Advances in NSCLC Biomarker Testing

CME and CMLI will be available for listening to this podcast in the ASCP store. The American Society for Clinical Pathology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. ASCP designates this enduring material for a maximum of 0.75 AMA/PRA category 1 credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity. The views expressed in this podcast do not necessarily represent those of the institutions that employ our guests. This podcast is supported by an independent educational grant from AstraZeneca and Duchy's thank you. Welcome to ASCP's podcast Inside the Lab where we discuss anything and everything that concerns today's pathologists and laboratory professionals. My name is David Ritter. I'm the producer of Inside the Lab as well as a medical anthropologist and I'll be your host today. We're doing a deep dive into emerging biomarkers in NSCLC, how to prepare your lab to use them and what you'll need to know. We have two outstanding guests joining us today who all led and introduced themselves. Dr. Chivicula, would you like to go first? Thank you, David, for inviting me to this podcast. I'm a pathologist and who has recently joined UCSF and before that I was in a community practice in Sarah Healthcare and before that where I was involved with the lung cancer testing and before that was a University of Pittsburgh where I was trained and also was an associate professor there. That's standing. Happy to have you. Hey, yeah. Thanks for the invitation. So my name is Ying Chenglou, I'm a pathologist at Mayo Clinic. I'm a lung pathologist on the AP side but also a molecular pathology on the molecular side. So I do a little bit both and then lung cancer kind of in my interest both clinically and in research. Oh, fantastic. Well, we're so glad to have your expertise on the show. So let's get right into it. So let's start for listeners who may be unfamiliar with lung cancer diagnostics or who are new to practice. For those listeners, I'm curious. What did NSCLC biomarker testing typically look like about 10 years ago and how does the scope of testing today differ from the era that came before it? So 10 years ago, so let's look at about like about like 2013, 2015, they kind of range. So we know at that time there's a guidance that publish to tell us what to test. I go back to look at that at that time the most popular test or the test we need to do are eGFR, elk and PDO one and most of them need to be test in the advanced stage. So that's what 10 years ago, but first forward now, we know there's a couple of things change. Actually, a lot of things change. So first, there's more targets, more biomarkers beyond those two or three based on the NSC and guidance now we have for like 12 markers or even 40 markers. Now we need to test those that keep adding up. The second one is the test strategy at that time, like single gene test is probably the mainstream because we only test those few genes. Now most of the guidance subjects like panel testing to lump those markers together. The third thing is the detail. So at that time, it's just eGFR. And now we know that all eGFR mutations are the same. There's LA50AR, there's X-O19 deletion, there's X-O20 insertion, there's T719M. So different mutations have different rule and different response to different drugs. So we know the details more. The fourth thing is the stage. At that time, it's only the advanced stage they need to be test. Now the field is moving earlier and earlier to earlier stage or those perioperative test team. The fifth thing is the histology type. I was thinking at that time most of them are the adenocasinoma, need to be test. Now more and more testing expanded both Nangsmocell-Casinoma and also in the squamous cell-casinoma camp. And the sixth thing that I can think about is the protein markers. At that time most of those molecular markers look at the DNA RNA, but now more and more protein markers are available for testing for those ADC drugs, which we can discuss later. But those are the things that right up my head, I can think about there's a lot of changes from 10 years to now. So 10 years ago in community cancer centers when the guidelines have come, it was a chaos. So the pathologists, there was totally a gap between the pathologists and the oncologists. And we did not know what the tests were until we get a requisition from the oncologists. So there was a lot of confusion and among the oncologists, there was a disparity among what do we test and what not to be tested and we were not doing it in-house, the testing and would be sending out to the larger laboratories. So that was all playing 10 years ago. So that's where we work. You guys are touching on so many key topics of this conversation. I'm hearing test prioritization, I'm hearing working in the departmentally on cross-special T teams. I'm hearing just so much that we're going to get into in the show. So let's fast forward to today and let's talk about some of the differences between now and now. So there's new targeted therapies. There's advancements in technology like NGS, there's changes in professional guidelines. In addition to that, there's more biomarkers than there used to be. There is an earlier window of testing, we're not just seeing blade-stage testing. I'm curious, how do you think those forces reinforce one another? The technology, the changes to workflow, how do we sort of get to where we are today? Yeah, I think it's more streamlined now of what to test. And as Dr. Losan, the single gene testing was very popular and still is, but then we created panels, the laboratories where we send out the sample, created testing panels that we could easily send those samples to that particular, with the particular panels. But the question comes when