Tumor Testing and the Transformation of Lung Cancer Treatment: The Future of Tumor Testing
Progress is being made every day in the fight against lung cancer and incorporating tumor testing and precision medicine into a person's treatment plan creates a more targeted or customized approach to treating lung cancer. The American Lung Association convened a panel of experts to share the latest developments in this exciting area of 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 Sherri Millis M.S., Ph.D., Senior Manager, Clinical Collaborations Foundation Medicine Inc.
Generously supported by AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, Pfizer, and Merck & Co., Inc.
For more information, visit Lung.org/tumor-testing.
Carly Ornstein: Welcome to our program, Tumor Testing and the Transformation of Lung Cancer Treatment.
Carly Ornstein: The American Lung Association thanks AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, Pfizer, and Merck & Co. Inc. for their generous support of their program.
Carly Ornstein: I'm Carly Ornstein, the National Director of Lung Cancer Education at the American Lung Association.
Carly Ornstein: During this conversation, I will be joined by Dr. Justin Gainor and Dr. Sherri Millis, as we discuss the future of lung cancer tumor testing and precision medicine. Dr. Justin Gainor is an oncologist and assistant professor of medicine at the Harvard Medical School and Massachusetts General Hospital Cancer Center. Dr. Sherri Millis is the Senior Manager of Clinical Collaborations at Foundation Medicine.
Carly Ornstein: We are also joined by several lung force heroes in the audience, as well as hundreds joining us online. If you are 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.
Carly Ornstein: Let's get started. Thank you Dr. Gainor and Dr. Millis for joining us today. So for those of you who didn't join us for our overview of tumor testing conversation earlier in the day, I wanted to ask Dr. Gainor to provide us a brief overview of what is tumor testing and what does it mean for lung cancer patient?
Justin Gainor: Sure. So I think it would be helpful to begin by just talking briefly about what actually happens after someone has a biopsy, what happens next. At that point, it usually goes to a pathologist. So this is a physician skilled in looking at tumor biopsies, as well as surgeries that have been done. The first step is for them to decide is there a cancer there or not? And much of that is done just via visual inspection underneath the microscope.
Justin Gainor: What we're going to talk about today in terms of tumor testing is the next level, and that is trying to understand some of the things that we can't always see, and that is the genes within those tumors and whether there are genetic changes, and we call those mutations. So genes and DNA are the building blocks of life and we know that in the field of lung cancer, it's not just one disease, there are actually hundreds of different types of lung cancers and these are really defined by different genetic changes. And it's important to note that for the most part we're not talking about things that are inherited here. We're really talking about things that are acquired and really unique to the tumor, at least when it comes to lung cancer. This has bearing on how we treat lung cancer. We know that certain genetic changes enable us to use more targeted medicines that can have profound impact on a patient's clinical course.
Carly Ornstein: Great. Thank you.
Carly Ornstein: And then in addition to mutations, are there other, what we call biomarkers or things that are in the tumor that can help inform a patient's treatment?
Justin Gainor: There are, and you've used the term biomarker and there are different types of biomarkers, but today we're going to be focused on predictive biomarkers. That is, some test that helps predict how someone is going to respond to a given therapy. So in the field of lung cancer, some of our best biomarkers are genetic biomarkers and more recently biomarkers aimed at telling us about whether patients can respond to immune-based therapies or immunotherapies. And there, there's really been a flurry of research over the last several years. We don't have a silver bullet in terms of the best biomarker, but there are several that have become very commonplace. I would say the most important one is called PD-L1 testing, this is a test where you're looking for PD-L1. The way I describe it to my patients is tumor cells can cloak themselves in it and it's one way that tumors can evade the immune system by basically increasing the expression of this on their cell surface.
Carly Ornstein: Okay, great.
Carly Ornstein: If a patient has a mutation, it might inform whether or not they would be eligible for a targeted therapy and their level of PD-L1 might inform how they might respond to immunotherapy. Is that right?
Justin Gainor: Exactly. I do think it's worth mentioning that for some of these gene changes, they're binary, they're either yes or no. Whereas, the PD-L1 test, it's more of a continuum where it can be 0% all the way up to 100%, they're percentiles.
Carly Ornstein: Right. So with the mutations, you either have it or you don't. But with PD-L!, it's about how much you have?
Justin Gainor: Correct. And they can change over time.
Carly Ornstein: Great. Okay.
Justin Gainor: So, Dr. Millis, let's take us back to a patient has tissue removed from a biopsy, then what happens? Where does it go and how do we get results?
