeah, makes sense.

 

0:20:13.0 EV: That too, you see the dissociation in the benefit when you're following more than 10 years, so that gives you a little bit of the time horizon. Probably, it's better if you start recommending this when people are in their 30s, when people, they're in their 40s, and then basically you are protecting them for the ages where, most likely, their risk increases more substantially. And that's what I do. I also tend to look at comorbidities. You don't want to treat people that have hypertension, or uncontrolled hypertension. That have had, obviously, a past medical history with bleeding, GI bleeding, brain bleeding, things like that. Those are no-brainers. Where basically, you're starting to run into tipping the balance and the risk-benefit ratio is changing. So those are the considerations that I take. And then I, obviously, always tell them that this has to be done with the approval of their PCP because I am seeing these patients from a high-risk genetic standpoint. I see them, sometimes yearly, sometimes every other year. So that means that you're not directly taking care of all of this. So you have to engage the patient to engage the primary care physician and get that on board. So that's what I do.

 

0:21:38.6 TS: Do you tend to say, "I recommend this, but speak with your doctor about it," kind of thing? 

 

0:21:43.4 EV: So this is the recommendation, that's when it makes sense. I do think that you would benefit from this. Now, we need to collaborate with your primary care physician, because I'm not going to be there all the time and this is not where the patient is going to run if there is any issue, right? The last person that, probably, they are going to think about calling, it's me, right? 

 

0:22:05.5 TS: Yes.

 

0:22:06.3 EV: No. To be quite honest, right? 

 

0:22:09.0 TS: Yeah.

 

0:22:11.1 EV: So, that's what I tend to do. So that's what, again, it really strikes me when... And obviously, this is not a criticism of you guys in BMCC and panel but the adoption is not...

 

0:22:22.6 TS: I'm not on it anymore. [chuckle]

 

0:22:25.0 EV: Okay, and I have discussed this with Patrick Lynch, who is one of our...

 

0:22:30.2 TS: He's on the panel, yeah.

 

0:22:33.6 EV: Yeah. Exactly. [chuckle] So I have already talked with him many times so he's our representative.

 

0:22:39.7 TS: Yeah. And I think the language did get worked in just recently, the last year or two, if I remember. But yeah, it's a little soft at the moment. I've also thought over time that Vida brought up... Vida is an awesome genetic counselor. She used to work with a really fantastic doctor, but now does not anymore, at City of Hope. [chuckle] Just kidding. I'm talking about myself. Vida brought up, yeah, what age to start at. And so, I think these are the things that still to be maybe worked out a little bit. Because clearly, I think when it gets into guidelines, people want fairly concrete, like, "Okay, this... Do this now, blah, blah, blah." "This dose, all these things." And I feel like that's what's still is, maybe, a little up in the air. And, I think, people in the know, clearly yourself doing a lot of the research and you see the pros and cons, and can evaluate patients, that's one thing. And then, the other thing that I think is causing some delay here, truthfully, is, if you think about the patient population of Lynch syndrome, unaffected patients, or maybe patients that have been treated for a primary colon cancer or endometrial, or something. Who's really taking care of those people that are in the know? In today's era, even if you're going to a Lynch syndrome-focused clinic, like you're running, or we had at City of Hope, or some of these other major organizations.

 

0:24:09.0 TS: You're in very good hands. But most people are being seen by genetic counselors, being diagnosed, usually, there's not really a substantial follow-up at that time, there's some recommendations. And then, it becomes, kind of, a scope of practice question, sometimes, where it's... If it's not in guidelines, it's really, very clearly, in guidelines, it makes it tough for the genetic counseling community, who really isn't treating people with pharmacology, to then make recommendations to, even the primary care doctor at that point.