you incorporate NGS testing, you know, and it's all over the place in community cancer centers. I have seen more smaller practices, which have, do not rely on the single gene testing. They were directly sent it for NGS testing. Then the question came, the reflex NGS testing, do we do when you get a negative test or do we still confirm for the positive test? I still, I feel like incorporating NGS is something still as the markers are increasing now. I feel like in the future, probably NGS would play a much, much important role for the oncologists and for the molecular pathologists as well. I think it's still a little bit hazing in terms of how and what methodology we use for testing. Yeah, exactly. I think that if I need to pick one of the biggest drivers behind this, I think it's the new targeted therapies, because like lung cancer in the past 10 years, there's a lot of new targeted therapy get FDA approved, and those are really effective drugs, so I think that drives the field, the oncology field, they really want to do those tests, and then because there's a good drug, and then I think the professional guidance kind of follows, right, because we have to test it all over the place, then the professional society now set up guidance. Okay, now we need to test those, and then we can follow. And I think that the payers comes a little bit later, but does follow, because like earlier, the reimbursement was not there, and it was the thought is, oh, those are just research, so the payers doesn't pay, even though they're that good drugs there. But once those guidance are there, more evidence, and then the payer finally kick in, and it's well into cover those tests, then this is a very mature and established field that labs feel comfortable to round those tests, because the clinic will get reimbursed for those very important tests and benefit for the patients. And the technology, I would say, it was there, and just was there 10 years ago, but of course, now it's a little bit cheaper, a little bit faster, and I think there's also the self-read DNA, like 10 years ago, probably not much self-read DNA available, now available for more testing. So I think these all feed into each other to the practice now. I would like to add a couple of things here to Dr. Losa, very good analysis of this, that when we are doing the single gene testing laboratories, do some in-house testing among these, particularly the PDL1 testing, because the lung TPS score has come out first, and I think more pathologists are more, I would say courageous to interpret the PDL1 testing. So they want to keep the PDL1 testing in-house, and send the single gene testing out into the laboratories. So that's where they used to be a little bit of delay in the testing components or sending the sample for the testing. So I think that has shortened as the pathologists are getting it more and more aware of, hey, let's do this as two simple, divide the sample and send one to molecular testing, and then we add this one to, you know, we can do it in-house testing as well. So. Yeah, those are all great points, and I have to admit, my face is a little red that I completely forgot about the reimbursement issue. All of my questions are just about workflow and science, but you're absolutely right. I mean, the way that these pavement structures change is, I mean, that's the mean potatoes of how anything goes on. If you know what, it's going to pay the bill, those things are going to work. Yeah. The part about the payers is that, you know, for community practices, it goes to larger laboratories for testing. So it kind of surpasses the pathologists, so sometimes, you know, it could be in that mode as well, that we don't have to deal with that. On the log-in institutions, they will be very hard for them to look here. Let's get into some of these biomarkers. So we've seen growing interest in new and emerging biomarkers, such as, you know, her to trope to her three. I'm curious, which of these are the most clinically significant in your opinion right now? And what does the latest research suggest about how they may shape NSLC treatment in the future? I think the more commonly asked for biomarker by the oncologist is her to you, okay. So the research, the her to is getting more attention in the breast cancer field, but I think if the truly, if we, they have to test, I think it's the NGS test is the way to go. But I am a little bit concerned about that part of it, then, who is going to interpret that they need to rely on molecular pathologists to really review and see what the test results are. But her to is something that very commonly asked in getting actually more recognition in the lung cancer setting for the as a request for the test. Yeah, I really echo that so her to when they gather FDA approval for the pink cancer approval, which actually caused a lot of confusion for a lot of people because her to tradition in for lung cancer, it's a her to mutation on the molecular side, they have FDA approved the target therapy. Now it's a IHC approval for the pink cancer approval, which long is also eligible. So then we get like inquiries over the place. I want to do I see someone to do reflex testing to do a fish to see the amplification. And some also remind the day that we need the NGS for the mutation. So it's caused just a lot of the confusion with and in those ADC drugs now get approved. So with the her to and trope two and her three now in the line also bring up more confusion because the trope two have a FDA approval for lung cancer, but there's no IHC companion diagnosis attached to them. So kind of parallel to that doesn't need to read a trope two. On the other hand, there's a man. They also have the FDA approval for those protein markers, which is a three plus or more