Tumor Testing and the Transformation of Lung Cancer Treatment: Overview of Lung Cancer Tumor Testing
Precision medicine in lung cancer is treating a person's cancer based on the specific makeup of their tumor. The purpose of tumor testing is to look for changes in the cells that are causing the cancer to grow. Tumor testing and precision medicine can be confusing, but the American Lung Association convened a panel of experts to break it down for you and help make sense out of this exciting area in lung cancer treatment.
Moderated by our National Director of Lung Cancer Education, Carly Ornstein, MPH CHES, our panel included Justin F. Gainor, M.D, Center for Thoracic Cancers, Massachusetts General Hospital Cancer Center, and Assistant Professor of Medicine, Harvard Medical School; and Mark Pool, M.D., FCAP, Attending Pathologist at Rush University Medical Center. For more information about tumor testing, visit Lung.org/tumor-testing.
Generously supported by AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, Pfizer, and Merck & Co., Inc.
Carly Ornstein: Welcome to our program, Tumor Testing and the Transformation of Lung Cancer Treatment. The American Lung Association thanks AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, Pfizer, and Merck & Co., Inc. for their generous support of this program.
Carly Ornstein: I'm Carly Ornstein, a National Director of Lung Cancer Education at the American Lung Association. During this conversation, I will be joined by Dr. Justin Gainor, and Dr. Mark Pool, as we discuss lung cancer tumor testing, what it means, and who should be tested.
Carly Ornstein: Dr. Justin Gainor is an Oncologist and Assistant Professor of Medicine at the Harvard Medical School, and Massachusetts General Hospital Cancer Center. Dr. Mark Pool is an Attending Pathologist at Rush University Medical Center. We're also joined by several lung force heroes in the audience, as well as hundreds joining us online.
Carly Ornstein: If you're joining us via Facebook Live, you can post your questions in the comments of the feed, and hopefully we can answer a few at the end of our program. We'll try to address any questions we don't get to in future resources, so stay tuned. Let's get started.
Carly Ornstein: Thank you Dr. Gainor and Dr. Pool for joining us today. I'd like to start with the definition of some of the terms that we might be discussing today. Dr. Gainor, can you help us understand what tumor testing is and what it means?
Justin Gainor: Sure. Broadly speaking, tumor testing refers to doing additional analysis on a tumor in order to help physicians guide the best treatment choices. Importantly, this is typically done on a biopsy specimen, or a surgical specimen, so if someone's already had a surgery. It doesn't necessarily require additional procedures. This is something that has already been obtained if someone's already had a biopsy.
Justin Gainor: By in large, what we're gonna be focusing on throughout much of this discussion is gene testing. That is, we're looking at the DNA of tumor cells. DNA is the building blocks of life, the blueprints. We're looking for changes in the DNA, and we call those mutations. This is particularly important because we know that certain cancers, and specifically lung cancers, can have genetic mutations that help inform how we actually treat them.
Carly Ornstein: Great. Can you talk a little bit about the types of mutations, and how they actually work, what's causing the cancer to grow?
Justin Gainor: Sure. Here I use the analogy of a light switch, for my patients. For many of the genes that we're looking at, these are present in normal cells. When there's a genetic mutation in them, and at specific points, it changes the functional light switch. Normally these are under control. Turn it on, it tells the cell to grow. If you turn the light switch off, it says, "Stop growing." The problem with these genetic mutations is that the change results in the light switch constantly being on. It changes the function of that particular gene. The cell is constantly being told to grow, grow, grow.
Justin Gainor: Now we can take advantage of that therapeutically by delivering targeted medicines that actually shut off that signal. But it's just like a lock and a key. You have to have the right genetic change, and pair it with the right therapy.
Carly Ornstein: Do we know what causes these genetic changes?
Justin Gainor: That's a really interesting question. Right now, we don't. We know that there are some characteristic features of patients who have these particular genetic alterations. If we focus on those where we have FDA approved therapies, we know that by and large, these occur in patients who have never smoked, or who have a very light smoking history. We don't think that these genetic alterations are actually caused by tobacco exposure. These could just be simply sporadic events.
Justin Gainor: In all of the cells in our bodies, cells have to divide. When they divide, they have to copy all of the blueprints from one to two. You can imagine if I had you copy a book, letter by letter, you're gonna make mistakes. Most of those mistakes are inconsequential. But every once in a while you make a mistake in the wrong word, and it changes the meaning of everything entirely. My sense, even though we don't have direct proof of this yet, is that that explains a lot of it. We're actively looking though, if there are other causes.
Justin Gainor: I would emphasize that we don't believe that these are inherited. Outside of exceptional circumstances, these are not things that are passed down from one person to the other when we're speaking about lung cancer, and some of the genetic changes that we're gonna be talking about in lung cancer. In other cancers, certainly there can be these familial relationships. But the genes that we're gonna be talking about in lung cancer generally are not passed down from one person to the other.
