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Understanding Genomics and Genetic Testing in Cancer Immunotherapy

Above all, cancer is a disease of mutations. Some of these are inherited, while others are acquired throughout an individual’s life. While these mutations drive the tumor growth and survival, they may also holds the key to cures for more patients. In addition to guiding decisions regarding existing treatments, the mutated proteins that arise from genetic mutations can also serve as targets for the immune system and personalized immunotherapy strategies.

In this webinar for patients and caregivers, Corrie Painter, Ph.D., and Eliezer Van Allen, M.D., discuss the current state of genetic testing for cancer patients in the clinic as well as highlight efforts to tap into the full potential of genome-based medicine.

Corrie painter, Ph.D.A former CRI fellow from 2012-2015, Dr. Corrie Painter (@Corrie_Painter) is currently the associate director of operations and scientific outreach in the Cancer Program of the Broad Institute of MIT and Harvard. She leads the Angiosarcoma Project, a nationwide direct-to-patient genomics initiative aimed at generating the genomic landscape of this orphan disease, and she is working to build scientific resources to enable broad-scale rare cancer research across many cancer types. A trained cancer researcher with a Ph.D. in biochemistry, Painter serves as the associate director of Count Me In, which launches patient-driven research projects across multiple cancer types. In this role, she partners with advocacy groups and engages patients with metastatic breast cancer, angiosarcoma, and other cancers through social media in order to carry out the Metastatic Breast Cancer Project, the Angiosarcoma Project, and other patient-driven genomic initiatives where patients can consent online to donate their stored tumor samples, saliva samples, medical records, and their voices in order to directly accelerate the pace of discovery.

Prior to joining the Broad Institute in 2015, Painter was vice president and cofounder of Angiosarcoma Awareness Inc., a nonprofit devoted to fostering a collaborative atmosphere between researchers in order to generate data and reagents that can be shared by the sarcoma community as a whole. She continues in this role alongside her work at the Broad Institute.

Eliezer Van Allen, M.D.Dr. Eliezer Van Allen (@VanAllenLab) is an assistant professor of medicine at Harvard Medical School, a clinician at Dana-Farber/Partners Cancer Care, and an associate member at the Broad Institute of MIT and Harvard. His research focuses on computational cancer genomics, the application of new molecular profiling technologies to advance precision cancer medicine, and studying resistance to cancer therapeutics. As both a computational biologist and medical oncologist, he has specific expertise in clinical computational oncology and the development of algorithms to analyze and interpret genomic data for clinically focused questions. Overall, his research will make important contributions to the field of precision cancer medicine and resistance to targeted therapeutics via expertise and study in translational and clinical bioinformatics.

Previously, he studied Symbolic Systems at Stanford University, obtained his M.D. from UCLA, and completed a residency in internal medicine at UCSF before coming to Boston and completing a medical oncology fellowship at the Dana-Farber/Partners Cancer Care program.

The "Cancer Immunotherapy and You" webinar series is produced by the Cancer Research Institute and is hosted by our science writer, Arthur Brodsky, Ph.D. The 2020 series is made possible with generous support from Bristol-Myers Squibb, Alkermes, and Foundation Medicine.
 
Browse our Cancer Immunotherapy and You Webinar Series playlist on YouTube or visit the Webinars page on our website to see other webinars in this series.

Bristol-Myers Squibb; Alkermes; Foundation Medicine

I'm making a future where cancer patients partner with scientists to accelerate discoveries that will drive cancer immunology. -Dr. Corrie Painter, CRI Scientist

WEBINAR TRANSCRIPT

Arthur Brodsky, Ph.D.: Hello and welcome to the Cancer Research Institute Cancer Immunotherapy and You patient webinar series. Today is Wednesday, June 24, and the title of today's webinar is Understanding Genomics and Genetic Testing in Cancer Immunotherapy. Before we begin, I'd like to thank our generous sponsors who have made this webinar series possible. Bristol-Myers Squibb, with additional support from Foundation Medicine and Alkermes.

My name is Arthur Brodsky, and I'm the senior science writer at the Cancer Research Institute, a nonprofit organization established 67 years ago with a mission to save more lives by funding research that aims to harness the immune system's power to conquer all cancers. Now, it is my pleasure to introduce today's expert speakers.

First, Dr. Corrie Painter is the associate director of operations and scientific outreach, as well as the associate director of Count Me In at the Broad Institute of MIT and Harvard. She also leads the Angiosarcoma Project. Next, Dr. Eliezer Van Allen is associate professor of medicine at Harvard Medical School, as well as a medical oncologist at the Dana Farber Cancer Institute. He is also an associate member at the Broad Institute.

So thank you both so much for joining us today. First, I guess, let's start by defining what we're talking about. So what is the difference between genomic testing and genetic testing?

Corrie Painter, Ph.D.: Hi, everybody. First, I also want to thank my friends in the cancer community who really helped us refine the questions that we're going to be talking about today, as well as come up with some of the answers that we'll be presenting later in this webinar. I really appreciate each and every one of you. We couldn't do the work that we're doing without your deep partnership and commitment to helping us further our understanding of genomics in cancer research.

So I will say, when I first started in this field-- I'm both a cancer survivor and a scientist-- I would ask this question all the time, what's the difference between genetics and genomics? And when I would first ask that several years ago, there was all kinds of mixed responses that I would get, everything from they're the same thing, they're just nuances, to, oh, one clearly means one thing, and one clearly means the other. And it was pretty confusing. But over the last couple of years, I feel like the scientific community has kind of landed in a place where we all have adopted the similar way of referencing what genomics is and what genetics is.