than 50%. And that's a IHC approval. In math, we also know there's a man X-14 skipping, which is already FDA approved drug. Math amplification on the other hand is an emerging biomarkers in a clinical trial. Again, I think those are very interesting fields that the protein markers now come into the plate. And but cause a lot of confusion like what to test and also kind of blurred the boundary of those biomarker testing who is going to read them is the AP lab cannot read them or is a molecular lab need to test them. Yeah. So I just want to add to this very good thought process, just a little is that, you know, for the heart rate testing is traditionally used for breast cancer care. Then the gastric guidelines have come. And I do know that once I move from the east coast to west coast, things have changed. I see how the practice is very in how the Hurtu and both IHC and fish testing were practiced across the country. And some of the larger institutions would send everything for both IHC and Kagan fish testing. Some would stay for equal cases and then reflex it to fish testing. So that kind of confusion now is part of the lung cancer care as well. And some pathologists are kind of concerned like how to interpret the IHC testing as well. So that's where we are with the practice of the Hurtu. And talking about the C-MAT and the HALC one, we have used C-MAT for breast cancer research but when it comes to really for a drug approval and more important emphasis on some of the stuff, what we have to do, the HALC had the same issue. There was an immunizer chemistry for HALC one, which I see in some practices now, but the question is that, again, if it's negative, should we send it for single gene testing? What do we do for this molecular testing? Well, those are all still need to be answered probably in an algorithmic way. If we get guidelines in that testing pattern, that would be very useful. Both the oncologists as well as the pathologists. Indeed, there's a lot of confusion between oncologists, AP pathologists, molecular pathologists and different organs, as you mentioned. And then what guidance do we follow, do we test this or not? And I think probably we'll come down to the FDA approval, what's approved, what's not, and that's the current status. But interesting is those that are not approved yet may not be the case three months later because they are like emerging biomarkers way down the line. We say no fish testing for lung cancer right now, but who knows after a couple of months things may change. So it's just moving so fast. Yeah, and the oncologists do have a, I've noticed that they have their own experiences. So that kind of plays a role in type of tests being ordered and not being ordered as well. So I have seen that kind of a variation as well, you know. Yeah, just terrific. I mean, you absolutely just hit the next question I was going to ask, which was about what of the essential non-negotiable components of guideline concord and biomarker testing today. Yeah, I mean, it just like as these, as these testing processes become more and more complex and as more and more biomarkers come to light and as more like targeted drug therapies are emerging, all of these workflows have to be figured out and all these testing guidelines have to be resolved. And it is on the small task. Yeah. So that's a good question for those test prioritization. So our institution was, at the time we would discuss the reflex testing strategy. We talk about what's the test prioritization strategy. And I think at the end, our consensus goes down to follow the guidelines with, especially the first line approval drugs because many of the targets are, most of the name are first line, but some of them are second line approvals. So for patients that in general, we would like to get the first line test, cover the first and then plus the PDO one. And then if there's enough material or the setting is the reimbursements there, then cover all the second line markers as well in the panel. So if possible, cover all of them, but if we really need to pick one or the other, then go with the first line to be the non-negotiable component. Yeah. That's what I think. Yeah. Now, sanitization of any kind of testing where we have to start up with the first line testing and then reflexing all the stuff, we try to do at the community level, but the problem is still we are not there yet of which ones to be flexed and which one not to be flexed. So I think we still need guidelines for the testing as well. But I do feel that NGS will, because of the number of markers that are increasing and the test approval are increasing day by day, I think NGS will prey a prominent role. In the near future, compared to the last 10 years. So. Yeah. I want to clarify. I mean, we would like to do the panel testing to cover as many as possible. But if we need to choose, then go with the first lines. But I totally agree. We should not do single gene tests one by one nowadays. So as new biomarkers and targeted therapies emerge, how should pathologists and labs think about testing strategy and specifically how to prioritize biomarkers and decide what gets tested up front versus reflexively while remaining aligned with current guidelines. Dr. Lodi, you want to go first? Yeah. I know it's very difficult to, like, once you fit everyone, especially oncologists, they may reach out to us that the patients are in different situations. They want different things and in their priority, not just a lab priority, but a clinician's priority. And it's funny that we always know it's impossible to have a test that it's comprehensive, but also super fast and very low cost, almost free, and the lab do a great job. It's just impossible in real world. It just not exist. So I think a lot of the time