Carly Ornstein: Right, that makes sense. When we're talking about this tumor testing, which sometimes we call biomarker testing, or genomic testing, you mentioned that we're looking for these mutations, or these changes in the genes. What else can that testing look for?
Justin Gainor: This field has changed pretty dramatically over the last several years. I use the term targeted therapies, which is trying to pair a genetic change with a targeted pill directed at that gene change. That was really something that evolved beginning in 2004. That's when we developed the first targeted therapies.
Justin Gainor: In the last five to six years, there's been a second major paradigm for how we've treated lung cancer, and that's been using immune therapies. These therapies work very differently than targeted therapies. These drugs are intended to really boost a patient's own immune system, and use that to then attack the cancer.
Justin Gainor: Unfortunately, the biomarkers or the predictors that we've had for how those drugs are gonna work have been a bit more complicated. We don't have the silver bullet, in terms of predicting those. But to date, the best predictor that we've had is something called PD-L1 expression. Essentially this is a marker on the surface of cancer cells that indicates that those tumor cells are trying to evade your own immune system. That's another test that has been crucial for oncologists and pathologists alike, to do when someone's been diagnosed with lung cancer.
Carly Ornstein: Great. Thanks. Dr. Pool, you're a pathologist. I'd like you to speak a little bit about what your role is in this whole tumor testing process.
Mark Pool: Sure. The pathologist is really the unseen physician in the lung cancer team. We take tissue that's removed from some surgical procedure. It could be a biopsy, or a surgical resection of the tumor, and then try to look at it visually, do simply things like just measuring the tumor, and then look at it under the microscope to try to look at different attributes of the tumor in order to try to put it in a group of tumors that we know from previous history, from other patients, how they will behavior, or how they will respond to certain treatments.
Mark Pool: One of the most important things that we do now with genetic testing is to determine which is appropriate tissue to send for genetic testing. Not only are we taking the tissue and trying to maximize the information by looking at it under the microscope, but now we're trying to select appropriate areas of the tumor, to determine whether there's even enough tissue to do this testing, and then making sure that it's triaged appropriately.
Carly Ornstein: For those of us that don't know exactly what you're looking at under a microscope, can you explain it in layman's terms what you're looking for?
Mark Pool: Sure. Generally there's two or three major types of lung cancer. It's not all the same thing. We can tell these different types of lung cancer under the microscope. We generally look at small-cell lung carcinoma, and then another category is non-small cell. Out of those, which are most of the cancers, these are divided into squamous cell carcinomas and adenocarcinomas. It's adenocarcinomas, in particular, that we're really interested in, in relation to molecular testing. However now with PD-L1, like Dr. Gainor was mentioning, we're looking at all the PD-L1 expression on all lung cancers, regardless of this histological type.
Mark Pool: Some of the other things we look at microscopically are the extent of invasion, and other attributes. We lump this into tumor staging. The tumor staging is what's useful to physicians like Dr. Gainor, in terms of what do we do next with this patient? What are the treatment options, and so forth?
Carly Ornstein: Dr. Pool touched on this a little bit, but Dr. Gainor, I was hoping that you could further explain which lung cancer patients should get this type of testing.
Justin Gainor: It's a good question. By and large, when we're thinking about using targeted therapies, when we're thinking about using immune therapies, these are usually in the context of people who have metastatic cancer or stage 4 disease.
Carly Ornstein: That means the cancer has spread past [crosstalk 00:12:21] the lung.
Justin Gainor: That means the cancer has spread outside of the lung.
Justin Gainor: For cancers that are earlier contained within the lung, our primary therapies are things like surgery and radiation. But when cancers escape outside of the lung, we generally rely on drug therapies. That's really where these genetic tests and this PD-L1 test is most important in that setting.
Carly Ornstein: By drug therapy do you mean targeted therapies and immunotherapy?
Justin Gainor: Correct, and even chemotherapy.
Carly Ornstein: And chemotherapy.
Justin Gainor: Historically, when we've been treating lung cancer, now 15 years ago, when we talked about drug therapy it was only chemotherapy. Now it actually spans many, many different things. I think of this as these three big buckets of targeted medicines, immune medicines and then traditional chemotherapy.
Carly Ornstein: Great. Just to recap, when you have a patient, if the patient has stage 4 lung cancer, which means it's spread past the lungs, and it's non-small cell, and non-squamous, those are the patients that you're really looking at to see if they had mutations?
Justin Gainor: That's correct. According to all of the guidelines, those are the specific patients that everyone should be tested in that category.
Carly Ornstein: What about patients that don't fit into that category?
