How Cancer Genomics is Transforming Cancer Care - Sanjay Popat

So understanding our genes is actually the fundamental basis to understanding cancer and how we can possibly treat it. Most of the cells in our human body have a central structure called a nucleus. Within this nucleus are our chromosomes. We have 46 of these to be precise, and that's 22 pairs numbered one through to 22, 1 of which we inherit from our mother, and one of which we inherit from our father. In addition, we have another set of chromosomes called X and Y, which determine whether we are born male or female. These chromosomes, which look like the X on the uh, slide, um, are tightly coiled into strands of DNA, the basic building blocks of life. And it's our DNA, which is the blueprint of everything that the cell does. So the DNA is a sequence of letters otherwise known as nucleic acids, and it's that precise sequence of letters that determines how that individual cell functions. So how does this actually work? How does this miracle occur? Well, there's a lot of complex biology in this, so I'm not gonna go into a lot of detail. The Gresham College lecture that you're listening to right now is giving you knowledge and insight from one of the world's leading academic experts making it takes a lot of time. But because we want to encourage a love of learning, we think it's well worth it. We never make you pay for lectures, although donations are needed. All we ask in return is this. Send a link to this lecture to someone you think would benefit. And if you haven't already, click the follow or subscribe button from wherever you are listening right now. Now let's get back to the lecture, But essentially from the sequence of nucleotides of DNA, A modified copy of the sequence of nucleotides called Mr. NA is created and every three letters or bases is read. And each three of these are really important because they encode something called an amino acid. And the amino acid is part of a protein or the machinery of a cell. So from A DNA, it's made into an RNA and the RNA is then read within the cell and a string of amino acids is created and the string of amino acids get grouped together to form something called a protein. And it's the protein that does the business within the cell. So you can see how a sequence of DNA turns into a protein, which then does the function of the cell. And so the DNA is absolutely fundamental to how the cell works. So in recent years, we've witnessed three perhaps more, but I would suggest three major events which have allowed us to harness this basic biology to transform how we treat cancer today in the clinic. So what were these three? So the first of these is the publication of the first draft of the human genome in 2001. Many of you will remember this. Uh, many of you online will remember this. Many of you weren't even being born when this actually occurred. And I certainly was watching the news when it was there and I thinking, well, this is great, but it's not gonna change my life. But actually it has and it's changed everybody's life, everybody's life who's sitting and watching this presentation. It's actually quite amazing that prior to 2001, our actual understanding of the DNA sequence of all of us of the 23 chromosomes in human beings is actually pretty limited. We didn't really know that much about it. And the reason that this publication was so fundamentally important is it allowed us to understand what the normal genetic sequence is alongside all the normal variation that gives us all the people that are in this room. And because understanding what's normal allows us to understand what's abnormal. And this is really critical when it comes to understanding cancer. Now at the same time, time Magazine in the left hand panel published an influential article on how it predicted that we'd be using this understanding of genetics to work out what the right drugs would be to what we would give to patients in the clinic. And that is exactly the prophecy that has come true because that's exactly what we're doing today. So understanding the human genome allowed us to better understand the cancer genome. Now, we knew in the right hand part of this panel that if a sperm cell or an egg cell was born with error was, you know, developed with an error in the sequence or a mutation that gave it a different spelling in the DNA, then this mutation would be present in every single cell in the human being because it was present in the egg or it was present in the sperm. However, what we identify from understanding the human genome wasn't the figure on the right, which is that the, if the same mutation doesn't occur within the egg or the sperm but occurs later on in the development of the organ, such as for example, the colon or the breast or the lung or the skin, then that genetic abnormalities only present within that particular group of cells of that organ. And these group of genetic abnormalities that we call somatic mutations, which are different to mutations that you are born with. And we call these ones that you're born with germline mutations. And it's these somatic mutations of genetic abnormalities that occur within the cell of an organ, often late in life that we now understand are the spelling mistakes in the DNA that actually cause cancer and they're not present in other parts of the body. Now, when we look at the DNA sequence of different parts of the body, we see multiple different potential genetic abnormalities. And the commonest type of genetic abnormality we see in life is something where the spelling is simply changed. There's a spelling mistake that's called a mutation, and there are different classifications we can have for mutations. Uh, and these can be called transversing or translations, uh, where the letter can just be substituted. A C becomes a GAT becomes an A. Or you can have insertions where you can put, put two different letters in the genetic code, or you can have deletions where some of the genetic code letters are removed. Indeed, when we look at the DNA in more detail, we find many more different multiple abnormalities that occur in nature. We find sometimes structural abnormalities of the structure of the DNA and what I've highlighted in red is something called amplification where there are more than one copy or two copies of the same gene, multiple copies, and that shouldn't really occur. And these abnormal copies of genes themselves cause abnormal copies of proteins and then cause cancer. The other thing that we noticed is that when you can take a a set of chromosomes, sometimes the the nature of the chromosome becomes abnormal and the chromosomes become interchanged. And that's a process called gene rearrangement where genes which are normally not next to each other get fused next to each other and then abnormally switched on when they shouldn't be. And that's something called gene fusion or gene rearrangement. We also learned something quite interesting is that the DNA sequence doesn't all turn into a protein within the DNA strand. There are strands of DNA which encode the protein, and that's something called an exon. And there are large regions of the DNA which are just genomic junk. They're called introns. I'm sure they're not junk, but that's what we call 'em at the moment. So not all exons turn into proteins. In fact, you can derive multiple different proteins just by slicing and splicing all the different exons together. And that's how you get different types of protein from the same gene. And that's something called alternative splicing. And if you encode an error within the DNA of that particular sequence, you can result in abnormal alternative splicing or abnormal protein, which then results in a protein that shouldn't be switched on called cancer. Now lung cancer is a superb example for how abnormal genes cause cancer and how that can be identified and how that can be drugged through multiple large scientific studies. Looking at the DNA of the sequence of lung cancers, we've identified that a particular type of lung cancer called adenocarcinoma. We've identified multiple types of genetic abnormality, which we can see in the pie chart on the slide. And these are usually called mutations and sometimes they're called gene fusions and sometimes they're called uh, amplifications. But