 Understand really the genomics of kidney cancer and now, like immunotherapy, genomics is really what we think is going to alter the way we treat cancers in general. It's all about personalized medicine where what is it about your tumor that's unique, that's going to allow us to treat it differently. I think we are just scraping the surface right now. So Alex is going to help us understand a little bit about the basics and tell us where the field is headed and maybe tell us a little bit more about where we are headed in kidney cancer specifically. So thank you so much again for coming on a Saturday. I know he just told me that he was jeopardized meaning that he has to come in and work extra in the clinic, in the hospital, all I said was I just I'm sorry about that, but I'm glad you're here just to give us a talk and that's all I care about. Thank you, Alex. All righty. Can you guys all hear me? All right, great. Well, Sandy, thank you so much for that warm introduction and thanks for everyone being here. And it's definitely a pleasure to talk on this Saturday afternoon. So I was asked to speak about the genomics of kidney cancer and this is definitely a very large field. But we'll try to break it down into the next four sections. Let's spend a little bit of time talking about each. So I really want to start off with just an overview. What is genomics? What are genes? What are mutations? So as we all know, we have 46 chromosomes in each one of ourselves, half from mom, half from dad. And within these chromosomes, we have genes. And genes are really kind of the building blocks for all cellular processes. And each gene is composed of the A's, C's, T's and G's that we've heard about in biology. And any deviation from the normal sequence here, as we can see, for example, with this red C being different from the normal T, that's what we call a mutation. And this is one form of mutations. There are many other types of mutations that can occur. And these deviations from normal really make abnormally functioning genes and then proteins, which makes cells behave abnormally. And then the process becomes cancerous. So we've known about mutations. We've known about genes for a while. But why is it only recently we're using this in the clinic? And this has really been driven by both sequencing costs as well as sequencing times. So similarly to the development of personalized computing where we went from mainframe to many computers to now personal computers and even cell phones, the same kind of revolutions has occurred in sequencing. So while in the 60s and 70s, we used things called gel-based sequencing techniques, which would take sometimes weeks, if not months, sequence just one gene. This has been replaced initially with Sanger sequencing, which allowed us to sequence for a few thousand dollars a gene maybe in a few weeks and for the first time allowed genomics to enter the clinic to now something called next-generation sequencing, which really has opened up sequencing to the masses. Now sequencing can be done for a few hundred dollars for the cost of reagents and sometimes be done as quickly as just one week. So if we actually look at the cost of sequencing over the last decade or so, we can see that it's dropped faster than Moore's law, which is kind of the prototypical law for the cost and the power of computing over time. And this is truly amazing. So while the first genome took 13 years and over a billion dollars to complete, now we can sequence an entire genome in the span of just a few weeks for a reagent cost of just a few thousand dollars. And with this, there's barely been an explosion of genetic knowledge. And this not has only pervaded all aspects of oncology, but many other disease states as well, including genetic diseases, which we'll spend some time talking about. So I think before we kind of jump into kidney cancer, I think it's really important to spend a little time talking about the two main types of mutations that we may encounter in the clinic. One type is somatic mutations. And these are mutations that are not inherited, so you're not born with these, but you develop over time. So these are kind of the wear and tear mutations. The longer we live, the more toxin we're exposed to, the more of these somatic mutations we develop. And if we develop enough of them in the right cell and in the right order, we can actually go on to develop, for example, the kidney cancer. Again, these are not heritable mutations. So for these mutations, you cannot pass them on to your kids, for example. And the other side of the spectrum, we have germline mutations. So these are mutations we're born with. And these are mutations that we can then pass on to our children. Rare mutations from the germline can predispose us to things like kidney cancer and not only drive the development of kidney cancer, but if present, put our, for example, children at risk for developing similar conditions. So how does this relate to kidney cancer? Well, we know that histologically kidney cancer is not one disease. We might have been familiar, for example, from our clinic visits with clear cell carcinoma of the kidney with the most common histological cause. But there's many more histological subtypes. And we now know that these subtypes are really driven by changes or by different genomics underlying these various forms of kidney cancer. For example, the clear cell carcinoma subtype is really associated strongly with this non-hippo-lindow, the VHL gene. And then we can see the other associations listed here on this slide. But if we dig deeper, the associations are actually much more complex. So this is definitely not a slide I want anyone to memorize. But it really, I think it shows that really, the genetics are very, very complicated. So no two kidney cancers, even in the same histological subtype, are the same. Kidney cancers have many, many mutations. And really, the combination of mutations make each kidney cancer unique. And really, we're beginning to exploit this knowledge to see if we can actually personalize medicine for each individual's kidney cancer. And many of the genes listed on the previous slide are actually seen here in dysregulating the pathways, which the therapies we use in the urology clinic