Justin Gainor: As you're alluding to, that accounts for most lung cancers, but there are people who are outside of that. There the guidelines suggest that it also depends on some of the characteristics of the patient, some of the characteristics of the tumor itself. There are also large ongoing efforts in the United States and elsewhere looking at the importance of gene testing for these other tumor types, namely things like squamous cancers. Because what we know is that the gene changes for squamous cancers is very different than non-squamous tumors. The frequencies of these genetic changes differ. What we're looking for differs depending on how they appear visually underneath the microscope.
Carly Ornstein: Would you say the best thing is for a patient just to talk to their doctor about whether or not [inaudible 00:14:57] [crosstalk 00:14:57].
Justin Gainor: Exactly. This is something that should just be raised. Is this something that I should have genetic testing for in order to help guide therapy for me?
Carly Ornstein: Great. That covers the testing for mutations. What about testing for the PD-L1, which you said could be an indicator of how a patient might respond to an immunotherapy drug?
Justin Gainor: This is something that's really changed in the last two years. Now, any patient with advanced, and that is spread outside the lungs, non-small cell lung cancer should have PD-L1 testing at their diagnosis.
Carly Ornstein: The levels of PD-L1 will help indicate treatment, whether or not they might be eligible to be on an immunotherapy drug.
Justin Gainor: Correct. This is something that this field is moving rapidly. If you would have asked me this question in March 2018, I would have given you a different answer than I am today. Just speaking to how quickly the field is moving.
Justin Gainor: Now the paradigm is that if a patient does not have a genetic change, so we're not doing targeted medicines, which is the majority of patients will not get targeted therapy. For everyone else, all of those patients for the most part are going to be getting immunotherapy, and it's just a matter of whether you're going to add chemotherapy to that or not.
Carly Ornstein: Okay, interesting.
Justin Gainor: We use this PD-L1 score to help gage whether we need to do that.
Carly Ornstein: Great, thanks. Dr. Pool, can you tell us a little bit about the different types of tests that are out there to help reveal if a patient has these mutations or biomarkers?
Mark Pool: Sure. There's different levels of testing that can be done. For the last eight to 10 years, we really only looked at two or three specific mutations. The advantage to these was that they could be done relatively quickly, and lot of different laboratories could do them.
Mark Pool: The disadvantages were that number one, these were usually done in a sequential manner. One test was then, and then another test, and then another. That consumed not only time, but also valuable tissue. With small biopsies, sometimes you run out of tissue. We have to have tissue to make the diagnosis to start with.
Mark Pool: More recently, there's a different type of testing called next-generation sequencing in which multiple tests can be done on the tissue at one time. That's been great because you get all of this information off of one testing period. The downsides are that you get a lot of information, in addition to these most common mutations. It requires a lot of information support to sort out which are important, and like Dr. Gainor mentioned before, there's some changes that are inconsequential, or we don't really know what information they mean for the patient. The other downside is that they usually take about two to three weeks, and sometimes the oncologist is seeing the patient before they have all of this information.
Mark Pool: The PD-L1 test is a little bit different. That's a test that we actually do on slides, and that we examine microscopically. We do a procedure called immunohistochemical staining, where we use antibodies that are directed against the PD-L1, and then look for the level of expression in the tissue. Then we provide a score so that it's useful for the clinicians to decide whether anti-PD-L1 therapy is appropriate or not.
Carly Ornstein: Great. PD-L1 is treated a little differently 'cause you are staining on a slide for it.
Mark Pool: That's correct.
Carly Ornstein: Versus how are the mutations looked at, like under a microscope, a little differently?
Mark Pool: Right. The genetic testing is looking for signals that indicate whether a change is present in the DNA or not. It's not looked at under the microscope. It's really examined by instruments that detect whether the signals are present or not.
Mark Pool: If the DNA is normal, there would be no signal that the instrument would read. If there is a mutation, a change in the DNA, then a signal would be indicated, and so ...
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Mark Pool: ... then that would ... A signal would be indicated. The instrument and the computer behind the instrument tabulates all of these changes. And the results that you get are basically a list of all of the mutations that may be present. As we said, some of these may be significant and we know about and can link it up with a current or potential treatment. Some of them are inconsequential. And then some of them, we don't really know what the significance is. Part of the goal of getting as many patients or, ideally, all patients tested is to accumulate this data and then link these patients up with studies and see what these mutations really mean because some of them may be significant.
Mark Pool: Also, many of them are in very low frequency. They're less than 1% of all of the patients that have cancer. So it's difficult to group these patients into similar patients because they're so infrequent. By testing more and more patients, we develop this database.
Carly Ornstein: Yeah. That makes sense. In our next panel discussion later this afternoon, I think we're going to be talking a little bit about that and how this data can actually really help move lung cancer research forward.
Mark Pool: Right.
Carly Ornstein: Dr. Gainor, when you get this printout with everything that a patient has or doesn't have and a report from the pathologist with their PD-L1 levels, what's your next step? How does that impact your treatment choices for your patient?
