 want us to have enough time that you can have all of your questions answered. So we let the people grab food and get settled in, but I'm going to have Josh Gruber, one of our fellows in medical oncology, who's been working on a very unique molecular tumor board where actually people do these testing, and Josh helps us interpret the findings of these and come up with treatment recommendations. So I thought it would be great for Josh to give us a talk on genomics and thanks for coming. Thank you, Josh. Thanks, Sandy. So I'm really happy to be here, mainly because there's so much changing in cancer these days and a lot of it's being driven by genomics. And I think within the next five to 10 years, the field of oncology in general will be completely revolutionized by a lot of these technologies. So I hope to kind of turn you guys on to some of these exciting findings and tell you a little bit about how this pertains to kidney cancer. So the learning objectives for my talk are to talk about next generation DNA sequencing, talk about genomics of kidney cancer, the role of molecular tumor board in understanding mutations in kidney cancer and how that pertains to treatment options, and then talk about some of the clinical trials using molecularly targeted therapies at Stanford. So I know not everyone in this room is like me and thinks about genes and genomes every day. So I thought I'd start with just some basic biology about what I'm talking about. So as you may remember, everyone has 46 chromosomes, half from your mother and half from your father that are present in all the cells in your body, essentially make the blueprint for your body. And if you look at any one of these chromosomes, it's essentially just a string of letters which are the DNA and there are genes along this string separated by regions. And I'll be talking a lot in this talk about mutations. So just so we're all on the same page, a mutation is when a region or a base pair of the DNA is changed from what it normally is to something new represented by this red C here. So this gets to some of the excitement that's going on in the field of genomics right now. So probably five years ago, we were at this stage of genetic testing where we would test one to two to three genes at a time in a patient and we thought that was pretty snazzy. So now it is just really exploded. We're certainly testing over 200 genes at a time right now in people and in cancers. These tests of whole genome and medical exome are certainly being done routinely in the research setting and we'll probably move into the clinic in the next couple years. And all of this is being driven by technology. This sequencer machine can now sequence a human genome for $1,000 a pop in the span of two weeks and to realize how really phenomenal this is, the human genome was sequenced by a consortium of about 500 people in 2001 and it took 20 years and cost $3 billion. So it's just a phenomenal achievement for technology. And to compare it to something that we often talk about in Silicon Valley, Moore's law states that the number of transistors on a microchip doubles every two years and people argue about whether this is continuing or not. This is the trajectory for DNA sequencing over the past decade, which has just had this phenomenal explosion in the amount of sequence we're able to obtain at cost. So this is really what's driving a real revolution in genetics and genomics nowadays. So when I talk about genetics, just by way of definition, there's two sides to the coin and I'll talk about both of them separately. So germline genetics really refers to what you get from your parents and what you give to your kids and these are the genes that you've inherited and that you can pass on. Conversely, somatic genetics or genomics is just a term that we use to say that there are genetic changes occurring in the cells in your body that are not transmitted because it's in your arm or in your organ or something like that and it doesn't get passed on to your kids, it's just part of a change that we all accumulate as we age. So I'm gonna talk about germline genetics for the next two to three slides and then I'll spend the most of the time on the somatic cancer genetics. But germline or family history or hereditary or inherited genetics is important in oncology because we want to know if you or a family member has a gene that predisposes you to cancer and the reason we wanna know that is because if we find family members in your family that have the same gene as you, we could screen those people and either detect a cancer early or prevent it completely and we think that those are phenomenal outcomes and so that's really the name of the game. So in kidney cancer, there are probably 10 syndromes or 10 inherited diseases really that people can pass on to their progeny that give you an elevated risk of kidney cancer and this is kind of the medical jargon of the syndromes and what they're called. These are the genes that get mutated and this is the type or histology of kidney cancer that's associated with the particular syndrome and as a whole, these nine to 10 syndromes comprise about 4% of kidney cancer so it's not common but we do see it. And at Stanford we have a cancer genetics clinic. If you have kidney cancer in your family or if you or someone you know developed it at an earlier age meaning in the third or fourth decade of life rather than the fifth, sixth or seventh decade of life, you could be a candidate for having your DNA analyzed to determine whether you