target. So things like avarolimus, things like pazapinib, all of these target the pathways, which are dysregulated by mutations we discussed previously. So how do we tide this explosion of knowledge to actual clinical practice? And I think oncology is really an imperfect art. And this has been changing rapidly. But if we look at various disease states, the response rate for any particular oncology drug on average is actually fairly low. So what we've been doing historically in oncology is something called trial and error medicine. We try disease treatment A. If it doesn't work, we try treatment B, so on and so on. And then until we find something that works, wouldn't be great to actually know that treatment C is the right treatment up from the front and not actually have to go through two therapies, which were ineffective. So because of this, we've seen this explosion of personalized or precision medicine, where we're beginning to reclassify cancers, not based on the histology, but based on their genomic classification. So for example, you could have a lung cancer and a kidney cancer that are more similar because they actually share the same mutations, which may be targetable by some of these agents that we've discussed earlier. And because of this, we've seen kind of other cancer types really benefit from this genomic knowledge. So for example, in colon cancer, if somebody has a KRAS mutation, well, gosh, we know that urban tux will not work and the patient has spared that therapy. Same thing for lung cancer, if somebody has an EGFR mutation, we know for sure that Iresa is gonna be effective and that patient is spared chemotherapy. So this allows us to segregate patients who are likely to be responders or non-responders to particular therapy. And this gets us to, again, what are these mutations? And we can think of mutations largely as being either prognostic. So gosh, if you have this mutation, your cancer is gonna be more aggressive. It's gonna come back a little earlier versus predictive. And that's really the mutation that we care about most. And these are the mutations that say, well, if you have this mutation, for sure drug A will work or drug B won't. And right now in kidney cancer, we're at the prognostic stage. So we know many kidney cancer mutations are prognostic. So for example, if you have a BAP1 mutation, the survival is like this. And if you don't, for example, the survival is like that. But right now we're still struggling to find and identify truly predictive mutations that we can actually use to select the right therapy for the right patient. Because we'll talk a little bit later, that's changing rapidly. So in the clinic, when you're talking to your oncologist, what kind of tests may be discussed and what tests may you benefit from, especially in the metastatic setting? Currently, we're using things called panels. And you can think of a panel as a collection of many genes that we can sequence to basically try to find mutations that may be either prognostic or predictive in a clinical trial setting for your individual cancer. In the future, we think things like exomes. We're actually sequencing all the genes in the tumor. And that's around 20,000 genes may be used. Or even the whole exome, where we sequence all of the abnormal DNA and the cancer and try to derive knowledge from that. Currently, panels are what is being used clinically, but we do see the shift towards exomes happening very slowly. And we think maybe over the next few years, maybe that's the direction we're going to be taking. So how is this currently being used? So I think before we talk about that, it's good to look at how we use sequencing in the past. So before when we can only sequence one gene at a time, what we would do is we'd sequence gene A if it was normal. There's no mutation and we'd do gene B, C, D and E and so on and so on. And this would frequently take months if not longer to get done, because you would do this in a sequential manner. With panel testing, because you're sequencing a collection of genes at the same time, this can be done much quicker in the order of just sometimes a week or two. Where we can sequence up to hundreds of genes and get meaningful results back that can then inform clinical decision making. So right now, what's happening is that we're beginning to integrate genomic information into clinical decision making, both for prognosis. And we're hoping more and more for predictive purposes. So just like we would do a biopsy and interpret it or do a CT or an X-ray interpret that to use that to guide clinical decisions, we're now using genomics more and more primarily for the purpose of clinical trial enrollment. But we're hoping in the future for actually treatment selection. And this is becoming an integral part of many of our clinics. So how does genomic information really allow us to better select trials? Again, the old paradigm would be looking for individual mutations. So there's a trial that was enrolling based on mutation in gene A. You would test for that gene. If that was not present, you would test for a different gene. And frequently that led to really long delays in enrolling patients on clinical trials as you would kind of go again through this sequential process. Now with these next generation sequencing panels, we can test for many, many mutations. And assuming we find an individual mutation in each patient's tumor, we can actually then stratify patients to the right clinical trial in a much more efficient and a timely manner. So what trials do we have open at Stanford, which may be of interest to the folks in this room? Well, we do have the MATCH trial, and this is an NCI sponsored study, which again is using next generation panel sequencing to find mutations which may be actionable for folks who failed standard line therapy. We have some other trials, which again are based on a similar premise. So just focusing on the NCI MATCH trial, again, this is a trial that's multi-institutional, open all across the country, open for many cancer types, including kidney cancer. Where if folks run out of standard therapy options, the tumor can be sequenced. And the sequencing now is allowed to be done through companies like Foundation Medicine and some of the other sequencing