 So Alex wasn't here in the morning when I said that one of the great privileges of being in a place like Stanford is to train young people who have an incredible mind and it's really a team effort to be able to take care of patients. So Alex is an example of a trainee who's doing his oncology fellowship and he did part of his training at UCLA and did his medicine training here at Stanford and is a medical oncology fellow. We started this day talking about the gross kidney specimen and we have now boiled our day down to the cellular molecular level. So Alex is going to tell us about the genomics of kidney cancer and what's new. Some of those might not be completely applicable to kidney cancer but one of the goals of today's meeting is to have hope and optimism to see where this field is headed. So I'm really happy to have Alex talk today, hopefully when his slides are loaded. There they are. Thank you so much Sandy and thank you for everyone for joining us today and the organizers for letting me speak with everyone today. And I want to spend a little bit of time speaking about the genetics of kidney cancer and the learning objectives for today are, you know, what is next generation sequencing and how is it helping facilitate some of the new advances in the genomics and genetics of kidney cancer. Also spent a little time talking about kidney cancer genomics as well as hereditary kidney cancer syndromes as well as future directions in this field. So I want everyone to go back to their high school biology days. So we have to remember that DNA is present in all of our cells and DNA is partitioned between 46 chromosomes, half from mom, half from dad. And each chromosome is a collection of many genes and as well as some non-coding regions between the genes. And each gene is composed of nucleotides and these are the A's, the C's, the G's that we hear about in biology. And there is a normal sequence for every gene and deviations from that normal sequence are what we call mutations. And mutations can be as simple as a T to a C, but they can be more complex. There can be rearrangements, there can be deletions, there can be additions. But just remember, the mutations are deviations from the normal DNA sequence in our cells. And sequencing is the process of figuring out what these deviations are. We can't look at DNA, it's too small to see. So we have to use various methods to figure that out. And just like there's been a revolution in personal computing where we've gone from the mainframe to the mini computer and now to the personal computer, there's been a revolution in sequencing that has happened in parallel with this. So going back 40, 50 years sequencing was done using something called gel-based sequencing and this was entire laboratories, entire departments dedicated to sequencing, for example, one gene and that could take frequently weeks to months to get that accomplished. With Sanger sequencing, sequencing became a little bit cheaper, you could sequence a gene for a few thousand dollars, but it could still take a few weeks to get done. And that's when first sequencing started entering the clinic. In the last decade, something called next-generation sequencing has really taken over this field. And next-generation sequencing is the ability to sequence DNA extremely quickly in a parallel fashion and get just humongous amounts of information out in a relatively short amount of time. And with that advancement, we've seen the sequencing costs plummet. So compared to Moore's law, which is kind of the prototypical law about computing speed, which increases with a certain fraction every year, we've seen that the cost of genomic sequencing has actually surpassed that and has dropped in price at a rate that's unprecedented. So for example, the first human sequence, human genome sequence took 13 years and a cost of over a billion dollars to complete. Now we're sequencing human genomes in a matter of a week or two and in a reagent cost of just a few thousand dollars. So with this decreased cost, we've really seen an explosion in the genetic knowledge. And this spans many cancer fields, not just kidney cancer, but has really kind of opened up our eyes to the genes and the mutations that really drive cancer as well as drive the predisposition to cancer. So before we dive into the actual kidney cancer component of this talk, I just want to spend a few minutes talking about the two types of mutations that we frequently encounter. And this gets really confusing to, I think, a lot of patients. And it's something good to kind of go over. So there are two types of mutations. There's somatic mutations and germline mutations. And somatic mutations are what we think of as nonheritable mutations. These are mutations that we develop over time. These are kind of wear and tear mutations that randomly incur in all of our cells. They cannot be passed down. And these are the majority of mutations that our cancers develop. There's also germline mutations. And these are very different. These are much rarer. And these are present in all of ourselves. And these are mutations that are passed down in families. They're heritable. And in certain instances, can predispose individuals to various cancers, kidney cancer being one of them, as well as some other conditions. So first let's talk about somatic mutations. And then we'll go back to the germline mutations. So in renal cell carcinoma, we know that there are many forms of the disease. There's clear cell papillary, chromophobe, oncocytoma. And over the last decade or two, we've figured out that certain mutations correlate with these histologic subtypes. So the VHL mutation we've heard about, the CMAT mutation, these tend to go with certain histologic types of renal cell carcinoma. However, in the last five to 10 years, we've learned a lot more. And this slide is not something I want people to write down or understand. But it's just here to show that we understand that kidney cancer cells have many, many more mutations beyond just the prototypical mutations in the prior