Educated Patient® Webinar: GI Cancers Series Part 2: Translating Molecular Testing Results Into Precision Medicine in GI Cancers

Advocacy Groups | <b>GI Cancers Alliance</b>

Hear from an expert panel of health care professionals and advocates who will discuss topics for patients, survivors and caregivers on molecular precision medicine in GI cancers.

Martha Raymond

Welcome to today's live broadcast and educated patient webinar, GI cancer Series Part 2: Translating Molecular Testing Results Into Precision Medicine in GI cancers. I'm Martha Redmond Executive Director at the GI cancers Alliance. We are pleased to bring you this webcast presented by cure in partnership with a GI cancers Alliance and sponsored by Amgen Oncology and Elevation oncology. We encourage you to ask questions during the event, which you can submit by typing them in the Q&A box you see on your screen. Now it's my honor to welcome our panelists for today's webinar. Dr. Marshall, our moderator, physician, Executive Director of MedStar, Washington, DC integrated hematology oncology division, director of the Reusch Center for the Cure of Gastrointestinal Cancers, and Chief Medical Officer of the Lombardi Comprehensive Cancer Center, Georgetown University; Dr. Eng, Professor of Medicine and co-leader of the ICC Gastrointestinal Cancer Research Program at Vanderbilt University Medical Center; Dr. Ciombor, associate professor of Medicine, Division of Hematology and Oncology at Vanderbilt University Medical Center; and Dr. Pant, associate professor in the Department of Gastrointestinal Medical Oncology, at The University of Texas, MD Anderson Cancer Center. And now it's my privilege to turn the microphone over to Dr. Marshall.

John Marshall

Martha, thank you very, very much. And I will thank my colleagues in a minute, but I want to give a particular shout out to all you do with the GI cancers Alliance. For those of you who aren't aware, we formed a group where all the different GI cancer advocacy groups get to play under one tent. And we are so pleased that they have brought forward under your sponsorship, this program for our audience tonight, and our audience tonight is in for a real treat. Because I'm not talking these people are talking and these are not only some of my best friends around the world, really that an honor to know them and be a part of them. But they are also world's experts in the arena of precision medicine in GI cancers. And I want to sort of set the stage for our audience, that this is the second of three programs that we are putting on in this area of focus. And I just want to give a quick flashback for those of you who did not see the first of these it is online, it can be viewed. And in that a different group of us really drill down on what we mean by precision medicine, what is what is it to do a gene test or a protein test on a patient's cancer, maybe on the patient themselves? To find out if they have some inherited cancer problem? Why does it take so long? Why does my doctor note know where the result is in their chart? What is how does it we interpret the result? Why are there some mutations that matter a lot, and some that don't seem to matter much at all. So that is really what we drill down on the first session, distinguishing the testing itself. And on today, what we're really going to focus on is what tests do we need to order. And for different kinds of cancers, there are different menus of tests that we want to order. And many of us will do broad testing, or what we call next-generation sequence testing or broad molecular testing, where we will not just cherry pick one or two different gene tests, but get a huge panel of all the known cancer genes, for example, or even broader panels than that, believe it or not. And so what we're going to start with, and I'm going to pick on you Dr. Eng first is we're going to talk about some of the really high-level abnormalities that are commonly seen in GI cancers. And there isn't one that probably is more important than RAS and it's related pathway members, BRAF and others. So maybe you can kind of drill down on R-A-S. We used to think of it just KRAS, but maybe more broadly, RAS and its related Partner BRAF and others. So take us through that pathway.

Cathy Eng

Sure. Um, thank you so much for inviting me to participate in this. So we now know obviously that position oncology is key for our patient population to provide the most optimal treatment for patients. And we know for colorectal cancer that KRAS is a mutation that commonly develops earlier during the transition from becoming a benign cancer and with time becoming a true colorectal cancer. We've also identified KRAS is one of the first mutations that's very, very common in our colorectal cancer patient population. We're talking primarily in our stage 4 patients that we're doing this testing in, and about 35 to 50% of patients are going to have basically a KRAS mutation. And you can break that down even further, where there's even more specific subtypes of KRAS mutation such as we're now hearing about G12C, and new drugs specifically, specifically for that in colon cancer, which is pretty rare. It's less than 5% of our patients. But more importantly, it tells us that, in fact, although we thought RAS was not targetable, if you have a potential for further acknowledgment of the different subtypes, specifically in G12C, there are drugs now that are targeted ... for these patients and their tumor types. We also know that pathway is a critical component, basically, as you mentioned, regarding BRAF, or MEK pathway. And, really, I think the most important component also is to acknowledge the fact that we need to test our patients. We also know that when you look at RAS, we also have to take into account if you're newly diagnosed patient if you have a left-sided tumor or right-sided tumor. So if you have a right-sided tumor, and you have a RAS mutation, those patients not do not do fare as well, number one just for in regards to sidedness but number two, we know that they have limited treatment options. So that's the drawback about having a RAS mutation. So once again, it's really important to test these patients for this very common mutation. And now we also know that the BRAF mutation, specifically V600E, is less than 10% of our patients and can be associated with a very aggressive tumor type. And it's very important to test these patients, once again, with next-generation sequencing, if available, to ensure that if the patient has a BRAF mutation, there was targeted drugs specifically for the BRAF mutation in previously treated patients. And we also have a clinical trial currently ongoing for newly diagnosed patients. So we want to be able to help those patients up front. And that's why it is so critically important to identify these various mutations.