And you can think of genetics as all of the genes that are in your genome that you inherited from your parents and that you will contribute to any offspring. The way that I like to think of this is that I have the same DNA in my cheek cells as I have in my white blood cells. And if you want an analogy, it's like they have the same book. And all of the words are identical in my cheek cell and in any other cell of my body, but the words that are read are different. Even though the words are the same, if you read different words, you're going to have a different meaning. And so you have different things happening in different cells, even though the underlying DNA sequences are identical.

So that is what we refer to as genetics. Another word that we often use to describe this is germline. So the germline is what is in the egg or the sperm that gets passed on and happens to make you you. When you have the same DNA in a cancer cell, things get a little messy. Cancer doesn't have all of the same safeguards that your normal cells have in order to make sure that you faithfully copy all the words in that book. And so things get out of control. The cells divide rapidly, they grow really fast, and they don't have the same proofreading mechanisms. And so you accumulate mutations over time, and those mutations might make the cells grow yet even faster, and become more aggressive.

So the DNA in the tumor is different than the DNA that is in your normal healthy or germline cells, and the DNA in your tumor is what we typically refer to as-- when we test that, we're looking at genomic testing. So genetic testing is like your normal cells that you inherited from your parents, and genomic testing is from the DNA in your tumor. So I'll leave it there. And if anybody has questions, you can pop them into the chat box.

Arthur Brodsky, Ph.D.: Great. So there's a lot of things that people might associate with genome sequencing or genetic testing. What is the role that these currently play in our health in general, and in cancer specifically?

Eliezer Van Allen, M.D.: And so I can jump in on this one. And I'll say first, I want to also echo what Corrie said in the beginning. Thank you for giving us the chance to join this community and present today, or just have this discussion today. And also, furthermore acknowledge, just in light of everything that's been happening in the world, how much even more extraordinary the stress is for cancer patients, and family and friends of cancer patients. And so for all those reasons, we're thinking of you, and we're happy to be here to be helpful.

I also want to emphasize I think Corrie just outlined an extraordinary way to think about genetics and genomics. And I know that much of medicine is coming up with jargon to confuse people, and so I'll try my best to keep to some simple terms. But so that in case you've heard these terms before, inherited, germline, genetics, DNA you're born with. Sometimes, the genomics is referred to as somatic or tumor-specific or other jargon that we tend to throw around. And I apologize on behalf of the field for that.

In terms of how it's being used in terms of our health in general is increasingly sophisticated ways. The inherited genetics-- so again, the genes that you're born with-- are now being used to find people who might be at higher risk for developing certain diseases. Some of those diseases include cancer, but not just cancer, and do so in all sorts of sophisticated ways. There's a lot of other use cases there outside of health that genetics are being used for. Lots of interest in ancestry and whatnot.

In cancer specifically, it's actually been extraordinary to see how much genetics and the genes that you're born with and genomics and the genes that are changed, the stuff that's changed in your tumor have been used in cancer across the board. This is for everything from how do we pick what treatment or treatments to give patients or what not to give patients, all the way through to how do we find which cancer patients are not only at higher risk for certain complications, but also in whom we need to then talk about screening their family members, and everything in between. And that's sort of been touched on in not every cancer across the sun, but certainly just an extraordinarily large number of them, especially if we think about where the field was even just 10 years ago. So I'd say, in all sorts of ways, it's been quite impactful.

Arthur Brodsky, Ph.D.: That's great to hear. And I want to stick with cancer, but first I want to just kind of dive in on one of those points a little deeper. So the genetic testing, which is the germline DNA that we're born with, in our healthy cells mostly stays the same throughout our life, but what about the tumor DNA? We know that changes a little bit. So as that changes over time, does that mean that patients might require additional testing over time?

Eliezer Van Allen, M.D.: So that's a great question, and I think what you're describing is-- or the question you're sort of posing is a really open one in our scientific field, which is do tumors evolve over time? As they become resistant to the drugs we give them, does their genomic code change? And do we need to actually check multiple times to see how things have changed? The short answer is we don't know.

We don't know in totality, and I think it'd be very hard to generalize. However, what we're starting to see across multiple domains is that it is indeed true that you can find genomic events in the tumor after certain treatments that were not present previously, or not detected previously. And those events might be important for the next treatment decision. And so we can't say with certainty yet, but it's certainly plausible that the need to do genomic testing of the tumor more than one time will become part of a cancer patient's experience.

Arthur Brodsky, Ph.D.: Gotcha. And so now in the context of cancer, perhaps the most well-known or popular use of genetic testing would be, as you alluded to earlier, testing to see if people have genes that might predispose them to cancer. So maybe the most well-known one would be the BRCA gene, which can predispose people to breast cancer or ovarian cancer.

But before we talk about how genetic testing can be used to define someone's risk of cancer, I'd like to focus on how it's being used in people who currently have cancer. And you kind of alluded to it earlier, that after some of our treatments, the tumors can evolve, which can enable them to develop resistance against the treatments. So how is genetic testing being used, or genomic testing being used today in the clinic to help improve care for cancer patients, and can it be useful for all types of cancer?

Eliezer Van Allen, M.D.: Great question. There's no one size fits all to that one, either, but what I would say is that there are now enough drugs that depend on genomic events that can be found in any cancer that it's important to at least think about genomic testing of tumors really for all patients with advanced cancer. So for example, there's a genomic event called microsatellite instability that has an approval linked to an immunotherapy that can be found, albeit rarely, in almost any cancer you can imagine. And looking for that is of interest. There's a few other examples of approvals of drugs that are tied to a genomic event that are not specific to a given cancer.

And then on top of that, there are many examples of genomic events in tumors that are tied to specific drugs in specific cancers. So EGFR mutations in lung cancer, BRAF mutations in melanoma. EGFR and BRAF are just the names of two different genes linked to two different drugs. And it could go on and on and on. But there's a large and ever-growing list of such events that is a lot of the reason why that ended up prompting actually Medicare and CMS approval of tumor genomic testing for patients with advanced or metastatic cancer.

