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Biomarker Testing for Advanced Lung Cancer
Lung Cancer Biomarker Testing: Improving Turnaroun ...
Lung Cancer Biomarker Testing: Improving Turnaround From Presentation to Treatment
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Welcome, everyone, to Lung Cancer Biomarker Testing, Improving Turnaround from Presentation to Treatment. My name is Gerard Silvestri. I'm the Hildebrand Professor of Thoracic Oncology at the Medical University of South Carolina, and I'm being joined today by Wynette Scholl and Adam Fox, and I'd like to introduce them. Please go to the next slide, please. Wynette Scholl is the Interim Director of the Center for Advanced Molecular Diagnostics at Brigham and Women's Hospital and an Associate Professor at the Harvard Medical School. Adam Fox is an Assistant Professor of Medicine at the Medical University of South Carolina and a lung cancer pulmonologist. I wanna thank both of you for joining me today. It's so nice to have a sort of multidisciplinary team here to talk about molecular testing for advanced lung cancer. Can we go to the next slide, please? I'm gonna turn it over right now to Dr. Scholl, who's gonna be talking to us about what's required and what's needed to do adequate biomarker testing for advanced lung cancer. And then after that, we'll turn it over to Dr. Fox to talk about sort of policies and procedures around testing, and then we'll get to your questions. If you want, please put your questions in the chat box or the Q&A box, and we'll make sure that we answer them at the end of this talk. Dr. Scholl, please go on ahead. Yeah, thanks so much, Gerard. It's been great, of course, to work with both you and Adam on developing the content for this webinar. We've obviously had a lot of chances to talk about these topics together formally and informally. So great to kind of bring it together in this format. I do have the following disclosures not related to the content of this talk. So just to level set, I think we all recognize that diagnosis of patients with lung cancer is not always entirely straightforward, and that's particularly true for those of us in pathology. This, of course, is recognizing that the majority of patients who present with lung cancer clinically present at an advanced stage, which typically necessitates relatively minimally invasive small biopsies to render that diagnosis. So typically, these are small biopsy or cytology specimens. From a pathologist standpoint, this means that we often get materials that are somewhat suboptimal. They're often, as I indicated, quite small. They can be very limited in terms of tumor cellularity. And so we face a number of challenges. Number one is with actually rendering that diagnosis confidently to begin with, which is really essential for any of the downstream management. And then secondly is actually having enough material to be able to triage to the essential biomarker testing. Next slide. So I think the first question that comes up as a pathologist, what is the kind of minimum or maximum diagnostic workup that you should be implementing when you are dealing with the small, crushed, kind of dubious specimen from somebody who has potentially advanced lung cancer? And really question number one is, is IHC required all of the time? And the answer to that is it's not. There's certainly no diagnostic mandate for the use of immunochemistry. And in fact, if you look at the way the World Health Organization classification has built its texts, it's really very cognizant of the fact that there's incredible diversity globally in terms of access to resources for diagnosis. So the way we think about diagnostics and pathology really has to be very inclusive of all of the potential practice modes, practice environments. So really we remain kind of with a bedrock of histologic diagnosis. So if you have features that are diagnostic of say an adenocarcinoma morphology and a patient with clear cut clinical presentation as a lung primary, you can stop there. You render your diagnosis of lung adenocarcinoma and you're done. It's a single H&E slide. The rest of the material can be used for what it needs to be used for. Similarly for things like squamous cell carcinoma when you see obvious keratinization, you can just stop there. Of course, the challenges I alluded to is oftentimes the quality of the specimens we receive preclude that kind of immediate, okay, definitely this is adeno versus squamous and you do need to lean on IHC somewhat. So there's been a ton of effort. These types of diagrams at this point, I would say are kind of ancient. This is from 2011, the original iteration of this. And we've been just building and kind of riffing on this over time, pulling out one marker that's proven to be maybe less specific and slotting in another one. But really the focus of a lot of these efforts that have come out of organizations like the IASLC and have informed things like WHO classification are focused on really minimizing the use of IHC. And so this is a very complex algorithm, but suffice it to say, you have to think about the clinical context, figure out what kind of morphology you have. And if it's straightforward, you just render the diagnosis. If not, there's a stepwise approach to employing IHC. Next slide. In our own practice, we tend to use two markers and two markers only, sometimes just one in rendering a diagnosis of non-small cell lung cancer in the appropriate clinical context on small specimens. And those are TTF1 to confirm an adenocarcinoma diagnosis and P40 to confirm a squamous cell carcinoma diagnosis. And it's not always straightforward. And there's been a number of back and forth amongst expert diagnosticians about how to interpret it when it's maybe kind of a land somewhere in the middle, it's not totally TTF1 or P40. And so there's guidelines for the types of diagnosis you should render when you do have kind of more intermediate expression patterns, but it's all out there and anybody can employ these and really, again, try to focus on using the bare minimum of IHC to render a diagnosis. It's not always possible. And you always, again, have to keep in mind the clinical context. If you really just sort of employ the, it's either adeno or squamous or non-small cell NLS, which is what you could render if it's P40 and TTF1 negative you potentially miss the opportunity to diagnose, say a metastatic melanoma, right? Cause that can have morphologic overlap with adenocarcinomas or primary lymphoma. Or so you do have to keep in mind that the differential is broader than just those primary lung cancers, but most of the time you're pretty safe just employing these markers. Next slide. Okay, so let's assume we've gotten to the point where we've rendered a diagnosis and we've hopefully employed a minimum of diagnostic aids to get to that point. We have to start thinking about what we need in order to generate a quality or a reliable molecular result. So there's two major adequacy considerations that go into thinking about whether a sample is gonna work for molecular or not. And those are quantitative and qualitative considerations. From the quantitative side, you need to have enough input DNA, just period, right? So you have to have enough starting material that you can actually say, generate a PCR product or generate an NGS library. And then of that, there's a question of, okay, you have enough DNA, but how much of the DNA is actually the DNA of