they, they may need to, like, emphasize what they really want. So what I'm thinking is that in general, the comprehensive one would be good. But in some situations, for example, if the tissue is really small, then we need to triage things. If the patient needs a new adjuvant treatment, they need things that are really quick. Or the patient is really critical and then something quick. Then go with a faster speed to cover the bread and butter, even just the elk rice, even just the EGFR elk and PDO one. It's a sufficient for them to make a really urgent decision making. So I think it's really hard for the oncology practice to prioritize this, to have one shoe fit all for both the speed and the breadth of the test. Yeah, I do agree that one size doesn't fit all, but the problem here is that prioritizing trying to skip many levels in terms of advanced or medallic cancers, because time is the essence here. We have tried many, many ways to do the limited IOTC panels so that we don't waste time. Then I think the most successful one is dividing the sample into two specimens and send it out for molecular testing as soon as we get from the laboratory, the block. But the problem with these is that we do have medallic settings like a bone or somewhere we do not have enough material, but the pathologist is not comfortable sending without doing at least one or two IOTC markers to make at least a sense of what the cancer is. Once you do get medallic carstem, so we want to exclude that from the primary lung carstem as well. So there are challenges to the entire situation in real time, but I think the pathologists are navigating much more better now with how to haze in the process, we used to pick up the phone and call the oncologist, but you will not know the oncologist's name or anything because they're not yet assigned for the patient as well. But there are many ways to do this in an email quickly through a medical chart and all the stuff, but I think it's still institution-based, practice-based in how we haze in the process for the whole setting and not to mention the money also plays a role in this whole process. Yeah, I agree, like in a community practice setting, probably more the patients are like first-time diagnosis, the test strategy may be really different than the tertiary cancer center that they see those referral patients, they already fail, couple of lines of treatment. So the test in strategy, what they want to focus on, may be a little bit different in terms of picking the pain or size. And sometimes the patients travel to larger institutions, academic places as well. So there's a repeat testing from both places, so I do not know how that's handled because the patient leaves the community cancer center. So sometimes you do see that perfect as well, so. Yeah, it almost reminds me of that saying that you can have things done cheaply, quickly, or well done, and you can only get it. Yeah. Yeah. Yeah. Okay, so with guideline endorsed, broad profiling and expanding targeted therapies, how to lapse navigate decisions between IHC, PCR, and NGS in real-world practice. And what factors most often drive those platform choices? I would say money is, I can't always, an important thing, people have to look at the dollar. But I think the decisions also are based on what type of pathologists are in your practice. No one knows how to interpret an NGS if you're not a molecular pathologist, okay. But also what does the guideline, then we really bank on our guidelines, okay. So a single gene test versus any refluxing to other tests as well. So majority of the pathologists who are not into molecular pathology, they do rely on the laboratory, what they're offering, all these large laboratories where the testing goes. Is there a reflux pattern in the panels? And what are they offering, then they discuss with the oncologists? Still, in my mind, all the three components do play the platforms at CPCR and NGS as of now. But we might see a shift into, as I said, increase in the NGS in lesser for the PCR and stuff like that. So. Yeah. I think the lab would like to develop those tests. They have FDA approved companion diagnosis, that's kind of every lab wants to do that. But I think that the challenging part is like when to develop those, because when there's an FDA approved, the oncologists will want the test to be ready yesterday. But if at that time when it was approved, then the labs start to prepare the tests, start to validate those tests. It need another couple of months to make sure that it's validated. So there's a gap that oncologists are anxious for those tests be performed for patients to eligible for FDA approved target authority, but the pathology lab may not be ready. But for pathology lab, if we prepare everything when they are in clinical trial, some of the drug doesn't make it to FDA approved, then it's a lot of cost for the lab to develop tests and not use it at all. So I think there's other side of the lab is very difficult to catch up with all the clinical trials, with all the possible FDA approved down the road, both on the molecular side and the HC side, but we cannot be X to be ready, as soon as possible. That's a very hard decision for the laboratory, I have to admit. Okay. But once those testing priorities are established, what's specimen handling and tissue stewardship practices, such as biopsy triage, cutting protocols or cytology workflows, have the greatest impact on ensuring sufficient material for comprehensive biomarker testing? Yeah, that's a super good question, because I think those pre-analytical evaluation and concederation will traditionally be under-unphasized, and people don't pay attention to those pre-analytical strategies. So in our institutions, we know that lung cancer testing normally easily