Arthur Brodsky, Ph.D.: So sticking with genomic testing, what about with-- I know that, especially with immunotherapy, sometimes the tumors have been able to lose genes, or gain-- or mostly lose genes that enable them to escape the immune system's ability to attack it, and as a result, can make current immunotherapies, like checkpoint immunotherapies, less effective. But what about with respect to future treatments, especially as some cell-based therapies and some vaccine-based therapies are being developed that can allow doctors to target these unique mutations that are found in an individual's cancer? So how does the testing play into that today, or today and in the future, as these are developed?

Eliezer Van Allen, M.D.: So it's a great question. I think, for today, a lot of that work is happening in clinical trials. And in fact, there are even examples of what's called personalized cancer vaccine trials that are ongoing at multiple places in multiple ways. But what they're actually using is the tumor genomic information and what parts of the code, what parts of the book, to borrow Corrie's analogy, have changed since the tumor became a tumor, and how can you actually develop vaccines specific to those events. So that's one example. Those are in studies.

There's other examples of cell therapies that require knowledge about the preexisting tumor genomics, as well. And those have been used in certain cancer types already, and increasingly are being studied, again, for patients with a lot of other kinds of cancers, solid tumors and whatnot. A lot of that work is still sort of mostly in the clinical trial and research domain, although, increasingly, it's becoming part of what we hope will be sort of in our armamentarium, so to speak, going forward, really across cancer types. I don't know, Corrie, if you have any thoughts on that you want to add on, as well.

Corrie Painter, Ph.D.: I don't know that I have anything really to add on, though I did want to bring attention to some of the questions that are in the chat box that are kind of specific to this. We have one, Kelly was asking, is there a number for this, but I'm not entirely sure-- Kelly, you want to clarify what you're asking there. And then another one, and this is important and relevant to this point, is can the genetic testing help in immunotherapy?

Eliezer Van Allen, M.D.: So it's a great question. And I think this comes back to actually something I think is really worth emphasizing, which is there was, as of maybe a year or two ago, an approval about a specific genomic event in tumors that is commonly seen in some cancers, like colon cancer, but can be found in almost any cancer. Again, it's called MSI, or microsatellite instability. Again, going back to the jargon is certainly a phrase that we have multiple different words for, but MSI would be the thing you could ask your physician about. And that is specifically linked to selective response to immune checkpoint blockade, to some of the new immunotherapies like pembrolizumab that are on the market.

There was actually another announcement, I think last week maybe, even, about an additional genomic event, basically a count of a certain number of mutations that, again, are actually linked to some of the immunology behind how these immunotherapies work that may further expand patients really across the board, regardless of what type of tumor you have, and having that be something that could be directly linking the tumor genomics to cancer immunotherapy. So that's a great question, and one I would say the field is moving so fast in that there was late-breaking news as of, like, a week ago about how fast this is moving, we think there's going to be more tumor genomic findings in time that will help understand these properties even better. But again, that's really at the cutting edge of this.

Arthur Brodsky, Ph.D.: Great. And I think that's such an important point. You bring up the microsatellite instability and the levels of mutations that a tumor has. And with that, MSI approval, that is approved-- patients can now get the immunotherapy I think after they've failed the first treatment. But it doesn't matter what type of cancer they have, to your point where, whether it's melanoma, breast cancer, brain cancer, if they have this tumor that's become genomically unstable, the evidence points that they're much more likely to respond to the immunotherapy, and they can now receive it.

But also, Corrie, I know you've done a lot of work with the Angiosarcoma Project about how to kind of improve this. So I was hoping you could talk a little bit about what's currently being done research-wise to improve these genetic and genomic tests.

Corrie Painter, Ph.D.: Yeah, I'm happy to. And to everybody who's putting questions in the chat box, thank you so much. We'll definitely see what we can do to field everybody's questions. Keep them coming.

So I certainly can only speak to the very small slice of the pie that I'm directly involved with, but the research world in general has a lot of different initiatives that are ongoing in order to improve those tests. What I'll say in general is that we don't understand a lot about what's going on in the DNA of cancers, in the cancer genome, just quite yet. And one of the ways that you could think about this is, you know, we go back to that book.

And if you just read all of the pages in a cancer's book, there would be all kinds of words that were messed up. And we wouldn't necessarily even be able to-- you wouldn't know how to pronounce them, you wouldn't know what does it mean if you say it that way, and you would need to look at each word individually. But you don't have that ability when you look at all of the [INAUDIBLE] because they're all contributing to what's going on in that cancer at any given time.

So you look at that book, and there's like tens or even thousands of mutations that are all there, and you might not necessarily know which mutation is actually making that cancer grow rapidly, or which one is responsible for it not responding to a drug anymore. In order to ask really detailed, specific questions like that, you have to take the research to another level, and you have to be able to come up with model systems. Model systems are ways that you can look at the cancer outside of, like, a full body, and try to understand each of the different aspects of the cancer that are contributing to the different things that make it grow aggressively or quickly.

If we look at the different types of research that are ongoing, you can have everything from cancer cells that are taken out of people and grown in a petri dish, and you might do stuff like put a drug on it and see what the effect is, and then look at how that might change the DNA, like Eli had mentioned, evolve in the presence of a drug, or you might do something like the research that Eli and I are involved with through the Count Me In program, where we're partnering with patients in order to ask them to help us with the research. We ask patients to help us build these projects. The projects are aimed at understanding what's going on in the genes of cancer patients so that we can ask those specific questions.