Justin Gainor: In my mind, it's a combination of things going to the decision making. Typically a patient will come back into the office and we'll review it together. If there's a genetic change in one of four genes, and we call those EGFR, ALK, ROS1 or BRAF, these are genes where if they're in specific places, we have FDA approved therapies, targeted medicines. And that is very straightforward because we know that targeted therapies are the best therapies for those patients.
Carly Ornstein: And we call those actionable.
Justin Gainor: Call those actionable.
Carly Ornstein: Okay, because there is a targeted therapy pill that's linked to treat the mutation.
Justin Gainor: Those specific mutations.
Carly Ornstein: Yeah. Okay.
Justin Gainor: And we have multiple clinical trials where we've compared giving a targeted medicine versus historical chemotherapy for most of those genetic changes, not all, because some of those are so infrequent you can't do those big comparisons. But in all of those studies, the targeted therapies have always won versus chemotherapy. They shrink the tumors more commonly, patients feel better, and they have a better side effect profile. For those, very straightforward, we give targeted therapies.
Justin Gainor: There's a whole nother group of gene changes where we know a lot about them. We know that they are activating, meaning that the light switch has changed, it's on. And we know that there are, so far, some effective preliminary drug data. These are drugs that have not been approved yet, they're in active clinical trials, but the data has been very promising. For that, I would group things like RET or something called MET. Those are examples of where response rates to targeted medicines have been very, very high, but we just don't have the regulatory approvals just yet. For those patients, I still want to pursue targeted therapy, but what that looks like might be a little different because it might be in the context of a clinical trial.
Justin Gainor: If we don't have a genetic change or we do have a genetic change, it's just not something we can target, we don't have a drug for it, then we start looking at this PD-L1 score and we start making a decision of whether we should just do immunotherapy by itself or immunotherapy with chemotherapy. Into that decision making, it's not just the PD-L1 score, it's also the patient's preferences, what other medical conditions they have, how old are they, their functional status. A lot goes into that decision making.
Carly Ornstein: All right. The targeted therapy drugs, I'm sure they each work a little differently based on the type of mutation, but basically they're just targeting the mutation instead of generally killing cancer cells and healthy cells, right?
Justin Gainor: Correct. They're targeting the mutated protein. Right.
Carly Ornstein: Great. Okay. When should a patient be retested? Let's say the patient had their tissue tested initially before they started any treatment. When, if ever, is it appropriate for them to have another test?
Justin Gainor: I think this is a great question. And there are lots of layers to this, so I'll be very interested in your thoughts as well, Dr. Pool. The first question I would ask is how comprehensive was their initial testing? If this is someone who had one or two gene tests and they were negative, that might be someone where you do a more comprehensive panel, looking to find whether there are alterations there.
Carly Ornstein: Right. Maybe they were doing what Dr. Pool was saying. Maybe it was a few years ago or not, but they just were looking for EGFR, or they're looking for ALK-
Justin Gainor: Correct.
Carly Ornstein: ... instead of all of the possibilities. And some of those mutations now are actionable that weren't actionable before.
Justin Gainor: Exactly right. Exactly right.
Carly Ornstein: Okay.
Justin Gainor: It is a bit sobering that, despite us knowing about these gene changes now for a while, and despite seeing transformative activity of some of these targeted therapies, even some of the most basic genetic changes like EGFR and ALK, rates are not 100%. We would think that's the case, but they're not.
Carly Ornstein: Rates of ...
Justin Gainor: Of testing.
Carly Ornstein: Okay.
Justin Gainor: Even in the United States, there was a recent paper from last week was showing that ALK testing rates were only 60%. So clearly we need to do better. That number should be 100%. So I would ask first, how comprehensive was their initial testing. If it wasn't comprehensive, that's something that you might pursue. There are various reasons why they may not have had comprehensive testing. There may not have been enough tumor biopsy material. That might be something that there's a conversation about. We might want to get into are there other tools to test outside of just looking at the tumor material.
Carly Ornstein: Meaning that when they had a biopsy and tissue was taken out of their lung, there wasn't enough to do the testing.
Justin Gainor: Right. Right. There wasn't enough tumor there or it's been exhausted with other tests.
Carly Ornstein: Okay.
Justin Gainor: In terms of, say they've had comprehensive genetic testing and, by and large, if you have one of these genetic changes like EGFR, ALK, ROS, these are mutually exclusive. If you have one, you don't have the other. I think that's something important to note. And those don't really change over time. Those are present in every single cell. The medical term or the scientific term we think about is these are clonal. They are present and generally you don't lose those genetic changes.
Justin Gainor: The reason to retest, though, is to see if there are additional genetic changes on top of that. When patients receive a targeted therapy, say a patient has an EGFR mutation or an ALK rearrangement, when you treat with a targeted therapy, over time the tumor can develop resistance to that targeted therapy. Commonly, that resistance is through additional genetic changes in the tumor. That may be one place where we would want to repeat genetic analysis. We wouldn't go back to the first biopsy, though, because the cancer has changed. We would actually want to do another biopsy to see how that tumor has changed. Again, with the thought process being that we can potentially change to a different targeted therapy. We can use that information to guide our decision making.
