Educated Patient® Webinar: GI Cancers Series Part 1: From Symptoms to Testing and More


Hear from an expert panel of health care professionals and advocates who will discuss topics for patients, survivors and caregivers including diagnostic workup in GI cancers and the importance of testing.

Martha Raymond: Welcome to today's live broadcast and educated patient webinar, part one of our GI cancer series, from symptoms to testing and more. I'm Martha Raymond, Executive Director at the GSK GI cancers Alliance. We are pleased to bring you this webcast presented by CURE®, in partnership with the GI Cancers Alliance, and sponsored by Amgen, and Elevation Oncology.

There are just a few important announcements before we begin, we encourage you to ask questions which you can submit by typing them in the Q&A box you see on your screen. You will also be receiving a survey via email tomorrow. As a thank you for completing the survey, you will be entered to win a $200 Visa gift card.

And now it's my privilege to introduce our esteemed panelists for today's webinar. Dr. John Marshall, physician Executive Director MedStar, Washington DC integrated hematology oncology division, Director Ruesch Center for the Cure of GI Cancers, and Chief Medical Officer Lombardi Comprehensive Cancer Center at Georgetown University Medical Center; Dr. Elizabeth Montgomery, clinical professor, director of Surgical Pathology Fellowship Training Program, and co-director of Pathology Reference Services at the University of Miami Miller School of Medicine; And Dr. Christopher Lieu, associate professor, associate director for clinical research and co-director of the Gastrointestinal Medical Oncology at the University of Colorado Cancer Center. And now it's my pleasure to introduce our moderator, Dr. Marshall.

Dr. Marshall: Martha, thank you very much. And thank you for participating in this. We will get you back on, I assume, once we kind of go through our comments, because you're so helpful in organizing these things and bringing out the best in us. So we really appreciate it. And for all the audience out there, for me, this is the best way I can spend an hour. These are some of my favorite people on the planet. And I never get to see them in person anymore very rarely. And so to spend an hour together talking about this important topic of precision medicine and pathology and our interaction is really my treat. So thanks to Martha and thanks to (Dr.) Chris (Lieu) and Dr. Montgomery for joining us today.

And I'll just kind of kick us off with some high-level questions, and I'll address them initially to Dr. Montgomery. And I think pathologist, you know, we keep you people in the basement, although I see you have a window, which is very nice. A lot of people don't appreciate the role of pathology, as much as they should. Patients often never meey their pathologist who's read their tissue, or understand the process that's going on. So we thought this whole series was best kicked off with talking to not only a pathologist but a brilliant and experienced GI pathologist. So thank you for joining me.

You know, when we you will get tissue from a variety of sources, somebody's had a surgery, and the surgeon decides to send you some of the tissue. With a cancer diagnosis, you get often a lot of that. On the other hand, sometimes we'll order a biopsy where somebody, a gastroenterologist might take a piece or interventional radiologists might put a needle in something, and then that gets handed off to you or your team. Could you, from your side of things, once we've done that on our side, patients often perceive that part of the formula what happens next; where does it go? What do you do with it? How does it work? Give us your spiel.

Dr. Elizabeth Montgomery:All right, ready for this spiel? So if you’re an lucky or unlucky person having a biopsy, it's quite common. Anybody who has a colon will be offered colonoscopy starting at age 45. Unless, of course, you have special risk factors that my team — these great guys know better than I do — will be asked to go for colonoscopy or if you're having trouble swallowing someone might put a tube down your mouth and then into your esophagus, your swallowing tube, to take biopsies and there's literally something that looks like a pair of pliers but very tiny with a little stack in it and it's put down inside you and literally a bite is taken out of your tissue. It pops right back out same with a call and palette and then it's dropped into a little container containing actually slightly poisonous substance called formalin; it's a liquid, and it causes the tissue to become a bit firmer, and it makes sure that the tissue doesn't rot so that the DNA is preserved. If it just sat in the cup, it would just turn into mush and smell terrible. And all the DNA would degraded. And that's going to be become very important. So once that happens, we go through a series of steps. And a very interesting thing happens. First, we put various levels of water in the tissue. And we do these sequential pourings in of different fluids. And eventually we have 100% alcohol, like the kind that you would drink, except you wouldn't want to do that. And then eventually, because alcohol can, can dissolve oily compounds, the alcoholic face is then turned into a wax phase. And it's literally paraffin wax like you would make a candle. So this is a sample taken from someone's colon … you can see these little pieces of tissue notice I can touch them safely. I won't catch anything from touching them, then, very, very thin slices are made from the stuff in that's embedded in paraffin. And we eventually will be interpreted.

Dr. John Marshall: How do you pick what goes in the wax? How do you how do you decide what you're going to preserve for long term?

Dr. Elizabeth Montgomery: So if somebody has a biopsy of his or her esophagus, or stomach or colon, all of it goes in, nothing is discarded. On the other hand, if you go to Dr. Marshall, or Dr. Lieu, and you take chemotherapy, before you have an operation, then a giant hunk of tissue is taken out, for example, a segment of coal and it could literally be this big, we'd literally then dissect it open and look at it. And we choose the areas that make the most sense to turn into glass microscope slides. After two weeks after we put out a report that is discarded, so we have to do a good job up front. And the vast majority of the time we do, I am not going to lie and say, there aren't occasionally issues.

Dr. John Marshall: Big freezers have chunks of body parts down there, you end up with those green things in a file, right, that goes into a file cabinet somewhere and is kept for a long time.