they all function in the same way. These genetic abnormalities all change the DNA sequence to result in an abnormal protein within the cell, which is normally under very tight control and normally not functioning, but then abnormally forced to switch on without any regulation out of control outta the normal cell processes. And that effective switching on of that cell prevents that cell from dying at the end of its natural life, that cell then continues and grows and divides, becomes two cells because it's switched on. Those two cells refuse to die, become four cells, those four become eight and so on and so on. But each of those cells harbors the original genetic abnormality that was found fundamentally in the first cell when it was created to be cancer. Hence, we can see that the fundamental basis of many of the different types of adenocarcinomas that we seize is in fact a genetic alteration such as a mutation in the DNA that occurred in one fundamental cell, for example, within the airway, often many years before the patients go and see a doctor, these are called driver genetic alterations'cause they're driving the cancer, they're driving the cell to grow, divide, multiply, and replicate. And exactly the same genetic abnormality would be found in each of the daughter cells if we took a sample of it and decided to sequence that cell. But sometimes we find many other abnormalities. And one of the abnormalities that we find that causes cancer is something called amplification where we can look at the gene sequence and the gene sequence is absolutely normal. But instead of having two copies of the gene that we find, one from mom, one from dad, we actually have 10, 20, 30, in some cases even several hundred that results in multiple copies of the same gene that forces the protein to be switched on all the time when it's normally under incredibly good control. So I've talked about the first measure event, which is the cancer genome and our understanding of the, the cancer genome from the normal genome. So the second event that occurred was mapping of the human receptor protein tyrosine kin. That's a long phrase, isn't it? So protein tyrosine kinases were at that time newly identified major types of protein within the cell. So these are normally found on the cell surface. These function as cell receptors and they sense what's going on outside the cell and transduce those signals from outside the cell into the cell to instruct the nucleus what to do. Our understanding of the genetic sequence of these proteins was absolutely critical because when we analyzed this, we actually identified what the kinases do and how critical they are in regulating the cell and causing it to grow, divide, and replicate. When stimulated. The third major event that occurred was down to our medicinal chemists. So if any of you wanna be a medicinal chemist, please do so 'cause you're absolutely critical. Our medicinal chemists actually identified a new class of drug which did not exist before. These are called kinase inhibitors. So the first type of kinase inhibitors actually developed against blood pressure against hypertension. It never really developed further since then. But since then, we've noticed that kinase inhibitors are particularly important in cancer because this is a new class of drug. They're based on a similar biochemical structure. You can see it highlighted here, the PERIODO two 3D tine derivatives, which highly effectively switch off individual kinases. So I've told you that kinases are really important in cells because they regulate what's going on in the cells. I've told you that the DNA of the kinases can be abnormal because of the, because of the abnormal mutations. And now we've got a way to switch off these abnormal kinases because we have these kinase inhibitors. So if we put this all together, what does it mean? In the cartoon on the left, on on the left hand side, you can see that the genetic alterations which occur within the DNA of the cell result in an abnormal protein kinase at the cell surface, which normally regulates the growth of the cell. And these genetic alterations result in the kinase being constitutionally activated, switched on all the time when normally it's under pretty good control, on and off, on and off when it needs to be. These activated kinases result in a signal to the cell to say, grow, divide, replicate, do not die. And these result in the cell doing exactly that. And this whole process can be highly effectively terminated by giving a simple, straightforward tablet. This is just one of many tablets that I've photographed from, uh, those that are available. And the one on the left is a tyrosine kinase inhibitor, which switches off the function of the abnormal active kinase. Now the final event that transformed our understanding is in the field of the development of genetic technologies and their costs here when we map the costs of genetic technologies against Moore's Law. And you know that Moore's law has shown that the cost of computing has reduced markedly over the years, although the cost of my laptop seems to be going up every year, frankly. Um, then we know that the cost of genetic technologies have markedly reduced as well. And that is really quite revolutionary because that allows complex technologies to be routinely implemented into routine clinical care, something that wouldn't occur otherwise. Indeed, when we're trying to understand the genetic sequence or trying to understand the gene of the cancer in a human being, it can be analyzed through multiple different ways. We could, for example, do a very basic test in the laboratory to look at a gene called A PCR and that would tell us what the different mutations are within the gene. Or we could consider a more complex technology, something called whole exome sequencing when we're trying to sequence the coding region of many, many tens or perhaps hundreds of genes within the uh, DNA of that cell. Or we could go even further to look at the whole genome itself, something called whole genome sequencing. Each of these different processes has many different benefits and many different limitations actually. And each of them we use in various different clinical scenarios. Depending on the question that we're trying to answer, we may actually say we don't want to know about the DNA itself. We actually want to know about the intermediary products, something called RNA. And there are many different ways we can look at RN apac. It allows us, for example, to look at gene rearrangements and fusions in much more detail than we can do with, with, uh, limited DNA sequencing. And we can use some of these novel technologies which we now implement in routine clinical care. So I wanna spend some time talking about a, a disease which I look after and treat called lung cancer. And specifically a type of disease that I look after and treat called non-small cell lung cancer called non-small cell lung cancer.'cause the cells aren't small, uh, and a particular type of non-small cell lung cancer called adenocarcinoma, which is really a paradigm for precision oncology or personalized, uh, cancer treatments. So some of you will know who this chap in the right hand side of the slide is. He's Sir Richard Dol. And many of you will know that Sir Richard DOL presented his seminal epidemiology work in 1954, where he took a cohort of doctors that were born between 1,919 30 doctors 'cause we're all very compliant and we follow the law and we follow the rules by and large. And he followed them up and he looked at what happened to them and he demonstrated that those doctors that were smokers on average died 10 years earlier than those doctors that were not smokers. And we looked at the causes of death in those that had died earlier. By and large, many of them were attributable to lung cancer and he was the first person that purported a direct relationship between tobacco, smoking, development of cancer and death. Absolutely critical. So of course you are thinking that lung cancer is all to do with smoking, isn't it? And of course, if you live in a world where nobody smokes, then you're not gonna get any lung cancer. And that's sort of partially true. But in fact it's way, way, way off the truth because whilst the typical type of character that we