Carly Ornstein: They wouldn't change from EGFR to ALK, but they might change from EGFR to a mutation that indicates resistance to an EGFR drug, right?
Justin Gainor: Correct. Correct. So they can develop another mutation in EGFR-
Carly Ornstein: Another slightly different EGFR mutation that might mean they'll go on a second type of EGFR targeted therapy.
Justin Gainor: Correct.
Carly Ornstein: Okay. And then my other question is if you were tested and did not have any of these mutations, especially the actionable ones, is there any likelihood that you would then develop one of those mutations?
Justin Gainor: Usually not.
Carly Ornstein: Okay.
Justin Gainor: Many times, we see that there are other genetic changes in those tumors. But most of the time these are mutually exclusive. If you have one, you don't have the other.
Carly Ornstein: Or if you don't have it, you won't have it.
Justin Gainor: Correct.
Carly Ornstein: Okay.
Justin Gainor: Now, there are some important caveats there. I'd want Dr. Pool's input, too. First you need to actually make sure that it was a good quality specimen that was actually tested and you actually have confidence that you're actually testing the tumor and not just normal cells around that.
Carly Ornstein: Right.
Justin Gainor: The other thing is, and I think this is going to be a question mark as we start using other forms of gene testing like testing the blood. There's a newer technology called circulating tumor DNA where we actually look for these gene changes not through biopsies, but actually a sample of the blood. And looking for very, very rare quantities of tumor DNA that has been released into the bloodstream. And that's a prime example where, just because it's quote negative, doesn't mean it's truly not there. It may be that the tumor just isn't releasing the DNA into the bloodstream. So a negative test isn't really negative, it's more non-diagnostic. It's something that you may want to repeat down the road.
Carly Ornstein: Great. Do you have anything to add, Dr. Pool?
Mark Pool: I think the circulating tumor DNA has really let us off the hook in some respects because it's very frustrating to run out of tissue when we want to do these additional tests. Especially when the patients were initially diagnosed a few years ago, we didn't get a complete molecular testing profile done and they were negative at the time for EGFR or ALK. And now they have recurrent disease. And they undergo a biopsy procedure. We want to get a diagnosis, we want to get molecular testing. And either the sample quality is poor, which is what we assess the tissue for, or there's an insufficient quantity of tissue or there's enough tissue to run some tests, but not all of them. Circulating tumor DNA actually is one way we can get around that and maybe prevent the patient from undergoing a different procedure. Sometimes when we discuss these patients with the team it's decided, yes, we want to go ahead and do another biopsy procedure or maybe pursue serum testing.
Carly Ornstein: Is that what we call liquid biopsy?
Mark Pool: Yes. That is the liquid biopsy.
Carly Ornstein: Okay. Interesting. And then what about PD-L1 if a patient wasn't tested? That's fairly new. It's quite possible that you'll be seeing some patients that weren't tested for that. Can that test be done at any time on the tissue?
Mark Pool: Yes. Since that tissue is done on tissue that's been fixed and processed, we can always go back to tissue that's stored and do that test. It's not uncommon that we get those requests, several times a month, to look back in our archives and pull the tissue out and do the test on it.
Justin Gainor: Yeah, I completely agree. I do think that the utility of that test also depends where someone is in their disease course. I think going back and doing the testing is very relevant for people who had disease that was confined to the lungs and they had a surgery and then, unfortunately, the cancer came back. That's a place where really then you would want to test. If somebody, though, was in a situation where the cancer had already escaped the lungs and they've already gotten standard chemotherapy, that's one place where it's less important to do that test. It's very important at the initial diagnosis and less important after chemotherapy. And the reasons for that are, in the clinical trials that were done compared to other forms of chemotherapy after someone's already had chemotherapy regardless of whether that test is positive or negative, immunotherapy is better than other forms of chemotherapy. In my mind, if the test isn't going to impact what I do, I don't do the test.
Carly Ornstein: Right. That's a good point. One thing that I did want to touch on because I've been hearing about it is tumor mutational burden. Can you define that a little bit and explain what that is?
Justin Gainor: Sure. It's actually still a term that is in need of a uniform definition, I would argue. But intuitively, it's something where, think about this, the concept of using immune therapy, the central premise of it, is that cancers ... The more and more genetic mutations that a cancer develop, so the more and more mutations, the more and more it begins to look foreign to the immune system. If it has one mutation, it's pretty close to normal self, but if it's got 200 mutations, it begins to look much more foreign and is therefore more likely to be recognized by the immune system.
Carly Ornstein: And destroyed by the immune system. Okay.