 

0:24:47.9 EV: Yeah, no, I understand. And obviously, that is a really good point. And I do agree as well that... But, again, the issue with prevention, chemoprevention, and then hereditary cancer syndromes, is that, I think we are also very used to sort of a level of evidence. And we have to be fairly realistic. So how much evidence are we asking ourselves to have in hand to make a recommendation? And I understand, the guidelines are written to have a maximum in the level of evidence. But again, it's going to be very difficult. If you were going to wait to answer the question of 300 to the results of the cap through your study, we are not going to see that in the next 10 years. So maybe I will be by the end of my professional life when I am capable of writing level A recommendation. So I don't know. But people need answers right now. And again, we're not talking about giving a chemotherapeutic, that's, as well, one of the things that we... Now, going back to what you're saying, is obviously, "Who is taking care of the patients?" Is a very diverse population of professionals, with different backgrounds. And I understand. I think, also, that at some point as well, there is a value in referring patients, at least once, to high-risk clinics, that are maybe more nested in tertiary referral centers, like at City of Hope, MD Anderson, or many others in the country.

 

0:26:33.9 EV: Where maybe the patient can come once and get a set of long-lasting recommendations that then they can take to their local providers. And that goes... Feeds back, as well, to many of the things that we see when these patients come. Community gastroenterologist, with frequency of colonoscopies, and endoscopies as well, there is a lot of not ideal communication in that regard. So I think the value of getting these patients seen at least once and getting a firm set of standards that then they can take later to their local providers is also important there. And in that way, hopefully addressing this point like, okay, as a genetic counselor, you're supposed to do what you are supposed to do. You may not be comfortable making a therapeutic recommendation even if it's a chemoprevention recommendation. And in that way, working with a high risk clinic can make sense. I don't know.

 

0:27:40.3 TS: Yeah. And there's probably ways to clean some of that. It could be, yeah, consider aspirin based on risk tolerance profile or something of the patient, yeah, from a genetic counseling perspective. But yeah, it's pushing the limits of some of the comfort level. And then there's other trials going on, obviously, in FAP, and looking at other, even more chemo-type drugs like Everolimus and some of those that, that's not over-the-counter at that point.

 

0:28:15.9 EV: Right, exactly.

 

0:28:16.5 TS: So it'll be interesting... Like DMSO. It'll be interesting to see where all this goes over time, and there may be some rationale even if the benefit is not huge to keep it more on the over-the-counter type of chemoprevention, not sure.

 

0:28:29.6 EV: Well, I think chemoprevention is getting more and more complex, right? And you said Everolimus, at some point, there are trials with that. Or Lotenin, now with FAP, and DSMO, as you said. So I think things are getting a little bit more sophisticated. Again, I think these patients are going to need to come to a higher risk environment, at least to get some recommendation and expert advice, if we're getting heading into agents that have toxicity profiles that are a little bit more out of the over-the-counter kind of thing, right? That could be an issue. Now, and I think this is going to be something that is going to be growing and growing. We're running more clinical trials for chemoprevention with more sophisticated agents. We're getting... We're heading ourselves into immunoprevention. We're heading into vaccines. So I think this is something that we are going to see developing in the very near future.

 

0:29:45.4 TS: Yeah. So I do wanna get into that, the vaccines and immuno-prevention a little bit. Real quick though, to close out the aspirin discussion and Naproxen, which is what your paper was on. So what year... There's some chat discussion about when would you start age-wise. It sounds like you're starting young, but I don't know if you have in your mind a certain age, and it sounds like you do. 300 milligrams, I assume, daily, of aspirin. And then yeah, why not naproxen? Or where do you think that's going, the other NSAIDs? 

 

0:30:22.3 EV: Well, I think we are moving, hopefully, into... Obviously, the phase... The trial that we reported is a phase one safety. We were trying to get the safety profile when you're doing in a chronic administration, and we were trying to determine the dose, right? So...

 

0:30:44.6 TS: And this is just for context, this is the Naproxen discussion, yeah? 

 

0:30:47.7 EV: Right, the Naproxen discussion. But the co-clinical trials with animal were clear towards a benefit over aspirin. Now, that is not the same to say that Naproxen is more efficacious in humans, obviously, it hasn't been tested. Do I think that we are going to see a head-to-head comparison trial? 

 

0:31:12.2 TS: It's going to be tough, yeah. [chuckle]

 

0:31:14.3 EV: I don't think so. For practical terms, I don't see that happening, basically.

 

0:31:25.0 TS: And why do you think Naproxen would work better? I mean, just based on...

 

0:31:28.6 EV: Well, I think...

 

0:31:29.3 TS: The type of medicines? 