associate with lung cancer is the character in the cartoon or the left hand side, the chap with a pint in his hand and the uh, cigarette in his mouth all the time. The truth of the matter is lung cancer can occur to any of us, any of us in this room, whether we smoked or not. If you've got lungs, you can develop lung cancer. In fact, 20% of all lung cancers occur in people that have never smoked. Many famous people have developed lung cancer who've never smoked. For example, the late Roy Castle, which some of you all know about, and the late MP James Haw. And as our advocates say, if you have lungs, you can develop lung cancer who just don't need to be a smoker to be, to develop the diagnosis. Now when we look at lung cancer in never smokers, it remains a major cause of death. In fact, given that 20% of a big problem because lung cancer's a big problem, 20% of uh, a big problem is still actually a big problem at the national level. And in fact, lung cancer in never smokers accounts for more deaths than cervix cancer, more deaths than pancreas cancer and more deaths than pan than prostate cancer. So it is a big issue. Now, one of the fundamental issues we have with lung cancer and many internal malignancies is it's a cancer inside us. It grows inside us. It's not like skin cancer, we can see it outside. On the outside. We can feel that it's abnormal breast cancer. You can feel that it's not quite right. It grows inside and our lungs can take a lot of damage before we feel that there's something wrong. And we go to our doctors to say, listen, there's something that's not quite right. So picking it up at a very early stage when it's small within our lungs is really quite difficult. As a consequence, lung cancer's usually spread to other parts of the body at the time of the diagnosis, which means that usually it's what's called stage four. It's spread from the lung to many other parts of the body at the time at which it's diagnosed. And stage four, unfortunately, by and large at the moment, is generally incurable. Now one of the great examples of how we have implemented genomics and how it's revolutionized our cancer care routinely is the story of a drug called gefitinib, which some of you will have heard of, but most of you will never have come across, at least not in this audience, I don't think so here in 2002 AstraZeneca were testing a new kinase inhibitor. Do you remember I told you about these kinase inhibitors for very fancy new tablets, switch off individual pathways. This tablet didn't have a name. It was called a ZD 1 8 39 because at that stage it's a chemical, it's not a drug. We don't really know whether it's gonna be developed into a drug. We don't know what dose, we dunno what schedule. We don't really know who to give it to and we don't really know when it works, whether it works or not. So this drug, a ad 1839, very, very interesting drug 'cause it switches off a very specific kinase called the EGFR protein kinase. And we know that EGFR sits on the cell surface of the lungs and it's really, really important in signaling to the lungs within the lung cells. Now this seminal publication by my colleague man, uh, professor Ranson from Manchester, he demonstrated that he took a handful of patients with just good old fashioned lung cancer and lung cancer's. A serious disease gave a handful of patients this tablet called a ZD 1839 and a small number of them, the cancer just started melting away. Let me tell you, this does not happen routinely day in, day out. Wait, it does now, but not in 2002. It definitely didn't. So this is big news and it remained really quite unclear why some of those patients, their tumors were melting away. You can see in the CT scan in the left hand panel, uh, the, the gray bit at the bottom is all cancer and it's melting away after two months and after three months, the gray bit's been replaced with gray, with dark stuff. That's the air going into the lungs. So it really remained very unclear who was gonna derive a benefit and, and who did, who didn't. And the the um, benefit was really very rapid and very marked. So AstraZeneca developed a drug further and they gave it a name and that name was gefitinib and it gave, it was given approval by the regulatory agencies, including in the US the FDA. And it became in quite widespread use in major parts of, uh, Europe, uh, certainly in Asia and in the US And it became very unclear who was gonna benefit. But one thing that we noticed is that the people that benefited tend never to have smoked but not always tended to have East Asian or South Asian ancestry were often female as well. Subsequently, AstraZeneca did a large clinical trial. They randomly allocated several hundred patients with lung cancer to receive either gefitinib or not to see whether the drug worked. And unfortunately, and this was really shocking to many of us, and I remember being an oncologist at the time, it demonstrated that on average patients had no benefit from the drug. They didn't live any longer. So how does this work? How is it that we've got some patients deriving phenomenal benefit, but on average if we take a group of everybody in this room, it's really making no difference whatsoever. It is not improving survival. The FDA did what a decent regulator has to do. This stuff doesn't work. They withdrew it from the market, they said it doesn't work in the US and it continued to be used in other parts of the uh, world where it still had regulatory approval, especially in Asia where it was seeming to work really quite frequently compared to western populations. And this was really puzzled all of us because we didn't quite understand what was going on here. So this all changed in 2004. Two groups from the US we're looking at these patients with lung cancer. You can see the white stuff in their lungs on the CT scan that's bad. And they looked at people that were having gefitinib and they figured out what the biological basis of why gefitinib was working here. They took the tissue from patients with lung cancer, they did biopsy of their lung and they sequence the gene that encodes the EEG FR protein. They looked at the DNA of the EEG FR uh, gene. And lo and behold they identified that patients that harbored a genetic mutation in the EGFR mutation, which switched on the G FFR kinase to cause the DR the cells to grow, divide, and replicate were the ones that were deriving all of the benefit by and large. And those that didn't harbor a mutation in the EEG FR gene, by and large didn't derive any BIFF and benefit whatsoever. So this opened up the first concept of what we call precision oncology. You would only give the drug to those that had an EGFR mutation in their cancer because those are the ones where it's gonna shrink down, melt away, and give fantastically benefit. Whereas in other patients it's gonna have no benefit whatsoever. However, so on the basis of this and other clinical trial data, the other the FDA and other regulatory agencies, reapproved, gefitinib for EGFR mutant non-small cell lung cancer, the first genotype directed drug approval for a common cancer. And this has changed the face of how we treat many cancers today. So we know a lot about EGFR mutations now actually we've been looking at them for 20 years and uh, we know quite a lot. We know for example, that by and large they're not, they're not heritable by and large, you're not born with an EGFR mutation. It occurs as the sole fundamental driver occurring within your airway cell, well not yours, but one's airway cell at some point in time to cause that airway cell to not die at the end of its natural life, but to grow, divide and replicate. We know, for example, that they're predominantly seen in never smokers, but we can see them in smokers, right? Because smokers can also develop the same biology. And so you cannot tell whether a patient has got an EGFR mutation or not when they walk into the clinic. You actually have to take a sample of their tumor, you have to analyze it, you have to do the gene sequencing to see whether it's present. And we identified that the frequency of these d these mutations for reasons that we can discuss afterwards, seems to be much higher in eastern and South Asia than it is in Western Europe and in America. And so that exactly tells us why those early patients