Genetic Testing and Next Generation DNA Sequencing in Prostate Cancer

thanks for having me the objectives here we want to talk about the concept of synthetic lethality in the context of BRCA deficient tumors you know you've heard about this you know BRCA matters why does it matter of course it matters because of the implication in terms of screening and familial significance it also matters in terms of treatment because we are getting closer to having established treatments for for this specific subset of patients and I'm gonna go over some of that data we'll go over some of the actually I'm sorry we're not gonna go over the basics regarding ovarian cancer I added that out just recently we'll talk about PARP inhibition don't talk about why all this matters so you know very simply prostate cancer is a BRCA associated malignancy along with breast cancer ovarian cancer and pancreatic cancer and you know we keep making this point I know this crowd knows this point but really most the medical community still hasn't absorbed this point I gave a talk on this just a couple of weeks ago to a community of primary care physicians and asked them how many of them ask their female patients about their fathers and brothers with prostate cancer and the answer is almost none of them and no one asks about pancreas and no one asks their male patients about their mothers and their sisters with breast and ovarian cancer so we can see here that amongst localized cancers having a germline aberration deleterious alteration in brca2 carries in almost eight and a half fold relative risk of prostate cancer and brca1 almost a three and a half fold relative risk of prostate cancer over patients without these aberrations brca2 is about five times more common than brca1 so as what we spend most of our time talking about at least in prostate cancer patients that is that's the opposite of what you see in ovarian and breast cancers but it's associated with higher Gleason score higher stage and younger age of diagnosis right so the question was asked earlier about how does this impact PSA screening guidelines and the answer is it doesn't yet but I think we all know it needs to so that's a something in development as far as the data to think about what do we how do we counsel the patients where the germline inherited BRCA mutation they are considered high risk by NCCN guidelines of course that was always one of the things about the USPSTF stance is it never applied to high-risk patients yet of course those patients were probably ignored as well because that nuance was lost on most practitioners there's never been a debate that amongst high-risk patients PSA screening has remained appropriate but then you know the question is where do you when do you start what age is the cutoff 3 should it be age 45 of course we could have a another pro/con about that or perhaps ask the doctor Carlson and dr. Parsons what they think but amongst lethal prostate cancer 60% of mutation carriers of brca1 to an ATM report a negative family history and that's one of the most important points I think everyone needs to take home is that family history doesn't tell you who to test ok so how do we know that well this data was reported at ASCO a little over a year ago now it looked at over 1,100 patients with localized prostate cancer who had germline DNA testing in that population 199 of them had a high-risk germline mutation and then what they did is they took that cohort of 199 patients and they compared their family history to the existing NCCN guidelines and said if you follow the guidelines strictly how many of them would you catch and the answer is only 63% almost 37 percent of the patients who were carrying inherited deleterious mutations would not have qualified for screening by guidelines okay so so we can definitively say look the guidelines don't work and this is just the NCCN guidelines there's others but they all fall into the same category right they ask how many first-degree relatives you have with this list of cancers but what if you're an orphan right what if you come from a small family you have no siblings and your parents each have one or no siblings median number of children in the u.s. today in a family is two right so those kind of guy lines work really well if you come from a large family of eight children and and whatnot then you can use family history but for most Americans nowadays this isn't going to work so we're not doing it right okay and then and I think this is probably the most important point for people to take home and thinking about when do you test patience the answer is probably not family history okay that's not how you decide so then the next step in thinking about this though I mean we always talk about we have this 40-year long conversation right about the tortoises and their rabbits right how do you detect the lethal cancers those are the ones we really need to worry about don't worry about the ones that aren't going to kill the patients and we've already heard a lot of conversation about that so if we look at the metastatic population these are the men they're going to die of prostate cancer right with the development of measurable metastatic disease by conventional imaging maybe not the newest imaging but by conventional imaging eighty percent of those men will die of prostate cancer not with it those are my patients right by the time they get to me these men are going to die of their disease they're not going to die with it and in that population we see that the overall rate of germline mutations is much higher about 10 to 12 