have a syndrome that could be passed on to your children or that may exist in other members of your family and so you and your oncologist can talk about whether it makes sense to come see us at Stanford Cancer Genetics Clinic to do testing for these types of mutations and we do kidney cancer and we also do all of the solid tumors so. So now I'm gonna transition to cancer genetics or somatic genetics and really talk about the genes that drive cancer in cancer cells and the reason to understand this is to understand where cancer comes from, how these genetic changes affect the prognosis of the cancer, affect if we can predict which drugs to use and if a drug stops working try to understand why it stopped working and if we can do something differently. So I wanna say a word about where we stand in 2015 with our knowledge about genetics and genomics of kidney cancer. So this landmark paper from 2013 did a large analysis, a large genetic analysis of about 400 RCC tumors and they counted and characterized the genetic mutations in those tumors and this kind of staticky graph up here is just counting the number of mutations in each cancer. So each little bar is one tumor and you can see on average a kidney cancer has a little less than 100 somewhere between 50 and 100 give or take mutations in that cancer and we know more than that, we know exactly what genes are mutated and that's a lot but a short list of them is presented here and a blue mark means that in that particular tumor this gene was mutated et cetera for all of them. So you can see right off the bat that the majority of kidney cancers harbor a mutation in this gene called VHL which is very important for how we think about kidney cancer and I can also point out mutations in PIC3CA, MTOR and P10 and why is it important to know these mutations because the majority of treatments that we now offer for kidney cancer are based on these mutations. So all of these drugs that we've talked about today synitinib, serapinib, pizopinib, exidinib, bevacizumab, all target elements of a genetic pathway starting with VHL and leads to the production of these cytokines that stimulate tumor formation and blood growth formation and that's what these drugs are designed to inhibit. And similarly, I mentioned these other molecules, PI3K and MTOR and the drugs, Tempsterolimus and Everolimus were developed and are used in kidney cancer because we know that these mutations are common in this disease and that the pathway is driving cancer growth. So that's genomics in kidney cancer in general, but the real excitement about this is personalized medicine. How can we define the mutations in your tumor and use that to help you? So on the left side of this slide is kind of the old dogma of, or the current dogma even of cancer treatment which is to get a patient obtain their clinical information, have a biopsy, some sort of histology saying what kind of cancer this is and to prescribe a treatment based on that. And the new model that we're working in now is to take the biopsy specimen, do DNA sequencing, determine what mutations are in that cancer and prescribe treatment based on those mutations. So this slide essentially says the same thing with slightly more fancy pictures but we're taking the DNA from the tumor, sequencing it using the machines that I showed you about determining exactly what the mutations are and for many of these mutations, there are specific drugs that have already been designed that already exist that can be used to target that mutation. So that's the name of the game. So what exactly are we looking for when we do this type of sequencing? This pie chart gives you a sense of the types of genes that we commonly detect in tumors in general when we do sequencing. And these genes are specifically highlighted because for almost all of them, a specific inhibitor exists. So this is really what we're hoping to find when we do DNA sequencing of cancer. So there's this concept of actionable mutations and what type of mutations were actually finding in patients and this is a study of 2,000 patients who had their tumors sequenced by a company called Foundation Medicine and it just describes in general what they found when they did this analysis. So 95% of the patients were able to have the assay done and of those 95, 76% had something called an actionable mutation. And that definition of an actionable mutation is a little bit subject to change but they use the definition that an FDA approved drug is on the market for that mutation specifically or an investigational agent for that mutation exists somewhere in the world for that mutation. This is for all cancers in general, all cancers. Most of what I'm talking about pertains to all cancers today and when there's parts specific to kidney cancer, I'll highlight that. And so yeah, so most people, the large majority had an actionable mutation and many people had more than one actionable mutation meaning that the mutations they found potentially had drugs available to that mutation. So what we're working on now is a model at Stanford called Molecular Tumor Board where a patient has, their oncologist recommends that they have a biopsy sent for molecular or genetic analysis where the pathologist helps us extract the DNA, sequencing is done and then we meet together as a group of doctors, both the pathologists who analyze the DNA, the oncologists who know the patient and make the treatment decision and try to determine for the mutations that we're finding, does it make any sense to offer the