Hello, everyone. My name is Gerard Silvestri. I'm here with Adam Fox, an assistant professor of medicine at the Medical University of South Carolina, where I've actually practiced for 30 years come tomorrow. Today, we're here to talk to you about enhancing non-small cell lung cancer biomarker testing. And what we've done is put together a really practical clinical checklist. What we'd like to do is take you through that checklist, tell you really how important it is to think about biomarker testing as a pulmonologist for those with actually local lung disease and all the way up through metastatic disease, where it's imperative to sort of figure that out before your patients get treated, because we want them treated with the right drug the first time. We also want treatment to occur quickly, as quickly as you can. Through the work that Dr. Fox has done and our lab has done, we've kind of figured out that, man, even in a place like a university hospital, sometimes that test that we're in can get disjointed. Patients wait a long time to get their biomarker testing. And so what we want to do is take you through what we think are the important aspects of getting biomarker testing in a timely fashion. Yes, that's us. You've seen us already. These are our disclosures. Most of those are for research studies that we have in biomarkers. And so I'm going to turn it over to Adam for a second. I actually think this first line really encompasses everything. If I can make a tagline for biomarker testing, I would use this tagline. So Adam, please take it away. So our goal for lung cancer, for precision medicine for lung cancer, is to coordinate systematic, comprehensive, and timely testing to assess all eligible patients to really deploy a biomarker-informed treatment plan. And so even if they don't have a biomarker that's positive, it's still informed by what biomarkers their cancer has. And so to take you through this kind of common diagnostic pathway that patients go through, this is, everyone comes in with different symptoms and imaging, but this is sort of a common pathway. At the left side of the screen, advanced lung cancer is suspected or any lung cancer suspected. So some sort of biopsy is performed. Cancer is confirmed. Biomarker testing then has to be ordered. So somewhere along this time frame, someone on the team has to order biomarker testing. And then those results have to be available, ideally before any treatment is delivered. And so this time frame can take weeks and weeks to complete. And how does each patient complete this pathway within the shortest amount of time with the best amount of information? And of course, staging happens across this entire timeline from the very first image that's taken to which biopsy is chosen. But all of those components together really inform the treatment plan. And I feel like, Adam, that what we've noticed in our institution, but also in some surveys we've done nationally, is ophthalmologists kind of feel like their work is done after the biopsy is performed and they refer the patient out for treatment. Unfortunately, if you wait until the patient's referred, for example, to an oncologist, they may wait two weeks for that appointment. And then if biomarker testing is not done, then it could be another 10 days to two weeks before they have that testing available. And all that time leads to tremendous patient anxiety. And more importantly, it can lead them to start treatments that they shouldn't get before they have their testing done and back. So this is what we call a biomarker checklist. That checklist is available through CHESS, and so it'll be highlighted. And we want to take you through this checklist now and talk you through some of the important points. So take it away again, Adam. So this first series of slides is really going to focus on institutional coordination of a biomarker testing program. And then we'll go through a case-by-case kind of checklist after this one. So obviously, this is going to take time to establish. Not all these checkboxes can be done in one day or a single meeting. And of course, we're going to have to collaborate with all of our different subspecialists. So the first checkbox on this list is really to identify all the relevant stakeholders for precision medicine at your local institution, considering staff, where procedures take place, clinic staff, and anyone who procures biopsy samples, of course. I mean, there's a couple on there that really jump out. Everyone thinks it's about the medical oncologist who a lot of times orders these tests. But the two that jump out to me are pathologists. You need to bring the pathologist in early for several reasons. One is to figure out if they send their pathology out, if they keep it in, how do they want the specimen prepared to get the maximum use out of that specimen? And the other is interventional radiology. I know we believe and we should believe that we do most of the biopsies through EBIS, for example, for advanced lung cancer. But many biopsies in many institutions are done through a trans-thoracic needle aspiration approach. And if they're not in the loop, again, those patients can't get tested in a timely manner. So those are the two that sort of jump out to me. Of course, nurse navigator for your cancer clinic would be really, really important. And before making any kind of changes, you have to know what the current state is your institution. So we'd ask people to sit down and describe how does biomarker testing currently work? And then a big question, define patients that you and your local community believe are eligible for biomarker testing. This is different than 2010 to 2015 to today, and it's still going to change over time. So this checklist leaves us just a little bit vague because you have to look at the most up-to-date information and guidelines as to who should be eligible for biomarker testing and for what biomarkers. But everyone should get together to ensure that everyone knows what kind of local practice should be. So out of five years ago, it was we only test for advanced metastatic lung cancer. Then it moved back to, oh, well, you know, maybe 3A, 3B we should be testing for. And now we're looking at doing biomarker testing from 1B, stage 1B, all the way through to stage 4 and looking at those patients to see if they develop an answer that requires adjuvant biomarker directed therapy after surgery. For example, those that are EGFR positive