slide. Furthermore, it seems that no two kidney cancers are the same at the molecular level. The mutations that are present in one person's kidney cancer are very different than somebody else's. There's definitely overlaps. There's groupings. But the actual mutations are slightly different between everyone. And because of that, we've really started working out some of the pathways in kidney cancer. And these are the pathways we've talked about today. And we've talked about the various drugs to target these pathways. However, oncology still remains an imperfect art. I think we select drug A. And hope it works. If it doesn't, we try drug B and drug C. Across various diseases, oncology still has some of the lowest response rate to any one drug. So if you try drug A across various cancers, the response rate is 30%, 40%, much lower than other diseases. For example, diabetes and some infectious diseases. So how can we improve on this? How can we better select the right drug for the right person? And the solution here is personalized medicine. And more frequently, we're calling this now precision medicine. And personalized medicine refers to tailoring and medical treatment to an individual. And more importantly, the individual's particular tumor. How can we harness that information about the various mutations to make sure the right drug is selected for the right individual? So what we've been seeing is this shift from an anatomic classification of cancer to a genomic classification. So while in the past, we would say you have a cancer of the lawn, the colon, the kidney, now frequently we're saying you have a cancer with this mutation. It doesn't matter where it initially started. So in many cancers, this really has changed how cancers are approached. For example, in colon cancer, we test for KRAS mutation. If it's absent, we know urban tux is very likely to work and we choose that drug for that patient. In lung cancer, we test everyone for an EGFR mutation. If it's present, that patient is spared chemotherapy and goes on a pill called iressa. And we know it's very likely to work. While if that mutation is absent, we know that drug is inappropriate. So that allows us to better select out the patients and put them on the appropriate therapies up front without doing kind of this iterative approach that was used before. Kidney cancer is a little bit behind the times, but this is changing rapidly. So we know that many mutations are prognostic. So for example, having expression of BAP1 is a good prognosis. But if it's mutated, we know that's associated with a bad prognosis. So far, however, we've not been able to identify any mutations that are predictive. That means if you have this mutation, you're more likely to respond to a certain drug and that drug should be selected over something else. And that's really the ultimate goal in the genomics of kidney cancer. So where's the testing? You know, how can we get this testing out to patients? And it's currently available. So there is now testing that's being done. I think many of you might have had a foundation one test done if you have metastatic disease. And that's a panel test. And a panel test is a way of testing many mutations at once. So this is the benefit of next generation sequencing. So testing for 50, 300 genes now that are known to be associated with various pathways in cancer. Some of these have drugs that are approved for these mutations. Others are associated with clinical trials, many of which are ongoing here at Stanford. In the future, we think exome and whole genome sequencing may be important. Exome is basically a large panel of all the genes. Our cancer cells have 20,000 genes. And basically, if we sequence all of those, that's called an exome. A whole genome is sequencing all of our DNA. And that's around 3 billion base pairs. And that's around 100 times more than an exome or around 10,000 times more than a standard panel. Currently, exomes and whole genomes, though sometimes they're offered through commercial laboratories, we still don't believe they're clinically useful. There's just too much information. There's just too much noise. However, panels are currently being used and may be appropriate depending kind of what stage of your disease you are. So what is the benefit of panels over traditional genetic testing? So in the past, we used to test one gene at a time. We would test gene 1. If it was negative, gosh, we'd test gene 2. And so on. Frequently, that would take quite a while and would have high costs. With panel testing, testing a lot of genes at once, we get an answer quickly and more economically. So we think that genomics, and this is happening today. It's not the future. It's today. It's being streamlined into the current clinical workflow. So before, we would do tests such as a biopsy and interpret that biopsy or a scan, interpret that scan. More and more, we're doing now genetic testing and interpreting that and using that to kind of guide decision-making in folks with usually metastatic cancer at this time. And this is important currently in clinical trial enrollment for kidney cancer. In other cancers, we're using this to directly treat based on various protocols. But for right now in kidney cancer, really, this is important for clinical trial selection and enrollment. So clinical trials based on genomic technologies used to be very difficult to do because there's 20,000 genes. There used to be hundreds of trials finding the right trial for you, especially if you have a rare mutation. It was very difficult. Kind of going back to that old slide, we would test GNA. And if the GNA was not present, you don't qualify for trial A. And you have to kind of go down that list. And frequently, that could be very long and difficult because there would be not enough tissue. With these newer panels that can be done clinically now, a big kind of benefit of that is, gosh, if you have mutation B, when you need a clinical trial and there is a clinical trial available for patients who have mutation B in their cancer, we can quickly link you