patient drug based on that mutation? And then we give those outcome of that discussion to the treating oncologist and share it with the patient as well. So this is being done in the context of a trial which is really just an observational trial at Stanford where we're just asking what is the feasibility of doing this in adult oncology at Stanford? And the patients that we're really focused on at this point are patients with stage four or metastatic cancer and it can be any solid cancer who have used at least one accepted therapy or they just happen to have a cancer that there's no great first option. So those are the types of patients we're mainly working on right now. And what kind of genomics are we interested in analyzing? And we're pretty agnostic at this point. There's a lot of DNA sequencing services available both through Stanford, through the community, through private companies that are coming online very rapidly, it's a very rapidly expanding biotechnology space right now. And as a molecular tumor board, we're willing to look at anything that you guys have or have had done in the past. So Stanford has its own cancer gene panel that we're offering, but a number of other companies, I mentioned Foundation One, Genomics done with other medical centers or other biotech companies in the area. So if you have sequencing done and you have mutations identified and you and your oncologist don't know what to make of it, we're very happy to look at that and we like to do that. So this is an example of one of the patient reports from the Foundation Medicine Genomic Analysis. Oops, obviously the patient's name has been redacted, but the important part is that, this is a head and neck cancer. There were four genomic alterations identified. It lists them here. This one actually had two alterations. That's how they got to four. And then at the bottom, they list whether there are any FDA approved therapies for these mutations in this particular type of cancer, which was no, but there are FDA approved therapies for this mutations in other types of cancer. And there are also clinical trials available based on these mutations that these patient could qualify for. So this is just a very similar snapshot of what the internal Stanford Genomics report looks like. It has a lot of the same information. So what's known publicly about the utility and outcomes of using this type of approach to deliver oncology care. So one of the previous Stanford Oncology Fellows, Lincoln Nadal, went to Intermountain Health Medical Group in Utah and he reported this summer on a cohort of 210 patients that had genomic analysis performed on their cancers in their health system. And what they were able to show is that, let's see, they had 210 patients. They were able to get adequate sample from 195 of them. And only 2% of them didn't have any mutations. So the vast majority of patients had mutations that they were looking for that they could detect. And of those, 132 had this so-called actionable mutation. And of that, 132, they offered, prescribed and the patient received therapy in 103 of those cases. I don't have the breakdown, yeah, I'm sorry. And what they did, yeah, I'm gonna show you. So in order to make a meaningful result, what they did is they took the patients, the 103 patients and matched them with other patients who were the same age, same gender, same diagnosis, same number of previous treatments. This arm of patients obviously did not have any sequencing but did get more of a conventional chemotherapy. They didn't get nothing, they did get something. And then they compared it with the patients who had the sequencing and got treated with the sequencing directed therapy and looked at the progression free survival at cost of care, et cetera. And what they found, surprisingly, is that the patients who were treated in this modality who had their tumor sequence actually seemed to be doing better than those who did not go through this type of pathway. So you can see these types of progression free survival curves where the patients getting the targeted therapy have an increased amount of time on the therapy. And they also calculated cost associated with doing this. There's some concern that these targeted therapies are very expensive, but this was actually not found to be the case. They're actually very equivalent in terms of the cost to the healthcare system. Is it testing infusion? Yes, it was total cost of everything. Infusion, drug, testing, et cetera. So I wanna pivot for a second and talk about the types of genomic trials, running currently and opening soon at Stanford. I'm going to specifically focus on these three ones, signature, my pathway and match, because they are all not disease specific and they all accept patients with kidney cancer. So this first one I'll talk about is my pathway. It's a trial currently open at Stanford. It's specifically designed to find patients with mutations in these four genes. These four genes all have specific drugs paired to them where if the patient has a mutation in this drug, we would certainly consider, sorry, a mutation in this gene, we would certainly consider giving this drug as therapy. Yeah. Things in genes in cancer that are the same as, I mean just any cancer, the same as in kidney cancer? I am trying to say that we're looking, right? We don't know exactly what's in everybody's cancer because it hasn't been available to do that type of analysis outside of the past couple of years. So now that we have the tools to do that, I think that it