to neoadjuvant chemoimmunotherapy followed by surgery, you can't know what to deliver to those patients without doing the biomarker testing. So and that might change next week, something can come out and say, hey, look, these patients, there's a new drug with a new target. They have to be tested for this in this stage with this type of cancer. And so these next two slides put some of those considerations for advanced stage. You know, everyone should get a PD-L1 immunotherapy test. And then there's this recommendation in the guidelines for testing all patients, the non-squamous considering for squamous. That's because actual mutations do occur in squamous histology. It's just at a lower rate than the non-squamous histology. And with newer biomarkers like KRAS G12C, maybe this will change in the future. But for now, really, that's why we say we should all get together and decide locally what our practice should be for standard of care for our patients. A drug like you're mentioning for early stage considerations, at least EGFR, ALK, and PD-L1s for those who may be eligible for adjuvant or neoadjuvant therapies to direct their use. So we would say to prioritize tissue-based comprehensive biomarker testing in the advanced and metastatic stages. And so by comprehensive, we mean testing for all of the potential therapies for which they may be eligible. So that means more than just one or two biomarkers. And in selection of this test or this series of tests you're going to do, you have to really see what's there on the ground locally. Do you have the capacity to do testing in-house? If so, how comprehensive is that testing? How good is it? And what's already being done to one or more commercial laboratories? So this is something in terms of turnaround time, costs, and capabilities that one has to kind of assess locally. And Adam, at our place, what was so interesting is once we start digging into this, just you would think we would know this. Adam and I see five to seven new lung cancers a week. We live, eat, and breathe this stuff. And yet when we start digging into it, it was like, well, wait a second. Sometimes it gets sent out. Sometimes it doesn't. Why? No one really had a good reason for us. And so just mapping out what your institution does to do this biomarker testing is really, really important so that you can know once you send your specimen down from EBIS or other types of bronchoscopy, you know what's going to happen at that time and what you're going to order, et cetera, et cetera, or what your team's going to order. And then, of course, there is an established role for serum-based biomarker testing. But this has influxed just over the last couple of years. Certainly for someone who can't get a repeat biopsy or is too high risk or has already failed for some other reason, it certainly should be strongly considered. But there's all sorts of timing and patients in which people are kind of investigating when to use this serum-based testing. So again, we should be prioritizing the gold standard, which is testing on tissue. And I think this is going to be a space that continues to evolve, even just over a couple of short years. Yeah, I think it's really important. I can't say this enough about tissue. You want to get as much as you possibly get. At our institution, we're taking five or six extra EBIS passes after our non-site cytopathology says, yes, you have cancer, just to make sure we have enough for next generation sequence testing. And so we are all about tissue conservation, making sure that you maximize the tissue that you have. And then, of course, if that fails to produce enough DNA to do next generation sequencing, or if the patient have recurrent disease, we may try serum-based testing, which, again, is in evolution. Right now, we would argue that the standard of care is tissue-based testing. Just a quick side note there to keep in mind, serum-based testing can't assess for PD-L1 status, and a negative result can't really be trusted. If you really have a high suspicion this patient should have an actual mutation, this would not be adequate, as it was named. The next things on this checklist are really about making sure everyone knows what you need. So we've kind of already described knowing what assay and everything, but everyone needs to know what that assay is and what the approximate tissue requirements are and what to do with it. Yeah, and pathology is a really good partner here, right? And so I often joke around that, you know, go buy a cup of coffee and go to the bowels of the hospital, because that's where pathologists usually hang out. They're very happy to see other humans and sit down with them and say, hey, how much tissue do you need? What do you like it in? Do you like it in cytolite? Do you like it in Hank's solution? How many passes do you think is good? Should we look and see how many times we've had this really new buzzword in precision medicine, quantity not sufficient, QNS? And we keep track of that at our institution, because we want to make sure we're giving them adequate specimens. The last thing you want is to have a patient go through a second procedure, which is really, you know, it's hard enough that they're going through this early, hey, I might have cancer, but then to put them through a second procedure, it's just heartbreaking. So you also want to establish a clear responsibility for who and how ordering the biomarker testing is going to happen. This was a topic central to our third webinar, of which this is number four, and really talking with your team, what team do you have, what expertise do you have, and who's going to order this biomarker testing throughout your institution from any number of directions. Right. And again, we are agnostic to basically who is doing the ordering. What we're saying is you need to have a process for that. So whether it be at the site of the biopsy, so for us in our bronchoscopy lab now, if we know we have an advanced or metastatic patient and onsite cytopathology says, yes, Gerard, you have cancer, we get those extra passes. The order goes in immediately that we want PD-L1 and next generation sequencing performed on that specimen. And so that's sort of reflex testing, right? And we're going to get to reflex testing. We think that that's the way to go, that if the pathologist has an order, when a tumor type and a certain stage comes in, they can automatically send it out to be tested immediately or