providers, including Stanford's sequencing panel. And if any actionable mutations are identified, then a drug can be selected and then prescribed for that particular mutation. And again, this is just shown here schematically. And really the interesting thing is that even though we're looking at all of these genes and all of these drugs, many of these targets are the same ones that are abnormal frequently in kidney cancer. So definitely there's a lot of overlap of this trial's targets with what we know is frequently abnormal in kidney cancer. Furthermore, there's additional clinical trials open in the US looking at even more rare mutations. So we're beginning to realize that, again, cancers are so different, even kidney cancers that, for example, very rare mutations, if we find those, can be targetable. And I think that's really a reason to kind of look frequently when standard therapy options become unavailable. For example, n-track fusions are a very hot topic in oncology right now. So if this n-track fusion is present in a cancer, there's two trials open which have response rates over 50% in other cancer types. And these are currently enrolling kidney cancer patients. Also activating that mutations are now implicated in certain hereditary forms of kidney cancers and there's trials open for that. And even at Stanford, we have a trial for folks with these are homologous recombination deficiency mutations, which again also can occur in kidney cancer, the ability to get this specific drug, which is a PARP inhibitor that specifically targets this pathway. So again, many options there and really the only way to know if you would qualify for one of these options is to look. So I think talking about genetic testing with your oncologist, when standard therapies stop working, if that ever happens, it's really an important thing we encourage all our patients to do. So now let's switch focus to germline mutations again. So these are hereditary mutations which may be implicated in development of kidney cancer in certain individuals. So what I tell my patients is that even though cancer is genetic, so we know every cancer has certain mutations, only 10% of it is inherited. And that works out very well actually for kidney cancer, where it's around 10 to 12% of kidney cancers have some kind of hereditary predisposition. So these are some of the syndromes that we look for in clinic, especially if there's some concerning features, either a strong family history of cancer or some other rare forms of birth defects. Again, this is not something I want you to memorize, but just be aware that we look for this very closely in our patients. What I do want you to think about is kind of what are the indications for genetic testing. So again, this is for germline genetic testing, seeing if you have an inherited version of one of these mutations. And what we currently are saying is that if you have an early onset kidney cancer, less than 45 of the age of diagnosis, if you have multiple primary cancers in one person. So if you have, for example, two different kidney cancers, or kidney cancer and a thyroid cancer, which was diagnosed separately, again, that may be an indication for genetic testing. If you've had two, more than two family members with kidney cancer, which are immediate family members, again, consider talking about germline testing with your doctor. Or if you have more than three family members with one of them having kidney cancer, that could be you or somebody else, and any other cancer, again, that would be an indication for testing. And then we'll talk a little bit more about this, but if you have family members with kidney and some other rare tumors, again, that may be an indication for genetic testing. So I always, you know, we are always asking, you know, what's the point of knowing if I have one of these rare mutations that I may be able to pass on? You know, how does that really change my management? And wouldn't just not cause me, you know, more anxiety to know. And I think for a while that was a valid argument, but I think now we're knowing that the more information we have, the better treatment decisions we can make and the better guidelines and screening recommendations we can make. A lot of these hereditary mutations are associated with other cancer types. So if we know about that, we can consider earlier screening for other cancers. And for many of these mutations, if your children are at risk or other close relatives, they can then be easily screened and they can take appropriate precautions to catch any type of tumor that they may be at risk for earlier. Before, for example, it becomes something of a problem that requires more intensive therapy. So I always put up the slide as well. And these are the red flags that you may have something that's genetic driving your kidney cancer or somebody's kidney cancer in your family. So if any of these terms are familiar to you, you know, you may want to discuss with your doctor possible genetic screening. Again, a lot of these are very rare conditions that have run very closely with hereditary forms of kidney cancer. Yes and no. So OMA means growth. So Lyoma would be a growth of a smooth muscle. So again, I think what you're referring to here is if you have family members with other type of cancers or if you have more than one type of cancer, those would be indications. But these are usually, these terms are part of rare genetic syndromes that run with kidney cancer. Yeah, it's part of a very rare genetic syndrome that can predispose to kidney cancer. So again, we can maybe save a few questions for the end, but just cause we have a few more slides. Yes. So based on current guidelines, so you have a kidney cancer and your son has a different cancer. So technically it's hard to say, but the risk is lower. But if you had another family member with another cancer, then the risk would be a little bit higher. So again, that these guidelines kind of help us decide who should we screen. And then future directions. I think this is kind of the really exciting things that are going on with genomics of kidney cancer. I think we might have mentioned this earlier today, but liquid biopsies are really something that's taking the oncology field by storm. We've