becomes imperative to start to look and see what we can find. So so far you haven't seen any differences. In terms of what? Say breast cancer to kidney cancer. There are certainly differences, yes. There are certainly differences in the types of mutations that kidney cancers get compared to breast cancers. Absolutely, yes, absolutely. So the my pathway trial. So again, and a theme with all of these trials is that they're targeted to patients with stage four tumors including kidney cancer that have at least tried one prior line of therapy, one accepted line of therapy or do not have a standard line of therapy. And for most of these trials, they will have to have a biopsy done either in the past or if not recent enough, what you and your oncologist can decide together, a more recent one could also be useful. So the way that we think about treating people with this molecular guided therapy is to have a biopsy, do the profiling, determine whether there is a mutation and if there's one of the mutations interested in in this study, one of the four that I showed, the patient would become registered on the trial, they would receive the agent and they would take the medicine as long as it is effective for them. This particular trial has the option built into it that if at any time the patient had progressive disease while taking this study agent, they have the option of getting another biopsy to determine if something has changed in the cancer and now that there is a new mutation, they could get another drug also in the same trial. The next trial I wanna talk about is the Novartis Signature Trial. Novartis is a drug company that's had a lot of success making small molecule drugs towards cancer mutations. They have a fairly large pipeline of drugs that are entering clinical trials and the drug company set up this trial as a way to move the drugs to the patients faster with the idea that if we tell patients that we have a drug targeted to a specific mutation, they will get their sequencing done with their oncologist wherever they may be and they will contact us and tell us that I may be suitable for your trial. So currently they are listing three drugs available to patients. However, I'll say that they're offering changes periodically, probably every two months or so they offer or swap in and out different drugs depending on what efficacies they're seeing or what they're trying to target or whatever results they're finding. So if this is of interest to you, I would encourage you to look at their website just to make sure that the mutations that you're looking for are actually the ones they're still offering. So currently they have three different drugs targeted to four to five different mutations and the way that this works is essentially any center can enter this trial as long as it's a center that has some experience with clinical trials, it's not necessarily needs to be open and running at the time when you're doing your genetic testing. If you find a mutation that fits their profile, your oncologist will call the company and they would open the trial specifically for you and their timeframe is within three weeks. So that's pretty exciting. Another clinical trial that is not open yet but is supposed to open any day now is the NCI match clinical trial through the National Cancer Institute. It is nationwide study. It has the largest number of drugs available on it to date. It's a large compendium meaning that many different drug manufacturers have entered together to offer drugs, a smattering of drugs, some of which are approved, some of which are not approved for, again, all solid tumors including kidney cancer. The only difference between this trial and the other two ones that I mentioned is the biopsy and genetic analysis is more stringent in this trial. They will require your biopsy to be sent to one of their specific testing sites. So what I would imagine would happen is that most patients would have some sort of local genomic analysis done and then that mutation would have to be recertified at one of the four national sites in order to get entry to this trial. And they have a number of reasons why they set it up that way regarding kind of quality control issues, but that's the way that the trial is set up. So anyways, this one is supposed to open any day now. So we're looking forward to enrolling patients on this shortly. I wanna present one case from my own practice. I mainly see colon cancer. So, but as I said, for most of what I'm talking about, I think that the actual type of tumor that we're treating is not that important. The most important thing is to find a mutation for which an existing drug is available. So this is a patient who had colon cancer. He had tumors in the liver. He got three lines of therapy, which are FDA approved for colon cancer. After each one of these therapies, the tumors eventually grew. At this point, we biopsied this tumor right here and he actually had a mutation in a gene very unusual for colon cancer, which is HER2. And there exist a number of approved therapies for HER2 mutations. We gave him one, it didn't work, and then we gave him a second one at this point and he had a near complete response and shrinking of his liver tumors for over one year now. So it's really a remarkable, remarkable story for us and for him. So this is the type of thing that we're really hoping to find the types of mutations that we wouldn't normally think about, but that every individual is different and every cancer is different. So it's worth taking a look. So