up with that trial and kind of prevent any delay in trying to search for a right genomic trial for you. These are the trials currently open at Stanford. There are two main ones, the MATCH and the MyPathway trials. These are disease agnostic. So they enroll patients with any type of malignancy. And we're enrolling patients based on the status of their mutations in their cancer. So in a way, we can think of these as bucket trials. So the buckets are the mutations. And anyone can go into the buckets regardless of the cancer type they have. I'm just going to highlight the MATCH trial since this is probably the more relevant one for kidney cancers today. So the MATCH trial is run by the NCI. That's the National Cancer Institute. And this trial is having patients have their tumor sequenced for a panel. And it doesn't matter which panel you have done initially. You can have a foundation panel. You can have the in-house panel we do called the stamp panel. And if we find certain mutations, you are eligible for currently approved drugs in other cancer types, but which are predicted to work based on that mutation of interest. Currently, the mutations that are available are these ones. And again, this is not something to remember. But many of these overlap with known mutations involved in kidney cancers. And this is currently open and enrolling patients. So moving on from the somatic mutations, I think it's good to just review the germline mutations and how those apply to folks with kidney cancer. So germline mutations, again, are the ones that are heritable and which predispose the cancer and are present in all of ourselves. So we frequently say that all cancer is genetic, but only 10% of it is heritable. And in kidney cancer, that's actually worked out pretty well, around five to seven. Some people say up to 10% of all kidney cancer has some heritable component. There are many heritable kidney cancer syndromes. This is just probably one-third of them. Some of them have strange eponym names, usually based on, I think, 19th century white men, like Von Hippel Lindau or Bert Haag Dubay. But more and more, the newer ones we're discovering are actually based on kind of the syndrome that is caused by this. For example, hereditary liomyomatosis and renal cancer is a newer, discovered one, which is caused by mutation in the FH gene, which predisposes people to kidney cancer. And also early onset uterine fibroids and uterine cancers. Again, knowing these syndromes is not important, but knowing when to seek out genetic testing for hereditary predisposition to kidney cancers is. So kind of the indications for kidney cancer testing for hereditary mutations are early onset kidney cancers. Kidney cancers that were diagnosed before the age of 45, some centers will consider less than 50 for testing as well. Multiple primary cancers in one person. So for example, two unrelated kidney cancers in one person or kidney and a thyroid cancer really should start causing people to see, gosh, should I be evaluated for genetic germline testing? More than two family members with kidney cancer or more than three family members with kidney cancer and other forms of cancers. And then neuroendocrine tumors that run into family should also raise eyebrows and should have people seek out possible testing. So the benefits of testing, a lot of people ask, why would I want to know if I have a predisposition to cancer and possibly have passed it on to my children? Well, I think now this field is maturing. There are now screening guidelines for folks with mutations that predispose them to various cancer that can be initiated to try to catch some of these cancers early before they get to an advanced stage. Some of these are also mutations, possibly the risk can be mitigated by certain risk reducing surgeries or possibly even helping guide certain types of therapies. So P53 mutations are known to be associated with a syndrome called the Fermini syndrome and may not be very radiation sensitive, the tumors that come from that. So maybe radiation would not be the first choice there. But more importantly, to identify family members at risk and make sure those patients get appropriate counseling and screening. So I always put the slide up and this is basically a lot of rare disorders that if you know any of these disorders or they're present in any of your family members, you should consider seeking out hereditary kidney cancer testing. So all of these are rare on their own, but when present in a family member with somebody with kidney cancer really raised the possibility of the kidney cancer being part of a hereditary cancer syndrome. So again, I'm not gonna go into detail which what each one of these is, but if any of these look familiar to you and maybe talk to your oncologist about if a referral to genetic specialist makes sense. So just a few minutes I wanna spend about talking about kind of the future directions in genomics and kidney cancer. So liquid biopsies are something that is currently being used clinically, but we're still figuring out how to best use this. So Dr. Phan talked a little bit about some of these liquid biopsies and they can be either by looking at circulating tumor cells, the actual tumor cells that break off from the tumor and are floating in the blood or looking at pieces of DNA which have broken off the tumor and are floating in the blood. The form is called circulating tumor cells, the later is called circulating free DNA. And circulating free DNA is being used currently in maternal fetal medicine to test prenatally for fetal genomic defects before birth and we're using this more and more now in kidney cancer and cancer in general. This is still an active area of research. We think that this technology can be used for screening individuals who are high risk, seeing if individuals high risk for kidney cancer have abnormal genes in the blood which can signal that the kidney cancer is developing and at that stage maybe we'll do some kind of intervention to decrease the risk of it becoming a full blown cancer. We think it