get like 20 to 30% of Q&As are like upfront, Q&As rate, and that's a huge number because those patients could not get proper profile before they have to start treatment. So we try many, many different ways to improve that to decrease their number. A couple of things that we did before, one is like roast feedback immediately. So traditionally, our cytotech only feedback, the procedure list, if there is a diagnostic material. Now we ask them to be more proactive to say if there is sufficient material for downstream molecular testing. So sometimes a few sales can make the diagnosis, but we need more sales to complete the NGS panel. So we want them to feedback them at that time to get more tissue, rather than wait, and then have to do the procedure again. The second part is the grossing. So we know like if there's different core, we would like our grossing text to put them in different blocks. Because for diagnostic, we do not really need like two or three cores in the same block, and they got cut and stand together, and then exhausted. We would like to at least two blocks available. So then one block for diagnostic purpose, the other block can save for the downstream molecular NID testings, to triage the tissue in different blocks. The third part is the histology cutting. So we want to make sure those are likely in molecular testing, they got cut properly. A lot of the time we know that lung cancer can be exercised to liver, can be exercised to the bone. So if the liver cutting, cut, use the medical liver protocol, get the trichron and those things they are not useful, they need to save those to a proper protocol. So to just save down some slides for molecular testing. Same for bone, if a bone marrow biopsy and then subject to those bone marrow protocol, they ruin the specimen for molecular testing. So we want to make sure they don't go through decal and then have materials intake for molecular testing. And also some lab are adapting those cutting strategies to pre-cut insulin slides. As we know, every each time we re-face the block, we lost the tissue, so able to cut more conservatively or even pre-cut insulin slides is super helpful. And under diagnostic side, we also would like our pathology to decrease unnecessary IC. If this is a lung cancer, then a TTF and P4T may be sufficient. We don't need to expand a lot of the ICs to see where it comes from, even if the TTF and P4T is a negative. If the patient has a huge lung mass, that's very likely lung cancer. And then laundry a lot of ICs will waste more tissue and we would like to save those tissue for the molecular testing. And the fifth thing that we use is to utilize the smears. As we know, traditionally, we AP pedagy like to use tissue for molecular testing. But the smears are actually more intake cells. They are really good materials for molecular testing. So you, so while they are internal tests to take smears or consider sending out to labs, they use the smears. Those can actually significantly rescue a lot of the cases. They don't have material on the biopsy, the tissue, but have material on the smears. There's just a lot of areas for improvement that we keep trying to salvage those materials. I do agree with Dr. Lowe. I wish you can give more talks like this cancer centers for the specimen samples. I would say the top list is education and communication. So as a team effort, right from the cytotechnologist who is doing the roles to the pulmologist intervention pulmologist, to the pathologist, all this and to the oncologist. So it's a, everyone involved in this care should be educated and communication, a good communication is very important. We have struggled with the sample size over years trying to make a diagnosis. This is only the key thing for the pathologist, okay, we need to make a diagnosis. So we spent the short of your time making a diagnosis using a lot of immunostates. But we have cut down on the limited panels and talking to radiologists and what the, how the patient is presenting with. All those things have really played a crucial role in limiting the number of immunostates. The third thing is like dividing the specimen, okay, has also improved in practices and also emphasizing to send us to more rinse the needle into the formula and all those things have totally played a significant role in improving the sample size. But there's some challenges in terms of mystatic setting where we have very small samples. And I think I've wanted to mention is that if the, if the communication is broken down in particularly in some other cancer centers, here is what happens. The patients can present with mystatic brain lesions and if the neurosurgeon doesn't know who's doing the sample and not communicated of the prior history or anything. For them, the diagnosis only is for them is to make a diagnosis between a primary brain tumor versus mystatic other areas. And with a lot of macroses, they might not focus on the amount of the sample size and their instances when we have to go back for molecular testing because there was a mystatic lung cancer. So all these things play and I think that does just place a vital role in communicating with all the teams that are involved, including the cytotechnologist educating them, you know, get them more sample, get more sample, you know, those kind of things. Yeah, I think like traditionally we just make diagnosis, but now we have responsibilities more is to make sure we have sufficient material for those biomarker testing because those are the standard of care now, like a diagnosis of a dental carcinoma without able to do molecular testing and IT testing, it's kind of an incomplete diagnosis or incomplete workout, workout nowadays from colleges to take care of the patients. So yeah, the communication between different