run it in-house so that there's no delay between the time of biopsies performed and the tissues getting processed and then sent for testing. And if you're setting this up newly in your institution, or if you already had experience, you know these test results get hidden in all sorts of places in the chart. And so we think that really making sure that you have a plan for where these tests can go to where they're ready to all the team members is really important in planning for really setting up your institution's biomarker program. You know, here, I would say, Adam, that, you know, with our specialty, take us out of the cancer realm for a second. There's nothing worse than seeing a new patient with shortness of breath and not having a radiograph or pulmonary function studies, right? Like that's our, those are our two things that we know we want to have. And so oftentimes when we're seeing a new patient, we instruct our administrative staff, hey, get breathing tests, get a CT or a chest X-ray for this patient or gather that from another institution. What would be the worst thing is a new patient goes to visit their medical oncologist two weeks after they've had their biopsy only to find out that their medical oncologist can't give them treatment recommendations and shouldn't give them treatment recommendations because they don't have their biomarker testing results. And so having those results in a place where the oncologist has access, but also has them back by the time the patient gets to see them is really important. The last is the last couple bullet points here all about measuring this process and collaborating to improve it and streamline it. So first you have to measure something in this spectrum to know how well you're doing. So like Gerard said, we're looking at turnaround intervals. There's a lot of turnaround intervals. We'll look at some of those in the case, but trying to measure some turnaround time intervals, how often you're having different specimens from different sites be not sufficient for testing. And even are you testing everyone who you think should be testing? So it's going to be pretty tough to measure, but picking out several of these that are measurable within your electronic medical record or institution can really help fuel process. Yeah. And here, Adam, I'd say, I think when we started looking at our own data, we were pretty stunned, right? Like I was stunned at, and we thought we were doing a really good job with this. And we'd find patients that weren't tested at all. We'd find patients where, you know, even with the best of intentions, it was taking, you know, three weeks or more to get that data back. And, you know, we found places that were just incredible. Like, so if this one person was on vacation, like everything round to a halt, and there was no backup for that person. And so we didn't even know that until we really started looking into it. So keeping some kind of data around your turnaround time, are you testing all the people who require testing? How many specimens are quality not sufficient so that you had to go back and biopsy them or send it for a liquid biopsy would be really important. And so I urge you to think about what happens in your own institution. You know, these are the kind of quality improvement. I know some people, physicians are so busy, they don't, you know, sort of like to get into quality improvement, but man, this is one of those projects that if you get involved in it, you can be doing such a great job for your patients out the back end. So the next part is just actualizing these results. You have to have a plan to sit down, look at what you've measured, get feedback from different people about what barriers are being experienced, and try to improve this process. Because, you know, all patients are going through this in a different way with different barriers. But really, the goal should really be to have this done systematically for all those patients to make sure everybody gets a clear and equal plan forward. And, you know, I dare say this can actually be fun. I mean, I know that sounds horrible, but, you know, if you can put together an operations team and don't, you know, don't hesitate to get an administrative person from one of those specialties like pathology, for example, get a few of your doctor friends involved, get an oncologist involved, get a pathologist involved, a pulmonologist at the very least, maybe someone from IR, and sit down after you've gathered some of this information, you're going to need help outside the medical field. So admit a really strong administrative assistant who's dealt with this kind of thing before can be invaluable. So once that operations team gets together, it won't take long from there to come up with a really good process that you can present to the rest of the physician's care to these patient types. And then you have to establish a way to keep track of changes over time, both at your own institution, but also in biomarkers, therapies, indications for their use. We just kind of talked briefly about how this has changed in the last 10 years, and it's going to continue to change. And the way we all practice to coordinate this is going to continue to have changes over time. So we have to be able to communicate that across this entire team to care for patients. Yeah. And here, I would say, look, in the first 15 or 20 years of my career, there were two drugs, right? Like it was platinum-based chemotherapy. It was cis-platinum or carbon-platinum with one of a myriad of other drugs. Now, like every week, there are new FDA-approved drugs, and some of them require the same targets, like EGFR, but some of them are going to require looking for a new target, like KRAS G12C, for example. So you're not going to be able to keep up with that. I don't think pulmonologists should have to keep up with that. This might be one that's assigned to a medical oncologist, hopefully with a real interest in lung cancer, with a pathologist who understands what's going on. But there are FDA-approved drugs. And listen, if you're the patient, if that patient's your family member, you want them to get one of these targeted agents because sometimes there are oral medications that can increase five-year survivorship by logarithmically. So whereas we have almost no one surviving with stage 4 disease, if you can get one of these targets, it's not uncommon to live out three to five years past your diagnosis. So