Dr. Elizabeth Montgomery: In many institutions, forever in perpetuity. Unfortunately, because of storage issues, sometimes, in some institutions after a number of years, this the materials discard it. So for that reason, I know some oncology colleagues like to organize special testing right early on to have the information in case something goes wrong down the road. But let me show you what happens. So after all these things are done. This is a glass microscope slide. This is from a very large tumor. So that piece of pink stuff is the tissue that's been colored with a special dye to make it easy to look at under the microscope. And so that's just a small fraction of a giant tumor. In most situations, say you have a colonoscopy, this is all the bigger your biopsy might be. Same if you even have like a cancer of the esophagus, stomach or colon, it doesn't take much tissue to say that you have cancer. What we can't tell is how deep it spread into your body. We only know the type. So that's kind of what happens with tissue. And then of course, here's my trusty microscope, I look at this slide under the microscope.

Dr. John Marshall: And literally for the audience, just before we went on, on the air. Dr. Montgomery had one of her team come in and she reviewed a case and I said, you know, it's probably a quality check to make sure you've got the right things or maybe it's a diagnosis read.

Dr. Elizabeth Montgomery: It was from the right fresh from the operating room because there's a quickie procedure we can do if a surgeon is operating and see something weird and wants a quickie interpretation. So that's what that was. So the surgeon could figure out what to do next in the operation.

Dr. John Marshall: And it's so huge that you can get a piece like a bite from this alligator-clip size thing. You can get a whole piece of the colon and you can pick and choose what you want. Sometimes we have doctors can only sneak a little needle into it not even like us micro-apple-coring kind of thing, but just a few cells can be drawn up in to a syringe and we call that a fine-needle aspiration. But you say, even from something like that you could make a decision about cancer versus not cancer. But maybe what you lose in that is what we think of as the architecture or the exact relationship to normal tissues. Is that right?

Dr. Elizabeth Montgomery: That's exactly right. Actually, I'll show you another sample. This is again, you can see the pink there are little lines, this is actually a liver biopsy from a patient. And you could see that there are three little cores. But you can see a very small needle took that. But Dr. Marshall was talking about using an even smaller needle, and the advantage of the teeny tiny needle, of course, is that it's like getting your blood drawn. But the disadvantage, of course, is that we don't get as much tissue. And then if Dr. Marshall says, "oh, gosh, we need to do major sequencing," there may be insufficient material.

Dr. John Marshall: Yeah. And so in just a general sense. You know, we often take a week, sometimes, to for us to get your official report, we might get the quickie from the (operating room), but we don't get the official report. Can you talk a little bit about what that process is like. And if I could also go as far as if you've got a colon sample, for example, a whole colon for resection, the concept of staging cancers, and because that really falls to you guys to do that, you're the ones who officially call that state.

Dr. Elizabeth Montgomery: So that's a little more of a lengthy process. But actually, in most hospitals where I've worked, if somebody has a small biopsy from the gastrointestinal tract, the vast majority of the time, we can put out a written report in 24 hours, or you know, maybe that you have it in the morning of day one, and it's in the afternoon of day two. So things can be turned around quickly. Occasionally, though, you'll have a biopsy, and there'll be a delay, because quite frankly, nobody knows what the biopsy shows it some weird tumor that requires all sorts of ancillary or additional testing, and then that can get lengthy. As far as if you have, for example, colon cancer, and you have the length of your colon taken out, it'll be about this long. And you know, about like that around that, in a straightforward example, only takes two to three days. Sometimes there are delays, and I'm sure you've experienced them or there can be issues. So to stage. For example, for colon cancer, we look under the microscope and see how deep into the wall of the colon, we see the tumor cells, we also look for and you're certainly knowledgeable about this, both of you, we look for lymph nodes. So lymph nodes are these funny little, they're like your swollen glands. So if you have a sore throat, you'll notice you get these nasty little bumps. Well guess what, they're the same things outside your colon and cancer cells can get into them. So it's our job to find those cancer cells in the nodes. And sometimes that can require more than one attempt that can delay, especially if you're unlucky enough to have rectal cancer.

Dr. John Marshall: We'll get in the weeds of this, I think, a little later. But I was just thinking is Dr. Montgomery was presenting this that with radiology, you and I are very used to looking at scan showing them to our patients often. You know, in fact, we need to sometimes look at them to make judgments on things, we have a report. But we want to see the images, apart from say, a tumor board, where we're reviewing a new case and the like, I rarely pop down to pathology unless there's a questionable diagnosis to review that record. What's your practice on that? And at Colorado, you know, is the value and the trust that we have with that pathology read?

Dr. Christoper Lieu: Yeah, I thought that was that was such a great presentation, Dr. Montgomery and you know, she should be talking to our medical students. I wish I had that lecture when I was in medical school as well. I thought that was just such a great explanation. You know, John makes such a great point. One of the things that I do want to drive home is that in any patient that's diagnosed with cancer, you're already starting to see how many people are involved with your care that you may never meet. So even in this short discussion, we've talked about the absolute critical nature of the work that Dr. Montgomery and her colleagues and pathology play in diagnosing cancer. We're going to talk a little bit more about biomarker testing and, and molecular testing. We talked about radiology and a gastroenterologist and maybe an interventional radiology I just, and even surgeons who take this tissue out, and then obviously medical oncologist like Dr. Marshall and myself, and so you can see. And I hope people feel somewhat reassured that there's just these teams that surround each page and all really striving towards the same goal to get a good diagnosis and obviously a good treatment plan together. I completely agree with Dr. Marshall. You know, we don't very rarely do we go down to pathology, and discuss, you know, these findings. However, we critically depend on the reports that our pathologists provide. And Dr. Marshall had mentioned, like these conferences, where we may all get together and discuss these cases, look at some of the flies actually under the microscope, and there are times where the pathology is not very clear. And that's where we have conversations together as a team to determine, OK, do we need to go back and get more tissue? What are some of the other diagnosis diagnoses that we should be thinking about? And how can we do that together? Right, is that going to include a radiologist and interventional radiologist? What does the pathologist need? And then what do we need as clinicians?