may be important in diagnosis or staging. So for example, if somebody has a tumor that's not easily to biopsy, can we do liquid biopsy louder? Oh louder, sure. Can we do liquid biopsy to help aid in the diagnosis? And then more importantly, right now we're using this for treatment monitoring. This is a way to kind of trend the progress of our treatments over time and then eventually recurrence monitoring. So once the cancer is hopefully treated effectively, can we monitor over time the cell free DNA levels or circulating tumor cell levels to see before the cancer becomes clinically apparent if it's coming back? So there have been a few studies of this and for example, this is a study where they use cell free DNA in breast cancer. So breast cancer patients who had surgery to remove all of the cancer who were effectively cured and individuals where they saw cell free DNA levels rising and those individuals, the cancer always came back while in folks who can't cell free DNA level stated zero, they were effectively cured. And the benefit of this, gosh, why would I wanna know this is that frequently we can detect cell free DNA levels rising sometimes months or even a year before we see clinically apparent tumors on imaging. So this gives us more time to explore either clinical trials or other treatment options. So again, this is something that is being ordered in select patients right now. There are a few companies that do this. Garden Health, a new company called Grail Trovegene. So this is all clinically available but we're doing this in select cases because we're still learning how to use and interpret this technology but this is something definitely that's gonna be more and more prevalent in the next year. So we'll be all hearing more and more about these technologies. So this is kind of what's happening this year but what's gonna be happening in the next five years. And I wanna just spend one minute talking about immune therapy. So we know that immune therapy is closely linked with genetics. Abnormal mutations in our tumors cause alterations on the cancer cells which then sensitize them to our immune system. We use drugs like Nivolumab to increase that immune response but we need mutations. We need something called neoantigens and these are abnormal proteins on ourselves that are caused by mutations that our cancers have for the immune system to be able to pick up the tumors. Right now, we can identify neoantigens but we don't know which neoantigens are gonna trigger an immune response. So there's a lot of research currently being done at Stanford to identify if your neoantigens is likely to predict a response to immune therapy and if maybe it's not, can we augment that neoantigens ability to stimulate our immune system? So the first clinical trials of these augmented they're gonna be cancer vaccines are gonna be opening here at Stanford this year. They're gonna be opening in some of the GI cancers but maybe in the future they will also be available in kidney cancer. So I think with that, I hope we had a good kind of tour through genomic medicine as it applies to kidney cancer. And the way I see it is that genomics really ties patients together, kind of opens larger communities because certain mutations now are tying patients together across various tumor types, especially if they're associated with specific therapies. So I encourage you to explore genomic testing with your oncologist and see if it's right for you. And any questions, I'm more than glad to take. Okay, questions for Alex? This may be irrelevant but you see our age and many of us have grandchildren. Is there any way that we can preserve our information so that our grandchildren might benefit? Right, so I think if there are high risk features in your family history, getting genetic testing for the affected individual is by far the most important way of preserving that information for your children and grandchildren. Because if you're identified as carrying a predisposing mutation, it's then much easier to test for just that one mutation across your family tree. So we always encourage that if there is some concern for hereditary kidney cancer, to test the kidney cancer carrier and not start testing the children first. Can you talk a little bit about the cost to patients? I mean, who covers this test and right now? Yeah, so the testing would have to be done for hereditary kidney cancers. We would have to be done through our genetics department so you would meet with a genetics counselor first. You would then have your family tree mapped out and based on certain criteria, if you meet those, for example, the more than two kidney cancers, more than three cancers of any type across the family, if you meet those, then insurance largely pays for the testing. A lot of patients who seek out genetic testing who do not qualify for those criteria choose to pay out of pocket. We don't encourage that necessarily because there's a high chance of finding something that may not be a true positive. Usually testing now can be done at Stanford through some of these companies in the $500 to $1,500 range if your insurance does not cover it based on those criteria. Well, I'd say hi. I have a question about how you can use gene markers to predict proteins. Is the goal eventually that you basically individualize the, create, take the proteins and find some kind of pathway, something to bind to it and control cancer that way? So eventually everybody will have their own very specific cancer treatment. I know this is probably 50 years away or something. Yeah, so I think there's clearly a lot of interest in this now. There's, people are looking for these neoantigens and if there is a neoantigens, they're trying to make vaccines to some of these neoantigens to augment the immune response to this foreign protein which is found only on cancer cells, but not normal cells. This is still very early, but again, all of some of these technologies are entering clinical trials as we speak, yeah. All right, thank you, everyone. Thank you, everyone. Thank you so much.