Sherri Millis: Yeah. So after the biopsy is performed, a piece of the tissue is put into a specific type of chemical so that it is maintained and then the tissue is sent to a laboratory like Foundation Medicine. At the laboratory, the tissue is analyzed by taking that DNA, that component out that we're going to look at to see if we have these mutations, and it's taken out of the tissue and it's run on an instrument. The instrument is looking for changes in the DNA or changes in the genes and it's like looking for changes in the word.
Sherri Millis: So, if the gene is telling the cell to grow slow and there's an alteration that now says grow instead of slow, we're looking for that change in the word essentially. And so the instrument is looking for that, it identifies it, and we look at a large number of genes. Then after the instrument is done running the sample, it comes out, and we see these different alterations that are listed from the instrumentation itself, and that's considered the raw data. From that, we have analysts who look at the raw data to make sure that it's actually what we thought was seen on the instrument, and that information is then listed. So we'll have alterations in the genes listed and we have a cancer genomacists who then can associate those alterations with the targeted therapies that are available, that will target those genes and stop the cancer from growing.
Sherri Millis: So there is first the raw data that comes off the instrumentation and then there is analysis by the clinical staff to associate those alterations with the therapies. From this, we generate a report, and the report allows the oncologist to then identify what specifically is driving that individual's cancer and whether or not there are therapies that might be associated with predictive response to those therapies based on those alterations. That information is then sent to the clinician to talk with the patient.
Carly Ornstein: Okay. So to recap, the tissue goes into an instrument that is looking for changes or mutations. Then it spits out what it thinks it finds, and an actual person reviews it and compares it to make sure that it is correct. Then I'm a cancer geneticist looks at it and says, "Okay, based on what has been spit out and the available data, this is what we might recommend as treatment."
Carly Ornstein: Does that make sense?
Sherri Millis: Yeah. So it's based on the evidence that has been developed over time that a first, there are drugs that are developed and put on the market and we have an association between those alterations that are found different cancers and those drugs. So the cancer genomicist is associating that information together based on what's been published, what's known in the field.
Carly Ornstein: Great. Okay.
Carly Ornstein: I know that PD-L1 is looked at a little differently. Do you want to speak to that?
Sherri Millis: Sure. The majority of the tissue is analyzed for changes in the DNA. PD-L1, we're looking at protein expression. So the DNA is like the blueprint that's in the nucleus of the cell that tells the cell what it's going to do. PD-L1 is a protein that is produced based on that blueprint.
Sherri Millis: So, we take us section of the tumor and we look at the protein expression for PD-L1 and identify whether or not that is higher than we expected it to be for a normal cell.
Carly Ornstein: Great.
Carly Ornstein: Is sometimes done by a laboratory company or is it sometimes done in house at a hospital with a biopathologist?
Sherri Millis: Yeah. So some hospitals will run many of these tests individually in the hospital pathology lab, but alternatively, it can be sent out to what we call a reference laboratory to run either PD-L1 or analysis of the gene alterations as well.
Carly Ornstein: Great.
Carly Ornstein: Dr. Gainor, from a clinician standpoint, when you get this report, how does it help you when you're talking to your patients and help inform their treatment?
Justin Gainor: These are crucial components of actually how we treat our patients. When oncologist speak amongst themselves, if it's not enough to just say this person has lung cancer or this person has this stage of lung cancer. Part of that description is hearing what the genetic changes are and hearing what the PD-L1 expressions are. They're necessary components of what we need to fully understand and characterize a tumor and come up with the best therapies.
Justin Gainor: So we know that for patients who have cancer that has escaped out of the lungs, so we call that metastatic cancer or stage four lung cancer, the standard approach in that situation is to use drug therapy. We think about three big categories of drug therapy. We think of traditional chemotherapy, we think of targeted therapy, so trying to use, these are generally pills, and then immunotherapy, which are intravenous medicines that are given to boost one's own immune system to then recognize the tumor. Coming up with what combination or which one of those three we should use is really based on the genetics, this PD-L1 score, and then the patient, individual aspects of the patient's care, like their other medical conditions, their preferences, how fit they are. All of those things are you used to come up with a treatment plan.
Carly Ornstein: Great.
Carly Ornstein: I just wanted to jump back a second to Dr. Millis because I think that there's a lot of terms that are floating around that patients might hear like comprehensive genomic testing or next generation sequencing. Can you take a second and define some of those key terms?