interest? And for us, of course, the DNA of interest is that that's derived from the tumor. So that's the perennial question to the pathologist is how much tumor is actually present in this specimen? I will tell you, it's often a very difficult question to answer and I'll show you some of the, sort of what we can see in that regard in a couple of slides. But those are the two key questions. From the standpoint of quality, it's pre-analytics, pre-analytics, pre-analytics, and then what are the storage conditions? What kind of formalin did you use? Was it a bone biopsy? Did you need to get decals? If it got decal, what kind of decal was it? Because if it's EDTA based, maybe we can use it. If it's hydrochloric acid based, we can't. These are all these sort of factors that weigh into the preservation of the DNA, and then ultimately type of molecular assay you might be able to use. Next slide. And when you think about actually kind of providing a strict definition of specimen adequacy, it's often difficult. It depends on the type of test you need to have run. And that's really the validated performance characteristics of the test in the lab and the limitations of that particular test. And then there's this really critical interplay between the amount of starting material that you have and the quality of it. So it turns out if you have a really teeny tiny specimen, but it's a very high quality nucleic acid, so maybe it hadn't seen formalin fixation, which always degrades the nucleic acids, you may actually get away with sort of having an input material that's very, very lower, either at the low end or maybe even lower than what you're typically accustomed to using for an assay. In contrast, if you have kind of a crappy sample, sorry, excuse my French. If you have a sample that has, you know, for whatever reason has some more DNA degradation, you actually may just need more starting material in order to generate some kind of reliable results in that material. Okay, and so, you know, how much do you need? Well, again, it depends on the type of assay. If we're talking about in situ assays, you may need as little as 50 to 100 cells, which obviously you can enumerate by looking down the scope. That's typical for many of our FISH assays or say for our PD-L1 assays, we need typically a minimum of 100 cells to generate a reliable answer. Of course, when we talk about molecular, we're talking about the content of nucleic acid in that specimen. For focused high sensitivity single gene tests like droplet digital PCR, which can often get you a mutant detection level of say 0.5% or maybe 0.1%, it's just a single target, however. So you don't need much of it, but you just need enough to kind of have say a thousand molecules that you can interrogate. You can get away with something like five nanograms of input DNA in that case. For panel NGS, you need an order of magnitude more at least. So typically 50 to 100, several hundred nanograms of nucleic acid. What does that mean in practice for say a droplet digital PCR assay single target? You might be okay with say two or three unstained slides cut at five microns from a small core biopsy. For panel NGS, really the bidding usually starts at around 10 unstained slides. If it's a smaller core biopsy, if it's a large piece of tissue, you could be fine with just a single unstained section. But again, the quality is going to play and if it's very necrotic, you're probably going to need more than one that's really well-preserved tumor. Next slide. Again, sample size matters in terms of the amount of DNA that you need. And then obviously, as we've heard of talk about the amount of tumor that's in it, we actually did this type of analysis when we first launched our assay for next-gen sequencing for solid tumors a decade ago. We retrospectively went back and we didn't sort of a priori exclude any particular sample, but after we started testing, we retrospectively went back and we figured out what was that cut point at which samples really kind of just stopped working. And we realized in looking back at say 40 or 50 cases, that if the sample size was two millimeters of linear tissue or less, and again, looking at say core biopsies as a very standard type of specimen we were dealing with, we had a 80% or greater failure rate when they were that small. If however, we had at least three linear millimeters of that core biopsy, our failure rate actually dropped to less than 20%. So that was sort of right at that threshold of being able to pass the sample through. And that's been the rule we've employed for accepting samples since that time. And this is assuming somewhere in the ballpark of 10 unstained slides. Sometimes we can get away with a few less and sometimes we need a few more. Next slide. Okay, and then from the standpoint of tumor content, how much tumor do you need in that specimen? It depends on the assay again. So if it's that droplet digital PCR assay where there's a single target and you can see one in a thousand molecules to detect that mutation, the way I approach those is I say, I see that there's some tumor on this slide. It could be 1% tumor. I don't care. I'm gonna accept it. I'm gonna process it through. I just need to know there's tumor on this slide with a condition of other things. If it's a next gen assay, a large panel hybrid capture assay that takes two weeks to turn around and cost $1,000 to run in the lab, I'm gonna be a little bit more careful about trying to enumerate how much tumor is in there. And of course, we've carefully validated our assay around understanding the performance for different types of targets in FFPE tissue. We can detect a point mutation in a well-covered gene on our panel down to about 3% variant allele fraction. So we would need about 5% tumor to 10% tumor in order to see that. For a copy number variation, however, we need at least 30 or 35% tumor in order to see that type of change. So we have a general requirement of about 20% tumor to be accepted into our laboratory. That said, if it's a pancreatic adenocarcinoma, and if we can find that KRAS mutation and with sort of answers, in all likelihood that we are not gonna have, say, a fusion-driven tumor or something else like that that's targetable, we'll tend to accept it even if it's less than 20%, because it's very easy to see those KRAS mutations down to, say, 3% to 5% variant allele fraction. Okay, next slide. Okay, so here's, again, the question, how much tumor is in this specimen? And there's a core biopsy on the left, and then there's a cell block on the right. If you just kind of look at these, just at scanning power, you'd be like, well, there's clearly some cells in that core biopsy on the left. There is nothing in that cell block on the right. But if you look at these carefully, you'll realize that that's probably not actually the case. And going to the next slide, between careful examination at higher power of the core biopsy, and then ultimately when these were sequenced, looking at the variant allele fractions that we saw, and then sort of being able to back calculate how much tumor was actually in them, we're able to estimate that we had about 10% tumor in that core biopsy with a lot of obscuring inflammation. And actually, the vast majority of cells in that cell block were tumor cells. So it's helpful to have somebody who's got kind of some acumen for looking at cytology specimens. That can be a little trickier to ascertain what is benign versus what is