that were deriving the benefit from gefitinib tended to be East Asian, tended to be nevi smokers. We saw see a higher frequency in females as well. So this is one of the first cases of EGFR mutant lung cancer. We identified in our clinic in routine clinical care. These are the scans, the right hand scans of a patient that, uh, I saw she was a young never smoker, actually not similar to many people sitting in this room. And uh, she was feeling great. And over the course of about three months her cough, which was thought to be a just a cough, we all get a cough, didn't go away, got worse and worse and worse. And she ended up being hospitalized. Hospitalized. And she couldn't breathe. And she was in trouble. She was in oxygen, she was in big, big, big trouble. And this scan on the left hand side shows on the, you can see that there's this big dark black blob that's full, a lung full of air, but on the other side it's full of gray stuff and that gray stuff is thick, solid tumor, not a aerated lung. So what do we do? We take a biopsy of that, we send it to the lab, the lab does some fancy stuff. And at that time that fancy stuff was just looking at the EGFR gene. We weren't doing anything else at that time, just in 2004. And it came back and it showed that the patient had an EEG FR mutation. And we saw the patient we could access this drug at that time, gefitinib, we started on it. I said, listen, you don't need chemo. It's a waste of time. It's gonna be difficult. Start this tablet, start taking the tablet tonight. You get home. Make sure you go to pharmacy, pick up the tablet, start taking it. I caught up with her a few weeks afterwards and we did the CT scan. You can see the CT scan. That solid tumor on the right hand thing is completely melted away. I said to her, what, what happened? And she said, well, within three days I was able to breathe much more freely. I could come off the oxygen within a couple of weeks. I could get up the stairs after a week, within a month she was effectively living, uh, a normal life. And so this is a really remarkable benefit. It's almost like giving antibiotics for an infection. It just melts it away. We've never seen this with any form of treatment before in cancer. So moving forward in 2004 when we are classifying lung cancer by what it looked like under the microscope, we are calling it patterns of what it looks like under the microscope, either adenocarcinoma or squamous cell carcinoma. That was the traditional view. We move forward to where we are now in 2024. We actually know there are multiple, multiple types of genetical creations and they have different frequencies in Asia, which is on the outside part of the pie chart compared to non Asia, which is on the inside part of the uh, pie chart. And we know that we can sequence and genotype these, uh, genetic abnormalities in routine clinical care. And in fact, when we're treating lung cancer these days, you can't really treat lung cancer and give them the right, give our patients the right drug until you've taken the sample of tissue, put it through the genetic analyzer. The guys in the lab have done their magic and told us what's going on. In fact, as science has developed, we identified many other mutations. So this is a type of genetical creation. This is the next druggable alteration that we identified. This is called an ALK fusion. This is again, uh, another young patient that came to see us. Uh, now at that time, uh, a company called Pfizer were developing a very interesting chemical. This chemical was called PF O2 3 4 1 0 6 6. Very fancy name right? And um, it actually turned out that it's a very potent inhibitor of a kinase called ALK kinase. And they also at the same time with scientists, discovered that there was an abnormality that occurred in some lung cancers called ALK fusion or ALK gene range gene rearrangement, which switches on the ALK protein when it shouldn't be switched on. So they figured that if we give an ALK inhibitor to patients with ALK gene rearrangements, it would do exactly what we'd seen with gefitinib. And indeed, lo and behold, we see dramatic benefit. And this is indeed one of the first patients that we saw. You can see in the scans you've got all these white blobs, like little canon balls in the lungs. These are all solid deposits of cancer. If you'd taken this out, this would feel like a hard lump of concrete. It wouldn't be a soft flexible lung, right? Soft. And actually we, I, we took a sample of this patient's bi uh, biopsy from the lung, put a needle in there. The guys in the lab did some amazing genetic sequencing. It came back, it had a ALK gene rearrangement and ALK fusion. We were able to start the patient on PO 2 3 4 1 0 6 6, which at that time had been given a name and that name is crizotinib. It was the first licensed registered ALK inhibitor. And again, within a few days the patient comes off oxygen, they're feeling much better, they're really doing remarkably well. So moving to 2024, where are we and what are we doing? So we can take a whole group of patients now that come to our clinic at the time of diagnosis. We can take their tissue, they all look the same, they all look like they've got lung cancer. But we then use gene sequencing to identify which group of genetic alterations are present and try and match that to the appropriate kinase inhibitor to try and get this effect where we can rapidly shrink down the cancer. And that determines whether they get a simple, straightforward tablet or we treat them with immunotherapy, which is another treatment that my colleague, professor Larkin will be speaking about with or without chemotherapy. And uh, the question is how much of a difference is this really making? So in the early days our American friends did a what's called a clinical trial. And uh, this is a trial that they reported on in 2014 and they did something called the Lung Cancer Mutation Consortium Study, the LCMC study version 1.0. And here a few academic centers in the US because they had the technology at that point and it hadn't really been disseminated to the rest of the world, took newly diagnosed patients with lung cancer, they sequenced their cancer, they worked out what the genetic abnormalities were and they tried if possible, to match it to a tablet to if the one was available. And they simply looked at the outcomes, what happened to these patients if they had a genetic abnormality and they got the tablet, if they had a genetic abnormality and they didn't get the tablet and if they didn't have a genetic abnormality. And you can look at the survival and you can see that finding the genetic abnormality or the driver and matching it to the targeted therapy hugely improves your median survival. Huge improvements in quality of life as well. And so now in 2024, things are very, very complex because in patients with adenocarcinoma, particularly we should be sequencing their tumor at eight different genes. And within the gene we are looking for many hundreds of different types of genetic abnormality. And if identified, we are able to match them to the appropriate targeted kinase inhibitor. And these are the lists depending on which regulatory authority you are working by the FDA, if you're American, the MHRA, if you're British or ema, if you are according to Europe, uh, these are the different drugs of the kinase inhibitors which match to different genes which can have genetic abnormalities. And if you are thinking that you're gonna be really depressed because we've got a rubbish NHS, which doesn't do any good, actually, I'm gonna tell you a good news story.'cause in green, all the ones that the NHS funds for you free of charge no cost to other than the additional tax that we pay out of our routine care. Isn't that brilliant? So we have access to all this excellent genetic sequencing technology and the drugs to derive this in routine clinical care. But Houston, we have a problem. These patients are not being cured despite the cancer melting away because ultimately after a period of time, be it one year, two years, three years, even longer, the cancer reoccurs. And what we've identified is that if we give the selection pressure of drug treatment to the cancer, cancers are clever because they evolve over a period of time and they evolve and change and