Justin Gainor: And destroyed by the immune system. At the most simplistic level, it's really the total number of mutations in a particular tumor. Now there are many different ways to measure this. It depends on the total number of genes you're looking at, so how much DNA you're analyzing, and what the specific mutations that you're actually counting. Right now we're lumping all the mutations into one bucket, but there are many different types. Tumor mutation burden, or TMB for short, is really just some way to quantify the total number of mutations in that tumor.
Carly Ornstein: Okay. Which might give us information about how that person might respond to immunotherapy?
Justin Gainor: Correct.
Carly Ornstein: Okay.
Justin Gainor: This looks like it's an independent marker from PD-L1. They provide complimentary information. And it also is a predictor for responsiveness to immunotherapy. Now, it's a much more complicated one, though, than the standard PD-L1 testing that we've talked about. It requires much more of that bio-informatic support. Right?
Carly Ornstein: Right. Patient education is important. We want to educate patients about genetic testing, tumor testing, whatever you want to call it, and the availability of targeted therapies and immunotherapies. But really the physicians and the hospitals need to play a big part in this, too, so that patients aren't missed when they come in, especially patients that really should be tested. I was hoping that you guys could speak, maybe starting with Dr. Pool, about what you think needs to happen to get this testing done more reflexively on eligible patients when they see the physician.
Mark Pool: I think approaching lung cancer from a multidisciplinary team approach is how you make sure that you have pathways in place so that patients don't get missed. And if they do get missed or if there's pieces of the information that the treating physicians need, that there's communication between the surgeon, the oncologist, the pathologist to obtain enough tissue. To make sure that tissue is appropriately handled. And then to communicate those results in a timely manner so that the oncologist has that information when they see the patient. And there's not delays in terms of seeing the patient but not having all the information you need and in formulating a plan. It's also important in that we educate each other. I, as a pathologist, I'm learning what the oncologist needs in terms of what tests they want, what tests are going to be useful for the patient. And I learn from the surgeon some of the technical issues with getting more tissue or not being able to get it.
Carly Ornstein: I guess you need to be a little louder. Go ahead.
Mark Pool: I am finished. It's really just a multidisciplinary team approach.
Carly Ornstein: Okay. Great. Dr. Gainor, do you have any thoughts on how to get this done more reflexively?
Justin Gainor: I agree completely. I think it all boils down to communication. I do think you'd actually get different answers if you polled 100 pathologists and 100 oncologists about what's the best way to do it reflexively. At our institution, we actually don't do it reflexively because the oncology community at my institution actually wants to have some input into what specific testing is going to be done in what order. But that's not uniform. I think the bottom line is it's important to get the testing done and really have open lines of communication between pathologists, oncologists, surgeons. Cancer is something that can't be addressed by one-
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Justin Gainor: ... surgeons. Cancer is something that can't be addressed by one single specialty. It's really teams that come together, and you really need open lines of communication to do that.
Carly Ornstein: Right. That's what, I think, Dr. Pool is meaning by by multidisciplinary.
Justin Gainor: Correct.
Carly Ornstein: Lots of different physicians from different specialties all working together and communicating so that the patient actually gets what they need.
Justin Gainor: Right.
Carly Ornstein: Right. Okay, great. So now we're gonna take a few questions from our audience and try and address some that we received online.
Nicole Hampton: I have a question. Nicole Hampton. I'm with my mother, Cindy Hampton, a Lung Force Hero in Milwaukee. My question is, do patients have to be treated at big hospitals to get this type of testing?
Carly Ornstein: Dr. Gainor?
Justin Gainor: Yeah, so the answer is no. This is something that should be done regardless of where patients actually are getting treated. Now, the extent of the tumor panels, the gene panels can vary from institution to institution. But the core genetic changes with FDA approved therapies, someone should be getting access to that regardless of where they're getting treated.
Carly Ornstein: And do you have any tips for the language that a patient can use to kind of advocate for themselves?
Justin Gainor: So I think we've tried using some of that language today, which is I've heard about tumor testing or gene testing and/or what is my eligibility for using a targeted medicine? Those are some of the things that I think a patient or a patient's family would be wholly appropriate to ask.
Carly Ornstein: And advocating for next generation sequencing, is that the most comprehensive approach?
Justin Gainor: It's the most comprehensive approach in at least bringing it up. There may be times, though, where it's more appropriate to do a very rapid test based upon the clinical situation. So I think raising the question and then starting some dialogue about what are the pros and cons of doing that.
Carly Ornstein: Okay, great.
Cindy Hampton: Good morning. I'm Cindy Hampton, Milwaukee. Does insurance cover this testing?
Justin Gainor: So I can take that one, as well. In general, insurance does cover genetic testing if it's done for advanced non-small cell lung cancer. And this is something that should be standard of care. So regardless of where you're getting care in the United States, this should be a standard, and so as such, it's generally covered by insurance.
Justin Gainor: Hi. Dr. Renee Matthews, lung cancer advocate. If a patient's never had any testing done, is it ever too late?