Once we build a project with patients-- in my case, I built them with angiosarcoma patients, and in Eli's case, he built them with metastatic prostate cancer patients-- we can try to drill down on some fundamental questions by working with the patients in order to get their healthy germline or genetic base DNA and their cancer or genome-- sorry, genomic DNA from their tumors, look at them and compare them to each other, and then also take into consideration, how's that patient doing? Did they have really aggressive cancer? Did they respond well to different therapies?

And by looking at all of this data together, we can ask questions like, what are all of the mutations that we see in all of the patients that have angiosarcoma or metastatic prostate cancer? What is the impact that these mutations have on the rapid growth of the cancers? Do people with different mutations in their DNA respond differently to therapies? And does cancer DNA change when people are on therapy, meaning like does the DNA evolve and, therefore, escape the effects of that therapy.

If we can ask all of these questions, we can then feed the answers back into those tests so that, instead of getting reports that say variant of unknown significance, which is what a lot of people will get when they have their DNA report from panel testing or genomic testing, they'll get that set of words back that says, basically, we in the scientific world don't quite understand what the significance of the mutation is, and we're sorry about that, but you have it. And so all of this work we're doing-- not just us, but the entire research world-- is trying to converge on a world where we know what all the mutations do, and also what therapies we can give if you have specific mutations.

Eliezer Van Allen, M.D.: And I actually want to follow up on that because I think what Corrie's partly getting at is, I think, some of the answers that I've given already, which are, to summarize, we don't know yet. And there's so much we don't know. And I think part of the reason we don't know is because, in our sort of traditional way of doing these kinds of studies, we require patients to come to us in a very few select places around the country or the world, and to ask these questions. And so whether it's the cancer vaccines, the cellular therapies, some of the other discoveries.

The idea behind Count Me In, whether it's the Angiosarcoma Project or the Metastatic Prostate Cancer Project-- there's an ever-growing list of them under the Count Me In umbrella-- is that we can now actually bring the research to you, and you can actually join this movement wherever you are. And I think the hope is that we can cast a much wider net to really actually answer all of these questions more directly.

You know, I'm following the public Q&A section here, and there's some extraordinary questions. I think a couple of them have been what is the genomic state of the art for breast and prostate cancer. And those are two diseases for which there is a lot of movement, although the immunotherapy movement has been slower in those diseases than in others, outside of those two exceptions I mentioned.

And that's actually a lot of the motivation for the Metastatic Breast Cancer Project and the Metastatic Prostate Cancer Project, which is simply we just don't have enough data to even know. And so it sort of further reinforces that this space we're in now, this genomics and genetic testing in cancer immunotherapy is so far in front of the cutting edge of where the field is that you, the community here, have an opportunity to actually drive it. Patients and family members and the community itself is really actually going to be key to pushing this forward.

Arthur Brodsky, Ph.D.: Yeah, and I think that's a great point what you both have mentioned about how there's still just so much we don't know. I think back to when the human genome was first published in 2003, and a lot of people thought that was kind of the answer to a lot of things, and it was really just kind of the step zero almost, that we're learning so much more about how not only all of these genes interact, but which genes are turned on, and which different cell types, and how will those interact, a number of other factors that I could go on and on about. But I will stick to the genomics for now.

So traditionally, the only way to really look at a tumor's genome was to take a piece of the actual tumor out, but now, we're getting a little bit past that. And there's some terms that are starting to become a little more relevant that still might not be fully understood. So I was hoping we can go into some of those. So first, what is a liquid biopsy? And can you define the terms CF and ctDNA?

Corrie Painter, Ph.D.: Yeah, sure. So liquid biopsies are a relatively new phenomenon, which is they hold so much promise for us to understand what's going on in people's tumor DNA without actually having to do a biopsy of the tumor. So the word liquid biopsy really is just a fancy word for a blood draw. Or so what we're seeing is that tumors can release DNA from inside the tumor cells into your blood. Another word what is called shedding the DNA. And so if you take a blood draw, there's a chance that you may be able to actually see the tumor DNA floating around in the blood. Because it's in circulation with your blood, sometimes it's referred to as "C-T" for circulating tumor DNA. So that's ctDNA.

There's also regular normal cells that also release DNA into the blood, as well. So if you draw blood from any person at any given time, you're going to be able to detect some DNA in there, whether it's from healthy cells or from malignant cells. So if you look at just all of the DNA that's in circulation, another way that scientists refer to that is "C-F" for cell-free DNA.

So a liquid biopsy is really just a blood-- it's also referred to as a blood biopsy, but it's really just a tube of blood that's taken, and the DNA that's in that blood that's not encapsulated by any cells, that's just floating freely, is able to be just like the tumor DNA that would be extracted from somebody's tumor. And that way, you have a noninvasive way to go and try and take a look at what's going on in somebody's tumor, just by taking a vial of blood.

Arthur Brodsky, Ph.D.: And what would be some of the advantage of that, of [INAUDIBLE] the blood?

Corrie Painter, Ph.D.: Yeah, there are several advantages. First, just not having to go and get an actual biopsy. So it's much safer, much more comfortable. A lot of times, something that we underestimated was that, for patients who are undergoing constant therapy, like in the metastatic stage where they have ports put in because they have treatment at regular intervals, it's very easy for that port to be accessed by the person who's setting them up for their therapy anyway.

And so for them to contribute a vial of blood to have a testing like this done is much easier than even, in some instances, providing saliva. And so it's an easy way for people to be able to get that DNA. And you can get snapshots of what's going on in tumors over time because you can draw blood at much faster or greater intervals than you can actually getting tissue directly from a tumor.

So you can look at what's going on in that evolution that we were talking about [INAUDIBLE] serial blood biopsies and looking what's happening over time, though I don't think that that's like a commercial use of it just quite yet. But I could see it moving in that direction. And then lastly is that, instead of getting information from one tumor that you may biopsy, there could be several tumors, if you are in the metastatic setting, that all shed, and contribute to your understanding of what's going on across multiple different tumors.