 

0:31:31.3 EV: Yeah, I think it has a... And that's what we were trying to define, a wider net of biological effects. I think obviously, we have been thinking in naproxen or we have been thinking in aspirin, Naproxen, and even sulin back in FAP as cyclooxygenase modulators. That's what they do canonically. They modulate prostaglandin and then they modulate inflammation. I think there is much more into what they do apart from that. And that's, as well, what we were trying to explore in the clinical trial. I do think that Naproxen is going to have other benefits hidden there that, perhaps, aspirin doesn't have that much, or maybe they have a little bit but not that much. So I think modulation of stem cells is probably something that Naproxen does effectively. I'm not saying that aspirin cannot do it, but probably requires different doses of aspirin. I think Naproxen also works as an immuno-stimulant. Again, I think aspirin can do that, but probably Naproxen can do it more effectively or efficiently.

 

0:32:44.4 TS: And why not Motrin? Were you looking at ibuprofen and other NSAIDs? Why did you land on naproxen? 

 

0:32:51.4 EV: Because of the profile of side effects with, again, you tell me why not Motrin. Motrin, probably, is as effective as naproxen from the pharmacological standpoint and from the potential benefits on how they affect other pathways, but I think the safety profile of naproxen is beneficial in comparison to ibuprofen. Yeah. I think ibuprofen in that regard has more GI effects that basically pushes a little bit ibuprofen more towards the profile that you have with aspirin, and compared to naproxen.

 

0:33:29.6 TS: Yeah, and that's one of the bigger concerns just for everyone as is for the non-clinicians in the audience, it's, bleeds, GI bleeds. You can get ulcers, it can cause... These medicines if taken daily, chronically, you can get some major problems from them. So you do have to be pretty careful.

 

0:33:49.1 EV: Yeah, and that's something that, for example, I highlight to my patients. Even when I am recommending aspirin, it's like, "Okay, you can get stomach upset. It would be proven then, if you're nearing that point, to get your PPI or Proton Pump Inhibitor and basically making it more tolerable, but again, and I think, again, aspirin and ibuprofen tend to do more, more of that.

 

0:34:15.6 TS: Yeah, have you had any major complications from any of your patients? I did hear...

 

0:34:20.6 EV: No.

 

0:34:20.6 TS: Mike Hall said one of his patients, one time had a pretty good GI bleed that had to get fixed.

 

0:34:29.7 EV: And that is something that is consistent and that's something that I've seen. So we have to take that into account. No, I personally haven't seen any trouble, particularly, with my patients, and...

 

0:34:43.4 TS: Okay.

 

0:34:47.0 EV: But, yeah, acknowledging that that can happen, and that's a typical question that obviously, John Burn runs into every single presentation that I have seen him giving. Obviously, our colleagues in Europe are much more into cost and... Cost efficiency for their healthcare system, so they always get into that point when they talk about that, so how many you need to treat to see a complication and all of that, I think, conversation in US is a little bit more different. We probably are more focused on that individual patient, not that they are not, but their perspective is different. I think they approach the conversation from a system's point of view, rather than an individual practice point of it.

 

0:35:41.2 TS: Well, let's get into the vaccines a little bit 'cause I think that's incredibly interesting. So what...

 

0:35:46.6 Shelly: Can I ask...

 

0:35:46.8 TS: Oh, go ahead, sure.

 

0:35:47.3 Shelly: TJ, can I ask one question? Sorry.

 

0:35:49.3 TS: Yes.

 

0:35:50.0 Shelly: I'm curious, in addition to the NSAIDs, do you have any line of sight of other biologics or things that would target the immune system in Lynch syndrome patients? 

 

0:36:04.3 EV: So we have been... Well, it's a really, really good question. And one of the things that I try to articulate at some point, or at least introduce in the conversation was the use of checkpoint inhibitors. For example, I am talking about mostly drug development. And it was received with a lot of resistance, obviously...

 

0:36:32.5 TS: For chemoprevention, you're saying.

 

0:36:35.6 EV: For the chemoprevention, obviously, and therapy is well established.

 

0:36:40.1 TS: Right, yeah.

 

0:36:42.1 EV: Stage four, and even unresectable in that regard.

 

0:36:47.3 TS: Yeah.