they become resistant to the drugs that we expose it to. And then over a period of time these cancers will grow. So human beings are even clever. We're cleverer than cancer. At least we'd like to think we are. So we've done quite a lot about understanding what the resistance mechanisms are to the drugs. And that's of course through the great help and support of our patients who individually donate themselves for research. And I'm very, very grateful for all of our patients that have helped us. And there are a number of different mechanisms for which drugs stop working. There's one group of mechanisms, for example, called pharmacokinetic mechanisms. So for example, on the right hand side, patients may say, listen, I'm not gonna take this drug anymore. They just simply stop taking the drug. And that's understandable 'cause the drug is causing a whole load of side effects. The quality of life may not be worth taking the drug in the first place. It could be something pharmacological, maybe that there's a drug drug interaction re resulting in the reduced by availability of the drug. If you are taking the drug with food, maybe that's reducing the amount of absorption and you shouldn't be taking it with food. You should be taking it on an empty stomach. Maybe you're swelling it with Coca-Cola, which is changing the absorption of the drug in your stomach. And you don't really wanna be doing that. You wanna be taking it with some water. Or it could be that the drug is fantastic, but it's not getting into the places that it needs to get into. The classic place that it doesn't get into is the brain because the brain blood supply is protected. We've gotta protect the brain that, that, that controls us. So that's called a sanctuary site. But many of us have been doing biopsies in our patients where the drug stopped working. And then we've been sequencing the DNA of those cancers to see what has changed. And what we figured out is that there are what are called on and off target mechanisms. These are called pharmacodynamic uh effects. And what we see is that you can see that I've highlighted that the cancers change their DNA, they evolve new DNA mutations to then stop the drug from binding to the kinase to stop the drug from working. And you can have new DNA changes on the target on the actual abnormality, or you can have new DNA mutations which open up other signaling mechanisms within the cell to bypass what's already been inhibited. And that's called bypass tracks. And you can have really bizarre things that the cancers themselves just totally change. And when you biopsy them, it's no longer an adnan carcinoma. It's changed into something really quite different called, for example, a small cell lung cancer. And so we can see that genetic alterations occur in patients with cancer and that's really very effective. But how do we deliver this genetic testing outside the erudite laboratories and the high towers that many of us are in our academic institutions into routine clinical care so that the whole population can derive a benefit with quality, confidence and equity of care. So biomarker testing or gene testing I would suggest is quite a complex process. Somebody once told me that actually it's not that difficult. It's not rock rocket science. That was the head of the lab by the way. And I said, actually, listen, it is actually really quite complex.'cause we have to remember that you've got a patient who's been diagnosed, there's really quite sick, especially if they've got lung cancer, they're coughing, they can't breathe, they're pretty unwell, they've got significant medical complications. We have to obtain the sample from their lungs. Usually it needs to be analyzed in the genetic lab. That report then needs to get to an oncologist who then needs to understand it to prescribe the medication. That's quite a complex sequence of events that needs to occur for everything to work. So multiple problems can occur. Who orders the molecular test? Is it the respiratory physician? Is it the pathologist? Is it the oncologist? Well, the oncologist has never met the patient yet. They don't even know they exist because these patients are in the care of the respiratory physicians.'cause who knows whether they've really got cancer, maybe they've got TB or some other, uh, problem. How long does it take for the sample to get from where it's sitting to the lab because the sample's probably not sitting in the place where the sample was taken because everything is now centralized in different laboratories. It's probably in some remote location where it didn't start off with. Now generally the lab are doing a pretty good job in analyzing it, but actually are they analyzing it? Doing the right tests for what I as the oncologist want to know, they're basically doing the same thing day in, day out. It's like a factory, which is great, but maybe they're doing too much for the sample and I don't need this information or they're doing too little and I actually want some more information, uh, about this. And finally, who receives the report? Well, the person that's actually actioning the report is the oncologist and that's the person at the end of the chain that's never met the patient in the first place. So how does the person that's starting the chain know who the person at the end of the chain is gonna be and ensure that the report gets to that person? And how does the oncologist, who actually has probably never been trained in genomics actually understand any of this? Because when they trained in oncology cancer treatment was completely different to how it is now. So everything is very, very complex. Now, when we look at the tests that the laboratory do, there are many different tests that that they can do. They can do something called single gene tests, which are superb, they're very fast, but they can waste DNA and they tell us about what's going on within one single gene or not. And they can do something called next generation sequencing, uh, which are, um, uh, panel based tests. They look at many tens or even hundreds of DNA gene of the DNA in the genes. And they can look at the DNA and they can look at the RNA. And I would suggest this is what we should be doing as routine standard of care now. And actually many labs are are doing this. We can be using a test called immunohistochemistry, which is rapid, it's fast, but it sometimes gives you false positives, sometimes gives you false negatives. And sometimes you need to look at the DNA to really understand it. And you can be using a technology called fish or fluorescent in situ hybrid hybridization, which many people used to think is a gold standard, but actually can be quite slow and can really be quite problematic. And actually the gold standard is if you give the tablet to the drug, does the patient actually benefit really?'cause that tells you whether they, you've got a genetic alteration. So I've spent a lot of time talking about genetic alterations occurring within the cancer tissue itself. But what about the background? We need to understand the background of the, um, the tumor, uh, that we are looking at. So look here, we can see the front, we can see the deer, we can see the gazelle's, but we can't see unless you look very, very carefully what's going on in the background, which is this cheetah lying at the back, ready to pounce. And the same thing in genomics. We can look at the EEG FR mutation, we can look at the ALK fusion. But in the background, I want to understand the genomic architecture because I wanna understand whether these background mutations such as TP five three is going to cause any changes in how my drug works, whether it's gonna change the metabolism, whether it's gonna mean that the right dose is that the dose is correct for the patient and what their prognosis is. So I spent a lot of time talking about genetic alterations which occur within the cancer itself. These are called somatic mutations or so somatic alterations. What about genetic alterations that we are born with, right? These are called heritable mutations and they occur in all of the cells of our body. Can these mutations cause cancer? And if we know that they're there, can they help us treat the cancer? Well, all of you'll know that Angel, Angela, Lena Jolie's story about BRCA mutations