malignant, and actually make an accurate assessment of the true tumor contribution to a sample. Okay, next slide. Okay, so kind of to sort of pull all of these concepts together, as we're thinking about building a process in our laboratory, it's thinking about maintaining the quality of that specimen via the specimen stewardship that you need to supply both from the procedural rooms and within pathology. And so it's about maintaining a very short cold ischemia time. It's about standardized fixation, 10% neutral buffered formalin, like we've been harping on this forever, but that doesn't mean that all institutions actually are supplying this type of buffered formalin in their practice, trying to avoid decal as much as possible. And then there's a lot of strategies that you can employ in a histology lab to try to really kind of create a separate workflow for those samples that have a high likelihood of requiring molecular diagnostics. So when we get core biopsies for lung masses, we typically are separating out the core biopsies into separate blocks. So it's not like you put them all in one block and somebody accidentally slices through the whole thing in the course of creating sections, you've lost it all, like want to avoid that situation. But if you create multiple blocks, it creates some additional level of insurance. Careful embedding, like you really are very reliant on your histology workforce. This group is so clutch. They're just so important in having folks who understand what the requirements are for your tissue specimens, understanding how to embed them well, understanding how to actually section through them so you get enough information, but you don't waste it all before you get a chance to cut sections for molecular, et cetera. Working with your histology lab can be really critical. They know a ton that we don't necessarily appreciate as the diagnostic practitioners, and they can really help guide your practices for these types of procedures. Again, maintaining a short list of really helpful amino acid chemistry and incorporating the clinical information. So you're not going on a wild goose chase pursuing a strange diagnosis when it's sort of obvious to everybody else on the clinical team what the diagnosis already is. And then of course, if necessary, employing predictive markers in a reflexive strategy potentially, such as PD-L1 and maybe Alkenross IHC if that's working in your environment, or talking with your clinicians about how to incorporate reflexive strategies broadly, which Adam will talk about later. Okay, next slide. And then I wanted to talk a little bit about cytology in particular, since that's a really a big specimen type that gets generated from minimally invasive procedures. We did some analyses, and we're not alone in having done this. We did some analyses six or seven years ago where we wanted to understand the types of information we could generate from cytology preparations rather than standard biopsy or cell block preparations in molecular diagnostics. And when you think about the kind of typical specimens that are accepted into laboratories, there's a big focus on FFPE blocks in part because that's just how labs operate. Everybody's got processors that generate FFPE blocks and histology technicians that can generate them. From a cytology standpoint, there's all sorts of different ways to generate the cytology slides. And you have to think about actually validating all of the different potential preps that can happen in cytology within your molecular lab before you can accept those sample types. So you have to think very holistically as a molecular lab. But if you can do that and understand how those samples work on your assay and then formally validate them, you can then accept them as specimen types for routine clinical testing. So when we started looking at it, we realized that the quality of the sequencing data that we were getting from cytology preparation, such as smear preps and thin preps, and error drives, et cetera, was actually superior to the DNA, to the sequencing quality we were getting from FFPE materials, which is not too surprising because many of these cytology preps are not seen formally. And that's that key ingredient, which we rely on heavily, but it's very damaging to the DNA. So after we determined that they were high quality and we validated them, we incorporated it into our workflow as really a secondary material that we would obtain largely because it's a little bit of an additional complexity for our own internal workflow. And you also end up destroying that cytology slide when you use it. You have to remove the material directly. You're not going back to sort of a source like an FFPE block and comparing that to an H&E. You've got to destroy that original sample. So that would, for us, that meant we had to capture an image of the slide for really our legal record. We would then scrape the materials off and move forward to our nucleic acid extraction. Next slide. And we did that largely for DNA-based hybrid capture next-gen sequencing. There've been other groups that have done something similar with RNA sequencing for fusion detection and have demonstrated that if you combine the materials, including direct smears with, say, cell blocks, you can get close to 100% yield in molecular testing for fusion detection. Whereas if you're relying purely on the cell blocks, you get about 50% of that yield for detection on that assay. So really being able to use multiple sources of material from a given individual's procedure can definitely increase your molecular yield. Next slide. And in recognition of this fact, the 28, I mean, we're going back here five years, but we still don't have full incorporation, I think, of cytology specimens into everybody's workflow. But going back five years, there was a recognition of the fact that these were a great resource for patients and essentially explicitly stating that really any cytology sample with adequate cellularity, enough tumor content is going to be okay for molecular testing for patients with lung cancer. And I think we're all, you know, accept this. It's just that the operational incorporation of these samples can be the challenge. And a lot of commercial labs still don't accept this type of sample type in their practice. Next slide. Another strategy, which is really, really cool and slick and can potentially even save time is to skip the bit about getting the slide and taking the cells off and then putting it through a molecular diagnostic step, but instead to take the parallel fluid from which you actually created your cytology prep and using that for your molecular diagnostics. And there've been a number of groups in the last few years who have essentially shown if you take that parallel, say, rinse fluid from the FNA, EBIS-FNA or the CT-guided FNA, et cetera, you can see really reliable molecular results. In fact, some studies showing 100% concordance with what you would have gotten from say the FFPE cell block from that same material. So I think the challenge here, if you look at the next slide is thinking about how you incorporate that sample type into your workflow coming out of say your EBIS suite or where your cytologists are performing the rapid onsite evaluation. I will admit, we haven't quite figured this out yet in part because there's a lot of different inputs in terms of where the specimens are coming from, the timing of when you have, say, that fluid in hand, who has the fluid, et