percent of all men with metastatic disease will have inherited deleterious mutations in cancer associated genes and almost half of those going to be brca2 you add brca1 and 2 together and you're talking about 51% of patients so about 5% of all of my patients are going to have a germline aberration in brca1 and 2 about one or two percent are localized patients but of course brca1 and 2 and ATM I mean this family of genes is is only part of the list you know as we know now in this modern era where we have TCGA we have large sales seek a large-scale sequencing studies across tumor types there's a long list of very common aberrations in any given cancer and those might be mutations they might be fusions they might be amplifications and then there's a long tail of less common alterations and in prostate cancer what we see as in every other cancer and that is not one monolithic disease right it's not every pasta cancer is the same and you all know this you have patience with Gleason 6 prostate cancer who develop metastasis very early and die and you have men with Lisa 9 prostate cancer so you thought you know this guy's in trouble and 15 years later he's still coming back to your clinic and nothing has happened right so what is it one monolithic disease there's a variety of distinct pathways active and prostate cancer and what they're really ought to be what there needs to be is multiple different treatment paradigms based upon the specific type of prostate cancer that a patient has now prostate cancer is still one of the only one of the big four cancers at is long colon prostate and breast without genotypic definition in terms of subtypes of disease and therapies directed to those specific subtypes so very generally and I'm not gonna go into this in great detail but this is a list of kind of the most common altered genes we see in prostate cancer and there's a couple of points to take away here one is that there is evolution across the spectrum of disease so you start early and of course the androgen receptor being right the key driver of disease no surprise that when you move from non castrate metastatic disease to castrate you suddenly get AR amplification well we've known that for many years right what gets forgotten is a small proportion of patients start out with AR amplification right in the beginning and in fact we know these guys are in trouble they have a very aggressive disease course early on there's the other alterations that are familiar to everyone here p10 deletion no surprise that gets somewhat more common as we march through the disease states p53 deletion p53 recall is the most commonly mutated gene in all of human malignancy right it's a master regulator of the cell cycle and repair and it becomes more frequently aberrant as you move through disease states and get the later stage disease it's probably a predictor of aggressiveness up front the question is is it a predictor or is it a differentiator in terms of treatment and so far we don't know and then it you'll run through the rest of it here there's BRCA there's a TM some other genes and where this became important then is finally and you've seen this paper three years ago this is the first paper that came out that said you know what you've got an approved therapy for BRCA mutant disease if you're talking about breast and ovarian cancer why don't we go ahead and try this in prostate cancer I mean those of us who work in this field have argued this point for many years I wrote my first ist on something like this back in 2011 didn't go anywhere finally in 2015 Johan de Bono's group carries the day and shows us a tremendous response rate right here's the PFS using a lapper Abbar pin have an improved PARP inhibitor and BRCA or ATM or other DNA damage response gene altered prostate cancer and they saw a tremendous response rate but in a single institution non randomized study and you know this is one of the things in oncology I mean we all know that when you have a single institution study that goes from phase 2 to phase 3 you know you lose about half of your response rate right it's always biased when it's single institutions so so you looked at this and you got we got FDA break through status for using a lapper it and so maybe you've seen your oncologist use this on some of your patients but of course we need the prospective data and so this is what dr. Crawford was just referring to this is data it's only a couple of weeks old I presented at the prostate cancer foundation meeting last month and this is looking at recap ribs and one of the FDA approved PARP inhibitors in breast and ovarian cancer this is a phase 2 study there's also a companion phase 3 study going on so the phase 2 is happening in the post docetaxel space the phase 3 is happening in the pre docetaxel space do PARP inhibitors work in prostate cancer so I'm not going to spend a lot of time just in the interest time on this slide but the way this works out right there's two different populations and metastatic prostate cancer there's patients with measurable disease by which we mean soft tissue disease that we can apply standard response criteria to write shrinking of tumors versus growing and then there's patients with non measurable disease ie those patients with bone only disease where we don't have radiographic evidence of response we just have radiographic evidence of non progression and it broke it down stratified patients according to what kind of alteration they had in the interim analysis of the first 85 patients enrolled if you look at the patients with responsive valuable that