Mark Pool: I can take that one. Most of the time, we can do these tests on tissue that's already been processed and archived. So we can always go back to that. Occasionally, there are some tests that require fresh tissue, but for the next generation sequencing, PD-L1, generally we can do that on tissue that, even if it was obtained years ago.
Carly Ornstein: This is actually a follow-up question I have to that. It seems like one of the difficulties with this is that there needs to be an appropriate amount of tissue taken at the time of the biopsy, but a patient might not know that they have lung cancer at that point, right? And they certainly might not know to ask about tumor testing. Any thoughts on how we can communicate better with the physicians performing the biopsies so that they know that this kind of testing is gonna be coming and they should remove an appropriate amount?
Mark Pool: I think from our team approach, everyone is aware that we need a certain amount of tissue. We certainly discuss in tumor boards how much tissue is needed so the minimal amount of cells or DNA that's required. The problem is sometimes the tumor's difficult to get to or the tumor is associated with a lot of necrosis, meaning that the tumor is growing so rapidly that it actually dies, the tumor cells die themselves. And so we need viable live tumor cells in the biopsy material to do this. So sometimes that's a problem, too, just we don't know really what the quality of the tissue will be until we can examine it on the microscope.
Mark Pool: Also, because of lung cancer screening, a lot more small nodules are being removed with the idea that maybe they are cancerous. And so we still go through the same process of obtaining tissue for molecular testing, for example, just in case it might be a tumor. And so we need to have a dialogue with our labs or with commercial labs that we're sending these tests out to to make sure that if it's not tumor that we don't do testing, and if there is tumor there, we need some kind of quality assurance that we actually are testing the tumor cells and not normal cells, like Dr. Gainor mentioned before.
Carly Ornstein: Do you think there will ever be a time when a liquid biopsy, like a blood draw or even saliva, will be able to replace the tissue biopsy from the lung?
Justin Gainor: No. Well, at least for the initial diagnostic biopsy. I view liquid biopsies as really complementary, not a replacement for. Because what you can't get by a liquid biopsy is actually the architecture, what do these cells actually look like. You're just finding the DNA. So you can't see this is a small cell lung cancer, this is a non-small cell, this is a squamous cancer. You can't figure that out from a liquid biopsy. It's one of the principle limitations of it.
Justin Gainor: And so it can provide complementary information, though. So say you already have a diagnosis, but there's insufficient material to do the comprehensive gene testing. You can try to get it via liquid biopsy. Or if someone is already on a targeted medicine and is starting to develop resistance and it's hard to get another biopsy, that's another place where liquid biopsy would have utility.
Carly Ornstein: And what about, I don't know if this is also considered liquid biopsy, but taken from their sputum or the mucus in their lungs?
Mark Pool: You mean cells that are in the sputum?
Carly Ornstein: Yeah, like coughing up something that will have cells in it that will give us information. Does that have a role?
Mark Pool: Sure, we can do molecular testing. If there's enough cells, those kind of samples we can do additional testing on PD-L1 and molecular testing, as well. The challenge really is, again, getting enough cells in these samples Sometimes we're making diagnoses on a handful of cells and feel fortunate just to be able to say it's cancer or not cancer. But the paradigm is evolving past that just from saying yes, there's cancer, no, there's cancer to yes, there's cancer, and there's these additional markers or mutations and so forth that are very important now in treatment.
Carly Ornstein: This is kind of what we call precision medicine, figuring out not just the type of cancer you have, but as much about your cancer as possible and pairing it with the best treatment possible, right? Okay great.
Carly Ornstein: We're gonna take a few questions from our Facebook audience. The first question is, how does a patient know if their tumor has had next generation sequencing or any type of testing?
Mark Pool: I think that's a challenge, especially because this information may reside in other places, so for example, sometimes we have patients referred to our institution, and we don't really know what testing they've had previously. So again, it goes back to communicating with the oncologists or surgeons to find out what has been done so far so we don't reduplicate testing. But also, if testing hasn't been done that we acquire the appropriate tissue.
Carly Ornstein: This is a question for Dr. Gainor. I'm hoping that you can clarify a little bit. We had a question that says, are you saying that immunotherapy doesn't work after chemotherapy?
Justin Gainor: No. No. So I'm saying it works regardless of whether or not you have that PD-L1 score.
Carly Ornstein: If you had chemotherapy first?
Justin Gainor: So, yeah. So the role of that PD-L1 test, really it's an imperfect predictor. So if you take 100 people with lung cancer, only about 20% will actually respond to immunotherapy. If you use that PD-L1 test, it actually brings it up to about 40%. So it's still not perfect. And so the role of that PD-L1 test is really to help you prioritize at point should you use it.
Carly Ornstein: Well, what point do use the immunotherapy?