cetera, and kind of aliquoting that can be challenging. But I think it's a puzzle that can be figured out at institutional level. And if you can figure it out, you potentially could very substantially accelerate your access of your molecular lab to potentially diagnostic material. Okay, next slide. And then of course, everybody loves ctDNA testing. It works great in many scenarios. It doesn't work as well in some other clinical scenarios. It's always faster. It's pretty much, I mean, I guess I should never say anything is always, but it's pretty much always faster than say going from the point of getting a tissue biopsy to getting molecular results. And that's because it cuts out this whole sort of, get the patient in the IR suite or into the interventional pulmonology suite and get the material and then go through processing and then do your diagnosis, et cetera. So, you know, it's great. It's a really wonderful complimentary strategy for accelerating turnaround time because you can kind of cut out that tissue processing step. But again, it's not gonna be 100% clinical, have 100% clinical sensitivity, particularly in patients who don't have extensive disease. So particularly those folks who have thoracic only disease, it may not be an informative assay. Next slide. Oh, a little animation. Okay, great. So, you know, I've alluded to this already. I think one of the things that we've tried hard to do is to, again, enhance the processes that we're working with within our system to increase the likelihood that molecular testing is gonna be successful. Our initial foray into this was very simply making sure we had a label on those specimens from patients who had lung masses that were getting biopsied where a non-small cell was suspected and triggering an order up front for unstained slides to be cut that we could use both for our diagnostic IHC, any predictive IHC, and then have sufficient leftover. So we almost always have 10 leftover to send for molecular testing when that was warranted. Next slide. And I would say it doesn't just have to be that histology protocol where you create unstained slides up front, figuring out ways to incorporate your cytology preps, and then other bodily fluids, the rinses that we talked about, or in the cases of patients with leptomeningeal disease, figuring out ways to incorporate CSF specimens, which actually work great, on next-gen assays for detection of tumor variants in patients who have a suspected leptomeningeal spread of disease. And one of the kind of tricks that more labs have employed over time is instead of going through kind of a conventional two-week turnaround time for a big hybrid capture next-gen assay is to utilize maybe in a stepwise fashion some more integrated systems where you can generate a result of a more focused panel over, say, a day or two from a small set of samples. Next slide. And then once it's in the lab, it can get complicated, and we have our own set of challenges in the molecular diagnostics lab that we always have to kind of keep on top of to keep turnaround time down. You can go ahead to the next slide. And so here's just a sense of where the turnaround time comes in from the laboratory standpoint. Sorry, this is an animated slide, Adam, or I'll have to just have you go through it. So there's obviously getting a sample into the lab, and I think Adam will talk a bit more about that as well. There's the process of getting the nucleic acid out of the sample, setting it up on the bench for the sequencing chemistry, doing the actual sequencing, running an informatics pipeline, doing the technical review and the quality control review. The pathologist looks at it and integrates it all, and then it's able to sign it out. And this typically takes two weeks. These are the numbers that you see, and this is why. There are a lot of steps to these processes. And you can kind of keep it consistently at this turnaround time if everything's kind of running smoothly, but you take out a key member of your accessioning team for advance it. And all of a sudden you go from, say, a two-week turnaround time to maybe a two-and-a-half or three-week turnaround time. So you've got a backlog getting those specimens into the lab, and then you sort of couple maybe absences on the front end and then a shortage of pathologists signing your cases out, and all of a sudden you're consistently looking at three or three-and-a-half-week turnaround time. So it's a very kind of personnel-dependent process. And these are the sort of charts I was showing, peri-COVID, when everybody left to become a chicken farmer after kind of COVID came and swept through, all of a sudden we were all facing these incredible shortages and couldn't get things done as quickly as we wanted to. Next slide. So I was just gonna end with a quick case presentation to kind of tie a lot of these concepts together. And so this is a gentleman who was 75 with a history of Rett-rearranged metastatic lung cancer, who had received a Rett therapy on trial and he progressed. Then he actually did really well with chemopembro and for two-and-a-half years, then he finally came on therapy. As they were following him, about six months later, he was found to have a pericardial effusion. And ultimately he went for an echo. He had high pericardial pressures. He actually emergently went for pericardiocentesis, and that was confirmed to have metastatic adenocarcinoma. It was actually a really incredibly cellular specimen. He continued to have worsening of shortness of breath. There's some consideration of what to do next in terms of therapy. And a pericardial window was placed and a request for genomics was placed at that time to guide further therapy. So if we go to the next slide. And so this is kind of what happened from the lab standpoint. And I bring this up because I got some queries from some very high-profile individuals in my own institution saying, where's the answer to this molecular result that I've been asking for? And in this particular case, we get an order and we start looking for the material that we need. So it became clear based on the record that the pericardial window biopsy was hypocellular from a tumor standpoint. We had to go after the cytology. We look into the cytology record and we actually prospectively document the cellularity of the different preps that we create in the lab. And so just by glancing at the report, we can say, well, the tumor cell proportion looks really low in this case, less than 20%. Is there another sample that we could chase? And in fact, there was another pericardial fluid. There would be two separate pericardiocentesis. So we went to another one. We contact a site of pathology and we said, give us the best smear prep from that particular date. They got it to us and just the vagaries of emails back and forth and samples moving from one part of the department to the other. It took till day four for us to get that specimen in hand in the molecular lab. It was confirmed as adequate by the molecular pathologist on call, passed to the wet lab and put in xylene because you've got to take the cover slip off. And it took four days to get the cover slip off the cytology prep. So here's one of the challenges with the cytology preps and why doing things like the fluids or the supernatants can really help with that turnaround time challenge. Once we're able to get the cover slip off, it's all systems go. We get them to the library prep and we sequence it. This particular