teams, different players, let them know that once they have any thought about a non-smart cell lung cancer, think about tissue, think about more tissue to fulfill the downstream incinerated testing is super important for everyone who touch the patient and the specimen. Yeah, certainly. Yeah, so many great points, new responses, just, you know, the importance of I mean, just like the notion of like pathologist being leader or in positions of leadership and coordinating a specimen collection, I mean, I wish I could give all your guidelines to anybody who worked in any sort of role related to diagnosis and in any hospital and that's so many great points. And, you know, and on the topic of, you know, pathologists being sort of leaders in like a sample collection, you know, I feel like this is an area where pathologists especially play a leadership role in ensuring patients are receiving a guideline recommended biomarker testing. I'm curious how you think pathologists can advocate within their institutions to promote appropriate inequitable access to NSLC biomarker testing. That's an important question how we play as a leader in this role. As I said, you know, there are many directions pathologists can play an important role, particularly in the cancer care in order to test to educating them and finally analysis of the reports, some of these reports as well. So one of the things is that no one is really not every practice has a lung pathologist or molecular pathologist. I think identifying the pathologists who are interested in going into this and collecting more information. So I think as directors or majority of times pathologists were involved, they can go and talk to them, you know, I have done in many situations for thyroid and lung cancer sharing, where I took all the literature, went to the oncologist sat there and I think even in the clinical, on the clinical side, the oncologists are also in community practice, they're not, they're identifying themselves as a lung oncologist, you know, all those things. So one person is responsible for collecting all the information and presenting to the group. There are other things that we need to do this, okay. So there is no standardization, but the larger community practices are coming up, the hospital systems are coming up with all the groups, the hospitals involved under the same, same umbrella of the healthcare system, trying to standardize some of this stuff, reviewing the literature, what the practice, identifying the practices within the same hospital system, for different hospitals, you know, and trying to see where we can come up with some standardization across the board. So those are things are really happening and I think that will improve in near future. Yeah, I think it's also paradigm shift for pathologists because traditionally, AP pathologists make the diagnosis and don't care about the downstream treatment that much. And for the molecular lab or IT lab, we just perform the test, whoever orders it, we just perform it because we kind of like just do it. But now, because we know a lot of the time the oncologists really want when they see the patients, all the biomarker workup has been performed already, rather than wait on their name to initiate and the patient have to wait another couple of weeks. So a lot of the institutions really press from the oncologists I really want to have such like reflex testing, to have pathologists order those biomarker testing at the time of diagnosis to save time. But this is a very difficult situation for pathologists to order the test at that time. I think for both two components, one is the pathologist will feel challenged what test to order because we need to understand the patient's stage to know the situation, even financial situation, or if it was previously tested, to pick the best test for the patient. And that's a lot of work, not just make the diagnosis and write down the order, have to kind of review the chart and make the best decision for the patient. And the second part is the regulation, because pathologists and molecular labs are not allowed to order those predictive tests. We are okay to order the diagnostic tests, but we are not allowed to order those predictive tests. We make the pathologist handcuffs of not be able to order those tests. We know a lot of the institutions now work with the reflex testing strategy, have the practice agreement from oncology practice to kind of allow pathologists to put in the order. But it's really strange to be to my opinion is that those are those are professions that pathologists put in time and effort to make professional decision. But it kind of like we need the practice agreement to have the oncologist let us to do that. It's really awkward. So I think as a society, we probably need to push those two things. One is that this is a profession, then we are allowed to order those tests, because those are for patient care. Those have really legit value there for us to order them. And the other one is that it's kind of an encounter, right? But we're never able to build those. So a lot of the pathologists feel really kind of on top of their diagnosis things. They are asked to review those and put in order. But those are extra work, but not actually be reimbursed. So a lot of the pathologists feel really hesitate to take on those jobs. Oh, there's a lot of burden. And if those are counted as an encounter and allowed a reimbursement to facilitate such kind of profession and work, I think they will significantly improve this process as well. I totally agree on what you said, Dr. Love. So but within the very comes to reflect testing, which is very important. And we have gone through many phases of it, like where and also differently to oncologists have different view. We