Sherri Millis: Sure. So next generation sequencing is a newer method of testing the cells and the DNA within the cells that goes beyond the historic methodologies, which would test a single gene at a time. We are now able to test many, many genes at the same time. And so that's why it's next generation sequencing. We can, for example at Foundation Medicine, we look at roughly 324 genes at the same time. So we're gathering a lot of information about many, many genes that historically was not something that could be done. So the technology has advanced us to the point where we can really analyze a lot of genes at the same time.
Sherri Millis: So in addition to that, there are levels of analysis of the gene. We can look at a single point in the gene that is most often altered, which is called hotspot sequencing, or we can look at the entire gene and determine what might be altered across the entire gene. So again, comprehensive genomic sequencing is really doing a much more thorough analysis. It's not limiting us to looking at a single point in a gene, but rather looking across the entire gene. And so the newer technology allows us to look at many genes and the entire gene, not just a single point.
Carly Ornstein: How has this already impacted lung cancer?
Sherri Millis: This has had a huge impact on lung cancer in that analysis of this large number of genes has allowed for identification of genomic alterations that previously had not been known. So for example, one of the genes called MAT, M-A-T, has an unusual way of splicing itself together during processing of the cell, and it was identified in our lab that there are alterations in this particular processing of this gene that had not been previously seen in lung cancer. The recognition of this alteration then led to the ability to use a new targeted therapy to treat patients who have that MAT splice site alteration. And more recently RAT alterations have been identified, they're complex rearrangements, harder to analyze in traditional testing, and the ability to analyze these alterations again, has led to pharma companies developing novel drugs that are likely going to be FDA approved in the near future to help the patient.
Carly Ornstein: Great.
Carly Ornstein: Speaking of helping the patient, Dr. Gainor, can you just review, which types of lung cancer patients are most likely to benefit from this type of sequencing?
Justin Gainor: So I think it's worth a first reviewing how we approach the different stages of lung cancer. If lung cancer is localized to the lung, then we typically pursue a surgery or even radiation with the goal of completely eradicating it, that's the standard approach and we rely less on drug therapy. When cancers though have escaped a lung, we know that a surgery or radiation can't completely get rid of all of those cancer cells. And so we rely on drug therapy. Right now, the greatest need to do this genetic profiling is for patients who are requiring drug therapy, so a patient with more advanced lung cancer. The guidelines suggest patients with non-small cell lung cancer, so that's about 85% of lung cancers, and specifically a subgroup called nonsquamous, which just really defines how things look underneath the microscope. That's not to say that patients who don't have that specific subgroup shouldn't be tested, but that's currently what the guidelines would suggest.
Carly Ornstein: We touched a little bit about on the last panel, but since we're talking about the future of tumor testing, do you foresee that group changing, the guidelines changing to open that up to people with different types of lung cancer?
Justin Gainor: I do. I do. Because what we've come to recognize is as we've started doing these larger and larger panels, we've come to recognize that there can be clinically significant, but very, very infrequent subgroups. So some of the alterations that Dr. Millis just described, MAT is present, these splice site mutations are present in about 3% or 4% of people. RAT is even less common; 1-2%.
Justin Gainor: We've now found something called NTRK, which is 0. 03%. So, as we do more and more of these broader efforts, I think we're finding smaller and smaller pieces of the pie of these genetic alterations. My hope is that we will continue to identify targetable genetic changes as we begin to look at other forms of lung cancer.
Carly Ornstein: What percentage of lung cancer patients generally have a mutation that's actionable, meaning there's therapy that is available to treat them?
Justin Gainor: Yeah. And I think that's the important part is actionable because if you do sequence a lung tumor, you're going to find a genetic change, it's just, is it actionable? And it varies, it varies also based on ethnicity. But in the United States, there are four genetic changes where we have FDA approved therapies. So these are EGFR, which is found in about 10-15% patients. ALC, which is 3-5%. ROS1, which is 1-2%, and BRAF in a very specific genetic change there, which is about 2%. So we kind of add all those up and you can see is about 25% of patients will have a targetable genetic change.
Carly Ornstein: Great.
Carly Ornstein: Do you think that, that number is going to grow as we ... well, I guess as we would test more people, we could expect that number to grow, or do you think it'll probably stay around the same?
Justin Gainor: Well, what Dr. Millis was alluding to is that there are additional genetic changes that aren't one of those four where we don't have FDA approved therapies, but we've already come to recognize that these genetic changes are targetable. So prime examples are MET exon 14, as well as RAT rearrangements, and there are several others where we now have several clinical trials using different targeted therapies directed towards those genetic changes and seen very promising results. We're just waiting on the regulatory aspects and additional data, and we all anticipate that drugs will be approved for those specific genetic changes.