John Marshall: And often we're going back we're having to make the decision clinically is do we repeat biopsies? And how do we repeat the biopsies and knowing the limitations of well, putting people through them, first off scheduling them, everybody's eager to get it done, because they're nervous that they might have cancer. So they want to tomorrow. And you know, we have to have everything from pre-authorized to making sure it's safe and the team and other teams involved in biopsy. So we don't go about this lightly. Just because of the barriers that are out there. Dr. Montgomery, let me come back a little bit to you a lot of the tumors in GI cancers that we all take care of have a lot of this stuff called meusa, and it's not cancer itself … cancers and other tissues make this. And so often, we'll get biopsies where there aren't very many cancer cells, there's a lot of scar (tissue) may be or a lot of meusa, but you and you have to kind of look around for the evidence of a cancer cell there might be the piece might be big, but the amount of cancer in the biopsy may be small. Could you talk just a little bit about that? And ultimately, as we talked about making the diagnosis of cancer, but what you sometimes can't do if the if there's not that much tumor cancer in the specimen.

Dr. Elizabeth Montgomery:So yes, you're right, there are sometimes cancers that are mostly composed of literally goop like mucin is like, I'll say it in a vulgar way. It's like the snot that comes from your nose. It's just this goopy yucky stuff. And for example, some colon cancers, just pour it out. And as Dr. Marshall indicated, if a tiny biopsy is taken, you might just get that well, snot and not get the cells that are making the snot. And then of course, regular old colon cells can make the identical appearing mucin. So smart gastroenterologists who are taking biopsies and smart surgeons who are taking biopsies, make sure they do a lot of little bites just to get around those sorts of issues. And that's a really good point. Because there might be somebody in the group who's had a biopsy and been told, “Well, we have no answer.” And I can't even imagine how frustrating it is. But it's a real thing. And it's legitimate. And if you go to if you go to a really, really experienced colleagues, they know that they have to do way more bites than one would think.

Dr. John Marshall: We've even gotten to knowing that one bite is not enough for our genetic testing to and when we're sending somebody for not only a diagnosis, but knowing that we're going to probably want to do genetic testing. Our colleagues now are in the loop on doing enough, you need to get enough to do some of the genetic testing. So might some people say why did they need to do by biopsies? Well, so that we have enough of that. And I realized that all this not and colon discussion is dinner time for many people. So we have to you know, I'm hoping people haven't turned us off from from that.

Chris, let me let me shift to you for a minute because, you know, our essential pathology, cancer or no stage, how far it's through, is it involved in lymph nodes, et cetera? That's the key elements that you know so much of cancer now is more than that. Not a one size fits all, are some key genetic tests, molecular tests. should pay more broadly that needs to be done to sort the different kinds of patients and their different kinds of tumors. And even more esoteric type beyond that. So maybe could you talk a little bit about some of the kinds of tests that we need to run and, and then maybe Dr. Montgomery will talk a little bit about how those tests are run and the different methods of them. So Dr. Lieu, take us through the oncology lecture on my offseason and precision medicine.

Dr. Christopher Lieu:You know, this is a big topic, right. And we could fill up easily to a whole hour talking about biomarkers. And I know that there'll be additional sessions talking about what we do with a lot of disinformation. I think the best way to really start this discussion is to talk about a very clear distinction between hereditary genetic testing, and then true cancer, you know, mutational mapping or what we call biomarker testing. So I want to make sure that the audience is very clear that these are two very distinct things. When we test somebody's genes, we're talking about the genes that you've inherited from your parents, we call that genetic testing, which oftentimes is done either with a blood draw, or even collection with saliva, and what is this test? This really tests the genes that we inherited, and then may pass down along to our children? Why is that important? It's important to know if there's a genetic predisposition in the family to develop cancer, that might explain why somebody may have developed cancer, but it also has ramifications for screening for cancers in the future, but also somebody's children in terms of what their risk might be for cancer. Now, that's kind of hereditary genetic testing, and a lot of what our discussion is going to be focused on, is this idea of tumor testing.

John Marshall: Give us some examples of some of those. I'm sorry, Chris, I'm interrupting. I know, the please give us some examples of some of those inherited cancers that people that may know the names.

Dr. Christopher Lieu:That's a great point. And so the most common one that we think about in GI cancers is something that we syndrome that we call Lynch syndrome, also called hereditary nonpolyposis, colon cancer, or H NPCC. But patients that have Lynch syndrome, and this is an inherited condition, right? which predisposes you to develop colon cancer along with other cancers, such as uterine cancer, or esophageal cancer, or even bladder cancer. And so why that's important is because that really impacts the screening, because you start screening for these other cancers, like a uterine cancer, or ovarian cancer, or even a bladder cancer or a stomach cancer. So that has those implications, but also has implications for somebody's children and other family members as well.