really important to learn what's coming down the pipe. Doesn't have to be you, but there has to be a plan to capture the new FDA-approved targets with drugs to target those mutations. So I want to pivot here to the case-by-case checklist, or really focusing on individual patients and how to do this for an individual patient. And so this goal is very similar to the institutional goal, but brought down to the single patient level. We need to get the best image and biopsy procedures to provide all the information we need, diagnosis, staging, and biomarker testing to really deploy that therapeutic plan that's informed by that biomarker data. So first, this is just a blanket statement across the entire process. Any time where there's uncertainty over diagnosis, what procedure is best, is there a role for biomarker testing, what stage is the patient, you know, having a multidisciplinary team, like a two-word discussion or other kind of collaboration is always going to be best to get those questions answered where there's any uncertainty. The rest of the checklist is going to be this kind of before and after kind of diagnosis scheme. So you can see for the before diagnosis, you want to make sure the patient knows that biomarker testing and some of these precision medicine therapies might be relevant to them, especially whether there's a very high suspicion for non-small cell lung cancer, because that testing, as we've already talked about, takes time. And any time the patient's waiting for any of this information that we need to put together a two-word plan, they're usually anxious about it and they want to know what the holdup is. And so, you know, I think letting them know up front there's going to be an extra wait before we can put your plan together for this one test that is so critical can really help with some of that anxiety they may experience. Yeah, so I think I've said this so many times, but it bears repeating. If you look at psychological studies, you would think that for a patient with lung cancer, the most psychological distress would be right before they die of their disease. I certainly thought that. But actually, if you look at studies in a continuum from when the patient was told they have lung cancer to if they pass away, the most stressful time is when they've been told they might have cancer and they receive their first treatment. This is incredibly stressful. There's a ton of uncertainty. Am I going to live? Am I not going to live? And so, getting them prepared is important. And of course, they want to be treated yesterday, despite the fact that a lung cancer might have been there for a number of years, starts at one cell and then has to divide, divide, divide. They want to start treatment yesterday. I often say to my patients, it is more important for us to get this right than get it quick. And I tell them, look, we're going to try and be bold, right? But to get you maybe a drug that would be the whole run ball for you, we might have to wait a little longer to be certain that we're getting the right treatment for your disease, for your stage, irrespective of, by the way, whether it's a biomarker directed therapy or not. So, the next, like we've already said in the original statement, kind of goal here is to get the right biopsy, make sure there's enough tissue per diagnosis, staging information, and biomarker testing. Yeah. And again, here, things, for example, we covered in other webinars, like bone biopsies, even though it might stage the patient as metastatic, you have to decalcify them. And it's often difficult to run next generation sequencing or do mutational testing on a bone biopsy. So, if you give them the choice, for example, if you have advanced lung cancer on the mediastinum, as well as positive bony mets, it's probably better to go to the mediastinum and get enough tissue for biomarker testing. Those are the kind of considerations we'd like to see. And I think, look, like we're pulmonologists, we like to do bronchoscopy, but if it's a better, if there's a two centimeter lesion right underneath the rib cage, right next to the chest wall, it might be a better, you know, use of time for that patient to have a transthoracic needle biopsy rather than another test. So, we want to get the patient the right biopsy, whether we do it or our colleagues in thoracic surgery or interventional radiology do it. You want to make sure whoever's performing that biopsy knows that testing is going to be needed or likely be needed and what those tissue requirements are. So, that's very similar to our institutional make sure everyone's on the same page kind of. Yeah. So, you know, again, for our IR folks, we want them to get a good number of core tissue biopsies so that they know, like, this is a patient with no or suspected lung cancer that we need enough tissue for biomarker testing. Our IR folks are great, but if they don't know that's what they need to do, they might just do one or two cytologic biopsies and really say, oh, yes, this is cancer. And then they just move on to the next patient. We can't have that. We need to make sure they know that we need core biopsies from what they do and plenty of tissue. So, then this is kind of like the second half of this checklist, and these occur after kind of a diagnosis is made. And this arguably before or after, but you want to make sure there's an order plan established for getting biomarker testing performed in a timely manner to prevent any delays. Yeah. And we certainly believe that that order should go in at the time of diagnosis. We don't think it's a good idea to wait till pathology runs through all their information, it gets back in the chart, goes to the oncologist, oncologist has a visit, and then orders the biomarker testing. We believe that at the time of diagnosis. And in fact, we actually believe it's our responsibility as opposed to anyone else's to get that testing order. The next two bullets are about communication. We want to make sure that there's a plan for the biopsy results and the biomarker testing to get communicated to the patient and the oncology team in a really reliable way. We should be considering repeat biopsy or serum-based testing in cases where there's not enough tissue for biomarker testing. Yeah, we want to keep that rate low, well less than 10%. And I think here, I'm really, as much as I don't like to do repeat biopsies, if it's going to make a huge difference for the patient, if