as resistors valuable 45 of them or I'm sorry PSA response evaluable 45 of them had a BRCA alteration 18 had ATM another 22 had others and we won't linger too much on those 46 patients had radiographic disease that was a valuable 25 of those 46 7 brca1 2 and if you look here at the at the overall response rate by resist criteria measurable disease in patients with a BSc a12 alteration the complete impartial response rate was 44% okay which is really good in the medical oncology realm and this is still early because of because of as you'll see in a later slide a lot of these patients are still on therapy this is very much in line and better than quite a few of the currently fda-approved drugs in prostate cancer this is what we call a swimmers plot so these all the patients on studied receiving root cap rib with a brca1 or 2 alteration and what this shows you is time on treatment so that's weeks across the bottom each lane each swim lane then is an individual patient the arrow means they're still on therapy so you have a patient there that's 52 weeks out the red is from the time of initial treatment the orange is when you develop radiographic response so what stands out in this slide number one is most patients develop a response very early the responders are generally developing a response by eight weeks so that's a 30% reduction in tumor volume and you see the majority of responders remain on therapy right we don't even know yet how long the the actual progression-free survival will be but this is incredibly encouraging early data and then if you look at the rest of the genes and then this is an important point right we're talking to bucketing patience how do we take genetic data turn it into different phenotypes of disease breakdown prostate cancer from one monolithic disease to a variety of different diseases ATM has long been thought of as a DNA damage response gene but in fact it's very different than BRCA it doesn't directly interact with the DNA to fix repairs it's more of a monitoring gene and what we see is that PARP inhibitors have almost no efficacy whatsoever in this population at least we're kapor it doesn't see DK 12 another gene that we're going to talk a little bit more about gets categorized as a ddr gene but you know it's its function is much different it leads to a different phenotype of disease that we're gonna talk about in a bit probably shouldn't be treated with PARP inhibitors at all and then amongst these others we saw response and grip 1 and fan K altered disease this is the waterfall plot showing by what percentage the tumor shrunk in this population of patients so all these patients on this end their tumors grew all these patients on this end their tumors shrunk and the value of a plot like this is instead of getting that arbitrary resist cutoff of 30% that somehow being significant right as if the patient with 32% got a benefit in the patient with 28% didn't this just shows everybody as a composite and gives you a more global sense of the response and so if I set suffice it to say this is a good response the red being all the BRCA patients all right so moving forward looking at PSA response rate the PSA response rate in brca1 to alter patients 51% right so this is late stage patients already treated with chemotherapy already treated with abiraterone and enzalutamide you get a 51% in this population that's doing very very well that's better than anything else we have in this population and here against the waterfall plot of the same so again this is it's a very good-looking waterfall plot I mean this kind of results to get us excited in medical oncology and then here again ATM no response right so even though ATM and BRCA are traditionally bunched together when you talk about it from a genetic perspective from a malignancy perspective this is not the same disease cdk twelve very little response as well okay so that's that's where the field needs to go right we are close soon we'll have the first fda-approved treatment selection biomarker and metastatic disease we expect it to be BRCA alterations the specifics of that is something we have to delve into a little further and kind of beyond the scope what I was gonna go into here but in terms of talk about mono allelic loss versus by allelic loss and specifically which alteration should qualify and which one shouldn't but we're starting to understand I mean there's plenty of emerging data that there's a lot of other phenotypes of disease that matter so Mik is frequently amplified in metastatic prostate cancer and we see an amplified in about 10 to 20 percent of the disease and these are patients that are heading down that neuro endocrine small cell pathway these are patients whose prostate cancer ends up looking like small cell lung cancer at that point it doesn't matter what you do the androgen receptor Lupron or anything else nothing's gonna touch it other than aggressive chemotherapy we've never had a biomarker for it so we've generally classified this on clinical grounds you have no PSA you've got visceral disease you know but even those aren't very good indicators cuz I got plenty of patients with no PSA but I can treat them with androgen directed therapy and shrink their measurable disease there's our B deletion and depending upon you know the status of disease and and what you read now this is happening probably in about 40% of disease but this starts to talk to tell us about AR resistance so the question we often get asked is well what do you do you do in lieu pronto you're doing chemo are you doing Zytiga probably where we should