John Marshall: And I think a lot of I was going to add in the BRCA mutation, which everybody's heard of, because Angelina Jolie and other famous people, this is associated with breast cancer, but those of us in the GI cancer world know that pancreas cancer is, is there as well with the BRCA genes, so and then there's some specific ones for gastric and some others. So there are inherited syndromes that we look to. And I, you know, there used to be I don't know if you guys agree with this, but it used to be we only really pick patients who seemed very high risk, but we're increasingly testing people and finding that when they don't even fit our sort of classic algorithm. So don't be surprised if you're a patient if your team wants you to do what we call germline or genetic testing, to see if there's something running in the family. So sorry to interrupt, Chris,

Dr. Christopher Lieu:I think that's a fantastic point. And, you know, I think it is important for people to understand that it's actually in the guidelines to screen patients for Lynch syndrome, and also screen that have colon cancer, you're supposed to be screened for Lynch syndrome. And our pathologists like Dr. Montgomery actually do this, oftentimes reflexively. And what I mean by that is, I don't even order it, pathologists do it, which is great, because that's the way it's supposed to be. pancreas cancer, same thing. We're supposed to be screening all of our patients for BRCA mutations just like Dr. Marshall mentioned. And then, you know, really what we're going to talk about over the next 10 to 15 minutes is this concept of, well, what are the mutations that are specific to the tumor? What are the mutations that exist within the cancer? Now, these are different than the genes that we inherit from our parents, right? These are, this is a mutational map of the tumor. And oftentimes, we call this molecular testing or biomarker testing. Why is this important? It's important because in the past 10 to 15 years, just like Dr. Marshall said, it used to be a one-size-fits all you give chemotherapy, it doesn't matter what mutations that a tumor has. Now, it's critically important to know what mutations a cancer has in order to personalize recruitment. And what I mean by that is that if There's a gene that's mutated and a cancer that can be attacked or targeted by a drug, then we would want to know that because the outcomes for those patients that received targeted therapy, or in some rare cases, immunotherapy, they may benefit from that treatment and therefore not only live longer, but live better. The other main take home point that I wanted to, I want to I want to bring up is that not everybody needs extensive genetic testing of their tumor, if they have an early-stage cancer, and why I make that point is because we only want to order a task in medicine, if we can act on it, if it provides information that can improve the treatment of our patients. But if you get diagnosed with a very small, stage one colon cancer, and that thing gets cut out and that's it, we don't even do surveillance for those patients. You don't need to spend $2,000, doing a genetic map of that tumor, because we're not going to do anything with that information anyway. And so a lot of the information that we're talking about in terms of biomarker testing, and testing a tumor for mutations is really mainly directed towards stage four, or metastatic disease. And, John, I know you and I are going to talk a lot about that, about how we do that, the ways we do that, and why it's important for treatment. But I do want to make that point. Very, very clear.

Dr. John Marshall: Yeah, and let me take something back to Dr. Montgomery. Because you know, most of our audience, most of our patients, most of our oncologists know the difference between a CAT scanner, an X-ray, a PET scan, and MRI, we even kind of know how they work a little bit, we can even read them a little bit. But a lot of our doc's and certainly our patients don't understand the different kinds of molecular tests that can be done. And Chris alluded to, right away, you guys doing the Lynch testing, if you will. And these are some proteins that you measure. And that's a little different than genes, we don't need to get in the weeds of all of the molecular biology, but genes are the DNA and the RNA, they make proteins. And you can quickly measure whether those proteins are there or not using a technique called immunohistochemistry. Could you give us a quick and dirty onimmunohistochemistry? And how that's done?

Dr. Elizabeth Montgomery:Absolutely. I can even do a show and tell. All right, cool. Yeah. histochemical stain? There we go. I knew right here. All right.

John MarshallSo this is in keeping with when you were talking about earlier that sometimes it's hard to figure out what a cancer actually is. You use these immunohistochemistry stains sometimes to classify the What kind of family it belongs to. This is a similar discussion.

Dr. Elizabeth Montgomery:Yes, that's right. So sometimes, just doing an analysis of the proteins, you know, proteins, like you get from meat that a tumor produces can give you an idea of what special type of tumor it might be. So I've shown you before what a regular slide looks like, it's kind of pink. So I'm … showing the slides, it doesn't show any patients. So you can see that a regular slide that's extremely quick and dirty to look at is sort of pinkish, this is an immunohistochemical stain. And it's brown. And that brown represents precipitate of a protein. So I hope you that the folks on in the audience are familiar with antibodies, you probably know that you make antibodies to infections, and you get immunizations as a child to make antibodies to diseases. But you can also make antibodies in the laboratory that react with certain proteins. And, you know, think about it you get your measles vaccine when you're a kid, and that makes you form antibodies that react to it. Well, in a test tube, we can make antibodies that react to different types of proteins. Drizzle them on a slide, and then we put another reagent on that makes those things turn usually brown, sometimes red. So for the Lynch screening, it's actually even better when we see colon cancer because we look for these special proteins that are called DNA mismatch repair proteins. And your body has them, my body has them hopefully, unless you have a horrible issue. And their job is when your DNA is replicating to make new cells. They fix the mistakes that are actually made and that's their whole job. Some people don't have them in their whole body, and some people don't have them but only in their tumor. We take tumors in every single colon cancer case, and we test them for these proteins. And the good news is if the proteins are abnormal, that doesn't 100% mean that you have Lynch if you don't want to have genetic testing. So it's not really genetic testing in a tumor, even though it can give us clues that a patient has Lynch syndrome. So it's good because it gives you guys information about what chemo might chemotherapy might work. And it's also good because it's not a direct genetic test if someone is nervous about having a genetic test without their consent.

John Marshall: Yeah, thank you. That's perfect. Chris, can you sometimes figure out from the tumor testing what the germline with the inherited stuff is? Or is that is that always two different tests? I know, it's a contentious issue.