focused a lot of attention previously in looking for actual cancer cells floating around in the blood. Sometimes we could find those, but sometimes we can. And we've realized that instead of looking for cancer cells, let's gosh look for cancer DNA that's in the blood. So we know that as cancer grows, cancer cells die and shed DNA and that DNA can be found in the blood. And by detecting this DNA in the blood, we can tell not only what mutations are found in the candy cancer without necessarily having to re-biopsy it, but we can actually track how much kidney cancer there is. And if kidney cancer is present or not, for example, after a curative resection. So this allows us to do something called monitoring or liquid biopsies to monitor certain cancers over time. Again, this is now purely done on a research basis, but we're thinking that in the future, this may become part of clinical practice. So for example, here you can see that this patient's cancer was treated after surgery, all of this abnormal DNA was gone. And then after surgery, it started going up and it was going up even before there was any clinical or radiological evidence of relapse. And this uptrend in this abnormal DNA then predicted relapse over a year before radiological relapse. So again, these are some exciting kind of developments in the field that really allows for ultra sensitive monitoring of possible residual disease. Again, currently doing this on a research basis only, but again, this is something you're interested in. We are starting to collect plasma from our patients to allow some of these tests to be done on a research basis. These are some of the companies that are currently doing cell-free DNA testing, which are actually commercially available. Again, we don't necessarily recommend using these tests for monitoring of disease, but they may be used sometimes if for example, a biopsy is too hard to do. We can sometimes use one of these tests to see if there's any new mutations present in the blood that may be actionable. Lastly, immune therapy, and I think we've spent some time today talking about some of the really exciting developments in immune therapy for kidney cancer, but really even beyond currently approved drugs we're looking for ways to predict who's gonna respond to immune therapy and who's not. And some of the approaches are actually looking for something called neoantigens. And we know that all of our cells have proteins which are on the surface. And we can predict that cancer cells, with their mutations, may have abnormal proteins on their surface. So why doesn't our immune system pick that up? And again, this really ties down back to genomics and mutations. So how can we find which mutations really produce these neoantigens or these abnormal proteins that are gonna be more likely to be picked up by the immune system and generate a response to this immune therapy? So again, these are studies in process. And we think hopefully in the future we can be able to use some of these techniques to really kind of even personalize immune therapy to each individual's tumor. So I think that kind of closes my talk. And really the way I want folks to think about genomics is that in a way it really ties patients together because as we know more about the individual mutations in the various cancers, really we're seeing communities build around some of these mutations just like there's now communities in building around cancer types. So I think definitely if you meet criteria for some of this testing, talk to your oncologist and I'll be available for questions after as well. Thank you. My own personal experience is that unless you push for it, even at a stage four, they're not going to sequence your particular cancer unless there's some special situation. Would you recommend that everyone who gets to stage four have their cancer sequence? There's information to be found there. But that doesn't seem to be the current practice. I think if current therapies are not no longer effective for stage four cancer, I do recommend everyone have their cancer sequence. I think sequencing the cancer very early, for example, right at diagnosis of stage four cancer may be less meaningful. And really I think the time would be actually at progression beyond standard therapies because you can really look at that time for all the mutations that are present at that time point. So if you sequence too early, you may actually be missing some of the new mutations that have developed over time. So the genomic costs are getting cheaper and cheaper but we've been seeing that for a long time and even that curve seemed to have flattened your chart ended in 2014. So when is it going to be inexpensive enough that it's commonly available to a lot of patients as part of the standard healthcare system and cancer treatment? Because despite that speed it seemed it hasn't gotten to where we thought it would be in 2017. Yeah, I think a lot of this also has to do with reimbursement. So I think even though some of these technologies are available reimbursement patterns have been spotty for a lot of these tests. And for example, the GARN test, I mean this is a liquid biopsy test that just like a month ago received reimbursement for the first time in a subset of lung cancer patients. Because reimbursement's really lagged, we found it hard to get some of these tests to patients. So I think again that's something we currently work with, payers and insurers with about but really reimbursement really drives adoption for these tests. Follow me. Yes. I would just add one more comment is that, I mean if you do a test we think that you need to have an actionable item, right? There should be something that we can act upon that test and prior to the match trial being available it's really been a challenge if we do a sequencing and we find a rare mutation that only happens in breast cancer for instance. I mean getting that drug available to the patient has been extremely challenging for insurance companies don't want to pay for something that hasn't been proven that hasn't been approved. So it's really been, it was a challenge till the match trial really came along where if we find something we could at least then offer an appropriate treatment. All right, thank you.