get is we should be looking at the biomarkers and bucketing patients and saying you're headed down the Zytiga pathway X Tandy pathway you're going to radium you're going to docetaxel D p53 same thing C D K 12 now this is very interesting you know we all want immunotherapy and prostate cancer doesn't work right you take Pember ilysm ab which is all over the television and it's approved in so many diseases and you see a 2 to 3 response entra sponsor 8 in prostate cancer talk about tumor mutational burden as the differentiator for how you should pick patients for immunotherapy well tmb and prostate cancer is typically very low now people say a cut-off at 10:15 your prostate cancer is more like 2 to 4 t mb low mutations but if you have cdk 12 deleted prostate cancer what we end up seeing is that you have a fairly high we should say really here not so much mutational burden but neo antigen load you get a high frequency of tandem internal duplications you get a high load of neo antigens generated by fusions so you get a lot of chimeric proteins through a process of chromothripsis and you get functional aberrant proteins with open reading frames that will generate neo antigens that anyway therapy can respond to and so what we're seeing is sed k12 predicting for response to immunotherapy but when you look at your foundation or Kara's report and they talk about tmb that kind of alteration is not counted so we're thinking these patients are immune resistant when in fact they're sensitive MSI high is another the same and interest at I'm I'll move on so then as a medical oncologist what I think about is how patients move between these states how they get into one state how whether they stay in it but what we also understand is that there's lineage plasticity and this is really how we start thinking about sequencing therapy and trying to be more sophisticated with our therapies because as dr. Crawford was mentioning earlier we can talk about mutations and alterations but the fact that matter is much of what drives differentiation in cancers is not mutations in genes but rather how those genes are regulated so epigenetic regulation the control of those genes most very few genes change in prostate cancer as it evolves through that state and I didn't highlight that list of genes that doesn't change at all but most of them stay the same and yet you go from this Gleason 6 indolent disease to this highly aggressive small cell cancer with brain metastases that's not the same process and mostly it's at epigenetic regulation what we start to realize with something like ARV 7 right so a rv7 is an inducible biomarker of resistance to AR directed therapy well you know AR v7 can come and go in a cancer you treat a patient with a bur at around suddenly a rv7 gets up regulated in the cancer cell and it's not going to respond to a B anymore you give them those attacks on the AR vh7 goes away and potentially you can retreat them again with a B or enzalutamide right the tumor evolves we're involved in a dance it moves left we have to move to block it it moves right we have to move to block it again and so if we think about this in a more sophisticated fashion where we want to get to is start doing liquid biopsies start doing continuous monitoring track the evolution as it's happening and block the cancer before it makes a switch right so instead of going treatment a to treatment B to treatment C and D and on down the line and then in hitting hospice you go from A to B to C and back to a and then switch over to B in combination with C and etc it said I move back and forth because we're taking advantage of the plasticity of cellular evolution alright so in summary inherited prostate cancer risk syndromes are under recognized both in practice and in research this is absolutely a problem we have to solve in terms of diagnosing patients who have germline inherited cancer predisposition genes and this leads to delayed diagnosis and it decreases cure right I mean each one of you will always cure more cancer patients than I ever will in my career right once they get to me it's too late you guys are the ones that cure patients so we need to identify these patients early we need the guidelines to evolve we needed to catch up to the data they're very much behind Kelly we need multiple new pathways for therapeutic not we need new drugs to hit these multiple new pathways and we need future treatment paradigms to incorporate germline and somatic mutation data deleterious BRCA gene alterations are likely to be the first treatment selection biomarkers and metastatic CR PC and PARP inhibitor studies are ongoing I showed you recap rate but there's no rapid Talas operable a prep and all of them are being tried in prostate cancer so the field is full of these studies right now I think as you all well know you know we start with testing these drugs in metastatic disease but ultimately we have to move them all forward right we start talking about neoadjuvant adjuvant studies getting these drugs earlier and earlier and you're going to see these studies there are already in the pipeline the co-operative groups are working on them the the industry is working on them so this is going to come to your clinic very very quickly thank you you

Channel: Grand Rounds in Urology

Views: 645

Keywords: Alan H. Bryce, genome sequencing in prostate cancer, BRCA, BRCA2, genetic testing in prostate cancer, DDR mutations, new pathways for therapeutic targeting in prostate cancer, grand rounds in urology

Id: CBkMpCPJyLE

Length: 23min 9sec (1389 seconds)

Published: Thu Feb 07 2019