Dr. Christopher Lieu:You know, I think that there's some times where you get information back on a mutational map of the tumor that may lead you to think a little bit more about genetic syndromes. And so, you know, I think sometimes you see what, what Dr. Montgomery talked about mismatch repair, we call that, you know, high microsatellite instability, when we're talking about molecular testing. When you see that in a tumor, you want to make sure and see if that was just the problem that was developed into tumor was that something that we actually, you know, got from our parents that in other words, it was passed down from in a hereditary fashion. And so I would say sometimes these reports that you get, can sometimes lead you to go back and actually do genetic testing. But, you know, you don't ever want to look at a mutation map with a tumor, and then use that mole, as the course of saying, Okay, well, there's a genetic hereditary issue here.

Dr. John Marshall: Thank you. So I want to get us moved along a little bit, could a different area. So this is looking at proteins, I want to get into the gene, we've talked about that some, and you can measure one gene, so you can take the tumor, take some of that, take a slice off of that block that Dr. Montgomery showed us. And chop that up, find the tumor and measure one gene in there. But with newer technology, you can take that out to measure actually, every gene, there are some groups that can measure every gene that there is comparing it to normal, whatever that means, and trying to say, is there a mutation or not? So this is that that more complex way of looking at it, we call next-gen sequencing, next generation sequencing. And it's quite a complex technology, quite a fancy test that is run, but it's becoming increasingly common. And Chris, maybe I'll start with you on this. Let's talk a little bit about where's the line on that because Dr. Montgomery is lab could measure 10, 20, 30 genes, I'm sure, maybe more, some of our health care systems, maybe yours, do 100 gene panels. And so they've decided they'll do that many in their own shop. And then some companies mostly are now doing every gene out there and use you partner, you sort of do a strategic partnership with them. Could you talk a little bit about the relative value of those because you hinted on it earlier? And I think it's really important for our audience to hear … one of the corollaries I always come back to and you to always know this about me. every breast cancer patient knows their genetics, they know if they're ERPR, they know if they're HER2, to et cetera. And our GI cancer, well, we don't have that same level of, you know, badge wearing, if you will, that they you know, that patients know that we know. And so I think that's part of why this is important that so can you talk a little bit about the different levels of testing for genes and why we might order one versus the other?

Dr. Christopher Lieu: Absolutely. It's such a critical point. And I like to divide this particular topic into three major areas that we always talk about speed. And what I mean by that is, how quickly can we get the information because we all want the information like yesterday. And so speed is an issue. Amount of tumor tissue is an issue. And Dr. Montgomery did such a great job of explaining what if you had this much tissue? Well, you could kind of divide it up and do as much as you want with it. But she showed you some very, very small core bar people Dr. Marshall even talked about just getting literally a needle and getting a handful of cells. And so how much tissue do you have? And then the third point, how much information are you going to get? And those three things are the things that we always think about whenever we send off somebody's tumor off for molecular testing. Speed. There's an issue because if you send off for one of these large panels that Dr. Marshall just mentioned, where we oftentimes partner with an outside company, and they do these exquisite analyses, sometimes it can take about a month, or even more to get that information back. And it can be really, really tough sometimes to wait that long. Now, Dr. Marshall said, well, at my institution, could you do a quicker and dirtier kind of test right? Could you do, instead of looking at 500 genes, can we look at maybe 20, or 30 genes, and yes, we can do that. And actually can turn that test around in about five days. Now, you know, five days may sound like a lot, but that's actually not bad. Because in the, in the meantime, you're kind of preparing for treatment and getting things set up. So what you're seeing is that, well, maybe we can get a little bit more of a targeted set of genes faster. Or maybe we can get a large set of genes. But it takes a lot more time. And the reason why this is important, because sometimes the treatments that we select is the are dependent on the mutations that exist in a tumor. In other words, the mutations that exist in the tumor may inform the first line of treatment that a patient may receive. And so oftentimes, what we do at our institution, is do the targeted panel first, because we can get that information back relatively quickly. It just gives us essentially what we need to know at that moment. And then we'll do a more extensive testing, where we test for 500 genes with partnering with a company that may take about three or four weeks to come back. And then that information comes usually after we've started our patients on treatment. Now the good thing about that is that we have the information that we need early, and then we get a lot more information later. The bad part of that is that we may exhaust the tissue with that initial batch of testing, which means that we would go back to Dr. Montgomery and say, “OK, can we send more tumor tissue off for additional testing?” And she say, “No, you've used up all that we have.” And that's when you're in a situation where you may have to go back and re biopsy. Why is this information important is because it may help us select a better treatment in the future. It may also help us with clinical trial selection in the future. And again, like we said before, many times, this is in the metastatic setting, and not necessarily for patients with stage 1 or stage 2 or stage 3, colon cancer, but many other like gastric cancers or even biliary cancers.

Dr. John Marshall: And we represent three different institutions here. And I suspect our (standard operating procedures) are each different. And I think our audience needs to understand that there is a local code of strategy and culture, because not all pathology departments all across the country can do what Colorado can do. Right? And Liz’s shop can do. So you might have, in your own hospital, that they'll have to send it out because their pathologists have decided that that's the best thing to do. I also want to say on the other side, and I think, Dr. Montgomery, it's a sensitive issue always. But I want to kind of bring it up is twofold on this side. One is I always used to joke that pathologists are like librarians and reference books, they didn't want to let their tissue that they regarding the patient's tissue, go somewhere. So those blocks, so if we order something, you usually shave it off, you keep the reference book and send what we call unstained slides, usually. And that's what Chris was saying, sometimes you can get to the end of the bread loaf, and there's no more to cut. So that's there. But there's also this issue, particularly on after an inpatient and you're a Medicare patient. Maybe our patients aren't aware of this, but there's a sort of law that says it needs to, they can we can order extra tests for 14 days. So a lot of times this turnaround time that Chris is alluding to the doctor loose leading to is because we purposefully sit on it so that we make sure and meet those criteria. We all think it's a crazy law, but it is where it is in the in our reimbursement system in our country. So could I set both set you up on that for Dr. Montgomery seem come right back at me on both fronts about sort of the reference book concept and being protective of the tissue and also some of the sort of system delays to get things out.