John Marshall

So let me come back. So it focused this time on colon cancer, we do see these RAS mutations and some other cancers as well. But we know a lot about the colon cancer. And so a lot of times you brought this out, it's really an important way to think about it is that for RAS mutation rules out some drugs means that we don't want to give medicines that predicts that the drugs won't work. A BRAF mutation brings in some drugs. And so I think this this distinction of mutations that are shaping our treatment decisions, giving the right drug to the right patient, but just as importantly, not giving a medicine that won't work to other patients. And so I think that's a great way to start our discussion. One other thing I've come to do more lately is sort of mutual exclusivity. And Kristen, we'll get a chance to talk about her too in a minute to that. You don't have both a BRAF and RAS (mutation). It's like one thing's broken in the pathway. But usually not too is that your take on it as well?

Kristen Ciombor

That is my understanding as well.

John Marshall

So if you have one, you probably won't have the other, but our argument is to is to test all of those. So those are those are very important. Dr. Ciombor, let's go to you next. Really one of the most exciting targets, if you will, that people are mixed about rooting for but not wanting at the same time because of the mixed signals that has is around MSI, PD-L1. We see it every night, PD-L1 is read during a commercial during "Jeopardy Tournament of Champions" every night. So I think our country knows about what PD-L1 is, but maybe they really don't maybe you need to set a straight. So in the sign PD-L1, talk about those markers a bit.

Kristen Ciombor

So we we've known for a while that microsatellite instability or this MSI. Also kind of on a related note, mismatch repair deficiency are really important markers to look for, especially we used to think only in colon cancer because it was potentially a screening test for Lynch syndrome, though not everybody who has MSI-high disease, has Lynch syndrome, certainly, but but it could help us, you know, kind of whittle that down. Now we know though, that it's that it's a predictive biomarker, meaning it helps us understand (and) it helps us identify the patients (who) can potentially benefit from immunotherapy. Microsatellite instability is across the border across any cancer. We can see it though it's in different prevalences you know, depending on tumor type. So we know in the colon cancer space actually metastatic colon cancer that's MSI high, we can start with immunotherapy right off the bat, we can skip over chemotherapy altogether. And for some patients that that can be extremely helpful. We're starting to learn that. Also, even in the earlier stages, immunotherapy may be helpful in rectal cancer and colon cancer. Being able to start with immunotherapy might be the strategy for the future, and it may save patients from radiation and some other treatment modalities. So it's a really important test to know right off the bat, no matter what stage of colorectal cancer and in general, you know, with all advanced cancers, whether you have microsatellite instability or not. Same thing with mismatch repair deficiency, they're tested in slightly different ways. So that's why they're they're kind of distinctive, but, but they're both biomarkers for immunotherapy response. Now, PD-L1 is a little bit trickier, and there are different ways to test for that too. And there's not a huge consensus on which is better. But but we do test for PD-L1, which is very common and really important in other tumor types, not just GI cancers, I would actually argue that in more tumor types, it's helpful then, then in actually GI cancers with the exception of maybe esophageal and gastric cancer in which it really is treatment changing, again, for responsive, you know, biomarker for response to immunotherapy. But that one is a tricky one because it is a spectrum of scoring system. So you'll typically either get a negative or a positive and then it can be a numerical value. And typically we think the higher the score that the more likely you may benefit from immunotherapy. But that's not a that's not true across the board with all tumor types, some some cancers, really we don't use PD-L1 at all. Colon cancer is an example of that where MSI is important, but not PD-L1.

John Marshall

Could you get in the weeds a little bit about why these two markers predict for immunotherapy? So I mean, we're gonna get later into like a patient's ability to interpret their own report. So you know, a PD-L1 of one versus a PD-L1 of 50, and maybe even you could throw in tumor mutational burden as a concept. Why why are they connected to why are these markers connected to potential benefit of immunotherapy?

Kristen Ciombor

So it all comes back to the immune system. And and as you mentioned it often, for instance, microsatellite instability is related to often tumor mutational burden. So you can actually have a non-MSI-high tumor that also has a high tumor mutational burden that can sometimes respond to immunotherapy, but it usually has to be very high for that to be helpful. But basically, what we know in MSI-high colon cancer, for instance, is that these tumors that are MSI-high have 1000s of mutations as opposed to the more sporadic ones, the ones that are microsatellite stable, which may only have a few mutations that we can identify on our testing. And those those mutations as act like antigens or sort of receptors for the for the immune system. And that's how the tumors become kind of immunologically hot, where it can be a perfect target for these PD-1 inhibitors and PD-L1 inhibitors to then come in and and work their magic. So usually, typically, PD-L1 score, the higher the better, though there are no true not necessarily true cut offs depending on the type of tumor type. So you can still, even at a low level, still get some benefit from immunotherapy depending depending on which to me you're talking about. MSI is more of an either you have it or you don't. It's not as much of a spectrum as PD-L1.

John Marshall

Yeah, I always thought that you needed PD-L1 there, if these PD-L1 drugs are going to work, but it's not a it's not completely connected, right, you can have these drugs work even in the absence of this. But in other cancers, having a high level is really required. Yeah, as you say, in our cancers, it's a lot grayer there. And that's why our patients are maybe hearing mixed messages from the ad during Jeopardy, and what they're hearing in clinic from us, right, so maybe switch gears just a little bit to her to which you know, most of us think about as a breast cancer target. And but, you know, we've crept over into the GI cancer world. So this is kind of related to Kathy's pathway that she was talking about, so maybe bring that around.