 

0:36:48.2 EV: We, for example, have a clinical trial in MD Anderson for MSI high patients where I have recruited many of my Lynch syndrome patients that have borderline resectable and locally advanced tumors where we have seen incredible benefit. The data is going to be presented in ASCO, this is a clinical trial, and also in ESMO DI, and it is quite astonishing, I have even seen, in the luminal, complete response of tumors. When you do...

 

0:37:23.5 TS: Yeah, that's incredible.

 

0:37:24.5 EV: You repeat colonoscopy and it's gone, but well, sometime we would do... We were talking about...

 

0:37:28.0 TS: And just for other people online, a lot of that is just not that it's essentially going down the mismatch repair pathway, TMB, MSI, those are the kind of tumors that really respond well to the checkpoint inhibitors, in general, like immune therapy.

 

0:37:43.0 EV: Yeah. And I have right now, for example, a patient in the trial that is benefiting spectacularly, we haven't even breached the conversation of doing surgery because the tumor is radiographically gone, and we're talking about a young gentleman that had a mass in the transverse colon that it was actually involving even the stomach, so it's quite nice, but again, going back to chemoprevention, again, the conversation shifts because now we are talking about a healthy person or at least a cancer survivor that has no evidence of disease, and we're talking about using agents that can induce immune thyroiditis, immune hypophysitis, a pattern of inflammatory bowel disease like. So we were not able to articulate a clinical trial, at least using funding from the NCI because the perception of the risk of potential secondary effects was too high, right? 

 

0:38:51.0 TS: Yeah, it's similar in my mind of using PARP inhibitors in a, BRCA One or Two patient for chemoprevention, you do have a lot of hematologic side effects, other things that it's just, it's hard to take a medicine like that sometimes and move it into, yeah, like you're saying a healthy person that really doesn't have any problems, not to say that won't happen, and maybe at very low doses, that it would actually work really well, I don't know.

 

0:39:17.6 EV: Yeah, and so then I think the problem is then the push back has been quite important, and we have missed the opportunity to discuss what should be the dose, now the drug developers bringing up the point that at least the generation of checkpoint inhibitors that we have, the side effects do not follow a clear dulled respond pattern, but I think obviously, there is not that many patients that have been treated with low doses, so I think at some point, we're going to have to bridge that gap, and I hope that that can happen at some point. There was a clinical trial for Lynch syndrome patients that Ohio State was able to articulate with NIVO and it was closed...

 

0:40:10.0 TS: Due to side effects.

 

0:40:13.4 EV: Not clear to me. I was not involved in the clinical trial, but it was... I think it was closed after three patients. I don't have... So the informal rumors is that it was not due to side effects, that it maybe was more a industry type of decision. But nonetheless, we're not going to learn any... Unfortunately, we're not going to be able to learn anything from that. So their response obviously is that I would love to see other agents, I hope that subsequent development of future immune checkpoints that hopefully may have less of a side effects, or maybe that we can revisit the issue of using them at lower doses. I do think that it's a very important question in the field. Which brings then, to the point that TJ was heading into is then vaccines. Because obviously, if immune modulation, we have been pushed away from checkpoint inhibitors, I think, then is when the field has tried to embrace more immune manipulation towards vaccines, which it's is kind of like a little bit more accepted. And now in COVID times [chuckle] even much more accepted because we are all thinking in vaccination all the time. So we have all, all of the sudden all of us have become...

 

0:41:44.5 TS: We've advanced our vaccines, and especially I mean, when people sometimes... I think it hasn't hit us yet, what we just did with all these vaccine rollouts is, we really created a whole new class of vaccines, with the RNA vaccines and even the Adenoviral vectors, just understanding a lot more. So I think we really advanced our vaccine knowledge as a whole, probably by 10, 20 years. So I don't expect just because we get a handle on COVID at some point, or we're pumping out now adequate vaccine or tweaking it or whatever, that all of a sudden we're just gonna stop advancing the science because we essentially cured a common version of the cold. Not to downplay cold, but Coronavirus is a major general cold virus, so the fact that we were able to even create a vaccine to squelch it, and to a good extent is pretty amazing. And then you think about like, "Okay, now what can we do with this?" And the reason these companies were already again kind of in progress was because there was so much anticipation around this technology and how you can use it, and even just the RNA side around cancer and everything, so.