in breast cancer. So of course we know that, uh, some mutations can occur in very, very, very low level in the population which cause cancer. But actually the classic example of how these mutations can help us drug cancer is the story of BRCA one, BRCA two mutations. So the institution that I'm working at, uh, was looking at BRCA one and BRCA two mutations. And these are very, very rare in the general population. Less than half a percent of the population is born with a BRCA one or a BRCA two mutation. But if you have these, these increase your risk of developing breast cancer. Prostate cancer, uh, gynecological cancers and even uh, pancreatic cancer and seminal work in our institution identified that if you have a patient with cancer and it's caused by this genetic abnormality, BRCA one or BRCA two, these cells can no longer repair their DNA. And if we give them a tablet called a PARP inhibitor, it can destroy that cancer cell. And this led to the first phase one trial led my co led by my expert colleagues in our institution where we found these patients with BRCA mutations. They were born with them, they developed breast, ovarian, uh, cancers. By and large, we gave them PARP inhibitors. And lo and behold, the PARP inhibitors were causing the cancers to be, uh, shrunken down beautifully. There's a great example of how academic research can really hugely influence, uh, uh, uh, cancer care. And uh, this drug olaparib, which is a PARP inhibitor, is now licensed and approved, uh, by and used in many, many thousands and billions of patients worldwide. So what about lung cancer? Do we see that lung cancer is heritable? Well, by and large it's thought that it's not heritable. Uh, and uh, EGFR mutations tend, uh, so mutations tend not to be seen in lung cancer that people are born with. But we're finding a more complex story and we're finding that in some patients with lung cancer, particularly EGFR mutant lung cancer, there is a heritable risk. We've been looking at this in our institution. We've implemented what's called mainstreaming genetic testing where we'll take patients with a high likelihood of having heritable mutations, people with EGFR mutant lung cancer and testing them. And we found that up to one in 10 of these patients were born with a likelihood of developing lung cancer, which has massive implications for their family and has huge implications for how we screen for this in the future. So are we able to do this? Are we able to test in detail? I think a lot of people got their head in the sand and they're really not looking deeply into whether patients are born with herital mutations.'cause we don't really understand what it means, how likely it is you're gonna get cancer, what we do about it when we are identifying it. But if we do a cancer test, we can potentially identify or at least get the signals to work out whether that mutation is something that's only in the lungs or it's something that you are born with and that needs further investigation. I think, um, it's one of the areas that I think will carry, carry on growing over the next few years. So we are testing our patients through, uh, a number of different, uh, genetic tests. And one of the, uh, issues that have come up is can we not do any of these genetic tests through simply the power of a blood test? We've actually identified that from a simple blood test. You can actually look at the plasma, which is the soup or the glute that all the cells are swimming in, in the blood. And if you look in the plasma at very, very, very, very low level, you can find small fragments of the DNA of cancer in a patient with cancer in the plasma from the blood. And so we are now in a position where we can simply from a blood draw, analyze these small fragments of DNA, which tell us about the genes of the cancer because these genes have been shed from the cancer and floated out into the plasma. And this is called something called circulating tumor DNA or CTD NA. So if you find this in the blood, the question is does this really reflect what's going on in the cancer? And the answer is, yeah, most of the time it does. There's very good concordance between the genetic alterations that we find within the blood and the genetic alterations that we find at very, very low levels in the, uh, uh, tumor. But sometimes what we find in the tumor, it doesn't reflect what we see in the blood. And sometimes what we find in the blood doesn't necessarily affect what we see in the tumor. And that can happen for many different complex reasons. And understanding these DNA fragments in the blood is actually even more complex than understanding the DNA fragments from a tumor. Because when we look at the genetic material from plasma, we've actually got three different genomes we are looking at. We are looking at the genomes or the DNA, which is derived at very low level from the tumor, which is the stuff that's in blue In that graph, we can look at the, the, the DNA and we can, uh, see whether it's actually derived from the white cells, uh, that we are born. Then the white cells represent the cells that we're all born with. So it's a heritable thing and that's called a germline genome. And sometimes the white cells change as we get older and they develop new mutations and that's something called the heme genome. So analyzing blood is really quite complex. Nevertheless, CTD NA, I think is gonna revolutionize clinical care and I'm a believer in, in the role of blood testing and ctd NA. Now here's what typically happens in the clinic to patients. They get referred to their gp, uh, they, they so go to see their GP and the GP refers 'em to the hospital.'cause the GP thinks they might have lung cancer. They attend the respiratory clinic. They've usually had a CT scan before they see the respiratory specialist. He looks at the CT scan and says, oh, I don't think this looks good. This might be, uh, cancer. They then go un undergo different scans. They then have a biopsy, which is a camera down the throat or into the chest to take a sample. The sample then gets looked at by the pathologist. He confirms the diagnosis of lung cancer. The pathologist then sends it to the molecular lab to do the gene sequencing. And the patient's waiting all this time to figure out what is going on. They see the oncologist, the oncologist usually hasn't got the results and the oncologist says, well, I'm not sure what I'm gonna do. I'll see you in a couple of weeks when we've got the results and we'll try and figure out what's gonna happen. A very unsatisfactory state of affairs, I'm sure you will agree, but what would happen if we, I implemented blood draw at the same time as we were doing the genetic testing of the tumor material to look for the DNA of the tumor in the blood. Wouldn't that speed things up? Wouldn't that tell us what's going on in more detail? Well, we've done this in our institution. We evaluated just under 250 patients that were coming through the doors and we published our results. And what we found is that there's extremely good concordance between the genetic ations in the blood and the tumor. But CT DNA analysis identified 25% more genetical alterations in blood then were found in the tumor. So the tumor is not necessarily the gold standard, but similarly, not everybody was shedding their genetic alterations into the blood. So ctd NA, the blood test missed 25% of genetic alterations 'cause they simply weren't shedding it into the blood. And we picked them up in the, in the tissue. And if you combine both of them, they're complimentary and increases the yield of genetic ations by nearly 50%. So, you know, if you're leaving no stone unturned, you do both the blood and the tissue. But the implications of implementing this are even more important. What we found is that ctdna is quick. It's much quicker than that long complex process I was talking about. And we were getting the results from the ctdna analysis eight days from the time of the blood draw compared to 22 days from the time of the tissue biopsy. And as a result, the clinicians were aware of the genetic sequence in a clinically meaningful way. And this is really, really important because it improved our results by nearly 63%. The, the rapidity. This has major implications because the genetic information is really critical