they have a non squamous, if they have some of the phenotypes that we consider really high likelihood, for example, a light smoking or never smoking Asian American female, we might say, no, no, no, no, like, let's go ahead and repeat this biopsy. And look, there are some times where the tumor is so poorly differentiated. You can't even tell whether it's squamous or adenocarcinoma and the DNA is just destroyed. And it might be impossible to be able to do biomarker testing. I get that. That should be the vast minority of patients. And for most patients, we ought to be able to get enough to do that. And then you want to make sure there's a clear plan in place for establishing the rest of any staging information that may be missing PET scans, MRI brains, any other suspicious sites that need to be excluded or included as metastatic sites. All of these things need to be handed off between the team to make sure that all this information is there because stage and biomarker testing, along with that either diagnostic histology all comes together at once to really, what is the best first line treat? Yeah, I mean, as much as we're emphasizing today, biomarker testing, right? Like the rest of the staging doesn't go away. Again, if they're seeing their oncologist two weeks later only to find out, oh, they didn't get the MR of the brain to make sure there were no brain metastasis in a patient with metastatic or advanced lung cancer, that it's another delay that's been added in. And we, again, we wanna limit those delays. I feel like the pulmonary community does a really good job of, I hope, of diagnosing and staging so that they do know that, you know, for patients with advanced disease and we wanna get a PET, we wanna get an MRI of the brain, and we wanna make sure that we've documented mediastinal disease in the chest. So those things I think we're good at, where we're hoping then to extend our skillset as pulmonologists is into the advanced biomarker of mutational testing. So I've got two cases. The first is a pretty straightforward case, but they highlight different aspects to these checklists into this kind of precision medicine theme. So the first case is a seven-year-old woman, no smoking history, presenting with cough, found to have a lung mass, and then also some suspected thoracic spinal mets. And they were brought to tumor board. Oh, sorry, first, we did, this was a patient of mine, and I did tell them, hey, look, I think we need to get a biopsy here. And look, this is gonna take time. I was preparing them for after whatever biopsy is done, we're gonna have to wait for those biomarker tests to be completed. Yeah, so poor Adam sat next to me in clinic now as a fellow and as an attending. I usually talk to my patients in plain English, and I say to them, look, this is a three-step process, right? And I put it in plain English. What is it? That's the diagnosis. Where is it? That's the stage. What can we do about it? Those are the treatment options. Some of that can get done simultaneously, diagnosis and stage, but we cannot give you your treatment options until we have all this information back. So we're gonna help you work through what is it, where is it, what can we do about it? And again, I urge them to be patient so that I can get them the right treatment the first time around. So we did take this patient to Children's Ward, I did, to really discuss what these spinal lesions were, to see if they were amenable to biopsy or not. A purely bony metastasis to the bone might require a lot of decalcification that degrades that DNA we need for a lot of our biomarker testing. But also if it's very soft tumor and kind of fleshy, maybe it's got plenty of good non-calcifying tissue. So we reviewed that case and the overall recommendation from our Children's Ward was let's just complete staging scans because we think this is metastatic cancer in an expedited fashion to really select the best, lowest risk site for biopsy for this patient. So this is images from the PET scan. You can see the right lower lobe mass was PET-AVID. This level seven subcranial lymph node actually wasn't actually noted to be abnormal on the non-contrasted CT chest. So this was an abnormal finding found there. These are the thoracic lesions that are largely bony seen on the PET. And then the MRI brain did have a couple. This is just one enhancing lesion suspicious for metastatic spread. And so with this data in hand, we all agree this is kind of overwhelming evidence of metastatic lung cancer as long as the biopsy was supportive of that. And so this patient got a bronchoscopy with EBUS of that subcranial lymph node for diagnosis and at least some staging purposes. So proving N2 disease better than biopsying the lung mass itself, which wouldn't prove any nodal or metastatic spread and more likely to provide biomarker testing than the both and with a better safety profile than biopsy of the brain. So the guidelines, which I was lucky enough to write in 2013 actually asked exactly for this. So we said, in every chance you could get, you should biopsy. And if this is a board question for the young people or people redoing their boards, you should biopsy the most advanced site for metastatic disease unless you have overwhelming evidence of metastatic disease by imaging. And in this case, it's clear that the spine and the brain both have lesion. Now, I can tell you if there was only one lesion, one tiny lesion in the brain or one lesion, particularly in the lower spine where it could be osteoarthritis and we see often in elderly patients with inflammation. No, that's not good enough. You have to try to exclude those. So you make sure that you're not taking your patient out of maybe treatment for stage three disease or even surgical treatments. But this case is different, right? You don't wanna do the brain biopsy. You definitely don't wanna do a spine biopsy, particularly because you can't get enough tissue decalcified. So for me, this is absolutely a case for EVOS. Now, had Adam showed us the liver and the liver had large lesions that were pet avid, that's a safe biopsy. It would diagnose and stage at the same time and would give us enough tissue for mutational analysis. But that wasn't the case here. I'm very pleased that you went ahead with EVOS. And can you tell our audience how many passes you've made of that subchiral Webster? So this patient, I think, had about four or five actually for just making sure we had good