Carly Ornstein: Right.
Carly Ornstein: So, Dr. Millis, you say that, and Dr. Gainor said this too, that when you look at a patient's tumor, you might find many mutations, several of which they don't have an actionable ... they're not actionable, they don't have a drug that can be treated. What do you do with that information?
Sherri Millis: So some of that information can be used for clinical trials. There are alterations that have not gotten an associated approved therapy at this point, but there might be therapies in clinical ...
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Sherri Millis: ... associated approved therapy at this point but there might be therapies in clinical trials. So getting patients onto clinical trails is helping both to identify whether or not that patient will respond to a drug that hasn't had the FDA approval yet and whether or not that drug might be good for future patients.
Carly Ornstein: So let's say a patient has a mutation that is not actionable, then a drug becomes approved by the FDA, do you then call that patient back, or call that doctor and say, "Hey, we might have something for you now and remember you tested positive for this mutation?"
Sherri Millis: Yeah, there is opportunity to amend or revise the information that came out originally for that patient to note that there now is a therapy that could be associated with predictive value.
Carly Ornstein: Okay. So, it seems like the more people you test you're kinda compiling these large datasets. Can you talk a little bit about how that data is used to help advance lung cancer research?
Sherri Millis: Yeah. So, Foundation Medicine has really been at the front of data sharing. We share data with a lot of organizations like the National Cancer Institute, nonprofits, we work with the academic institutions and community institutions as well, to share the information and to publish what is known to continue to advance both treatments for patients currently and to look at potential clinical trail development.
Carly Ornstein: So when you share that data ... The people that you're sharing with, how are they actually using it? Can you speak a little more specifically about the research?
Sherri Millis: Sure. There are many ways that the data is shared and used and often it's information that looks initially at what are the frequencies of these different alterations that have been found in lung cancer and then we partner with the pharmaceutical companies, if they identify an alteration like the [MET Splice 00:23:06] alteration, for which there might be an associated drug that has not yet gone through FDA approval to develop clinical trials or do other things to get that drug to FDA approval.
Carly Ornstein: Okay, cool. And I'm sure that patients have questions about patient privacy and ownership of the data. Can you talk a little bit about that?
Sherri Millis: Sure. So the data for a patient belongs to that patient and they can request to get their data at any time if the clinician hasn't provided that report to them directly. Foundation Medicine, as well as other commercial laboratories, follow HIPAA compliance and HIPAA is a privacy act that ensures that the patient information is not shared outside of the clinician and the patient.
Carly Ornstein: So when you're sharing data, it's all de-identified data?
Sherri Millis: It's de-identified data, typically in aggregate.
Carly Ornstein: Okay, cool. Seems like the more eligible patients that receive this testing, the more data we have, the more information we might be able to provide to researchers and help move the field forward. Do you have any thoughts on how we get more patients tested?
Sherri Millis: I think the first and foremost is education. This technology and utilization of genomic sequencing is fairly new, it's been available commercially less than a decade and so many of the oncologists who have been 20, 30 years in their profession are just learning about this in the last few years. So continuing to educate the oncologists, the pathologist and certainly the patients and their caregivers about the opportunities and when genomic profiling is appropriate is really moving the field forward and getting more patients to testing. When the testing is appropriate for their care.
Carly Ornstein: Do you have anything to add about that?
Justin Gainor: I would also say just communication. So, on the oncologist and the care team level. The oncologists working with their pathologist, working with their molecular pathologists, working with the individuals who are doing the biopsies and emphasizing that we need a biopsy not just to identify what type of cancer this is but we actually need to do a lot of additional testing. We need additional material and so when someone is going through a biopsy, keeping that in mind. Oncology is a field where patients are really treated with teams and keeping the lines of communication open.
Carly Ornstein: Right. So, Dr. Gainor I'm going to ask you to use your crystal ball and help me predict the future, which I know is a challenging task. But what do you think the next likely therapeutic target would be? Meaning the next mutation that would have an FDA approved drug.
Justin Gainor: So, here I would say that the most likely would be RET rearrangements, based on some very impressive data and the FDA granting breakthrough therapy designation.
Carly Ornstein: What exactly does that mean?
Justin Gainor: So breakthrough therapy designation is where the FDA says, "This investigational drug has shown promise," and encouraging activity and the FDA will give additional feedback and help a pharmaceutical company in guiding the drug to a potential registration. And so it's a specific pathway, it tends to be a more expedited pathway and there's a lot of back and forth with FDA and the particular sponsor of the drug. But it's typically when an agent has demonstrated some promise in early testing.