individual had confirmed that RET fusion that was seen originally and no other resistance mechanisms were detected. So we were able to give them some information, but unfortunately nothing they could actually act on directly. Next slide, and I think my final slide. So the final thing I just wanted to say is that I showed you some turnaround time metrics and we create these dashboards to actually follow those. Building these is an incredibly complex task. In order to do this, and we're doing this routinely for all of our next-gen sequencing patients now, we're actually able to track the turnaround time from the time that the order is placed to the time that that result is generated. To do that, we have to link into Epic, SunQuest, PowerPath, Clarity, a home-built system called NGS Review and another home-built system that we call the CM site and work with our accessioning team or pathologists, different ordering centers, just to put all that information in one place. So it's an incredible effort. Once you have it, it's amazing because you can create dashboards and you can provide data back to your clinicians like this OncoInquiry tool that you see here that tells them step-by-step where a specimen is actually located in the process. But it's a major institutional investment to be able to build tools like this. I think it's a need in the system in general for us to be able to kind of create these metrics that people can see real-time where their specimens are. Thank you very much. And we're going to move on to Dr. Adam Fox, who's going to tie this all together. I have two or three questions for Dr. Scholl and others. If you'd like to put them in the chat box, please let us know. And Adam, I'll let you take it from here. Perfect. This is my disclosure. And so I want to talk about key takeaways from kind of the entire webinar series and look at the role of the pulmonologist in biomarker testing and also the role of the multidisciplinary team. And I'll also end with a quick case. For those who maybe missed the first two webinars, I'm just going to walk through them just very briefly just to hit the high points. The first webinar was really highlighting the importance of biomarker testing and Dr. Bruce Johnson was our speaker. And the key takeaway one was, for me, was really the improvement in survival we've seen in advanced lung cancer. This is probably familiar to many who are watching here. But on the left side of the screen, we have survival curves for kind of standard platinum-based chemotherapy regimens with the median survival in advanced disease of only 10 months. And compared to a targeted therapy, this is a lectinib. And at the time of this five-year update for a trial comparing lectinib and crizotinib for ALK rearranged non-small cell lung cancer, these were advanced in metastatic stage. They hadn't even hit median survival at five years yet. They were just approaching it at five years. So the survival benefit is dramatic. Not every patient will have this mutation, but for those who do, it's life-changing. Number two was the improvement of survival in resectable non-small cell lung cancer. This is newer. There's several trials really showing this. I was just going to highlight one, the CHECKMATE 816 trial looking at chemoimmunotherapy for stage 1b to 3a resectable lung cancers. Note that those with EGFR and ALK alterations were excluded, and that's because they predict a poor response to immune therapy. They were randomized one-to-one to either chemoimmunotherapy or chemotherapy prior to surgery. And this is their survival curve here. And you can see there's clear improvement in those who received the neoadjuvant therapy. And then also impressively, achieving a complete pathologic response on the resection specimen was much higher in those who had the neoadjuvant chemotherapy and immune therapy. So the last ticking point is that testing for these kinds of treatments is underutilized. And so this was not presented in the first webinar, but this is actually a paper that Bruce Johnson coauthored, looking at SEER Medicare data, so nationally representative samples, looking at associations between biomarker testing within 60 days for advanced and metastatic lung cancer versus those who did not have biomarker testing. And they were able to find that there was an association with survival and biomarker testing. And then broken down on this other survival curve here, you can see those lowest curves, the poorest survival were for those who did not get any systemic treatments. The middle group of kind of three lines there, those are people who either didn't get testing or did get another treatment, maybe didn't have evidence of testing, but somehow got a tyrosine kinase inhibitor, a targeted therapy. And then you can see the best, the top curve there is people who had evidence of biomarker testing and who got the appropriate, assumably appropriate therapy. And so testing has to be translated into therapy as well, but this really, I think, demonstrates that connection. A quick wrap up for webinar number two delivered by Dr. Nick Pastis. This was on tissue acquisition. For anyone who missed, it had a really good deep dive into bronchoscopy, EBUS and adequacy of EBUS, and some of the kind of new technologies for bronchoscopy. The take home I wanted to highlight was really the goal of this initial biopsy. This is a key role that many pulmonologists play, whether they perform procedures or not, they often direct that initial biopsy and sometimes perform it. The goals would be to establish diagnosis, provide stage and provide tissue for biomarker testing. And if you can do all of that in one procedure, that's often the best procedure. We also have to weigh procedural risk and timeliness. And this is just one example that wasn't presented in that webinar, but is a great example for this discussion. This is actually out of an article that Bruce Johnson, myself, and Dr. Scholl and Dr. Silvestri, all co-authors on, looking at these exact issues of complicated patients of, well, where do you do the biopsy? What's likely to give us the answer? You can see in the first two A and B tiles, a lung mass that's PET-AVID. Tile C, a subcranial level seven N2 lymph node that's hypermetabolic and enlarged. Tile D, metastatic disease in the bone, very suspicious for metastatic disease. And then E and F, enhancing lesions on an MRI, suspicious for metastatic disease. And so weighing the risks and benefits for each of these, along with what's likely to give you the answer. So the lung mass might give you the answer, but gives you no confirmed stage information. Certainly this is highly suspicious. The tile D bone mets, again, the decalcification process, if you have the correct techniques may work, but often certain decalcification techniques will render the DNA useless. And the brain biopsy would give you stage diagnosis and tissue for molecular testing, but has significant risk involved with it. So for this case, we kind of argue that a bronchoscopy and EBIS is likely to provide that balance of risk and able to achieve at least metastatic disease confirmed, at least to the mediastinum. So confirming N2 disease and biomarker testing and diagnosis. But this is one of seven cases. So this is a great resource for anyone looking into procedure selection more, along with the second webinar. And then today we just heard a great talk by Dr. Scholl. I've heard many of her talks and I learned something every time. I look