I just wanna stop and summarize. The field of DNA sequencing is going through an explosion of growth right now. This is allowing us to uncover mutations that we wouldn't normally think about in cancers. This type of analysis is really best at this point for patients with metastatic cancer because we're offering treatments that are not the standard of care and have not gone through rigorous clinical trials. We kind of consider every patient to be their own clinical trial in this type of pathway. We are offering many targeted agents through clinical trials at Stanford currently and expect to have many more accelerating through the coming years. And lastly, coming back to my first point about genes passed on to family members, if you think that that may pertain to your situation, we're happy to see you in cancer genetics clinic. If you and your oncologist think that that's reasonable. So yeah, the future directions for this is that we will continue to identify more targets. The types of mutations we're looking for continues to expand and the number of sequencing things that we're looking for continues to expand. We will probably move into just sequencing entire genomes within the next five to 10 years in the clinic because the technology is available. There's this issue of whether to give one drug at a time or give, if a patient has multiple mutations to give two drugs to that patient at one time, that's an area of exploration right now. And I really didn't have time to talk about giving the time constraints, but it's also become possible to find mutations by doing a blood test which is less invasive than a biopsy. And I can talk about that if you guys have more specific questions about it. So I'll stop there and have any questions. Sure. It was really wonderful to see this. So I have two questions. One kind of relates back to the wonderful case that you showed before. And the question was is that you went through your test, you wound up finding the biomarker, you tried the drug and it didn't work. And it turns out now what's kind of interesting about that is so why? Yeah, great question. I don't know. I don't know. I mean in his case it was fortunate that we have actually, we have probably more than two, we probably have three targeted to that mutation. So yeah, and that's the case for a number of different mutations. Now I've spent a lot of time on watching videos, not knowing much about this stuff, but I saw something I saw really fascinating. There's the status based in the way, as near as I understand it, it works like this. There's the status of the tumor, but there's also the status of the patient. And in particular the patient, what the doctor went on and said, he says the global concept of wound up being what the tumor has done and is doing to the immune system. And in fact, the way basically, and in particular that struck me as being important because when you have these multiple lines of therapy as you're sitting there, continually not just bombarding the tumor with these chemicals, but you're bombarding the body and the immune system too, it also winds up changing through time. I was wondering as you're going on and doing this analysis of these particular things, do you simultaneously do an analysis of the patient and his immune system so you can actually look at two different points at the same time as opposed to just at the tumor? We do it inadvertently. As I talked about, there's this circulating tumor DNA where you can get essentially blood, right? And then sequence the blood, looking for bits of tumor DNA that happen to enter the blood. But what you also get is, I mean, you're not looking for it, but you end up getting DNA from the lymphocytes and the immune system as well. Yeah, so we do see things sometimes. And we see kind of, it's not a rigorous analysis, but we do see ways in which the immune system has changed based on the treatments people have gotten previously. You think that the treatment? Absolutely. Yeah, absolutely. Thanks so much for the talk, Josh. That was really good. I have a question that in Lincoln study, you already said that there's a 68% likelihood that there's more than one. How are you picking one drug or the other? And for your colon cancer patient, did he have more than one? Did he have more than one? I got it, I don't remember, honestly. So I'll answer your first question. So the question is how does the molecular tumor board decide what to treat people with? I wish I had an easy answer to that question. I think when I say that there are actionable mutations, I think we would always go with the drug that's easiest availability probably first rather than sending a patient to a clinical trial if there's a drug that's already on the market that is certainly targeted to that. I think that's one way to parse between the actionable mutations. But it can be difficult. And it's not a problem that we don't like to have. I mean, it's good to have multiple options, right? So we don't worry about that too much because there's always something else to try. One quick question. For the match trial, who's gonna provide the medications if you see there's a mutation? Will it be insurance or will the NCI provide? It's the NCI. Wow, and are we doing this? Yeah. Okay. I had a question in regards to colon cancer. Yes. In the event that the mutations defined a particular drug that hasn't been approved by the FDA for colon cancer, can that patient still have that, take that drug? So the question is, if they have a mutation but the drug that