Carly Ornstein: Great. Do you have any thoughts? Do you agree?
Sherri Millis: I agree absolutely and I think, adding to that, with the recent development of immunotherapies and as we learn and the evidence continues to build around those, that PD-L1 is one biomarker that is being used to identify whether or not a patient might respond to the immune therapy. But we're learning through the continuing evidence and more and more patients getting this comprehensive genomic sequencing that tumor mutation burden, another element of the tumor that says there are a lot of mutations in this tumor, is also becoming relevant as a genomic signature that might get a patient to these immune therapies. And we're seeing more and more approvals with the immune therapies around that.
Carly Ornstein: Great. What about, for those that do not have non-small cell, small cell patients or even non-small cell squamous patients who, if I'm correct, typically don't receive this type of testing. Do we imagine that we'll be discovering mutations or biomarkers in those groups?
Justin Gainor: Maybe we can take them one at a time. So I would say for small cell, we can focus on that first. So small cell constitutes about 10% of all of lung cancer. Up until maybe a year ago, the treatment for small cell really hadn't changed in about 30 years. We know that this is a malignancy where it's very responsive to chemotherapy initially but then when the cancer comes back it tends to be quite refractory in that setting.
Carly Ornstein: What exactly does that mean?
Justin Gainor: Quite resistant. So, if you try to give the same therapy again, it tends to be much less responsive. And fortunately, over the last couple years, we've seen that small cell can also be a malignancy that is responsive to immune therapies. So I think, in terms of targeted therapies, there have been large efforts looking at the genic landscape of small cell, we know that there are two very characteristic changes but neither of them are very ... aren't target-able right now.
Justin Gainor: So I think immunotherapy is certainly something that is very exciting for the small cell landscape and got our first approval for an immunotherapy for small cell and just within the last month we actually have a big clinical trial coming back positive, showing that the combination of chemotherapy plus immunotherapy was better than chemotherapy alone. So I think overnight that changes how oncologists in the United States are actually going to practice. In that most patients with small cell are now going to be getting chemotherapy and immunotherapy at the same time.
Carly Ornstein: And, real quick, for patients with small cell, do their PD-L1 matter? Or are they eligible for immunotherapy kinda regardless?
Justin Gainor: It's a great question. In that study, it was regardless of PD-L1 expression. So I would say that if given in combination with chemotherapy, regardless of PD-L1 expression. It gets a little bit more complicated if people have just had chemotherapy alone. It does look like PD-L1 expression does have some predictive power for using immunotherapy in small cell. As does TMB, this quantification of the number of mutations.
Carly Ornstein: That's the tumor mutational burden?
Justin Gainor: Correct. That also looks like it's predictive for benefit of immunotherapy. In particular, a combination of two immunotherapy drugs. It definitely looks like if you have a higher TMB that you're more likely to respond to two different immunotherapy drugs given together.
Carly Ornstein: Great. And then what about non-small cell squamous?
Justin Gainor: Yeah, so squamous, these are tumors that, for the most part, and there are always exceptions, they don't tend to have the same genetic changes that we see in adenocarcinomas, which have the genetic changes that we spoke about earlier, the EGFR, ALK, KRAS and MET. The National Cancer Institute has launched a very large trial trying to do comprehensive genetic testing of, in particular, squamous patients and trying to match them with targeted therapies. And that's a clinical trial that's now been ongoing for several years and it's a trial that's evolved over time as newer therapies have entered the landscape, such as the immune therapies. That trial has been modified over time. So it's given us input both on the genetic landscape of those tumors but also trying to find targeted therapies for those tumors.
Carly Ornstein: So, do you think we're on the precipice of any major lung cancer advancements? And if so, what?
Justin Gainor: I would say over the last two years it seems like every two to three months we have a major breakthrough in lung cancer. I tend to give lectures to our fellows on cancer immunotherapy and I'm constantly changing my slide deck every month or two because there's another breakthrough study. So, I think this is a really exciting time because I would anticipate even after this weekend we may see even more exciting data after another major cancer conference.
Carly Ornstein: Dr. Millis, do you have any thoughts?
Sherri Millis: I would add to that that especially in the immune therapy arena, as we amass more and more evidence around the specific genomics of patients, including both gene alterations and tumor mutation burden and PD-L1 status, we're starting to get nuances around what gene alterations might mitigate whether or not a patient with a high tumor burden or PD-L1 positivity is likely to respond to immune therapy. And so I think we've got some exciting times ahead of us as we continue to hone in on the different scenarios that will reflect on whether or not a patient is going to respond.