forward to seeing what Gerard picked up there to ask questions about too. But the key takeaways looking at her slides was really, we have to define what our local technology is. And even if we're sending out samples, not locally, that's still what we're using locally. So we have to understand what that technology is, what is adequate for that technology. And are there any practices internally that we need to be either using to help conserve tissue or better utilize tissue, especially for these small biopsies that we're used to attaining? So I wanna take a step back after that overview because that really sums up, I think, a lot of the issues from before biopsies have been done to getting the pathology done. And I tried to sum up the goal for really the whole multidisciplinary team in one sentence, and I hope it does justice to what the goal is, but it's to get a systematic and comprehensive and timely biomarker testing program to assess all the patients who are eligible, because that's changed over time and will continue to change over time, and then to deploy a biomarker-informed treatment plan. And so just like our CHECKMATE 816 neoadjuvant chemoimmunotherapy, you don't necessarily have to have a biomarker to get chemoimmunotherapy, but notably, EGFR and ALK are exclusion criteria. So it's not that you're going to be delivering a targeted therapy to those patients, but you at least have to realize that if they were to have those alterations, that those were not included in the trial and that maybe other treatments, they may be eligible for other treatments. And so not always do you get a biomarker-driven therapy, but it should at least be biomarker-informed. So this really sets us up to look at these intervals that patients experience. We took a deep dive on the pathology level, and this is kind of on the initial suspicion-to-treatment spectrum. This is kind of anecdotal. There's no guidelines for how long it should take between really kind of realizing there's a suspicion for lung cancer to biopsy, but a goal might be less than two weeks. From biopsy to having pathology results of interpretation of kind of histology or cytology, maybe a good goal would be less than a week. Ideally, biomarker testing will be ordered the same day that we know that this is non-small cell lung cancer. Of course, there's going to be difficult cases, but ideally at that time, we probably have a sense of what the stage is and what treatments they may need, and by then we'll have the histology or cytology result as well. And then this does have guidance for how long in the molecular lab to having results less than 10 business days is kind of the guidelines for that interval. So who should order testing? Which I think is what I'll argue is a really modifiable endpoint or time point for patients. And should it be pulmonologists? These are kind of the three big groups of actors who are in place to potentially order biomarker testing, and they each have their pros and cons. Proceduralists may not have the detailed information of which tests to order and which tests are indicated for each level of patient, but they often will have the suspicion of lung cancer and be the first to perform or direct that biopsy. They're also disadvantaged because it's a group of several specialties who may be biopsying or attaining tissue for patients with lung cancer. So if you get all the pulmonologists to order biomarker testing in a really systematic way, but maybe your surgeons and your interventional radiologists don't, then you're not really getting all eligible patients that are newly diagnosed with lung cancer they're testing. You've only fixed just a portion of them. So corralling all of these different specialties, there's some coordination issues with doing that. Pathologists, we're gonna talk about more in the coming slides, because often when people talk about reflex testing, especially in the literature, they're talking about pathology-driven or pathology-ordered kind of testing. So we'll talk about that. They may not have stage information, especially if they're in a separate private practice. So they may just have a sample and not really have an exact clue, might just say lung, and they may not know if testing is indicated. And there's some other issues we'll get into. And then finally, oncologists, they know the treatments, they know what people are eligible for in terms of their comorbidities and things and what the toxicity of these drugs are. But by the time the patient is getting to refer to them and seen by them, we've already prevented a timely ordering process in many cases. So that's their biggest detractor, is by the time they get to an oncologist, really the order and hopefully results could be performed. So focusing on the pulmonologist, I just wanted to show a little bit of data from a paper that Dr. Silvestri and I have published in recent years. This was a survey of over 450 pulmonologists in the U.S. And we asked them whether or not they tested, they and their institutions tested for various biomarkers. And you can see that pulmonologists are testing for biomarkers. They do have some awareness of them as well. Those with the oldest therapies, EGFR, ALK, and PD-L1 are kind of the oldest kind of therapies they're tested for more often. And at the time of the survey, Metinret didn't even have approved therapies. They were just in the clinical trial stage. And you can see there's differences in pulmonologists. So this breakdown between the two colors of blue is between general and interventional pulmonologists. And we think there's a volume outcome relationship here in that interventional pulmonologists perform more procedures for lung cancer and likely get referred more patients with lung cancer. So we think that that's the kind of connection there. Additionally, we know pulmonologists differ in their practices for even performing procedures. This chart shows the number of passes during a bronchoscopy with endobronchial ultrasound just for tissue for biomarker testing, so not for diagnosis. And the jury's a little still out on the exact number that's correct, but probably zero to two is not correct. It's probably low. The three to four is kind of the standard guidance for passes at a site for diagnosis, which is probably why that was a very common answer. And you have this section of about 30% of respondents who's really taking far beyond that to try to attain tissue for biomarker testing. Back to coordinating, we asked them who was responsible for ordering at their institution. And about a quarter of the time they identified their own specialty as the ones who were responsible to do the ordering, most commonly it was oncologists followed by pathologists. Only about half had any kind of policy to guide whether testing should be performed for certain patients by histology or stage. And if you think about it, we didn't say, do you have reflex testing? Do you have some amazing integrated EMR to get this done? We just said, is there any kind of agreement, any kind of policy that your team has gotten together? And only half really had one. And then testing is being done in a variety of locations. Mostly it's happening, at least in combination, outside the institution where biopsies are being performed. So what are some strategies that can be employed to help get testing done on a more systematic and timely basis? Most of this is anecdotal. There are health record changes that places have instituted to create