 

0:43:00.6 EV: Yeah, absolutely. So as somebody put it in the chat a case report from the oncology... In the general oncology, there is another one that I'm going to put in the general cancer prevention research. And it's a similar concept, basically, patients with Lynch syndrome that incidentally had been receiving checkpoint inhibition for other reasons. This case report is particularly interesting because you see the modulation of a scheme, a scheme neoplasm over time in this patient when he was treated with checkpoint inhibition. So that it speaks to the fact that you can prevent basically pre-malignancy and cancer using checkpoint inhibition.

 

0:43:46.6 TS: Yeah, that's great, yeah.

 

0:43:47.3 EV: And I think we are going to see that popping up more and more and more, because obviously, there is going to be patients that are receiving treatment and with these checkpoint inhibitors for other cases so...

 

0:44:00.9 TS: Yeah, and maybe, just thinking out loud, CMMRD, Congenital MisMatch Repair Deficiency syndrome, that's been so impressive on the checkpoint inhibitor side that I... And that it is a very serious disorder with a extremely high cancer burden, I could potentially see chemoprevention starting there, but the problem is these are just rare diseases, they are hard to get cohorts together, hard to get funding for trials, yeah.

 

0:44:27.1 EV: Oh, it's very difficult. I can tell you, again, the privilege that I have is that I am sitting in an institution that gets a referral of very complicated and interesting cases but my experience, and I have had a young gentleman with CMMRD, secondary to biallelic mutation in PMS2, and this young guy was receiving treatment for a brain tumor, which is very typical in CMMRD, and at the same time, presented with polyposis and we have seen modulation of the polyposis, coincidentally with being...

 

0:45:04.2 TS: Interesting, yeah.

 

0:45:05.0 EV: With giving treatment, giving him treatment, so...

 

0:45:05.7 TS: So yeah, maybe that's how some of this will come about, as just some secondary effects...

 

0:45:10.7 EV: Now...

 

0:45:11.0 TS: Yeah, that you're seeing.

 

0:45:11.2 EV: But what you are saying is true, articulating a clinical trial in this context is so difficult.

 

0:45:19.8 TS: Yeah, it's probably never...

 

0:45:21.1 EV: Pretty hard... Right, so getting these patients, it's just very, very, very, I mean...

 

0:45:26.3 TS: It could potentially through the international network or something, but yeah, it's just very challenging, yeah, and a lot of times, unfortunately, yes, when people are identified with CMMRD, they're already affected with some type of cancer often.

 

0:45:39.8 EV: Correct, correct.

 

0:45:40.3 TS: Because it's usually coming from PMS2 and MSH6, which isn't the most expressive in the heterozygote state through families, and so the families sometimes aren't overt, but then some child or something is born and they just have tons of cancer burden.

 

0:45:55.8 EV: Exactly. The patient that we were discussing in particular, obviously, is a PMS2 carrier, parents are Lynch syndrome carriers, known after the fact, and they never ran into any cancer issue, right so.

 

0:46:12.0 TS: Yeah, no, that's amazing. So yeah, so what, the vaccines... We have about 10 minutes left, so I definitely wanna touch base here. So where are those at right now, in your mind? 

 

0:46:22.6 EV: I think we are... Obviously, there is a group in Germany that has been working on this for decades, and they run the initial clinical trial that has been published recently in Clinical Cancer Research, although it was executed a long time ago, the so-called Mycorics trial, that Matthias Kloor is the, I believe is the first author of that publication. And tested the administration of three peptides, those are based on the assumption that these peptides are frameshift peptides, then therefore these peptides are not present in normal tissue and that they... These are recurrent peptides that emerge because as we know, microsatellite instability tends to accumulate in recurring loci across the genome. So they vaccinated a population of MSI High patients with these three peptides and then they saw an increase in immunogenesis. So...

 

0:47:31.9 TS: And so these are peptides that are being... I guess, I'm still trying to get my head around it. So they're peptides that are just of specific genes that are...

 

0:47:43.7 EV: Yeah, and I think it's in the publication. Well, I can find it and put it in the chat box, but... So if I don't...

 

0:47:49.0 TS: Are they related to the MMR pathway, is that...

 

0:47:53.3 EV: No.

 

0:47:56.1 TS: No? Okay.