Carly Ornstein: So it sounds like, with immunotherapy, the big excitement is we're finding biomarkers that will help us predict how a patient might respond to the drug and that's really important because it helps the clinician decide whether or not to give the drug. And with mutations, we generally know how they'll respond to a targeted therapy if they had the mutation, right?
Sherri Millis: Correct.
Justin Gainor: It's better. It's not perfect because we do know that having one of these genetic changes, like an EGFR mutation, when we see it, me as a clinician, can pretty much feel comfortable that that patient's gonna respond to therapy. So 90% of the time. But even within those patients who respond, there is significant heterogeneity. Some may respond for only four months and others ten years. And I think that's something that we're just scratching the surface of, right now, is are there additional genetic factors that are also present that also explain why someone may have a shorter or a longer response? That's something that we really need to look into more.
Justin Gainor: But the genetic factors are more predictive than the PD-L1 marker. So we clearly need better biomarkers there.
Carly Ornstein: Now while we're on the topic of mutations, something we talked about in the last session was that patients with certain mutations tend to become resistant to their targeted therapy. Do we know why that happens?
Justin Gainor: We know that this happens not just with cancer but also, if you've had antibiotics before, we know that just through, really, evolution that if you apply a selective pressure on something, the cancer or the bacteria is going to adapt to it. So we see that when we use targeted therapies. That over time you kill off the most sensitive tumor cells and the rest of the tumor cells can either already have preexisting genetic changes that enable them to survive or they persist and then eventually develop another genetic change that allows them to survive. So this is something where it's really important for us to understand the mechanisms that drive resistance, to then inform the next generations of targeted therapies.
Carly Ornstein: And is that kind of research going on now to try and figure out resistance mechanisms?
Justin Gainor: Certainly. This is research that we've been very active in at my institution. Which is that just not having a static understanding of a tumor, that as you apply a targeted therapy, that some point once the cancer grows we need to re-sample the tumor and understand how the genetics have changed and really using that information to then develop the next lines of therapy. And I think that's something that we've done from EGFR now all the way up to RET. And really doing that hand-in-hand as you're developing the first drug, anticipating that there will be resistance and trying to understand it from the start.
Carly Ornstein: Right. And Dr. Millis, thinking about your work from more of the genetics/genomics side, what are you really excited about in the future?
Sherri Millis: I'm really excited that we are continuing to identify alterations across cancers that are helping us to treat patients better and I'm excited about the advances that have been made in immune therapy because we are continuing to learn how to best apply when to utilize immune therapy and when not to. We're also moving into a generation where we're not just using the tumor but we're able to use what we call liquid biopsies or draw blood and get some of the same information that we get from the tumor. That's less invasive and it allows more patients to be tested. So we'll continue to develop better testing methodologies and identify novel treatment options.
Carly Ornstein: Great. Well, this was really informative. I want to go ahead and take some questions from our audience.
Martha: My name is Martha, I'm a 12 year long cancer survivor and very proud to be a Lung Force hero. My question is: are there any lung cancer mutations that are passed down from family members?
Justin Gainor: So, among the mutations that I described earlier where we have FDA approved therapies, EGFR, ALK, KRAS, BRAF, for the most part those are not inherited. There's a rare EGFR variant that can be but it is exceedingly rare. Most of these are what we call sporadic or somatic mutations which are really only present in the tumor and not present in other cells of the body.
Justin Gainor: That's not to say that isn't the case for other cancers but just for lung cancer that tends not to be the case. It's still important to take a good family history and it's also something that, as clinicians, this is, I would say, one of the challenges of when we do more comprehensive genetic testing, when we're testing for 300 genes, I'm interested in the targeted ones but if you're looking at 300 genes, what if I find a mutation in something like BRCA, which is typically we think of associated with breast cancer and ovarian cancer, but if I see it, then what do I do with that information? I have it, right? And so that's one of the challenges that actually comes up when we actually do these broader panels.
Carly Ornstein: So what do you do with that information?
Justin Gainor: Yeah, so, I think it's important to note that just because we see a genetic change in a gene does not mean it actually is an impactful change and has consequences. The analogy I give to my patients is think of a gene just like a street. There are various addresses along that street. Some of the addresses, you know, they're different houses around and some are more important than others and so just because there's a genetic change in a gene doesn't mean that it actually has any bearing on how that particular protein will get translated.