wait for the oncologists to tell us to reflect it. And then some oncologists call and said, why did you not do it? The reflex test. Sometimes we get this response as well. So but I think the laboratories have become much more the large laboratories where they do offer the reflex testing when this is what it is, this is what it is. So I think upfront discussing with the oncologists that this is a panel I'm going to order, you are seeing yourself the tests and thing. And because they get the reports first, then the pathologists. So yeah, anybody can be with them. So I think that communication is also helping for the reflex testing. Yeah, pathologists can kind of become a more active role, rather than a passive role in a path to be in a team to facilitate the proper testing. Let's try to look at our crystal balls and predict the future. So let's say like three to five years out, which biomarkers or technologies do you think are going to become essential components of NSCLC testing? And how should pathologists in labs position themselves now to ensure they're ready for both the scientific and workflow shifts that come with that? Wow. To predict future. That's always challenging. Yeah, even like right now I feel like challenging because there's a lot of trials like happening like all over the place. And then to to be able to know them and then predict what test they will have like clinical use is already very difficult. So I think like a lot of the time we need to like kind of like really get them in connected with oncology field because they take off those lung cancer patients. They have the clinical needs. So getting a good cut touch with them will always help to know what's coming next. I think the NGS part, I think NGS will keep going faster and cheaper and more comprehensive. So I think that's the road for the NGS that should be. So the NGS part will be good and probably even better reimbursement. And we can already see that because like let's again, expanding from just adenocarcinoma NGS model to squamous and also like from lay stage to earlier stage in a period operative situation. So I think the reimbursement will also go there. And I think the protein markers now we do I see like panel initially just pd01 now we do her to a mat and then there will be more and more coming. So I think we will soon get into the situation and we don't have sufficient material for both the NGS and a lot of IHC. So I think multiplex IHC probably will be needed down the road even though currently not a lot of success there. But I think like like panel IHC will be needed kind of like the NGS and replace of single GNPC yards. So I think that's the couple of things I can think about. Yeah, in the next five years, three to five years as you said, I am on the side where I believe that pathology practice is going to change enormously and I have been seeing the shift. And I think to me the pathologist no more should be playing the role of sitting by the scope and making a diagnosis, I think they do have to put on a lot of hats to come out and talk to the oncologists and educate them, you know, interpret in many, many roles they have to take the initiative. And I think the term alcopethologist is being used in some countries, I think I feel that's pretty appropriate in the situation that we are not just pathologists like making a diagnosis under the slide, you know, and the scope and, you know, on the side we have to do a lot beyond the slide to do to help the patients in the cancer care, the oncologists in the cancer care. And I also wonder how the AI platforms are going to help us in the near future. And that's a big question mark. And if you look at the pathologists, they're divided again on the concept just like any other people, but I think to me AI is going to change this entire field of cancer care in the next five years, and I think we should be prepared for that. And the older pathologists who are more into morphology and everything on ancient diagnosis, that's not going to be around, and it's going to fade away. And the genomic testing that I had to see is going to show a largely a huge makeover. And how we progress is we need to as pathologists should be also thinking about it and how we can play the most crucial role of this whole AI in infiltrating into the pathology world as well. Yeah, hopefully AI can help us, rather than replace us. Yes, and that's a big question mark, you know, are you a believer of that or not a believer? I heard many, many of the surgeons tell me that pathology and the radiology are going to fade away even the AI world, but I'm not sure about that yet, so. We'll see. I'm optimistic about it, but I think that's a great place to leave it is that as new biomarkers emerge and new testing regimens come up, they create a lot of uncertainty and additional complexity in the lab, and I think that that can be a cost for stress, but I think it's an opportunity for pathology to really step up and take a leadership role in figuring out all these guidelines and be active and sort of not only advocating for ourselves in the profession, but also advocating on patient care and sort of working through all these things with that in mind. Well, thank you again for joining us today and sharing your expertise with me and our listeners. To our listeners, remember to tell your colleagues about the podcast, and remember to subscribe through your favorite podcast aggregators so you don't miss favorite future episodes of the show. Also, don't forget you can receive CME or CML eCredit for listening to our podcast by looking for inside the lab on the ACP store on our website, www.ACP.org. Thanks you both, and we'll see you again next time. Thank you, David. Thank you, my pleasure. And Dr. Lowell, as well, so thank you, ACP.