Arthur Brodsky, Ph.D.: Gotcha. So before we move on real quick, I see that maybe we should spend a little more time discussing the microsatellite instability and tumor mutational burden that we brought up earlier. Would you guys be able to maybe clarify that a little bit more for the audience?

Corrie Painter, Ph.D.: Sure.

Eliezer Van Allen, M.D.: Sure. Yeah, so it's confusing. And just in case you're wondering, it's confusing to everyone, to many of us providers. So you're not alone. So microsatellite instability is a phrase that refers to a certain kind of change in the tumor genetics that results in a very specific pattern of changes across the entire genome. And actually, that pattern is very distinct.

And so it has its own name, microsatellite instability. It's oftentimes associated with just having a lot of mutations and a lot of changes in the code. And having so many of those changes, again, has this complex relationship with the immune system and, for many reasons, is why immune therapies tend to work really well in patients with microsatellite instability, which, again, is this sort of genome-wide change that has a very specific pattern and results in a lot of mutations.

That's one very specific category of a broader space of genetic-- genomic, excuse me-- genomic changes that can be under a category of high tumor mutational burden. So that simply refers to mutations of any cause. It could be from microsatellite instability or a host of other reasons. And there is a thought that a similar biology is associated with more immune responsiveness in patients of high tumor mutational burden, or TMB. That's sort of the acronym that's thrown around a lot. And those patients have a similar enhanced response to immunotherapy.

They're similar, but not the same things. You can have patients with microsatellite instability who, for a host of reasons, actually have a low TMB, and you can have patients with a high TMB who do not have microsatellite instability. The first FDA approval for an immunotherapy that was across cancers was for microsatellite instability. The one from last week was for high TMB. If you're confused by that, just know you are not alone. We all are, because we're all trying to wrap our heads around this and figure out how to make sense of this in real time, because, again, it's moving so quickly. I don't know if that was helpful or if I made things worse, but I'm happy to take another lap around that one.

Arthur Brodsky, Ph.D.: I guess I think one of the important things that I'd like to point out is, obviously, some of these mutations drive the cancer. They give them the ability to grow or resist the immune system, or just survive and thrive in general. But another really important point, especially in the context of immunotherapy, is these mutations, these genetic mutations, ultimately lead, or in some cases lead to proteins that are now abnormal and look foreign to the immune system. So that is one of the main reasons that, the more mutations someone has, the more likely there is to be these mutated proteins that, then, the immune system can recognize as foreign and respond to as if-- you know, the immune system, when it sees foreign, it doesn't know if it's from a virus or a bacteria or a cancer cell.

Corrie Painter, Ph.D.: Yeah.

Arthur Brodsky, Ph.D.: So the more of these mutations it has, the more potential targets for the immune system to go after it.

Corrie Painter, Ph.D.: Yeah. I would like to just take one little minute and expand on that also, because it's really kind of fundamental to understanding genomics and immunotherapy in general. So I'll stick with the same analogy. You have a book, and it has the words in it. And something has to read those words and turn them into something that has meaning. The meaning of the words are the proteins in your cells. And if they're wrong, if they're read wrong and they look wrong, just like Arthur said, your immune system has been trained since you were born to go through, crawl through your body and basically look at what is you and what is not you.

And everything in your immune system is geared to protecting you. And so it will totally ignore all of the [INAUDIBLE] that turn into proteins that it recognizes as you, but the second it sees something that's not you, that it was never trained to recognize, it is going to try and kill that thing. If it's inside of the cell, it's going to kill the cell. If it's outside of the cell, it's going to shoot antibodies at it and basically just try to get rid of it.

So when you have a cancer that has either microsatellite instability or, in the case of like angiosarcoma or melanoma, where the sun is beating down on the DNA and causing mutations, in either case, if the end result is that the DNA in the tumor has a lot of mutations, that's going to lead to proteins that your body was never trained to recognize. And just like we heard, if it looks like it's not you [INAUDIBLE] your immune system can go and attack and kill that that cell and/or try to take care of that tumor.

So a lot of what we're talking about and why these drugs have been kind of FDA approved is that, in these tumors that have a high proportion of proteins that are different than you, the chances that you can use a checkpoint inhibitor, which is just a drug that will take the brakes off of the immune system and allow the immune cells to go in and eradicate those cells that carry these different-looking proteins, is higher across all the different types of cancers, and it's a super unique way that we can combine the genomics plus the one drug across a variety of different cancers.

Eliezer Van Allen, M.D.: I actually, on that point, there's a question here about if you have a low tumor mutational burden and you are not microsatellite stable, does it mean immunotherapy will not work? And I just want to very emphatically state the answer to that is no, because these are not perfect what's called biomarkers, which is a word that defines the way we try to figure out which patients should get what drugs.

There are a lot of other considerations to be made. There are entire classes of cancers-- I'm thinking of kidney cancer, which is one of the ones that I treat-- that has no such thing as microsatellite instability or high TMB, or tumor mutational burden, but has a lot of patients who respond to immunotherapy in a similar pattern to lung cancer, bladder cancer, melanoma, and so on.

So I just want to be very emphatic and state that just because you have a tumor genomic test that does not show these things, it does not mean you are not a candidate for immunotherapy. That's a discussion you've got to have with your physician, because there are many nuances to that and a lot of moving parts that are happening in real time.

Arthur Brodsky, Ph.D.: Absolutely. So now, sticking with, I guess, the practical considerations for patients today, how is this testing actually done, and who is eligible? And does insurance cover the cost?