Kristen Ciombor

Yeah, yeah. So her team, as you mentioned, you know, we knew for a long time was really important in breast cancer. And and we're starting to learn from the from our breast cancer colleagues as well that, you know, and, and we're not we're trying to we're trying to keep up with them and Um, but but there are some differences and really important differences in GI cancer. So, so two tumor types we think of in particular, where HER2 is important are the esophageal gastric cancers. And interestingly, you know, that's an important thing to test out right from the beginning, the amplification are over expression. And then more recently in colon cancer, so so we know that it's not very commonly found, it's more commonly found in the left side of tumors, and it is more actionable or targetable. If if it also has a KRAS wildtype gene. So KRAS mutations, they don't they're not necessarily mutually exclusive with with HER2. But, but what we know from recent studies is that her two looks very targetable. You know, again, some of the breast cancer drugs that we used to use, trastuzumab, we use in colon and, and esophageal gastric cancers now, and there are some newer agents. So the mountaineer study in colon cancer just showed tucatinib/trastuzumab, so an oral pill and as well as trastuzumab looks to be very effective, even in patients who have had, you know, growth on on many different kinds of chemotherapies. So that's really exciting. It does look like in this case to, again, it's a spectrum, where, you know, the higher the overexpression of HER2, the more likely you are to respond to anti her to directed therapy. So that's really important. And sometimes it actually takes us a little bit of research to try to figure out how high this overexpression is from the common platforms that we test that we use for testing. But it is a key key feature.

John Marshall

That's great. So let's get out of Tennessee for a minute. Let's move further south to Texas where Dr. Shubham Pant is sitting at the moment, at least I think that's where you're sitting. And, and really, in your discussion about targetable is really a perfect segue over to the list of targets that we've asked him to kind of bring forward. And that is, when I think if targetable it's like, we have the key for that lock. And if your cancer has that problem, then the medicines we can do can undo that problem and shrink the cancers and have a more potent response than say our, if you will dirty bombs of chemotherapy that are just killing through other mechanisms, killing cells through other mechanisms. So should we really picked on you to talk about some less common but I think, equally important, because when you find them, there's a lot you can do about it. So maybe you can walk through some of the other targets that are out there that may be much less familiar to our audience.

Shubham Pant

Exactly. And thank you for the opportunity. John, I'm actually in Texas, I'm sitting next to the room where Dr. Eng used to be. Kristen, you're lucky to have her there. So

Cathy Eng

Did you take over my office?

Next door ... I could never do that. I would never do that out of resoect. But just trying to tell the folks in Tennessee how lucky they are to have Cathy they're amazing physician, amazing mentor. Coming to the coming to the you know, these needles in haystacks. So why should we even whenever people asked me for diseases like pancreatic cancer, why should we be doing we should be doing next-generation sequencing? You know, because they say, well, it's not nine in 80%, or 90%, clear as driven. So why should we be doing next gen sequencing? But my answer to that is if you don't look you won't find. So we really are looking for some of the needles in haystacks. And when I was in fellowship long back, if you had a patient that biliary tract cancer or cholangiocarcinoma, it was universally survival of six to 12 months, there was just chemotherapy out there, gemcitabine, cisplatin, and over the last decade over the last specially over the five years, there has been a lot of you know, now everybody is doing next-generation sequencing for for biliary tract cancer. So for liver cancer specifically, we have a number of targets, we know that every part of the liver is different. So you can have intra hepatic biliary tract cancer, which acts very differently than gallbladder cancer, which acts very differently than extra hepatic biliary tract cancers. So for example, when you're looking at the mutations, there's a mutation called FGFR. It's more of a fusion. So there's a kind of a fusion; the gene fuses to something else, and causes this mutation which causes the cancer to grow. And there are three in targeted therapies against it, which have which have been FDA approved and accepted approval in second line setting or after first line frontline setting in these patients. So it's been a very exciting journey in these patients with FGFR inhibitors, and it's only about 5% of intrahepatic. Cholangiocarcinoma is very rare subset. But if you find these patients, they get very durable responses to some of these agents, that prognostically that means overall, they're going to do better, but they do really, you know, they do really well with these agents. So it's I think that's a big win for sequencing and GI cancers, as Kristen was talking about. One of the upcoming targets actually building track cancers is also HER2-neu. So HER2-neu is overexpressed in about 5% of extra hepatic cholangiocarcinoma. It's actually about 20%, and gallbladder cancers. So again, when I said it's really different, is overexpressed. And you know, there have been studies which were presented in ASCO this year, in which the same compound which was an antibody drug conjugate on ADC against HER2, which was positive. So a big positive study in breast cancer randomized study coming back to breast cancer, we had a smaller study called the herb study, which was also showed high response rates, or in patients with biliary tract cancers or gallbladder cancers. We presented some of our data with another agent, which combines two antibodies together. And that also is showing responses in biliary tract cancers, also to drugs, which are used for breast cancer trastuzumab and pertuzumab, when used together was recently published, actually, and it is in the NCCN guidelines, which are some of the guidelines that we use in biliary tract cancer. So you know, it's amazing how these targets are almost tumor agnostic now that they go across different tumor types. MSI high, it's about 1% and will retract cancers also 1% high in pancreatic cancer. So there's, there's a lot of these smaller targets which are coming up ... So I was gonna go on pancreatic cancer now. So folks are very realistic about pancreatic cancer, you know, there's a poor prognosis, but I can tell you it 90% Yes, could be KRAS driven. We have other drugs for KRAS cancers also which are coming up, but 10%, a KRAS wild types, and that is for younger patients with pancreatic cancer, just like Cathy has a big, you know, big movement and, and for younger patients with colorectal cancer, which we're seeing more and more, we're actually now seeing younger patients have pancreatic cancer in their 40s. And they have a higher percentage chance of having a clear as wild type mutation. That means sorry, they do not have a mutation scare as wild type. But they do have mutations 30 to 40% of cases wildtype, pancreatic cancer can have targetable mutations. So there are other drugs called NTRK fusions. There are drugs approved for this. There's one another fusion called NRG1 fusion, and we've, we've had data presented where a couple of drugs are being developed to target that fusion, they can have RAF fusions, which can also be targeted with drugs called MEK inhibitors. So there are a lot of different moving targets in KRAS wild type, pancreatic cancer also, in addition, there's the FGFR that we were talking about and will retract cancers will fgfr fusions can be seen in pancreatic cancers also. And we presented some data with a drug called erdafitinib, which is a FGFR inhibitor at ASCO this year, with children up to 30% response rate in patients with pancreatic cancer, obviously, these were early data, more data data readout is going to come. So you can have you know, unless you look for these needles in haystacks, you're not going to find them. And these patients can get durable responses to these targeted agents. So we really need to look.