onsite on a slide. We did have a rapid onsite evaluation with pathology there. And then this patient had about seven passes to cell block since it took us a couple more to get good cellular evidence of malignancy on that first passes. We did about seven to cell block, dedicated to cell block for biomarker testing. Yeah, so, and that might seem like a lot for folks out there. Just wanna remind you that in the past, the literature suggested that after three to four EVOS passes, the level of yield didn't raise much. So if you did three or four passes, but that was for diagnosis. That was just, is it cancer or is it not? So yes, if you just are worried about cancer, making a diagnosis, three to four passes, you're fine. The problem is that you might not have enough tissue there to send off for biomarker testing. So I would urge people, if you don't have onsite cytopathology, six or seven passes, as long as the patient's quiet, it's such a safe procedure. Please get more and more and more tissue. So just a brief conclusion to this case. We had the EVOS adenocarcinoma was confirmed on psychology. We discussed those results and got through with oncology. And the patient did have an Exxon 20 insertion in EGFR, for which they met oncology shortly after. And so this is a pretty straightforward case. And for our checklist boxes, I was there and present for a lot of this. So I can tell you that I talked to the patient, that we presented the patient at tumor board, that we got these kind of sites that were going to be kind of this perfect balance or best balance, optimal balance of diagnosis stage, biomarker testing at risk of biopsy. I knew of our local requirements at the time. Next slide for the second half of the checklist here. And that we arranged and coordinated all of this stuff, because we've been working on coordinating this stuff within our multidisciplinary team already. Next slide, we have a little bit of a more complicated case. Just let me finish up on this by saying, look like there's a second generation EGFR tyrosine kinase inhibitor, osimertinib. And I have had patients just like that, what Adam presented to you, that are now three years out, three years out with an oral medication for wildly metastatic lung cancer, taking a pill, going to work every day, doing their jobs. If we had not done biomarker testing, this patient would have had traditional doublet chemotherapy with brain radiation, maybe some spine radiation if they had painful disease. And honestly, if they lived a year, we would have been jumping for joy. Now we have patients who were three years or more out on a second generation TKI. And you can take it, if it's out, they can receive another drug. I mean, the drugs for these targeted therapies are showing clear evidence of very much longer term survival. So that case was good in that patient was unlucky to have metastatic lung cancer, but lucky to have a mutation for which they can receive oral medication. And just to that final point, even if they had no actual mutation, which would have been really unfortunate, at least it wasn't unknown. You at least knew that you did a job of looking at actual mutations and that even if chemotherapy was their only option, you really knew it was their only option. So that was a relatively straightforward case in some regards of just, hey, look, this patient looks like they've got metastatic cancer. This is a little bit of a more complicated case. I don't wanna spend forever on it, but I think it illustrates that this series of checklists and goals really work for even really strange and complicated cases. You can see a left lower lobe mass with someone 65 presenting with weight loss fatigue. And again, no history of tobacco use, which does increase the likelihood of actual mutation, but doesn't guarantee it by any means. I have the times kind of to the side of each of these things. So day zero is the date they got this scan, left lower lobe mass. They underwent in just three days, this wasn't my personal case, but in just three days, underwent a Brodkoski with EVUS and mediacynal staging. They had an 11L that was abnormal and they did biopsies of 11L as well as multiple biopsies of the mass itself. Path did show adenocarcinoma. So just four days afterwards, adenocarcinoma both of 11L and the mass. They were presented to a ward at nine days from presentation. They recommended staging scans and plan for neoadjuvant chemoimmunotherapy, presumably before surgery and biomarker testing. The PET and MRI brain were done in pretty short fashion. You know, about a week later, they had both of these done. It showed a slightly larger mass at about a little over five centimeters and no evidence of metastatic spread. So this was clinical stage three biomarker testing. Specimen was received by the outside commercial lab at 23 days. So this was a bit of a jump and we'll count that as our order to eat. And then biomarker test results at day 30. They did have a PD-L1 score of 50%. And then other testing were negative, but much lower. Therefore, the full next generation sequencing was performed only immunohistochemical stage, which would be a suboptimal test for targetable mutations. Neoadjuvant chemoimmunotherapy was started, three cycles of that at day 42. Repeat PET shows decreased size and activity, but still certainly present. It proceeded with a left loral lobectomy, imidastinal lymphadenectomy. And unfortunately, a small neural nodule was actually excised. Frozen was negative, but was confirmed to be positive on final path. So we restarted the clock here because there'll be a new biomarker testing. So you see surgery is now day zero and final sign out of pathology was 12 days later because it was a larger specimen. So now we're at pathologic stage 4A. Repeat biomarker testing from time of surgery was 14 days later. And they detected an EGFR exon 19 insertion deletion, which is only prevalent in about 1% of non-small cell lung cancer. And they were started on oselamirtinib on day 53 from surgery. And six lung veterbal scans after starting have still shown no evidence of disease. So to look at this timeline for this case, for this first biomarker test, when they thought that the patient was early stage disease, you can see they did a really quick job to get a biopsy and to get a pathology result. Took them 16 days to get the order placed though. And the biomarker test result at seven days would be really quick, but remember they didn't