 

0:47:56.2 EV: One, if I don't recall wrongly, there's three peptides. One is TGF beta. It's a TGF beta receptor two, so it's a frameshift mutation that is going to impact in the coding region of TGF beta. I think the other one is called HT001 and...

 

0:48:15.9 TS: But why do you get these from the, just having problems with mismatch repair? Is it just kind of the common...

 

0:48:23.0 EV: Yes, right. So there has been as well, a very nice bioinformatic analysis performed by Colin, the group... I mean, it's Colin Preacher and J. Shinder where they were basically leveraging, for example, data from the TCGA and looking into the MSI, and basically trying to pinpoint if there are loci, microsatellite loci across the genome that are more susceptible to accumulate coding mutations, and you can even see a specificity at the level of tissue. So the recurring coding microsatellites are going to accumulate microsatellite instability in the colon are different from the endometrium and are different from the urothelium but there is a shared recurrency among the MSI high tumors basically. So the same thought is applied to Lynch syndrome carriers that the deficient mismatch repair system is going to basically induce recurrency in these specific prone sites, and therefore, vaccinating you for that is going to protect you over potential neoplasia that is going to emerge at some point.

 

0:49:48.7 TS: Yeah, it's interesting though to me that the proteins don't get rapidly broken down, that you can actually target them because usually they have nonsense-mediated decay or something going on, and you just wouldn't have much to target from a vaccine, I would think but...

 

0:50:00.3 EV: Again, again, and that is one of the issues. Immunoediting, right? So you have these flimsy peptides, part of those are naturally cleaned up by our non-mediated decay system, but there are some, again, that they're more prone to stay. And this is the concept behind the vaccine. In an essence, you have to equate it to a virus with the distinction that the virus is there, it's foreign, and it has those fixed proteins there. In some sense, the tumor, it's also foreign, it's foreign to you, in the sense that your... That mismatch repair system is broken and it's merging those neoantigens that are not native to your genome, and that is what you want to make your immune system able to recognize, so the immune system can clear out deletion when it's very, very... In very early stages basically.

 

0:51:06.0 TS: Yeah, yeah. No, really interesting, I mean, yeah, well, this is gonna be exciting to see where all this goes over time, yeah.

 

0:51:12.4 EV: Yeah. Obviously from a statistical standpoint, it makes sense then to vaccinate with vaccines that offer more broader recognition in terms of neoantigens. There are difference schools of thinking. Broader vaccines that cover many neoantigens or maybe more specific vaccines that have the concept that, "Okay, it doesn't matter. We just want to go after that neoantigen that is highly recurring and it's going to induce high immunogenicity, so if we can recognize at least one neoantigen and clear out deletion through that neoantigen, it's all that it takes," right? 

 

0:52:02.4 TS: Yeah, yeah. No, very, very interesting. And yeah, and then we'll see... Gene editing is gonna be coming along, and again, with the vaccine advancements that we just made with our pandemic, I think there's a lot of opportunity there, just replacing...

 

0:52:17.1 EV: Absolutely, absolutely.

 

0:52:17.7 TS: Mismatch repair proteins, not the protein but the RNA and then making proteins and things, yeah.

 

0:52:24.2 EV: Absolutely, now that we are also used to receive RNA based vaccines, the question is that what about a non-RNA based vaccine? Now, we don't even need to inject with adenovirus or peptides. Why don't we go to RNA, right? So I think the pandemic, for better or worse, has introduced... It's bringing up an entirely brave new world for us that may benefit patients with Lynch syndrome in particular so.

 

0:52:56.5 TS: Yeah, yeah, all kinds of hereditary conditions, so... No, this is great.

 

0:53:02.4 EV: As well.

 

0:53:02.5 TS: Yeah, well, so we have five minutes left. I don't know if there's any questions out there. Well, let's take a quick pause. If anyone has any questions, feel free to chime in. I know we've been filtering some through the chat here and there.

 

0:53:13.8 Shelly: I don't have any questions that have been sent directly to me, but I encourage people to unmute and ask them live.

 

0:53:22.2 TS: Yeah, feel free. Give it a second. We'll make it an awkward silence, that way someone has to chime in.

 

[chuckle]

 

0:53:37.7 EV: Yeah.