order sets and ordering prompts. There's a mostly targeting the proceduralists when the results from their procedures are either resulting. So that would maybe create a prompt to, hey, this is now indicated a biomarker test order, or perhaps at the time that they're placing their biopsy pathology order, there might be a separate order in the order set to indicate please complete biomarker testing based on the suspicion even before pathology is done. There's also designated ordering providers, and really any specialty could set this up, but it kind of runs to that problem that if you have a pulmonology clinic person or physician who's really gonna take charge of that, or a nurse navigator, they really have to see the whole landscape from the other parties, including interventional radiology and surgery to really make it systematic. And certainly you could have an oncology staff member or provider trying to order these in advance of visits, but those all have their limitations. There is one surgeon, Dr. Farhoud Farja's group does have an informatics-based ordering system that I've just learned about where the EMR recognizes his surgical pathology report to generate an order, which I thought was fascinating. And then the next couple of slides, we'll talk about reflex testing. And in the literature, you can set this up in several ways, but in the literature, this usually means that a pathologist is either prompting the order or placing the order. The rationale is that this should be kind of systematic. It might appear automatic to us, but certainly it involves a pathologist putting in an order. And as long as they're in the place to know who is eligible, then it should also be reliably so. It should reduce disparities because they're just looking at the sample and the history, not based off of any other types of clinical history or meeting with the patient or anything like that. It should improve the timeliness of testing because ideally, and hopefully, pathologists are in a place to prompt and know that this is indicated at the time of signing out the pathology sample and whether there's adequate tissue potentially. And it consolidates the need for knowledge to a single focus point. In most institutions, all biopsies kind of go to the same pathologist group. And so it may be kind of a bottleneck in the need for who needs to know exactly who needs testing with what assays and when. And there's multiple potential ways to achieve this kind of systematic testing. Again, you can integrate ordering prompts and order sets to allow your pathologist to do this because there are some barriers, as you might imagine. Everyone has to get together and have consensus on who is eligible and which ones are eligible for which biomarkers and which panels at which laboratory. We're certainly testing more patients with earlier stage non-small cell lung cancer. Just over the last couple of years, those trials and indications have come out. And so this is going to continue to change. And we have to integrate practices that may be separate. So if you have a private practice that's referring to a private pathology practice or maybe to multiple oncology practices, depending on where the patient lives, you have to have some kind of understanding of what an oncologist might use. And again, this is going to keep changing over years. So it also has to be updated, which this takes time of a lot of people to try to coordinate. For the pathologists specifically, there are compliance issues. And these are due to regulations that are designed to limit unnecessary testing. And so there's an issue if you're performing within your own institution, your own biomarker test panel, there's issues of self-referral. And so this is often ameliorated by the order. So a urinalysis with reflex to culture is an order. You could always order the urinalysis without the reflex. That's kind of a compliance workaround to have both optional. But if you say that you want it reflexed, then that kind of allows the pathologist to move forward and for there not to be concerned that they're kind of referring to themselves to gain business, let's say. And then there's also this issue with orders needing to come from treating providers, end quote. I consider our pathologists who show up to our tumor board treating providers, but it's not really necessarily the way it comes out in the compliance and regulatory world. And so ideally these orders from a compliance issue, from a compliance stance, people want to come from some kind of treating physician like an oncologist, I suppose. And so there are workarounds for that internally here at MUSC where we've gone through our medical executive committee and our pathology group to try to get this set up. That's still in the works, but we're making headway to get that started here. I wanted to provide one example of reflex testing that's published because this is the only mechanism that I'm aware of that has any literature base. It's all single center labs. And this one is as well from 2016 to 2018. The intervention was that pathologists would order kind of an institution approved and agreed upon panel for new patients with adenocarcinoma of the lung. It was also mostly just an advanced disease. Testing was also brought in-house and only looked at completed tests, which were just a couple of the limitations. But you can see, this is a chart showing the average turnaround time of biomarker testing. And the first row is a year prior to the intervention. The second row is the intervention year. And in the last row is one year after the intervention. And just by changing the time to order, they were able to decrease their average turnaround time from 52 to 15 days. And this data is a little bit skewed on that 52 days, if you look at it, but it's still quite impressive of a change to drop that many days out of the turnaround timeline for biomarker testing. I think what we can do is we're coming up on time and I wanted to give the audience to answer questions. Oh, yeah. I don't have a case, but we've had Lynette's case. So I'd like to open it up to the chat box for any questions, either in the question and answer or in the chat. And while we're doing that, I'm gonna ask Dr. Scholl a question. Dr. Scholl, you have so many resources at Mass General. What if someone has to send their specimens out? What few things, what two or three questions should they have to ask outside labs like garden or foundation? How should we interview them and ask them a question so that we know we're getting our money's worth and we're getting turnaround time and we're getting accuracy? What should we ask them? Yeah, I guess I would, obviously I think for a lot of these big laboratories, they actually have published their performance data for their assays. So that's sort of publicly available information and it's worth taking a look at those and it's worth ensuring that they have indeed been peer reviewed, published studies. There are plenty of maybe fly-by-night laboratories out there potentially that will promise the world but don't necessarily deliver. And if you don't see that sort of published data in the literature, I would be cautious. So, and you really wanna see that it's a CLIA validated, a CLIA certified laboratory and that they're offering clinically validated tests. So I think that I often take that for granted because that's the atmosphere I work in but you do have to be very careful of folks who may reach out and be like, oh, we