Justin Gainor: And so, the first thing is I look at the specific genetic change. I speak to my molecular pathologist. We talk about has this been reported before? In these large databases? Is it something that we know about? If it's not, if it's one of these variants of undetermined significance, I take a careful family history-
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Justin Gainor: I take a careful family history, and if there's anything concerning, I refer them to genetic counseling.
Carly Ornstein: Interesting. Thanks.
Joe: Hi. My name is Joe, and I'm here to support my friend Martha. My question would be what actually causes these mutations to happen, and how close are we to finding a cause?
Sherri Millis: I can take that one. Cancer is often considered a disease of the aging because over the course of our lives, every time a cell divides, that DNA is copied or replicated. And every time it's copied or replicated, there's a potential for it to be replicated incorrectly, for mistakes to occur. Over the course of our lives, we're inundated with carcinogens in the environment, sun damage, just breathing the exhaust fumes in environment, et cetera, so there's potential for the DNA to be copied incorrectly.
Sherri Millis: Most of the time our body has a mechanism to correct those errors, but that doesn't always get corrected. So, again, the longer the live the more often we have a chance for that cell the DNA incorrectly, and when it's copied incorrectly and it's a change that allows that cell to grow uncontrolled, then it can cause a tumor to grow and grow out of control and create that cancer.
Carly Ornstein: This is also something we touched on a little bit, but typically non smokers or those that have never smoked are more likely to have those mutations that we talked about. Why is that?
Justin Gainor: It's a good question. I think part of these are also ... We're talking about frequencies. I think it's much more common that there are specific modes of mutagenesis that is inducing genetic changes. For example, tobacco exposure ... If you do comprehensive genetic testing, it actually produces very characteristic changes in the DNA, and that pattern is different than an aging pattern. It's different than something called an [inaudible] pattern, and those different patterns can produce different types of mutations. We know that there are other very characteristic genetic changes occurring in people who have had a more significant tobacco exposure.
Justin Gainor: The most noteworthy one is called KRAS, which accounts for about 25% of patients with lung cancer. We've known about this for over 20 years, and it's been difficult to actually target KRAS for a number of reasons. But in the last two or three years, there's even been some hope about targeting KRAS, a specific variant in KRAS due to some very smart biochemistry. So our hope is that that in a couple years will also be in the group of targetable genetic alterations. But why never smokers in particular have EGFR, ALC ... We don't know. We also don't know why EGFR mutation, the frequencies 10% to 15% in the West and up to 50% in Asia. We don't know. But that's just what we've observed.
Carly Ornstein: Interesting. Does tobacco exposure impact PD-L1 levels?
Justin Gainor: It does look like tobacco exposure can be associated with higher PD-L1 levels. It's a bit complicated, though, because PD-L1 can actually be high for two reasons. Clinically, we lump them together. Typically we view PD-L1 as really a surrogate for inflammation. Basically, immune cells being near the tumor that cause PD-L1 to be high. Basically, your immune system being next to the tumor or within the tumor, and it's the tumor's response. Some of these genetic changes, though, such as EGFR or ALC, the genetic change by itself can cause high PD-L1 expression. But that tends to be not as predictive as the first mechanism driving PD-L1, so it's complicated.
Carly Ornstein: Yes. I'm gathering that.
Margot: I'm Margot. I'm also a lung force hero and also a small cell lung cancer survivor. Dr. Gainor, this question is for you. Is there any promising research on the use of stem cells in the lung cancer treatment, and if so, in what capacity, please?
Justin Gainor: I think we should start first with the definition of stem cells. Stem cells are really cells that have the capacity for self-renewal. In our bodies right now, most of our stem cells reside in the bone marrow. This is where our blood cells are born. And those stem cells give rise to all of the blood cells in your body, but when they divide, they keep the stem cell and the rest kind of come out. Where we've seen the greatest progress in stem cells is in cancer that arise from blood cells. That's where we've seen the greatest progress in stem cells. That's really where we've seen, in patients with leukemia or lymphoma, where we've actually used stem cells therapeutically in giving stem cell transplants. That's where it's standard right now.
Justin Gainor: Unfortunately, we haven't really made the leap to take stem cells from those hematological malignancies into the solid tumors. But where we are starting to see some progress is it's in the same vein as immune therapy but modified a bit, and that is right now most of the immune therapies that we've discussing are where we inject antibodies into the body and those antibodies try to stimulate your immune system. In the last couple years, there has been a technology called Car T-Cells, and this is technology where a patient has their immune cells taken out of the body, they're genetically engineered in a lab, and then they're put back in.