do anything with an immunohistochemical stains and those stains are usually quick to turn around. Timed overall treatment was 15 days, which again is still pretty quick, but with some lacking evidence there. Test two was the surgical specimen. Time out though. So I just want everyone to sort of look at adding up those numbers. I wish that we had put in a column there, but three plus four is seven, seven and 16 is 23, another seven is 30, and then that's 45 days. So from the first time that the CT scan was done to the first time of treatment was 45 days. It's actually not bad, but we often think about this as pulmonologists in our world, right? Like, oh yeah, I got them in quick. I did the bronchoscopy. Understanding that all of those days count from when the patient's first told they might have cancer and that 45 day period. And I promise you that was actually short. I think that that's short. I think you're looking for most patients at 60 days, two months, right? If you look in the middle here and you see that 16 days in the middle, that actually could have been, that 16 days could have been peeled off if the biomarker testing was ordered at that day four time to pathology result. If it was ordered there, some of that 16 days could have been peeled away or if it was ordered at the time of biopsy, it could have been peeled away. So we think that that is a really, really sort of, you know, difficult and unnecessary delay. Take it away, Aaron. And I think for tests too, if you look at the time to biomarker order, I think that's a surgeon who just found metastatic disease and did not want to. So I think there was a lot of probably urgency from a surgery perspective to really get that in quickly, which is great, but it'd be great if this was standardized to be one to two days or the day of pathology sign out would be even better. Yeah, so look, I mean, the difference between 16 days and two days, right? And then the other question you have to ask yourself is why is the biomarker test result back in seven days in one circumstance, same patient, and 14 days in another? So these are the things that you can figure out if you work with your pathologist in your lab to find out like, you know, what I've said to pathologists, they may be like, this is your grandmother. You really want her to wait two or extra weeks because we didn't order the test at the time that the biopsy was done. I think the answer is overwhelmingly no. So I do think understanding this is really important and taking it out just of the context of, oh yes, we do biopsies and staging and put it into the context of what the patient, the patient timeline is, what their trajectory is, is really important. So going to the checklist of this patient, you know, they did have a multidisciplinary approach from what we can tell reviewing this case. They certainly did. They presented a tumor board and were discussing with the surgeon plans for neoadjuvant chemoimmunotherapy. We don't know if the patient was informed of biomarker testing and whether this delay was of any consequence to them. It seemed like this, for what data they had, selected the best biopsy sites to give diagnosis stage and biomarker testing. We don't know if the physician was aware of how much tissue was needed. Certainly there was inadequate tissue for the tests they attempted to perform on the bronchoscopy. And after diagnosis, you know, there was a delay for ordering biomarkers. So we don't know if there was really a coordinated plan or not. It was certainly recommended by the tumor board, but it wasn't done, you know, efficiently as it could have been. There was a communication plan to the treatment teams, it seems, because that was a fairly expeditious kind of our review. And, you know, they had, I think, missed the case, didn't have enough tissue for that first test. So I think that they didn't think about a repeat biopsy because they didn't know it was there. And then they had a clear timeline and had very quick time to biopsy and obtaining their stage information for sure. So overall conclusions, everyone has to get together, all stakeholders across cancer care have to get together to really make a reliable, agreed upon plan if you're setting up biomarker testing for lung cancer. You really make it effective and efficient. And then secondly, we have to get that team together frequently because this is changing on a yearly basis as to what needs to be tested and at whom. And then finally, a myriad of presentations accompany all of these patients. Everyone's got different comorbid conditions and interesting imaging findings that have to be evaluated. But the goal remains the same, which is timely biomarker and full treatment for everyone who's eligible. So I just wanna tell you that what's so incredible is the support that CHESS and our partners, AstraZeneca, Sanofi, and Pfizer have put together $200,000 grants. And look, I've been a member of CHESS for over 33 years, maybe 35 years now. And we have been always at the front end of taking care of folks with lung cancer through our guidelines, through our education, our educational offerings, through things like this webinar. One thing that we really have wanted to do and have not always had the funding for is to develop research applications and grants. So this is a request for proposals. $200,000 grants are open for applications. And through these grants, CHESS seeks to evaluate the impact of biomarker checklist in achieving the following goals, increase proportion of specimens processed properly after biopsy, increase the number of patients tested for biomarker mutations, increase the portion of patients for whom biomarker enabled targeted therapy, and increase the care coordination among the various disciplines involved in lung cancer. So if you'd like to, and there's a QR code there that you could take a picture of, and we're gonna be advertising this in multiple different venues, we would love to see those proposals and see what you propose to do a quality improvement endeavor, to increase your testing, to see what interesting and innovative things are available to you as researchers and as those who wanna implement biomarker testing in your institution. Doesn't necessarily have to be an academic medical center. It could be a community site that's really interested in getting this right. And so we welcome those grant applications. We're gonna stop there and leave this on the board and open it up to