 

0:53:37.7 TS: And then you know Shelly...

 

0:53:39.0 EV: Oh, let me see if I can...

 

0:53:41.2 TS: Shelly, there was a recent paper, just to put on people's radar, since we're on the topic of Lynch Syndrome that I ask Shelly just to show and she can post it real quick in the chat, which is great, do you wanna give people a really quick rundown, Shelly? Yeah, the Rachel Perlman study, if people haven't seen it.

 

0:54:05.8 Shelly: Yeah. Yeah, I know, I personally could listen to Dr. Vilar-Sanchez all day 'cause he has a lot of interesting things to share with us, but the first thing we need to do is identify patients who have Lynch Syndrome and how is the best way to go about doing that, in Ohio State, as everybody knows on this call are leaders in this field, and do you recall Rachel Perlman had a paper out describing that Ohio in 2017, describing the whole state of screening patients, and they, in that paper, they described the 450 patients that were less than 50, the recent paper that I just posted looked at the entire population and what... They came out with three major recommendations, and then their overwriting conclusion is that about at a minimum, a 7.1% of patients with colorectal cancer, have a pathogenic mutation that is actionable, which is right in line...

 

0:55:10.6 TS: Hereditary.

 

0:55:11.1 Shelly: Hereditary, yes.

 

0:55:14.5 TS: Yeah.

 

0:55:14.6 Shelly: And that's right in line with the numbers that we see for pancreatic cancer, where all pancreatic patients get tested, as well as metastatic prostate cancer, so it's pretty significant, hopefully, this group will push that forward, so maybe some guidelines will change and make testing become a bit easier.

 

0:55:32.2 TS: And also, what jumps out to me in that paper is, if you just look at IHC and MSI by tumor testing, your miss is a substantial amount, I thought it was like 4.6% or something, I can't remember off the top my head.

 

0:55:46.0 Shelly: Yeah, well, the despite the MSI being more sensitive than the IHC, in this group, the MSI failed much more often, 14% compared to 0.3%. And so they recommend the IHC because for all the variety of reasons we know, you can target into the gene, less tumor used, but they really drove home the point that that 1.7% is probably an underestimate, it's probably much higher due to the prevalence of pathogenic variants, due to some of the implications, and if you solely rely on tumor screening, you're gonna miss a substantial number of patients, so.

 

0:56:35.3 TS: Yeah, with underlying mutations.

 

0:56:35.6 Shelly: Pretty exciting.

 

0:56:35.7 TS: Yeah, yeah, no, very, yeah, a big advance in the field, so yeah, we'll see how all this kinda comes together. So thank you for sharing that, Shelly. And I know we're at time, I appreciate everyone being on, and thank you, thank you, thank you so much Dr. Vilar-Sanchez, it's just really amazing to see... To get someone like you on here and just go through the expertise that you have on the research side and just give people a perspective of where the field's going when it comes to the chemopreventative opportunities, how you're implementing it in practice, is fantastic, then, yeah, and where the potential for vaccines may come in, and a lot of hope for patients with Lynch Syndrome and then, yeah, I agree, Shelly, ending on, now how do we identify people? So it's really that we have to pair that together and hopefully we can keep identifying more and more people and then have those people in a better set up for true prevention of some type. So thank you so much for coming on, I really appreciate it. You're a fantastic guest.

 

0:57:40.3 EV: Well, thank you for the invitation and, yeah, very, very interesting moment that we are all living in, this type of initiative, I think, is great and to have the opportunity to chat with all of you and share experience and knowledge, so anybody please do not hesitate if you guys have any questions or anything, they has to shoot me a quick email, I think my email is widely available through a Google search, but if not, it's [email protected], it's pre-described for, so... But thank you. Thank you for the invitation, TJ.

 

0:58:19.7 TS: Yeah, no, thank you, no, this is fantastic and hopefully, hopefully, we figure out chemoprevention before you retire.

 

0:58:25.1 EV: Right, Hopefully. We have still some years.

 

0:58:29.5 TS: I know. Thank you again.

 

0:58:31.2 EV: Thank you guys.

 

0:58:31.9 Shelly: Thank you, thank you.

 

0:58:32.6 TS: Thanks, Shelly. Bye.

 

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