Justin Gainor: These are therapies that, again, are mainly focused in the blood-based cancers like leukemia and lymphoma, but we're starting to do those studies in lung cancer. In fact, I'm currently running one of those studies at Mass General, and it's really just trying to use someone's own immune cells that have been modified to attack at cancer. I do know that there are plans to start thinking about doing that including in disease like small cell.
Margot: Thank you.
Carly Ornstein: Now we're going to take a few questions from our online Facebook audience. The first question is, how come some people respond well to immunotherapy and others don't? Would you like to take this?
Justin Gainor: Sure. There's a lot that goes into that, and I would break it down into a couple different reasons. The first is that they may not have something that's able to be recognized by the immune system. The basic premise of cancer immunotherapy is that cancer cells have developed enough mutations or certain mutations that make them look foreign to the immune system, and your body can distinguish the cancer cell from all the other cells in your body. It's possible that the patients who aren't responding to immunotherapy just don't have the right genetic changes that look foreign enough to the immune system. We call those neoantigens. They may just lack the necessary neoantigens.
Justin Gainor: A second possibility is that they have the right neoantigens, it's just the cancer cells have actually outsmarted it and they just don't express them on their cell surface. There is certainly data where we've started seeing that, that cancer cells can down regulate or reduce the machinery that typically puts these on their cell surface. So that could be another explanation.
Justin Gainor: And then the third is that the immune system is an incredibly complex system with many, many different cell types, and there are some cells that are pro inflammation and others that are anti-inflammation, and usually there's a balance in our bodies. But sometimes those cells can actually suppress the immune system around a tumor. And so right now we're really just scratching the surface for understanding why tumors respond to immunotherapies, why they don't, and also why they stop responding, so resistance to immunotherapies. This is really a field in its infancy right now.
Carly Ornstein: Great. Question for Dr. Millis. When a patient has this next-generation sequencing done, how often do they need that test done? And if they had a test done by one company, do they need a test done by a different company?
Sherri Millis: Those are great questions. To the first question, how often do they need the test performed, if it's a comprehensive test and then the patient goes on a targeted therapy based on the results ... The genes that are altered, once they stop responding to that therapy, it's a good idea to get a test performed again to see if there's a resistance alteration that has arisen as Dr. Gainor talked about so that we can identify if there's a second generation therapy that might work better in the next cycle. There are many different tests on the market. The most comprehensive test is going to give the most information about a patient's tumor, which is going to result in the most likelihood of identifying a potential treatment.
Carly Ornstein: Great. I think we have another one coming in, but in the meantime, I will ask you ... What has been the most surprising advancement that's happened in your career in lung cancer, I'll limit it, in the past 10 years?
Justin Gainor: I can go first. For me, it was the success of chemotherapy plus immunotherapy combinations, and I'll be the first to admit that I was dead wrong about the success of that approach. Part of it stemmed from ... It wasn't a sure bet that that was going to be successful. As oncologists, we're constantly telling patients who are getting chemotherapy that it's going to suppress your immune system. You have to be careful when you're on chemotherapy that your immune system is lower and calls for fevers and ... So there was a lot of concern initially that if we actually gave chemotherapy at the same time as immunotherapy that actually may blunt the effectiveness of the immunotherapy by simultaneously giving chemotherapy. And so there were a number of early studies were just testing the safety of that, and thankfully it looked like we weren't seeing that antagonism. We were actually seeing, what looks like, at least, additive effects and maybe even some synergy.
Carly Ornstein: That's why clinical trials are so important.
Justin Gainor: Right.
Carly Ornstein: Every advancement that we've had has come out of a clinical trial. Dr. Millis?
Sherri Millis: I would say within the last 10 years, the biggest advancement really has been the ability to do next-gen sequencing commercially at a price point that patients can get the testing performed and get testing performed on a large number of genes so that we get more information from every patient in order to better determine their treatment options.
Carly Ornstein: Great. Our question from Facebook is, we know that Radon also causes lung cancer. Does it cause specific mutations?
Justin Gainor: I'm not aware of any large-scale genetic evaluation to actually show that there's a specific mutational signature.
Sherri Millis: Yeah, I'm not aware either.
Carly Ornstein: Sounds like more research needs to be done in that area. That's very interesting. Okay. Thank you so much, both of you, for your time. I really appreciated talk with you, and I think that we can all agree it's a really exciting time in lung cancer, and just hope that the developments keep coming. A recording of this video as well as additional resources will be made available at Lung. org/Tumor/Testing/Videos in the next couple weeks. Thanks again to AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, Pfizer, and [inaudible] Company, Incorporated for their generous support of this program. Thank you.
Page Last Updated: November 9, 2018
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