From the pathologist perspective, what's your perspective on this thing?

Dr. Elizabeth Montgomery:We're less covetous of hanging on to the blocks than we used to be because oncologists and surgeons have gotten savvy about generous sampling and going back as needed to get more tissue, but there are medical legal issues too. So we have to have things on track. But you're absolutely right. Some of the finance issues become a thing. I know in our institution, we try to at least get the patient tucked in, before the order goes out. And I think part of that is the is the two-week thing. Like for example, if someone walks in the door here and has biopsies of a stomach cancer, right up front, we do her to testing by this simple method. That's quick, we test for these mismatch repair proteins right up front. And we test right up front for so called PD-L1, which is just the entry path into immunotherapy, which I'm sure will come up as the sessions go on. And that we can turn around in 48 hours. And if the surgeon has been sensible, or the gastroenterologist has been sensible, there is plenty of tissue to then pack up and stand for other ancillary testing. So there's some reason for the madness. But I know sometimes it must be extremely frustrating. But at least the oncologist can say, “OK, let's start with this until we have better information.”

Dr. John Marshall: That's terrific. I want to remind our audience, there are some questions coming in. So please keep those coming. We will take some time in a minute to break off to do those questions. But Chris, I want to give you the floor to sort of take us home on this. And I put a lot on you for this last session, this last discussion. So two things I would love you to talk about. One is blood testing. And in here, you've got two branches of the MRD stuff that you can describe very well, and picking up genes. So this is blood going to replace tissue testing for some of this, or is it how does it supplement one? And then could you just high level prepare people for the next session that will have about the actual markers that we do in GI cancer? So I realized that those are two hour-long discussions themselves. It's given, given us a high level on blood versus tissue, and some of the key markers that people need to know about

Dr. Christopher Lieu: Such great points. And I'll try to keep this somewhat succinct. But these are pretty big topics. I know that the audience that is joined here is very savvy. And so you've probably heard this term of liquid biopsy. And what does that mean? You know, it's interesting. And, and there's been a lot of technology really developed over the last couple of years really trying to refine this. And that is something called Cell free DNA. You may see this called cfdna. If you if you read it also circulating tumor DNA or CT DNA. So our cells turnover all the time, through a natural process of cell death called apoptosis. This is just when our cells kind of die when they're supposed to die, and they turn over, but they release DNA into the bloodstream. And this is not dangerous or anything, your body metabolizes it very quickly, usually within minutes. But if we do a blood draw, we can actually capture parts of that DNA and sequence that. So if a mother is pregnant with a child, you can actually capture fetal DNA in the mom's bloodstream. And again, you can actually sequence out the baby's DNA. And in the same technology, the same thought is that if a patient has a tumor, you can actually do a blood draw and the fragments of tumor DNA floating in the bloodstream, and then you can sequence it. So what does that information provide you potentially two things, it can tell you whether or not there's the molecular presence of cancer in a person's body? In other words, what if you believe that you have a patient with colon cancer, there's nothing on a CT scan, but you detect circulating tumor DNA, that means that there might be microscopic tumor cells in the body, we call this minimal residual disease, or MRD. So the presence or absence of tumor DNA in the blood, and tell you potentially if there's the presence or absence of cancer in the body. So that's one application. The second application is in somebody who has known cancer, you can actually collect the same circulating tumor DNA or CT DNA and sequence it that can provide information about mutations. And so this technology has actually gotten significantly better over the past couple of years. And a lot of times you can actually get a very dynamic read in terms of what we take the existent a patient with cancers body by drawing their blood and sequences and looking at for mutation. John asked the question, is this going to work? tissue testing not right now, it will not but it might in the future, depending on how good these assays get. But the way I use these, these tests is number one, it can be sometimes helpful for detecting what we call a minimal residual disease. The second thing is, imagine a situation where Dr. Montgomery has utilized all the tissue under no tissue lab. And for one reason or another biopsy may be very difficult. We can get a blood draw and use the CT DNA testing to at least get a sense for what mutations exist. That's a very, very good use, I guess that the technology John,

Dr. John Marshall: Let me drive you one next step, because a lot of our patients now are asking us about the screening blood tests, looking for cancer. So you can send $1,000 bucks to GRAIL, a company, with your tube of blood and now they'll basically do the same analysis you're just describing that would, you know, they're hoping would replace colonoscopies and mammograms and PSAs and the like. There's a hot this a hot debate, right, this topic, and it's the same essential technology that we're leaning on in our therapeutic decision making in cancer patients. So is this where it's going?

Dr. Christopher Lieu: So John's trying to get me into trouble here. So and I love this question. This is really my response, I would say that technology has actually outpaced our ability as providers to know how to use it, and to know if the test will save lives, because that's what we're interested in. And so imagine this situation, you get a blood tests for cancer, you're just looking; you don't think that you have cancer, and it comes back to —

Dr. John Marshall: Your job offered it to you as a sign on bonus, they're going to throw it in, right? Companies are doing this.