Eliezer Van Allen, M.D.: So testing, if it's a test off of the tumor biopsy itself, that's a test that your doctor can order. And that's facilitated through your doctor and the hospital system. Those tests, there is a Medicare approval for this. I mean, obviously, every insurance company is going to have a different coverage pattern. If it's a liquid biopsy test, again, it's a similar kind of procedure. Because it's a simple blood test, it can be done sort of through your hospital system.

I would say that the insurance coverage is probably going to be a little bit more complicated there. I think it's, again, a conversation you should have with your medical team as to sort of the specifics about you and whether those things are covered. But then those things go off to the companies, and the test comes back to your doctor ideally, typically, within a few weeks.

Arthur Brodsky, Ph.D.: And as we've been talking, a lot of this still is very cutting edge, especially the liquid biopsies. We're still trying to optimize them and determine where they can be most valuable. What about patients on clinical trials? I know that the costs of drugs are covered for there. Is it possible that the costs of the biopsies might be covered under there for patients on clinical trials, as well?

Eliezer Van Allen, M.D.: It should be. I suppose I can't speak for all clinical trials. I would say that we certainly do our best to think about all of those considerations upfront, and make sure that any cost that might be sort of attributed to the study are covered by the study. It's not a perfect system, I'll be the first to admit that, but sort of every effort is made to try to make those coverages possible.

Arthur Brodsky, Ph.D.: I can appreciate it's definitely a complicated system.

Eliezer Van Allen, M.D.: Yeah.

Arthur Brodsky, Ph.D.: So now, I'd like to go back to, at the beginning, I mentioned I think, in the popular consciousness, the most well-known form of genetic testing is to see if someone has the BRCA gene or something else that might predispose them to cancer. So could you talk a little bit more about how this is used to determine the risk of cancer in healthy people? And also, how do consumer testing kits, such as 23andMe, where do they come into play here?

Eliezer Van Allen, M.D.: It's a great question. So again, just to reorient everyone, we were spending most of our time talking about tumor genomics, or somatic genomic testing. I think we're pivoting back to inherited genetics or the germline genetics. To go back to Corrie's analogy, it's the book, your book of life, your--

Arthur Brodsky, Ph.D.: The original copy.

Eliezer Van Allen, M.D.: [INAUDIBLE] not the changes in the tumor. The way it's being used now is sort of, I'd say, in a few different capacities. It's in patients who have a very strong family history of cancers who may not have cancers themselves. They might be referred for, again, germline or inherited genetic testing to look for a cause. If a cause is found, that might lead to different screenings. So if they find something, they might have more MRIs done frequently or other kinds of tests, colonoscopies and so on and so forth, to try to find cancers earlier than they would for other folks.

And similarly, for patients who have cancer and who have these inherited events, it's relevant for two reasons. One, it's relevant for so-called cascade testing. So that's a phrase that means, if they find it in you, then they at least want to present the conversation about whether any family members that are related to you specifically also want to be tested. So that's the cascade of testing, so to speak.

And then likewise, there's increasing evidence that some of these inherited genetic changes-- so not the changes in the tumor, but the changes that you were born with that actually impact the tumor-- have treatment impact. And some of the same concepts we were just talking about in the tumor also apply in the germline or inherited genetics. So microsatellite stability and immunotherapy, BRCA1 and 2, and certain other drugs. There's a lot to consider there, and a lot of ways it's being used.

To your question about some of the consumer testing kits, I'd say some are comprehensive and some are not. And I would strongly advise patients to talk with their medical team to try to navigate what tests or tests are appropriate, because even for some of the vendors that offer these tests to the consumer specifically for cancer screening, there are actually different flavors that they will offer. So for instance, they might have like prostate cancer specific ones or colon cancer specific ones. And so it's a nuanced conversation that you should definitely have with your treating providers, and don't assume that a consumer test that you might have done for some other purpose is going to be comprehensive for cancer screening.

Arthur Brodsky, Ph.D.: Gotcha. And I do want to just follow up on one point you made with respect to the microsatellite instability, and that there are some-- some people can inherit genes that may make them more predisposed to that. And one prominent example is Lynch syndrome, which-- could you explain a little bit about what that is, and how it plays into it?

Corrie Painter, Ph.D.: Oh, and also, before you do, can you fold Li-Fraumeni in there, as well? Since we did have a question specifically, and they may be able to be coupled together in the answer.

Eliezer Van Allen, M.D.: Right. So again, inherited genetics are the changes in your DNA that you're born with. Some of them are very well known, and have been sort of described and sort of named by certain people who made these discoveries [INAUDIBLE] different names about them. Lynch syndrome, in a lot of respects, encompasses the genes or the changes that are things that cause microsatellite instability in tumors. Those same events can happen in the tumor and are not Lynch syndrome.

So I guess here I am going around in circles, but that is a very specific clinical situation that we think about that is distinct from other germline or inherited genetic syndromes, like Li-Fraumeni, which involves a different gene and has a different set of considerations associated with it, both for screening and for potential treatments. Maybe I'll stop there and see if that addresses-- because just to be clear, Li-Fraumeni and the P53, the gene that's related to it, is not part of the same things as Lynch syndrome, which is not part of the same thing as other diseases. And again, because the genome is so vast and there's so many changes that can happen, each of these things has a different pathway associated with it.

Arthur Brodsky, Ph.D.: And from my understanding, a lot of these genes, they don't all do the same function, but from what I understand, they all kind of intersect at a cell's ability to repair its DNA. Is that correct?

Eliezer Van Allen, M.D.: For many of these things that are involved in inherited genetics that lead to cancer predisposition, the common sort of point of biological sort of relevance is the ability to repair your DNA, yeah. It's just that I don't want to say that too narrowly because I know that whole thing is just a massively complicated system. So, yeah.