Justin Gainor: At what point to use the immunotherapy. And part of this is historic in that it reflected that these drugs were initially approved after chemotherapy, regardless of whether you had PD-L1 positive or negative, those drugs were better than chemotherapy. So that's why I was saying that after someone's already had chemotherapy, there's a less of a need to actually do that testing.
Carly Ornstein: Okay. Great. And can you talk a little bit more about the PD-L1 levels? What are the ranges, and what do the ranges mean?
Justin Gainor: So this, thankfully I would say, we've gotten some clarity on this point in the last several years. It was very complicated around 2014, 2015 because there are multiple of these immunotherapies, and in each of the different immunotherapies would use different cutoff. Even the same drug would use a different cutoff whether someone had chemotherapy or not. But fortunately, there have been major efforts, collaborative efforts between industry, academics and industry partners trying to harmonize those efforts and looking at how closely if you did one PD-L1 test, does it replicate another one? So long story short, I think the most clinically relevant cutoff is 50%. So 50% of tumor cells expressing PD-L1.
Carly Ornstein: Would that be considered a high level?
Justin Gainor: That'd be considered high.
Carly Ornstein: Okay.
Mark Pool: So if the tumor is less than 1% expressing, so the tumor cells, less than 1% show this positive PD-L1 reaction on the stain, we would call that negative. And as Dr. Gainor said, if it's more than 50%, we would call that a high expression. And so anything in between, between 1% and 49%, we call that low expression. And so we give that information. It's not just positive or negative, it's really whether it's high, low or negative.
Carly Ornstein: And depending on that score impacts whether or not maybe they go on immunotherapy before or after chemotherapy?
Justin Gainor: Yeah.
Carly Ornstein: Complicated.
Justin Gainor: Yeah. And the bottom line, now because these drugs were initially all explored second line, meaning after someone had already received chemotherapy. Once the drugs were approved there, then they started being looked at first line. And so the most relevant thing now is someone who's newly diagnosed, they haven't received any therapy, it's going to be immunotherapy, plus or minus chemotherapy.
Carly Ornstein: Got it. Plus or minus chemotherapy. Great. One more question. We've talked a little bit about clinical trials. When might a clinical trial be the right choice for a patient, specifically around this issue of tumor testing and immunotherapy and things like that?
Justin Gainor: I mean, maybe I'll weigh in. I am a clinical trialist, that's a lot of what I do. And I would say that it depends. A lot of people have strong feelings when they hear clinical trial, thinking that oh, it's just because I've exhausted other options. And I want to emphasize that that is not the case. Even things like phase one studies right now may be the most appropriate thing to even start with. We've been fortunate in the lung cancer world, where we now have multiple drugs that have been approved on the basis of a phase one study. So phase one studies historically were just about dose. But as you start using very targeted, precision therapies, so you have a biomarker, a test that can identify group most likely to respond, and a very targeted medicine, you can see dramatic activity, even in that phase one study.
Justin Gainor: And so now the trend with all of these targeted therapies is that we're seeing activity in the phase one. And so if someone has one of these genetic changes that is actionable, where we know a lot about it, but it's not approved yet, I would argue that for those people, depending on what the target is, sometimes a clinical trial may actually the most appropriate very first therapy. It really depends.
Justin Gainor: And this speaks to the fact that sometimes the regulatory aspects, so getting a drug approved, commonly lags behind the science. And so we may know a lot about it. A classic example right now is [RET 00:55:28]. So this is found in 1%-2% of people with lung cancer, and we now have several drugs that have shown responses above 70%. So marked shrinkage, but those drugs aren't approved yet. So if I saw a patient with a RET rearrangement right now, I would out them on a phase one clinical trial because the current data has been so promising.
Carly Ornstein: Great. Do you have anything to add?
Mark Pool: I get these reports myself, and I'm always to curious to look at them, mainly if it's one of the big four mutations, fine, but I'm always interested to see these additional mutations for which there's phase one trials, and then that kind of triggers me to start looking in the literature and see are there mutation-specific antibodies that we could maybe do faster or what are some other techniques? Because these are gonna be escalated once they're approved and so forth. So I agree with Dr. Gainor, it's a whole new world opening up.
Carly Ornstein: Great. Well, thank you so much for your time today both of you. A recording of this video, as well as additional resources, will be made available at lung.org/tumor-testing-videos. So that's lung.org/tumor-testing-videos. And that will be available in the next couple weeks.
Carly Ornstein: If you're tuning in live, we'll have another panel discussion with Dr. Gainor, and we'll also be joined by Dr. Sherri Millis from Foundation Medicine, and we'll be discussing a little bit more about the future of this very fast-paced field. That discussion's gonna happen at 2 p.m. Eastern, 1 p.m. Central.
Carly Ornstein: So I wanted to thank again AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, Pfizer and Merk and Co. Incorporated for their generous support of this program. Thank you.
Page Last Updated: November 9, 2018
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