Dr. Christopher Lieu: In this situation, imagine your anxiety level, if the test shows that it's positive, but you have no evidence of cancer, then you undergo a mammogram or a colonoscopy, or upper endoscopy, and you spend about $10,000. And all those tests are negative, and the test is positive. That's a real problem. The other part about these tests is what we call sensitivity. And what I really mean by that is, if the test is negative, do you truly not have cancer. And I would say the data here is still very, very mixed. And so I do want to drive home the point that I do believe this technology will get better. I think that this is a new frontier that is going to change medicine, but it is very early right now. And nobody can tell you right now that the utilization of these type of tests will save lives. And I think that that's really important. So it's early. And I'm very hopeful, optimistic, but it's still very, very early. And I do not think that they're ready for primetime. So that's the that's the key

Dr. Elizabeth Montgomery: Thething about KRAS mutation to nothing. We see them all the time,

Dr. Christopher Lieu:Right. And what Dr. Montgomery is really pointing to is the fact that you can actually develop mutations in your body that are completely harmless, but it's a natural process of aging. So you don't want to call that cancer if it's just kind of like a normal kind of benign mutation that exists in your body.

Dr. John Marshall: So an old guy like me, I got to have at least one or two of these bad boys. Right. Younguns know you're OK.

Dr. Christopher Lieu:You know, one of the big things that I would just say is the biggest take home point for our audience is truly this. And it really is just a handful of questions because this is a very complex field, where the biomarkers or the testing or the results can influence a person's treatment plan. But that's not the same with colon cancer, pancreas cancer, breast cancer, bile duct cancer, stomach cancer, they're all different. So it is a very, very complex field. So if you feel overwhelmed even hearing this discussion, that's very normal. I just wouldn't really empower patients to ask the following question. “Has my tumor been tested for biomarkers? If it hasn't? Will it be? Or why aren't this testing not being done?” And the answer might honestly be as simple as, “You have stage one cancer, I could order the testing, but it'd be a gigantic waste of money because it won’t influence our decision.” That's fine. If the answer is, hey, has my tumor been tested for biomarkers, molecular testing? And the answer is yes, it has been the follow up question is simply, “How will that impact my treatment?” And those are very, very reasonable questions that deserve very, very straightforward answer. And I don't want you to feel disheartened. If the answer is, “Yes, we did test your tumor, but there's just nothing actionable.” That's OK. At least a test will have been done. And you have the information because who knows? What clinical trial are what therapeutic is going to come up in the future? You're armed with that information. But if the answer is, “Hey, yes, we did. And, you know, even though you're on this treatment right now, if this treatment doesn't work, now we have a really great targeted or immunotherapy option to treat you with in the future.” That's exciting. And that's what we want to offer more of our patients. I just want to drive that home as the key take home questions for your providers. That's very, very easy to ask, and very, very easy to answer in all honesty.

Dr. John Marshall: Cool. We only have just about 10 more minutes or so in our discussion. And there are several questions that have come in, I want to invite Martha Raymond back into our room, there she is, welcome back. And I, we can sort of see what's come in. And I wanted to start maybe by asking, Dr. Montgomery, one of the very basic questions, you look under a microscope over there, and you say that's cancer, what are you seeing what's different about a cancer cell versus to the eye? We've talked about sort of the genetics and all that, what's it look like? What's a cancer cell look like?

Dr. Elizabeth Montgomery: They have a lot of different shapes and sizes, and we compare them to normal tissue. And generally, for example, with colon cancer cells, hopefully you guys remember your basic biology, you remember that a cell has a nucleus, and then the cytoplasm and cancer cells tend to have giant nuclei, and they are making all this abnormal DNA, which kind of blows up their nuclei. So then the ratio and the volume of the cell between the nucleus and the cytoplasm increases, so there's proportionally less cytoplasm, they also make abnormal shaped glands. So there's a way glands look, their little round circles under the microscope, and the ones in cancer, become irregularly shaped, so we can pick them out. And in fact, it's interesting and sort of scary, but pathologists are not perfect, some make horrendous errors. Most don't, and most cases are diagnosed perfectly. But if you hand me a slide of a colon biopsy and say is this cancer or not cancer, and I say it's cancer, odds ratio of it being cancer in the tens of thousands. And the standard testing is cheap and quick, compared to all the new techniques. And that's why it hasn't vanished after literally hundreds of years. Because it can be done quickly and inexpensively and give really good information really easily.

Dr. John Marshall: Martha, you've been monitoring the chat, and questions while I've been dealing with these two people. So what kind of questions we've not been out at a you want to pose?

Martha Raymond: There's some great questions coming in. And this has just been so educational and informative. So thank you all so much. One question. Is CT DNA testing available at all cancer centers in the United States? Or is it only available at the larger centers?

Dr. John Marshall: Chris, I think that yours.

Dr. Christopher Lieu:So many institutions actually aren't doing their own CT DNA testing. And a lot of this is actually sent out to third party companies. And so if CT DNA is something that you are interested in, getting, at the first, honestly, the first conversation is really with your provider, because everybody's situation is very unique and specific. And so the question really is, “OK, well, why would we be drawing it? What information could be gathered that we don't already have?” One of the most important things is, you know, how would this test change my management, depending on the results? And if the answer is it wouldn't change anything, then it may not be the best use of time or resources to send it. But having said that, literally, you know, in any oncology practice, you can access these tests, because these are national and international companies that do this type of testing and can provide the blood draw and you're the office just has to fill out a requisition. But I think really, the key first step is, is this something that would help me if so, why, and if not, tell me why you wouldn't help me. And I think that that will help you make a really, really good informed decision.

Dr. John Marshall: I just saw a related question in the chat somebody's post saying awesome presentation. So well done, team. This patient who's this person has typed in that three years out from a colon cancer diagnosis is getting and is no evidence of disease and is getting colonoscopies and things like that, or any of the tests appropriate for this person to be doing? And if it was anything at CT DNA, but you're three years out, would you? Would you do something like that, Chris? Or would you say we're probably OK?