John Marshall

Yeah, that's so good. That's really very clear. I wanted to for our audience, make sure they understood that wildtype is not me in college, it actually could have bolded that, but it's

Shubham Pant

already above John, because that was

John Marshall

normal wild type is what we call the normal gene. But I wanted to kind of shoot come back to you with the question about tests. I mean, when we do CAT scans, you know, say everybody thinks their CAT scanner is better than the other. But we all pretty much get the same test when you order a CAT scan, or all genetic tests the same can can patients assume that if their doctor is ordering a genetic test, that they're going to get all of the things that you we've listed?

Shubham Pant

Yeah, John, great question. So I think you alluded to this in your previous talk also, previous session, also in which there are two kinds of testing germline, which is again, this is what your parents can pass on to you. And it's hereditary. And you can have somatic which is testing in the tumor tissue. So great example is pancreatic cancer, that if you have a germline mutation and BRCA 1 or 2 (which) appears in about in 10% of patients, that is actually you have an approved drug or library, which is a drug target, which a PARP inhibitor, which targets this certain mutation germline, in the somatic, which is a tumor tissue, we do see some responses, but it'snot to that level that we see in germline patients. So it's very important to distinguish it. When it comes to the different testing platforms, and there are numerous of them out there, you know, every institution, big institution have their own testing platform, or their commercial testing platforms out there. You know, it's a, I think, wherever you can get tested is fine. It just should be a clia-certified test. That means it can be clinically used for your physician. Some may have more genes than the others, but overall ... it's this test which has been certified to use in the clinical sense, that's what I would do.

John Marshall

Cathy.

Cathy Eng

I mean, I think we would all agree, though, right, we also would love to have tumor tissue if it's available. Because that obviously gives us more potential mutations that may be identified. And then keep in mind, obviously, certain platforms have DNA versus RNA, where you can pick up some fusions, and where with other platforms, you may not have that opportunity. So there are some fine differences. And I just think it's really important to keep in mind, if we don't have tissue, right, then we will opt for a blood sample for mutation analysis, but that we would always try to retrieve tissue if available.

John Marshall

And that's why we want you to go through that biopsy and get a big enough piece, if you will. So we can test it, because not all these tests do the same. And I will, our audience needs to know, I mean, the four of us know that not everyone in the medical profession understands this, that the different tests, they think they're getting a comprehensive test. And so it covers everything, when in fact, they're not completely sure of it, what's supposed to be in there. And even for the four of us, there are things that change year to year, even six months to six months, where the test from two years ago is no longer up to speed for how we need to do it. So everybody needs to understand one of the reasons we're holding these sessions is to the smarter you all are, the better, we will be at making sure you get the right answers and move forward. Kristen, I'll pick on a new next, I always think about whenever I get a new genetic report back from a patient, it's on, I get actually a little excited, to be honest, which I'm going to show, right. And so I also, once I open it, it sort of puts me in a mindset for that patient, opens up some doors closes others, maybe surprises me. So maybe talk a little bit about, you know, from the physicians perspective, how we take these reports and sort of begin to translate them into therapies.

Kristen Ciombor

I have the same reaction. It's like opening it opening a surprise gift. In some cases, a gift you don't want. But hopefully in you know, as we get more research and understanding behind these, these targets, you know, we have more positive predictive biomarkers, meaning these are actionable, these are things we can we can utilize the information and treat that patient accordingly. So we're used to be when I think back even say 10 years ago, when we sent next-generation sequencing and that, and that was kind of the earlier stages, we really only could use it, it was really only used to select patients for clinical trials. Often it wasn't we weren't using it in our day-to-day practice, because we just didn't have the data that showed how we were to do that. So you think about how far we've come and even the last decade to say, you know, now, I mean, truly, you need the information upfront before you make any treatment decisions for the most for the majority of patients, especially with advanced GI cancers, where you know, your first line, your first line of therapy is really is really decided by this. So you think about microsatellite instability, you think about whether there's a RAS mutation or BRAF and, and so it really is critical. I think the communication to patients and caregivers to is something we could probably improve upon. And I do get sometimes, you know, sometimes the patients get an alert from our medical record that they, you know, there's this report back and, you know, talk about intimidating to try to figure out what this all means. So, you know, we tried to try to sit down with patient at their next appointment, say, "OK, this is what's important. This is what we can kind of put on the backburner and may or may not become important in the future. But this is how we're going to use this information right off the bat." And I think the key is to get the information as soon as you can, because it can change therapy right up front.