questions. And Adam is the keeper of the questions. Adam, go ahead. Well, the first question was talking about the timeline for the first case. And unfortunately, I don't have that timeline readily available. That patient was seen on a Tuesday and presented at multidisciplinary thoracic tour board the next day on Wednesday. And if my memory serves me that those staging scans were done within a week. We have a nurse navigator who when things are really, when time is really of the essence, really calls and coordinates these scans and they were probably done within a week or a week and a half. And I think if I remember correctly too, I had actually ordered an interventional CT guided biopsy. And as soon as we got those path results back, I mean, those imaging results back, we converted to a bronchoscopy because we could do it quickly. And it was kind of the more favorable test. So unfortunately I didn't have the time to break down all of the timelines for that first case like I did the second case. And some of Adam's career development awards, we are looking at large data sets to see if we can sort out just how much this happens and when it happens in both our institution, but in many other institutions across the United States. While we're doing this, you're gonna see a biomarker testing assessment come up on your screen. We'd ask you just to go ahead and click those buttons while the questions come up. Adam, go on to the next question. I think we're still waiting for a few questions to come in, but I think while we're on that topic of time to treatment, I think that like you said earlier in the talk that 30 days even from time of suspicion to starting a therapy is maybe even rarely achieved. With all of the different times of setting up biopsy, getting results, ordering the results and getting them back and then getting it all put together, I think we're easily, like you said, I think a short timeframe might be more like 40 or 50 days. Yes, and I published this study with a woman named Katie Melheim and some groups from the ASCO where they looked at what that delay meant. And particularly some of the younger oncologists around the United States actually started chemotherapy if they thought that the testing was gonna take longer than two weeks. So they would be starting perhaps drugs that could make patients sick and then wait and not be able to restart the medication once their biomarker testing came back. And so again, I think it's imperative to get that testing done right out of the gate so that the patient gets the right therapy the first time. Have any other questions come in, Adam? Our next question was about hospital end patients newly diagnosed with lung cancer, perhaps incidentally either out of nodule and who may be uninsured. Yeah, you wanna take the first part? I'll take the uninsured part if you take the hospital part and tell them what that means, yeah. So there is implications for extra barriers for especially for biomarker testing for patients who are inpatient. The way Medicare, especially if Medicare is kind of the paradigm for most of these patients in terms of insurance, Medicare reimburses outpatient procedures and inpatient procedures differently. Outpatient procedures is fee for surface. So if you do a test, you get reimbursed for the test. And inpatient, it's all lumped together under a diagnosis code. And so unfortunately, the people who are looking at reimbursement for various tests will see an outpatient that money comes in for that test or at least it costs no money to the hospital because if a commercial lab does it, they bill directly to Medicare or to insurance for that. But for inpatients, when it's run inpatient, that looks to be an extra charge to people and that disrupts care in some ways. And so it's just like a sick patient in the ICU, extra days and extra care will cost money. You only get reimbursed for these diagnosis related codes for who's admitted. And so I think we argue that this is a rare instance and that we should try to avoid any delay in ordering biomarker testing if it's really as time sensitive as it often can be in the metastatic stage. If it truly is just a lung nodule, an early stage cancer, well, maybe we couldn't wait those two weeks for which Medicare would bill it separately to allow other work to be done. Certainly, the patient still needs probably staging scans or maybe even invasive mediastinal staging with bralotoscopy. But we would probably argue to advocate for those inpatients who are really, they're inpatient perhaps because of their cancer, because of pneumonia or compression of great structures that really biomarker testing can't wait. And I wanna add a piece about the insurance. So when you're negotiating, again, once you put together your little, your team, your operations team to look into this, if you're ordering this outside of your institution, if you are sending it out to, for example, Foundation One or some of the other, Gardner or the other biomarker testing groups, they do have patient support areas for those that are uninsured. So if the patient doesn't have money, they will, particularly, and I get them to agree to that. Look, we're gonna be sending you all our other cases. We may have patients, everyone now and again, who have no healthcare insurance. This testing is expensive. Will you test those patients for us free of charge? And the agreement we've had when we send our things out is that absolutely they will. Well, I guess then, and we are up right around the time. We have a few minutes left. We'll give you a few minutes back in your day. Adam, I really wanna thank you both for helping with this webinar, but also for really dedicating the early part of your career to helping solve this problem for our patients. I wanna thank our audience who's always great and I think hopefully got something out of this. I know some of this was pretty dry, but I hope that you took away something from this. I also really wanna thank AstraZeneca, Sanofi, and Pfizer for supporting this grant and also supporting this webinar. And of course, as always, thanking the CHESS staff who help us keep on time, get the webinar set up. And so thank you guys as well. I guess this will end our webinar and we appreciate y'all being here. Thank you.

biomarker testing

non-small cell lung cancer

checklist for clinicians

coordination

communication

measurement of testing process

case studies

research grants

targeted therapy