have the magic sauce here in our laboratory, send us your samples. You really have to do your homework before agreeing to do that. Again, for many of the big commercial labs, that data is very much publicly available and I think they can offer a very reliable service. And I think from the standpoint of actually handling the tissues, the question of how they interact with your institution, both in terms of how they can dock in with your pathology department from the standpoint of sending tissues out, what does that process look like? Who are their contact people on the laboratory side? How do they work with the pathologist? And if you connect those folks, like the intake folks on the lab with your pathology folks who need to send that material out, that can be a really critical step. And then on the back end, if you will, for the results delivery, do they have a mechanism to feed results back to you in a way that it makes it easy to integrate into your EMR? One of the things we found when we interviewed different places was that they require different amounts of DNA. Is that something we should be asking? Well, I think the equivalent question is how much material do you need? Do you need 10 unstained slides? Do you require 20 unstained slides? Can you work with us? Like, is it a hard stop? If you don't give us 20, we're not gonna test it. Or is it, we can be reasonable and we'll look at the case and we'll figure out, okay, we can go with five on this one, et cetera. Like again, how flexible are they? And will they reach out if they need more material or would they just say, close it out, we're not gonna, we're done. Different labs may have different strategies around dealing with problematic specimens. And we often get, we get so much of this, it has to be a cell block. It has to be core. It can't be cytology. But I just want you to reiterate to our audience that cytology works, man. Just taking enough, as Adam pointed out, taking enough specimens is the important thing. Yeah. Yeah. And I think that it's sort of, it's gonna be an ongoing conversation with the bigger commercial laboratories around accepting those sample types. And maybe there's a function of needing to standardize some of the cytology preps. As I mentioned, there's a lot of different ways you can prep a sample and you do need to validate those different types of preps. So if there's a mechanism that we can kind of have an end to end where we know there's a certain prep that's used every time for a certain sample type and that we know is validated by a commercial laboratory that they can accept, that can begin to at least incrementally increase the opportunities for some of our cytology specimens to be accepted into a commercial lab. Great. Thank you. And Adam, there's a question that just came on. Does it matter if we take the biopsy sample from metastatic lesions from a lung carcinoma instead of the primary lung carcinoma? I'll have you take a quick crack at that, please. Yeah, absolutely. I think it does matter. And I think the preference would be to take this sample from the metastatic lesion if possible. It goes back to webinar number two and also the recent publication we've had out kind of describing these different scenarios. You have to weigh the risks and benefits to that biopsy of the metastatic lesion. But in many cases, confirming that metastatic stage is important, especially if it's only a single site. We'll find false positive pets for maybe an infection for a mediastinal node or maybe degenerative arthritis in the spine that looks like on PET that it's a lesion, but maybe on MRI or on further review, it's just severe osteoarthritis changes. And so when possible, you wanna confirm that diagnosis and stage. There is a little bit, and Dr. Scholl can maybe comment on this, there is a little bit of issue with tumor heterogeneity for biomarkers, more for PD-L1 that I'm aware of than for the genetic markers. But that's not typically something that we would put into where should we biopsy though. Yeah. I can comment on that briefly. The genomic drivers are typically not heterogeneous. In fact, I'd say they're never heterogeneous if you're really talking about a single clonal process. The heterogeneity tends to come in with tumor suppressor genes that are maybe second hits. The other passenger mutations, mutational load can vary from site to site potentially. I would say that you have to be careful in patients who have a significant smoking history and maybe some more field effect in the lung. Chasing a primary lesion, particularly if it's potentially multifocal disease in the lung, chasing a primary lesion may not give you the full information about what's actually in a metastatic site because a patient could have two distinct clones in the lung and maybe you biopsied the one that hasn't metastasized. And we've seen this before with some of our KRAS mutated patients where the patient is say treated for KRAS G12C based on the biopsy of a lung. And then when you do a follow-up biopsy at the time of recurrence of a say abdominal lymph node, you discover it's not actually a G12C mutation probably because it was a different clone that it ended up spreading. So I would agree, I think probably chasing the metastatic site whenever possible is probably gonna give you the most relevant information to that systemic disease. Thank you very much. Adam, could you go back just a few slides while we wrap up here back to your statement of multidisciplinary statement? Because I do wanna end on this. First, I'd like to thank both Dr. Shull and Dr. Fox for their amazing lectures here. I want everyone to just focus on this last thing because I think of all the things we've talked about today, communication is absolutely the key piece and coordination communication between pathology, oncology, pulmonary, IR, surgery, and the group together to get the best plan for comprehensive testing so that patients can get the best possible treatment. I think this should be the hashtag of this lecture. I wanna thank our speakers. I wanna thank the CHESS staff. I wanna thank AstraZeneca who supported this work and everyone, I hope you have a good day and thank you so much for joining us for this webinar.
Video Summary
In this webinar, the speakers discuss the importance of biomarker testing for lung cancer and the challenges involved in the process. They highlight the need for a systematic and comprehensive biomarker testing program to improve patient outcomes. The webinar covers topics such as the role of pulmonologists in ordering biomarker testing, strategies to improve testing turnaround time, and the use of reflex testing by pathologists to ensure timely and accurate testing. The speakers emphasize the need for coordination and communication between all members of the multidisciplinary team involved in lung cancer care. They also address the challenges with specimen adequacy and the importance of understanding the requirements of different molecular assays. The webinar concludes with a case presentation to illustrate the concepts discussed. Overall, the speakers emphasize the importance of biomarker testing and provide insights on how to improve the efficiency and effectiveness of the testing process.
Keywords
biomarker testing
lung cancer
systematic testing program
patient outcomes
pulmonologists
testing turnaround time
reflex testing
pathologists
multidisciplinary team
specimen adequacy
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