John Marshall

I was interested. You know, in the first episode, we talked about, say breast cancer, they don't even start without ER, PR or HER2 et cetera. But they've developed systems so that they get those back really very quickly. Whereas a lot of our testing can take time and actually need confirmatory. So Cathy, I'm gonna pick on you and I know you've had a very busy day, but this was one of my former fellows called me today. I just have phone number on my cell I didn't know actually hesitated but answered that I was glad I did. She had a patient a funky tumor, it was carcinosarcoma in the colon. So we'll start there, but the IHC so the protein analysis that they got back right away had one missing protein, but she had sent it for broad molecular profiling. So the pathologist had read MSI based on the protein. Then the the gene analysis came back, microsatellite stable All, but the tumor mutational burden was like 40. So here's a doc that's trying to decide whether to give immunotherapy to a patient in a difficult tumor to start with, and has conflicting molecular data. So I was like, you know, it was a tough answer for me, because I felt like, I would want to try some immunotherapy. But my enthusiasm was less because of the the MSI genetics, but the TMB was high. So I, you know, even I, first interested in what you think about that, but it gives an example of how complex this can be when we get a result back.

Cathy Eng

That's a very challenging situation, obviously. And when you see that you have loss of expression, you do get excited, right? And you're thinking, well, then you're all set. You know, in that scenario, you know, and we also know that there is data to say that there is concordance, right, between your NGS testing, and your microsatellite testing as well. So it is a challenging situation, but I'm almost once again, I don't know much about this case. But you know, if you if you really trust that pathologist and you believe that IHC is correct, and then you have a high TMB, it almost makes me feel more comfortable with accepting the fact that that is a microsatellite-high tumor. That would be my impression, especially if you have this once again, I don't know much about the case.

John Marshall

It was it was an adjuvant question. So it makes it a little easier. But so we can move on. But I don't know. But, Shubham, let me move over to you because I got a zinger for you. So what if you do one of these panc(reatic) profiles, and you get back somatic, so the tumor has a BRCA mutation, and we've got therapies that are approved for germline? Do I have to do germline? Is that enough? And I get a lot of calls like that? Is it? Is it really the biology is matters? What's in the tumor and not what's in the patient's? So these are the kinds of questions that are coming up as we this moving target. What's your take on that?

Shubham Pant

That's fair, John, thank you. And thank you for that question. The tough questions. But to answer your question, I think really the germline should be done in all patients with pancreatic cancer because we can really catch you know, these BRCA 1 and 2, and we know the and we also know the responses early so if they get some platinum-based therapy, you can introduce a PARP inhibitor, or even going to different platinum therapy. So instead of getting FOLFIRINOX you could give them gemcitabine/cisplatin, which really has a higher response also in these patients with with pancreatic cancer. Now, again, if your somatic was had BRCA testing, I would test the germline also. Because, you know, it could be just somatic. You know, we have cases in which it's, you know, it's just in the, it's kind of just in the gym in the DNA in the tumor, but it's not in the blood, not like a CT DNA, but not in the germline or in the germline testing, but it is in the somatic testing. And really, when we look at the data on the somatic testing, it's really not that robust. So patients who've been pre exposed to a platinum agent, which is mostly FOLFIRINOX in our frontline setting in pancreatic cancer, and they are refractory that means they have their tumor has grown in spite of that therapy, then they really don't tend to seem to get a good response with the so called you know PARP inhibitors. So it's a it's a complicated, multifaceted question. Now if they were platinum sensitive, then I would be fine giving them PARP inhibitor, but I would do a confirmatory germline testing via proxy.

John Marshall

You guys couldn't have been better at answering those because it basically is the point as soon as I throw out to us, a result like that, our brains just start to track down a pathway of data, right? So that's specific for that kind of patient. And instead of just treating everybody the same, we all of a sudden, designate a different set of treatments, a different set of expectations from our side. And, and that's why it's so important that we have these tests in hand, because otherwise we're sort of flying blind, and making guesses. So our audience should really appreciate just how valuable this is to us. Cathy, let me come back and pick on you. But this is not picking on ... So I know you're such a good patient that we all are good patient advocates, but I know you're particularly strong about this. And so what should the patient know? What should they know? Should they keep it in their diary? Should they how do they know what should be tested? Where do they go for the information to know what their cancer what they need to know about their cancer?