Arthur Brodsky, Ph.D.: Corrie, I didn't know if you had anything to add before we.

Corrie Painter, Ph.D.: No, I just guess I would say that different syndromes may contribute to those same things we were talking about before. For example, Lynch syndrome often will lead to high tumor mutational burden, and therefore, people with Lynch syndrome may, though they don't have other characteristics or have cancers that are traditionally thought to respond to immunotherapies, may indeed have a good response.

And so again, really talking with a genetic counselor, as well as your physician, if you have any of these predispositions to see if that's playing a role in the genomics of your cancer, and whether or not that then would make you a good candidate for immunotherapy, I think, is really important. And so a big take-home is, whenever you have questions, to really dig deep with your physician, and, if at all possible, with a genetic counselor.

Arthur Brodsky, Ph.D.: So are there any drawbacks or safety issues associated with these tests, or maybe any reason someone wouldn't want to do them?

Corrie Painter, Ph.D.: Yes. And so I'm going to take that question, and I want to give a little bit of a preamble, though, before I dig into this. I went ahead and turned to my cancer community. And when I say that, I mean really, in social media, I'm connected with cancer patients across so many different types of cancer. I've been an advocate for over 10 years after my own diagnosis with angiosarcoma, and have worked closely with metastatic breast cancer and prostate cancer and esophageal and stomach cancer, brain cancer, other sarcomas. And so in my kind of social spheres are patients that are kind of representing from all of these different cancers. And I asked them this, because I feel like the answer to this is not just like a set in stone answer. A lot of this is perceived risk and what people have experienced themselves. And who better to answer this question than cancer patients?

So I do want to say I have a variety of answers from patients. And I don't want to just put this out there to scare people, but I think it's absolutely important for everybody to learn from each other. And so I'm going to go ahead and kind of read what patients said when I asked them this very question. There was a variety of different answers. Several people said to me, I have no concerns at all. In fact, it brought me great peace of mind to be able to have a sense of what's going on in my genetics. And I had a great genetic counselor who went over all of the risks associated with any of the things that popped up in my results, and it was really good.

And so that's like one end of the spectrum. No concerns at all, really happy that they did it, and felt like they had peace of mind as a result. And then there were other people who shared other things to consider. More than one patient had concerns that their employer would gain access to their data and discriminate against them. Luckily, we have laws in place to protect against this, but folks are concerned that laws can change. Their DNA is not going to change. And if their DNA has been put out there, and somebody owns that DNA and the laws change, what happens to them?

And along those lines, could they be discriminated against with respect to insurance? Could their children be discriminated against in any of these domains in the future, as a result of them getting tested? Because you do share your DNA with your relatives. So what is the impact if somebody owns your DNA code, and they do something nefarious to yourself and to other people around you? I think that's mostly theoretical because we do have laws in place right now, but it's a concern, and something I think people should certainly be aware of.

Another concern is-- and this came up a lot, actually, and it was written in different ways, but ultimately, people had concern about the anxiety about knowing too much about their predispositions. And what do you do with that information, especially if there's nothing you can actually do, if there's no treatment, and you just have this kind of hanging over your head that there's something in my DNA, and I can't do anything about it, but it's there. And now I'm just sitting there, waiting and waiting and waiting. And so some people felt like that was something to give them tremendous anxiety.

And other people thought, for the exact same reason, that it was empowering to know. And so what some of the people that responded to me said-- and they're so right-- it's just such an individual choice to do this. It's an individual choice, but to go in and understand what you're getting involved with is so critically important. And the best person to help you think through that is a genetic counselor, because they will tell you before you get the testing done, these are the risks to you knowing, this is what we, if you did have something in your DNA, what we could do about it, and so on and so forth. So it can help you understand what you're getting involved with if you do have that level of anxiety.

Another important point that I wanted to put out there was somebody brought up-- and this kind of piggybacks off of what Eli was saying-- that there could be a false sense of safety if receiving results from a consumer testing company. A consumer testing company may not give-- like, they may sequence one tiny little part of one gene and say whether or not you had a mutation there or not, but that doesn't necessarily mean, if you don't have something, that you're out of the woods.

There's those things that we talked about, the variants of unknown significance, and/or other parts of the same gene which may be equally as concerning, but that the consumer test just didn't even look at. And so if you get that test and it looks like you're good, you may not go and really monitor closely things that, if you never had that test, you would be more prone to take a look at because you might feel like you're safe.

And then the last one, which kind of fleshes out a little bit what I said at the beginning, is somebody was concerned really who owns my data, and what does that mean? What are the implications? Are they going to sell my data? Are they going to make money off of my data? And so really, breaking it down, privacy concerns, other people knowing what the results are and discriminating against you, ownership concerns, and the personal reflection of what you would do with information concerns. And then I think I'll stop there.

Eliezer Van Allen, M.D.: And I would just-- I think it was an extraordinarily well sort of put together set of concerns. And I think I will just say on personal anecdotal experience that I've seen come up in conversation over the last five to seven years this has really snowballed clinically in different ways with different patients, and again, would just emphasize that [INAUDIBLE] you should not feel like you have to make these decisions and thought processes alone, and that there are trained professionals whose job it is to exclusively help you navigate these precise issues and make the right decision for you, which is going to be a very personal one.

Arthur Brodsky, Ph.D.: Yeah, great points by both of you. So now, kind of on the background of what we've been talking about it, that it's still kind of early in our understanding of all of this, so how do doctors make sense of these results, and how accurate are they?

Eliezer Van Allen, M.D.: So that's a big question. I would say, you know, certainly five to seven years ago, most medical oncologists were not that comfortable with these test results, and especially the tumor genomics, because again, the inherited genetics were being handled by genetic counseling teams that were very experienced with this. But for a lot of us in the cancer community, we were sort of given these reports-- they just started coming, and a lot of folks were perhaps not entirely sure what to do with them.