for our drug decision making. And it turned down, it speeded up the time that we could get people on treatment from 35 days to 16 days. A difference in nearly 54%. Believe me, if you've got a relative in that situation, every day is absolutely critical. So it has other implications. What happens, for example, if the patient has, or we think they might have lung cancer, but they're really frail, right? Do I really wanna put them through a biopsy? The biopsy might be really risky, right? I might cause a blood clot or I might cause a bleed or I might cause the lung to collapse. Is it really necessary? What happens if you've taken the biopsy and the pathologist says, well I've only got a few cells on here, I can't do the molecular analysis. Well, another thing that you could do is to do a blood draw at that point. Uh, and that might help us, uh, uh, identify uh, what we are going to do and uh, give us the genetic information to really guide our decision making. And we can do this by looking at blood draw at the time of, uh, suspected diagnosis. So what we are doing here is speeding the blood test up. So we are not doing it later down at the point at which we know the patient's got cancer, but we're doing it at the point at which the patient walks into the hospital.'cause we think they've got lung cancer, we've done the scan. So let's just do the genetic testing up front. Wouldn't that speed things up? Give us much more information much quicker.'cause it only takes a week to get the result, right? So when Covid hit, COVID was bad for many, many different things. But Covid was good because actually we implemented this because we couldn't do any biopsies. It was all shut down. We couldn't do anything 'cause it was a covid generating procedure. So we did a small, uh, pilot test test. We tested 49 patients and we were actually able to start one fifth of these patients on their targeted therapy before or at the same time as we knew that they had cancer. And indeed, we've now, uh, been working, uh, uh, uh, with NHS England. But before I do that, I'll show you the scans. This is a a, a patient who, uh, was in the pilot program. You can see that lump, which I've highlighted in red. Uh, we weren't able to do a biopsy because of Corona. Uh, we did a blood draw, showed that this patient had what's called a medex on 14 mutation and were able to start a met inhibitor called tetin. At that time, cancer shrinking down beautifully and almost several months later, we had the result that it was an adenocarcinoma that was driven by a MET 14 from analysis of the tissue. So we've been working with NHS England and they've really recommend taken up our guidance, which is that we start implementing ctdna right at the beginning of the journey in the respiratory clinic. And there's an ongoing implementation, uh, uh, pilot program of this in the clinic with 700 patients in England, uh, are being tested. We've nearly completed that and we're going to, uh, nearly complete phase two, which is 1800 patients all having ctdna tests at the same at the time that they walk into the clinic. And if this is implemented in routine clinical care by NHS England, uh, England will be the world's first country to implement ctdna at scale, uh, which will be absolutely marvelous for us. So in the final few minutes, what does the future hold? Well, you won't be surprised to learn that there's a huge amount of activity ongoing with genomic technologies and their implementation.'cause listen, tech's getting more and more complex, isn't it? And so implementing tech is getting more and more interesting. So when it comes to tissue analysis, our understanding of the complexities of the human and the cancer genome, well, I would suggest very much in the infancy. The more we analyze, the deeper we go, the more we find the more questions we have. So we've been talking about gene testing of many, perhaps 10, 20, 30, 40 genes. But once we start doing whole genome sequencing, we find many more complexities and patterns in the genome. And we've been doing some whole genome sequencing in part of a hundred thousand cancer genome program. We know, for example, if we do whole genome or whole exome sequencing, we can do cluster cancer genomes into 21 different signatures. We've got a signature of genetic mutations that incur in people who smoked. We've got a signature of genetic mutations in cancers that have occurred in people who've had exposure to UV light melanoma, for example. But how are we gonna use this in the clinic? I'm not so sure. We need to figure out how we're gonna implement this in routine clinical care. Similarly, we've got a massive explosion of implementation of CTD NA into our clinic. For example, if a patient's undergone curative surgery, if they're lucky enough to have stage one or stage two cancer, it's fairly easy to do a CTDNA test to see if I can find any fragments of the alleged cancer, which has theoretically been cut out floating around. And that's called residual tumor derived, uh, DNA. So we know that that can be done. So that's called technical utility. But does that actually mean anything? Does it actually change what we do if we give patients more treatment? Does it actually increase the cure rate? That's the clinical utility and that's not necessarily being proven, uh, to date. And what are the pros and cons of this, uh, technology? So similarly, we can take a group of healthy individuals and ask all of them to have a CTDNA test. Don't worry, I'm not gonna do that. You're safe in this audience. And if we detect CTDNA tests that might tell us if you've got cancer, that might tell us if you've got cancer months, years before you end up seeing a doctor. We know it's possible. We definitely know it will pick this up. But what does it mean? Does it actually change anything about what would happen to us from a natural lifetime viewpoint? We just don't know. We don't know the clinical utility. We know it picks up cancer. We know it picks up late stage cancer very well. It's not very good at picking up early stage cancers. There's quite a big job still to be done improving the clinical utility. So with that, I'd like to close and I would like to thank you for your attention and uh, I'm very happy to take any questions if there are any. Thanks for your attention. Thank you very much Professor Poppa. That was a really easy to understand overview of a very complex subject that spans over 20 years of development. So thank you so much. Um, so for everyone in the room who are watching online, you can use the QR code that's displayed on the screens above using your phone to ask any questions. And we also have a roving microphone within the room. Please just pop your hand up. I'm pleased to say that we already have a few questions for you. That's exciting. Before We move to them, I have one last logistic point that is that stay with us this evening. If you would like, there'll be some drinks including glasses of wine served. Please click the back door. If you're watching online or on demand, please feel free to go to your wine rack and join us. Uh, so to go straight to the questions, if you don't mind, I'm gonna go to one of the, the most recent ones that we were asked because I think it follows on really well from what you're finishing on. And that's just maybe there are more in the audience wondering this. Could you please repeat what CTD NA circulating tumor DNA testing is? Yeah, So circulating tumor DNA is basically when you take a blood draw and in the blood, the blood is composed of lots of cells. You got your red cells and you got your white cells and they're swimming around in a group of soup. And that group of soup is called plasma. And if you look in that plasma at very, very, very, very, very, very low, low levels, you will find small fragments of DNA. The question is where has that DNA come from? And we know that if you've got cancer, we know that those DNA fragments have probably come from the cancer. So we can take a blood test and we can look at the plasma and at very, very, very low levels we will find DNA. And that DNA in a patient with cancer reflects what's going on in that patient's cancer. And it's even more exciting than that because for example, if I take a biopsy of a patient with cancer, I'm putting a needle into one