Cathy Eng

Yeah, I mean, it is. It is a struggle. I think at times for patients that they just don't know enough information. I think sometimes and I think they suspect that everything's been done that needs to be done already. And they that we should have all the answers. But the reality is, I think for any state specifically for any cancer patient nowadays, as Kristen stated, everyone should be tested for microsatellite instability, right, that is such a key part of what we do, regardless of the tumor type. And actually, as ship have mentioned, for pancreatic cancer, all patients should be tested. But in general, I think, you know, it is critical that for specifically for stage 4 patients testing needs to be completed. It is, as Kristen stated earlier, it makes a huge difference on what clinical trials you may participate in, it makes a big difference in providing precision oncology, which is what we always have to provide for our patients, if there's something that is targetable. And it really sets the stage for the sequence, right. And so I think that that is really also a key component of why patients really need to ask their doctor have, do I have an inherited form of cancer? And has the testing been completed? Was it available on the tissue? Was there enough tissue to be tested? And if not, can I do some type of testing through simply a blood test? Because you know, that that can be done, I think it's just really important that patients feel informed, that they're engaged in the discussion in the conversation, that I think is a critical component to providing the best care possible.

Shubham Pant

I hadn't been one more thing, you know, to add to that, and I've got a patient with net for that is that patients really need to be their own advocate. So if they really take one thing away from the show, a couple of things is, really, if you have stage 4 cancer, GI cancer, please, you know, talk to your provider about doing the next-generation sequencing, and hear them out about the pros and cons. I mean, there may be pros and cons to every patient case. But we think in majority of the case of the GI cancers, definitely with, you know, cholangiocarcinoma, I would say in majority of them, maybe hepatocellular is a little different, but majority of them really should talk to their provider about doing a next-generation sequencing because one is targetable alterations. The second thing is I had a very interesting case, patient who came down from another state to move to metastatic pancreatic cancer, stage 4 pancreatic cancer to move down to Texas to be near his family. And he was he said, you know, if I'm not going to live that long, I just want to stay with my sister spend my final days here. And he was on gem/abraxane for two years, which is rare, as you know, in pancreatic cancer. And ... he had a next gen-sequencing done locally. And when I got a sequencing report, he had an NTRK fusion. And it's really sad, it really said that, you know, it said, you know, if you really look at the patients can look at the report themselves, a lot of these reports say FDA-available therapies available, you know, what I'm saying, if you really look at the report, so I think patients can be their own advocates, they can, you know, ask for that next generation sequencing. Also, they, you know, maybe they should look at their own tests and kind of go through it, but their physician if they see something like this, because these tests normally give, even they talk about if there's anything FDA approved for them, clinical trials is different, those are a little bit harder to navigate, but they are FDA approved. So I instantly call the patient I said, "Listen, ... this is like, you know, again, finding that needle in a haystack." You don't find it unless you're looking specifically for it. And, you know, we're, you know, we really do this day in and day out, so we can spot it. And we like I said, with Kristen, Cathy, and what you said, John, is it's like opening up this, you know, like not a Pandora's box, but you know, opening up this kind of, you know, this rapport and thinking if you can find something, and this was one of the first cases of Adric fusion that I found, and you can imagine how excited I was that it was. So those are the things that really patients can be their own advocates about the next gen sequencing. And also maybe just speaking at the report, the first couple of pages to see if there is you know, they talk about some any available FDA approved therapies.

John Marshall

So I give them their report, and they try to walk them through that... Kristen, what I was gonna say is that, like, we are teaching hospitals, doctors are busy, doctors and private practice are busy. So, you know, it can be like one more step of, you know, just we don't have time, but it seems like to me, it's really critical for us to be educating our patients to make sure that they know and if patients shouldn't be too careful with us, if they don't know they should, it's in their rights to know this right? And so if their doc's angry at being asked, and, you know, they'll Calm down, it's okay to ask.

Kristen Ciombor

And I think it's important also that, you know, it's not just physicians these days. So our advanced practice practitioners or you know, our NPs and our PAs are often well versed and we try to teach our, our nurse practitioners you know, what we know and how it's evolving because they're, they're great allies and and help us with patient care as well, as well as some of our clinic nurses. So you know, a lot of this is moving really quickly and changing by the day. So it's important for the whole team to be up to speed not only the physician and patient, but kind of all of the caregivers as well.

John Marshall

I always think of it as opening a Willy Wonka Chocolate Bar and

Shubham Pant

wondering if you have the golden ticket to better one than Pandora's box.

Cathy Eng

So one day, Kristen did have an NTRK and we share the same clinic day and I was so jealous, because I felt like she won the lottery. I felt like a lottery that

John Marshall

day, I've only had one so far. So but I keep looking, keep looking. I got two more subjects. And so I want to make sure our audience has time to to put in some questions. And we'll leave some time for questions. But Dr. Pant, what I want to talk about with you is sort of tying clinical trial accrual to these genetic tests. So I got an email from a company I partner with that one of my patients had a mutation that allowed them to be eligible for a particular clinical trial. Well, it turned out that this patient is fine and doesn't need a clinic. It doesn't have cancer at the moment. So it worked out. OK. But, you know, all a lot of these reports have pages of clinical trials that are out there that this their mutation targeted into. So maybe talk a little bit about the connection to clinical trials in these tests. And we'll get into a little bit about how do you pick which one, which one, would you hop on a plane to get? Well, first, just big picture, talk about clinical trials and genetic testing.