The good news is that a lot has happened in the last five to seven years. The content in the reports themselves have improved significantly sort of from the companies and the vendors that provide these tests to help guide clinicians on how to interpret them correctly and how to consider a lot of the sort of nuance that I think Corrie was mentioning that the patients have brought about, well, how do we know it tested the right thing, or did it look at the right part of the tumor, or was there a technical problem, so on and so forth. And so doctors have got a lot better of that and, similarly, have gotten a lot better at understanding which of the sort of list of things that they see can actually be acted upon more directly, and how to best consider which things might be relevant for a clinical trial or might need to be explored in some other way.

So I'd say there's been a lot of improvements, although I'll be the first to admit, and even this is true my own practice, as somebody whose entire academic career is basically studying this, that I still sometimes struggle interpreting some of the results in individual patients because the results are either confusing or contradictory or unexpected for any given patient. And I think that just speaks to the sort of real-time uncertainty that we have in this field. We just don't know enough about enough people from enough different places and with enough different experiences to confidently act on a lot of stuff we get in these reports.

In terms of the quality of the tests, I would just defer to our regulatory bodies have a few. There are some tests that have gone through sort of like extremely rigorous testing evaluations to make sure it's vetted. And those are the ones that tend to get reimbursed by insurance companies. So, so long as one is sticking in that realm, I suppose those are things that I would think about.

Arthur Brodsky, Ph.D.: Gotcha. So we're almost out of time now, but I was hoping that each of you could leave us with your kind of final thoughts and what you think the most important message is for patients.

Eliezer Van Allen, M.D.: Dr. Painter, do you want to go first?

Corrie Painter, Ph.D.: [INAUDIBLE] I've said it a couple times, but I do see a lot of questions popping up, you know, there's still so much to know and learn. I'm sorry we could not get to and address all of the questions. Maybe we could do a follow-up at some point, and really drill down and dig into a lot of the concerns and questions that people have. I think the take-home from me, just based on that alone, looking at the chat box is that we have a long way to go in terms of bridging the gap between what we know and what we don't know on the scientific side, and what patients know and what they want to know on the patient side, and that we are at a really unique time where we can come together and address these things.

I would say, in the interim, when you have these questions, really leverage your medical team. Don't hesitate to reach out and demand answers. Not that you have to demand anything, because I'm sure everybody is there to help you, but really, don't hold back. I think people have a tendency to think, I only have five minutes with my doctor, and so I'm going to, you know, just like here are a couple questions. But my advice is to draft all of these questions that you have, and just keep asking your medical team to meet with you until you have these answered.

Meet with genetic counselors, too, because they're just an excellent resource that I personally didn't utilize until it was like nine years into my own personal cancer journey, and I had so much-- I was on the side that had peace of mind after talking with them, and learning about my own risk factors and the risk factors that I was likely to pass to my children. So that's my takeaway, is that we have ample time to come together and learn from each other more, as patients, scientists, and doctors, and that we should all be leveraging our medical team for the most amount of information we can get.

Eliezer Van Allen, M.D.: I couldn't have said it better myself, so I won't try. I will say, you know, I'm approaching the 10-year anniversary of moving to Boston to start my medical oncology training in the summer of 2010. I remember this because I remember me and my co-fellows being laughed at by some of the senior physicians about two things. One, whether we could just do genome sequencing at scale in cancer patients to help guide treatments, and two, whether we could actually harness the immune system to treat cancer.

10 years later, the field is unrecognizable compared to where it was when I started not that long ago, and those two things we almost take for granted. It's almost taken for granted now that we have these incredible immunotherapies that we have that are so effective for so many patients, that we can do genome sequencing in all sorts of complicated ways and use that to guide patient care, and that we're really actually moving the field forward. And so there's profound optimism.

And I would just say that the real way to take the next major leap forward is that patients are going to have to really be-- they're the ones that have the power. You have the power to actually make the field sort of take these incremental but good steps and turn them into major leaps, because at the end of the day, we still just don't know enough about most people in most cancers with most settings and most drugs. And so until we figure out how to do that as a community, I think we won't be able to make that big leap. So my hope is that we can all continue to come together in venues like this to have these conversations and really take a big leap forward together.

Arthur Brodsky, Ph.D.: Great. Yeah, we covered a lot there. And I hope that our audience found it as enlightening as informative as I did. So for more of our webinars and the additional resources that we have for patients and caregivers as part of CRI's Answer to Cancer educational programs, we encourage you to check out our website at cancerresearch.org/patients.

Here, you can read and watch stories by others who have received immunotherapy treatment across a wide variety of cancer types. You can register for one of our virtual immunotherapy patient summits, browse our entire library of past webinars, featuring the world's leading immunotherapy experts, and access information on other resources, including treatment, emotional support, and financial assistance. You can also find help locating an immunotherapy trial that might be right for you.

Finally, I'd like to thank our sponsors one last time for making our webinar series possible. Bristol-Myers Squibb, with additional support from Foundation Medicine and Alkermes. And I'd also like to thank, recognize and thank BioRender, whose platform was used to create the title graphics today.

So thank you all so much for your attention today. I hope you found today's webinar very informative. And again, you can watch this and all of our other webinars on our website at cancerresearch.org/webinars to learn more about immunotherapy options in a number of cancer types. Dr. Painter, Dr. Van Allen, I just want to thank you both so much again for taking the time to speak with us today and for the amazing work that you are doing to improve care for patients. And I'd also like to thank our audience, who was extremely engaged today. And I hope you all enjoyed it. Thank you.

Eliezer Van Allen, M.D.: Thanks so much.

*Immunotherapy results may vary from patient to patient.

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