the mutation is for is not approved for colon cancer, can they get the drug? Yes. And the answer is it's complicated. So sometimes we have to ask insurance to cover it and we have to tell them why we think this will work and we end up doing ascending them the mutation analysis and arguing with them a little bit to tell them this should probably be tried and that often works. And another way to do it is, for that particular patient, there was a clinical trial also available so he can also get the agent on a clinical trial. That's another way to get the drug. Are you typically successful with the insurance companies? Yeah, if there's a mutation that suggests a drug, yes, we're typically successful. Thank you. No. So for solitude, do you do an amplification process at some time? Yes. Yes. How do I amplify it? I mean, I don't know exactly, I'll be honest. Yeah, but it's molecular biology and it's all been worked out and it's science. So cool. Okay, yeah. So it's an open question that has not really been addressed in clinical trials yet. The companies that offer that type of test have no indication for using a liquid biopsy to replace a traditional biopsy and they really argue that it should be used in conjunction with it because the data is not there to say that it is a replacement yet. For now. For now, yeah. So if someone has a cancer, any type of cancer, so how many generations has to be worried about? Like, let's say if my forefathers has kidney cancer, is there a way, looking at my gene expressions or DNA sequencing, can I tell like, yeah, some of your forefathers has this type of thing so you should be like checking with your doctors often? So you're asking me if you have a relative, like a grandfather who had kidney cancer, is it possible that you inherited it from him? My question essentially is how many generations will it be impacted? Is it immediate, like his children or his children's children or something like that? So if a patient or a person has a mutation that's germline, right, that means that mutation is in every cell in their body and it will, well in most cases, it's a 50% chance that it will be transmitted to the next generation, right? So, 5-0, yeah. So not every progeny will inherit that mutation but there is some sort of risk, right? So that's why we need to go and actually test those people to see whether they carry the gene or not. I have a follow-up question. So yeah, should we like directly talk to doctors that we have had this kind of history and can you please do these tests? Yeah, whatever. Yeah, that's exactly what we would do. We would see you in genetics clinic, we would take a very detailed family history, going way up into your family tree to find out which generations had what and also other different types of cancer could also be helpful to coming to a diagnosis and then based on what the family looks like, we would suggest certain genetic testing to try to figure out whether there is or is not something in your family. That's true. Yeah, thank you. Inherited cancers for kidney cancers about 5%. So of all the patients with kidney cancer, of only about 5% of those will be ones that have been inherited from their parents essentially. Well, that depends. You either have or have not inherited it. Yeah, I mean, not all siblings will necessarily be affected. You may not have inherited it, even though your sibling has. Yeah, what is the percentage of inherited colon cancer? Yeah, I don't know, I haven't looked it up recently, but I think it's about the same, yeah. So how do people get referred to, if they are interested in the genetics clinic, how do they get this information? The Genetic, the Molecular Tumor Board? No, the referral to your genetics clinic. Is it on the website? Can they get access to? Yeah, so I mean, it would be the same referral process to see any oncologist at Stanford. We are also oncologists, so they can make appointments either by calling the Stanford Cancer Center or be referred directly from your treating oncologist. Is there a kidney cancer specialist on our Molecular Tumor Board? Or... Yeah. That depends on the cases that we're seeing that day, but we always talk to the treating oncologist when we give our recommendations about what... But you, for example, recall a cancer. Yeah, I would say on a day-to-day basis, we do not have one of the kidney cancer doctors, but in the cases where they're referring their patients to us, then, yes, they have come to our tumor board and discussed their patients, yeah. Yeah, so when cancer is inherited in the family, generally speaking, there is a 50% chance that a parent will pass that on to one of their children. Yeah. So each child has a 50% chance, right? Can you say my child? Sure, I mean, either way, right? It could be your parents passing it on to your generation, or you passing it to your progeny. It depends on which bloodline we think that the mutation is coming from, right? If we think this has all come from your mother's side of the family, but you have cousins on the paternal side, we would not consider them at risk, right? It has to be transmitted through the blood, so it would be the other side of the family. Yeah, I mean, inherited cancer can strike any type of cancer, and it's most common in breast cancer, but yeah, yeah, and we see patients for all of the different cancers we see for genetic analysis, family analysis, absolutely. Okay, thanks. How about a round of applause for Josh for talking on a very tough subject, but very exciting for the years to come.