Shubham Pant

Thanks, John. So we have another one more hour left for the show, I'm guessing. 30 minutes, I'm just joking. I'm just doing perspective, I'll give perspective. So I think really if you had to do one thing with targeted therapies, you really look for the clinical trials, which are showing, you know, an annual annual physician should know this, because a lot of this data comes out if it's highly targeted towards a mutation. So let's say if you have a KRAS G12C mutation and are eligible for G12C inhibitor that's highly targeted towards the mutation; if an NTRK fusion and FNN trick and butter that's like the you know, that's the nail and the hammer, you know, you've got a you've got the hammer, if you've got an NRG1 fusion, and if you have, inhibitors towards that those are the ones in a way that I would fly for essentially. There are a lot of generic ones; what patients have to understand if they really want to talk to their physicians, these are mostly in phase 1 trials, but I think patients should not, you know, when they look at the consent form, it's it's safety and tolerability. They should not get scared about reading that because a lot of phase one trials now offer these targeted therapies which are effective even at lower doses. So they can definitely ask their physician, hey, how many patients with this mutation have been on this trial are using responses on this? And they can kind of talk to them, you know, what are the side effect profile, and those are the points of discussion that patients can do. So the lot of generic trials, but if you have these specifically targeted trials, then then those are the ones that patients should get on a plane for I had one patient by one of my first patient that MD Anderson had an NTRK fusion, the trial was going on at that time, flew in from the Northeast, and she still comes in and sees me, and it's been six years since I've been here. So that is the power of that and that patient started on a phase one trial off that enteric drug. So that is, you know, that is the power of the response when you get that these are durable responses and MSI-high patients. That's also like Cathy said, and Kristen said, that's the cure, we never used to see cure. with stage four, we always tell the patient that's treatable, not curable, treatable, not curable, right. We say that every day. But these MSI high these drugs are game changers, some of these enteric few, you know, NTRK, fusion drugs are game changers, that they can really have this long tail as we call it. It's not the two year survival. But you see these graphs in which those patients just keep on living beyond year two, three, and four, with the tumor being suppressed. It's almost like we have our foot on the neck of the tumor, we don't allow it to grow. So those are the trials that will travel for.

John Marshall

I think that patient really just wants to maintain their one case status. That's why they're we can we can debate that later. I'm the oldest member of this crowd here. And I can remember when phase 1 studies that you mentioned, every patient could get in them. And and now you it's a very, very specific subgroup of patients. And so I'm hearing a lot of frustration from referring physicians frustration from patients themselves, that there are really not in Any early-phase studies unless you have one of these very specific options for I'm assuming that's the case at your all centers as well. But, you know, are we learning? are we opening new doors is really what I'm, I'm getting to. Kristen, Cathy, what do you think we're getting more targets?

Kristen Ciombor

I think we're definitely getting more targets, you know, they the hard thing is that they're, they're this smaller prevalence targets. So it can be hard to, you know, fully accrue the studies, say on one institutions now, you know, we see multiple institutions banding together to try to get the this research done. And I do think, you know, for patients, it requires a lot of work to be on a trial, you know, and really, I am more and more impressed every day by, by what patients go through to be on these studies for no guaranteed benefit, we always are hopeful that they're gonna benefit. And we've all seen, you know, instances where patients lives have been dramatically changed for the better from trials. But I do think it's, you know, it needs to be a two-way conversation between the physician and the patient and understanding kind of what, what those what the options are trial and on trial, and then I think it is getting harder, unfortunately. But we are we're learning, we're learning more biology, not only targets, but classes of agents, other new chemotherapies, I mean, you know, I'm always astounded at how much things have changed, even in the last, you know, 10, 15 years since I was in training and how dramatically, our care has changed of patients, too. And hopefully that will continue.

Cathy Eng

Let me just I fully agree, I think that there's definitely a lot more targets, that is definitely a bit more challenging, as Kristen said, because there's a lot of boutique mutations. Now, to which it's harder if you know, we work at large academic centers. But not all, community practices have those opportunities to open up those very select trials due to the fact that they're rare mutations, and it makes it challenging, because there's obviously a lot of money in order to open up a trial, and you want to be able to enroll so many patients, given the time and effort it is to activate a trial. But I do also want to emphasize because this is a patient purchase participation form. It is critically important patients participate in clinical trials, we cannot get drugs FDA approved. And last, we have patients that participate in clinical trials. And here in the United States, we do not do as great of a job as our Asian colleagues and our European colleagues. And I think it's just really important for patients to understand not every single trial has a placebo. And they shouldn't be fearful, just looking at the trial and the possibilities. Exactly as as Shubham stated, you know, there's going to be some potential toxicities listed. But some of these trials have significant importance. And the only way we make advances in the way we treat our patients is if we have patients participate in clinical trials, that we can get to the phase 3 studies that we need to do.

John Marshall

Absolutely sometimes not even need to do phase 3, if the phase one looks better. Let me let me invite Martha back in because we have about 10 more minutes left. And I know you all have had a busy day. And with a little bit more work to do, including tucking in people at home and things like that. So we really appreciate the time you've you've spent. So Martha is an expert on the patient side of things as well. So I don't know if there have been any questions added into the chat are things you would like to bring up?

Martha Raymond

Sure will thank you to everyone really informative conversation. We had some really great questions in the chat. And I've consolidated them a little bit. The first one is, as we mentioned, it's so important for patients to be their own advocates. If if their physician doesn't recommend testing, should they ask for next-generation sequencing? What do they ask for? Anybody?