Dr. Christopher Lieu: So I would say you're probably well, congratulations. And you're probably doing great. I mean, you know, and it would make sense that a lot of people that are on this call that have earlier-stage colorectal cancer, this is all really, really fascinating. The question really be is, you know, how would this impact my surveillance plan? And I would say, you know, again, and that's very specific situation, you're probably good. I would make sure, again, the recommendations are that any patient diagnosed with colon cancer get green for Lynch syndrome. And our colleague, Dr. Montgomery is the one who does this, because she talked about this idea of testing for proteins called mismatch repair proteins that needs to be done on all diagnosing the colon cancer, just, you know, I would make sure that that has been done, because that's a good screening exam for Lynch syndrome to make sure that there's no hereditary issue involved here.

Dr. John Marshall: OK. Let me do a quick follow up to Dr. Montgomery, there's one here in the in the chat. The pathologist says no evidence of cancer, but the area that they think they biopsied is, say PET positive, or lighting up on a scan? Is it possible that they just missed it that they really didn't get it? I mean, what are some of the possibilities when you don't find cancer? But we think there's cancer there?

Dr. Elizabeth Montgomery:Are you saying in the setting of a big operation, we don't find it?

Dr. John Marshall: Like a scan and some maybe an IR biopsy, is what I'm thinking.

Dr. Elizabeth Montgomery: Sadly, the options are twofold. One of the options is that the needle missed the tumor, and then somebody needs to try again, which is very unpleasant if you're the person having a repeat needle biopsy. And the other option is that you just have some sort of scar tissue or something, or even some inflammation from an old infection or something that lights up on the scan. And it's nothing. But sadly, if you are in a position in which somebody thinks you could have cancer from a scan, and a tiny biopsy is done and no cancer is found, you really need to consider the possibility that the darn needle just didn't quite get where it was supposed to get.

Dr. John Marshall: We had a case of this just in the last night before this, we were on our multidisciplinary tumor board and we had a biopsy and it looked abnormal, but we couldn't take it over the line of cancer. It looks say suspicious, but we couldn't say for sure. And believe it or not, we've we find ourselves on this line, not uncommonly.

Dr. Elizabeth Montgomery: Especially now we're taking I mean that the new technology for radiology colleagues is just spectacular. And they become so good at getting needles into teeny tiny places, but they're not perfect.

Dr. John Marshall: Are there any other high-level or any other questions coming in that you want to throw out there?

Martha Raymond:I guess one would be: are there resources for patients that may be apprehensive about getting testing?

Dr. Christopher Lieu: Yeah, you know, I think that each disease type has just amazing patient advocacy groups, the Colorectal Cancer Alliance. Obviously, if you have colon cancer, for pancreatic cancer groups, like PanCAN have really developed great resources around this, you know, as it always is, your provider, your oncologist will be your best source of information to at least start. Reading about this on the internet can quickly become extraordinarily overwhelming. But it is great to be armed with this information. And I would actually start with the patient advocacy organizations because they've all have done such a great job. And then you know, that might give you some hints in terms of some of the questions that you want to ask your providers. I just want to reassure everybody, you know, these discussions that you have with your providers with your oncologists are critical. And don't be afraid to ask these questions, because you'll learn a lot. And honestly, you might remind somebody like myself or even John to think a little bit outside the box. And that's not always a bad thing.

Dr. John Marshall:Well, I find myself, you know, when patients ask this, I'll say, “Yeah, we did it.” And then I'll say OK, but I want to find it. And I'm going into my EMR. And I will realize that maybe we did it but I don't have the result, actually in my in her patient's chart, or maybe my memories not so good anymore, and we didn't ever do it. And so, we need it's a partnership. It's a team in there in the patient and their family and their village is part of the team. And so you know, if your provider is hurt by this, they'll get over it …That's OK. And yeah, so it's important. And it also, you know, to the precision medicine testing has had a fairly awkward evolution in terms of insurance coverage early on, it was being done and not necessarily routinely covered. But to do the test, there's, again a law that says we have to send a bill, there is no law that says you have to collect. And so patients are getting bills. But … some burly guy didn't come to your door and expect some money. And so patients were afraid of these tests, because they were getting these bills, and they felt responsible to pay them quite honestly. And but it's evolved now to where most of these tests are being covered by insurance. And so and they aren't cheap, but we need to push the other side of things is they tell us so much, that they make us more efficient, that we don't give you treatments that won't work. We find the treatments that do so it's really critical.

So we are about wrapping up. But I want to give a special shout out to Martha and the GI cancers Alliance. So GI cancers are a bunch of different diseases. And while we think of new as one family, you don't necessarily you think of yourself as a colon patient or pancreas, cancer patient or stomach or other. And so the purpose of the GI cancers alliance is to put us all under one point when it's appropriate to be under one tent and a discussion like this. We are all family under this tent. And so Martha, thanks to your leadership, we were able to provide this kind of information. So Martha wanted to take us home and close this out.

Martha Raymond:OK, great. Well, thank you, Dr. Marshall. And I would like to just say another quick thing about our GI cancers Alliance. It was founded by Dr. Marshall. And we represent all of the GI cancer disease states, so any of our patients’ caregivers listening today, if you have questions for any type of specific GI cancers, you know, we can help you find the information. So please don't hesitate to reach out. And again, I'd like to take thank Dr. Marshall, Dr. Lieu, Dr. Montgomery, for this really incredible conversation. Our host today If you'd like to watch a replay of the webinar, it will be housed there. And again to our sponsors, Amgen Oncology and Elevation Oncology. Thank you for your partnership. And we look forward to seeing everyone again next time. So thank you.

Dr. John Marshall: Thank you. My thanks, everybody. Have a good evening.

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