Shubham Pant

Yes, I can take that. Thank you, Martha, for that question. Yes. So I think that's what they should ask for is that can we get next-generation sequencing on our tumor? I think sometimes, it could be that there's not enough tumor. So you can actually do circulating tumor DNA or CT DNA assays, you know, on on some of this specially in key patients with colorectal carcinoma or bile duct cancer, where you have targetable mutations. I can't think of any physician who would not do a testing for colorectal cancer in this, you know, in identify because they're FDA-approved agents, but they can ask for for some things. Let's say pancreatic cancer is a good example. Yes, they can ask for next-generation sequencing of their tumor, and sometimes the tumor tissue is not not available or it's not adequate to do it. Like I said, then you can do a circulating tumor DNA, or you know, I would even recommend if, if it's not, if it's safe to do, then maybe do a repeat biopsy to really get that tumor tissue, because we can really unlock some, you know, the clinical trials or some standard of care therapeutics.

John Marshall

And then you guys, I think, have your own testing internally. But, for example, we here in Washington, decided to have strategic partnerships with companies who do this. So patients need to be aware that their team, their medical team might have a different way of doing it. But almost every health care team out cancer care team out there has some strategy to ensure that they get state-of-the-art testing. But it slips people's minds, I think the patient needs to know that, you know, sometimes we get caught up and we you know, we were treating we using something that is standard that doesn't require testing, we look back and say it's never been done, or and to our surprise, so it certainly advocate to make sure it has been done is important for everybody. Thank you.

Martha Raymond

And as a follow up for long-term survivors that may not have had testing or had it, you know, maybe 10 years ago, I think is Dr. Eng mentioned, is that something periodically that survivors should ask for, you know, the newer type types of tests? Kristen?

Kristen Ciombor

Yeah, I think that's a great question. So as we're seeing patients live longer, you know, that's a real good question. Because our technology, our sequencing technology, is ramping up so much. And we're finding new targets that never used to be actionable. So in some cases, we can go back and look at at the at the old reports, and that's sufficient, in some cases, we do need to do newer tests. Additionally, there are some instances in which the tumor profile can change over time. And we need to we need to identify that as well. One example of that in colon cancer, sometimes, patients who start out with a normal version of the ras gene and get treated with something like panitumumab or cetuximab certain drugs targeting that the EGF receptor, sometimes they can actually develop RAS mutations over time, and that can change how you treat them in the future. So that's not always standard of care. You know, that is definitely a case-by-case situation, but just wanted to bring out the point that sometimes the mutational profiles can change over time. And that can be an important thing to ask about, too. What is more likelihood that my cancer no longer has that profile, you know, should we retest, but also making sure that you have the most up to date and current technology and current genes that we know are actionable and tested for is really important.

John Marshall

In our systems are learning as we go. So there is often a concern about insurance coverage and doing repeat biopsies and these blood tests. And it's, it's a little gray, I have to say out there about what is covered and what's not and what's really required and what's not. So we're at this where we are torn between wanting to be sort of push the envelope state of the art, but also good stewards of our nation's money, our patients money, and the health care dollar. So there's always a tension between those two, and this is one of those places where that tension is, is certainly felt. Maybe we have time for one more. Is there another question out there?

Martha Raymond

Yeah, so something I think that's important for all of us. You know, and as advocates, we we all try to provide our patient communities with the very best information we can and so many of our advocacy partners, you know, especially in the GI space pan, can colorectal cancer, Alliance, etc. have amazing advocacy tools to help patients find clinical trials. But I'd be interested to learn, you know, what, what you recommend for patients, if they are looking for a trial?

John Marshall

They might want to jump in.

Shubham Pant

I can take that. So ours is when you're looking for clinical trials, again, it is it is it is very complicated. Unfortunately, the best source is obviously their physicians who can help them guide them about you know, look at because there's a lot of additional information given a lot of the straws may be open may be closed may not be relevant to the patient's case. So let's say for me, we run a number of targeted trials at MD Anderson for pancreatic cancer and biliary tract cancers. That's what I do predominantly, is we get emails directly from patients, saying, "Hey, you're the principal investigator..." They know if you go to clinicaltrials.gov. It lists the principal investigators. They reach out to the trial teams, but the best I've seen as physicians, that their physician, they can go to physicians who can help them and advocate for them, I get emails from physicians who say, "Hey, I understand this," because obviously they have made, you know, training. And they understand that the pathways and everything a little bit better, which may be relevant to the patient's case. So I would really have this conversation with the patient and their local physician, I think that's very fruitful. And I've had physicians email me, and patients show up here at Anderson, you know, to enroll on clinical trials, but you're right, it is it is exceedingly complicated to look through these trials to know which one is which one is relevant to that that specific case.

Cathy Eng

I would say that, yeah, I would just chime in and say, it's really important. If you're not sure, have your doctor reach out to somebody that does know the data, because we all traveled to national international meetings. So we know most of the ongoing trials. So um, but we all have connections with those in the community, please just reach out. I'd rather you reach out to us and asking your doctor to reach out to us rather than just proceeding with the standard of care if there is something that is specific to that patient that they may have grown to benefit from. So

John Marshall

Phone a friend. That's right. Yes. Well, listen, Martha, thank you very much for coming on and helping to moderate and I will want to thank everybody here for taking busy time away from family and cleaning up work to join us. So, Martha, if you want to close this out, take it away.

Martha Raymond

Sure. And again, thank you to everyone our wonderful panelists, Dr. Marshall, Dr. Pant, Dr. Eng and Dr. Ciombor, incredible conversation. This webinar has been recorded. So it will be available on cure today.com In the next day or so. And we look forward to seeing everybody for part three of our webinar series and GI cancers. And again, thank you to cure today and to our sponsors, Amgen, and elevation oncology. So thank you again.