lump. Nobody wants that, do they? Right? I mean, who'd wanna volunteer to have a needle to go in your chest? Definitely not me. So isn't it be easier to do a blood test? But if a patient has got more than one lump in their body, they've got a lump in their lungs, they've got a lump in their bones, they've got a lump in their liver, that blood test will tell us about the DNA of all of those areas. So it tells us about the whole cancer picture, not just the little bit that my needle's going into. Very clever. Absolutely. And I think just adding onto that, when you do the biopsy, there's every chance that you miss because it's such a heterogeneous group of cells that you can absolutely miss some of the information. And I think it's, um, it's really wonderful that we've been able to move towards this. One of the key things is tissue is the issue. So being able to, to do this is great. Uh, so one of the ones that's been, um, highlighted as po as as popular is, do you believe there could be a risk of speeding up the development of medication treatment resistant cancer through using the targeted treatment options? Yeah. So is targeted treatment gonna cause more resistance of, of the cancer? So by and large, no. Uh, it doesn't do that actually. Um, because cancer's gonna change whatever you do to it. So if you don't do anything to the cancer, it's gonna grow and evolve. And each time a cancer cell grows and divides and replicates, actually errors come into the replication process. So the daughter cells aren't quite a hundred percent of what it starts off with. It's about 98%. It's got 2% new genetic crap that's built in, uh, that's a technical word. Uh, and um, when you apply a drug onto a cancer cell, whatever drug you give, whether it's gonna be immunotherapy, whether it's gonna be chemotherapy, whether it's gonna be hormone therapy, whether it's gonna be kinase inhibitor therapy, cancer will evolve because cancer changes all the time. It's a living organism, it's a living beast. Whatever you do, you apply a pressure on it, it will find a way to change.'cause it doesn't like to be constrained. So what we've gotta do is to make sure that we can kill the bits that we can kill and then map and kill the bits that we've left behind to try and eradicate it the best that we can. Exactly. Hi, uh, thank you for a great session, Sanjay. Um, I was just wondering, you sort of touched on it, the end. Um, what would your thoughts be in terms of any side effects or ethical issues with mass screening of individuals or mass genetic testing of uh, seemingly healthy individuals? Yeah, so the question is really when it comes to ethical issues, it basically boils down to are you gene testing that human being to see whether they're born with a heritable condition or are you actually testing them to see whether they've got any, um, picture of cancer in them? If you are testing a human being to see whether they've been born with a hereditary condition, you can't really do that without actually having an ethical discussion with that patient as to what it means as to what the pros are, what the cons are, whether it's useful for that patient or not. But what you can do is to ignore all of that information and not even look at it and just focus on the stuff that tells you about whether that patient has cancer or not. And we sort of did that in the a hundred thousand genome program because we were able to do that and we were saying to patients, do you want to know? Do you wanna opt in to the information that might be garnered about the hereditary bit or do you wanna opt out where you don't want to know about that information? And when you are opting in the information that's being provided to the healthy people or the uh, uh, patients with whatever condition it was, were very, very carefully chosen when our understanding of the relationship of that gene and the disease is rock solid.'cause do you remember what I said at the end? I said, our complexity of understanding of genes and diseases only just at the beginning. So just because you have a genetic abnormality doesn't mean to say you'll definitely 100% develop that disease in your life. That's the percentage probability of that occurring is called penetrance. And the penetrance of many of these gene disease effects is way less than a hundred percent. So there's a lot that we still need to learn. And of course there are ethical issues and that needs to be discussed at scale. But usually when we're talking about cancer detecting, we are not talking about these hereditary issues. Okay. Moving back to the, the questions online, do patients often receive targeted therapies alongside chemotherapy and immunotherapy or is it one treatment modality attained? Yeah, great question. I think, um, the answer to that question is it basically depends on the type of cancer, but fundamentally we give them, well, when we start off treating patients, we generally give them as individual treatments. When it comes to targeted therapies, I'm talking about, um, immunotherapies and targeted therapies generally don't mix very well because of various, um, side effect issues that one can trigger. Uh, with the other, uh, we can combine chemotherapy with targeted therapy, but we do that under very specific circumstances when we are wanting to drug very specific issues. But by and large, what we want to do is, 'cause we know that, that the abnormal genetic abnormalities that we are looking for are fundamental drivers. They're in each and every single cancer cell. It's driven that cancer to grow. We want to cut that cancer at the tree roots. We don't want it to grow and divide. So we generally use single agents. And when we use single agents, we minimize our side effects and that gives patients the best quality of life. Mm-Hmm, Absolutely. Are there any updates on why the EGFR mutation, uh, is more common in South Asians? Oh gosh, that's another lecture in itself. Yes, professor, I did what everybody asking you that one. So we, we are not sure we know is the answer. Uh, but there are some very good data coming out which confirm. What we have previously identified is that there's a very strong link between air pollution and lung cancer in never smokers, particularly EGFR mutant lung cancer. And we're talking about pollution, we're talking about the diesel microparticles that we're all worried about. And we see a lot of epidemiological links between pollution in Asia, uh, exposure to diesel particles, exposure to wood fumes. And people don't like long burners for the same reasons, not just because of green, because there actually is some risk with that exposure to charcoal fumes, exposure to kerosene fumes and other Ignatius uh, um, uh, fuels. We know that this tends to cause a variety of abnormal processes to occur within cells. And great work done by, by my colleague Charles Swanson and others in the UK have confirmed that exposure to pollution changes the way cells behave, which makes them more likely to develop a random mutation. Why it's the EGFR mutation that occurs, we don't really know. And that's other work that the ourselves and others are doing. Um, but there's definitely a link with pollution, which is probably contributing a lot to that. Okay, thank you. Uh, we have time for one more question. So I'm gonna go to one here unless there's a burning one in the room. Um, and just to reassure you that, that there will be other opportunities for these questions to be answered by profess poppa including a panel session on the 12th of March. So pleased to register for that as well. So a bit of a tough one to finish, uh, in terms of trying to keep it short. So what do you see as the biggest opportunities and challenges for genomics and other omics to improve cancer care over the next five to 10 years? Uh, twofold answer, uh, implementation once you've figured out what the solution is, because the solution is never the same as what it's implemented. And the biggest challenge, I think before it's implemented is actually our understanding of omi because actually our understanding of OMI every year, I think I've solved it, I know what's going on, but then another paper comes out or have a chat with my colleague down the corridor and he's found something else and it's just completely destroyed one theory and opened up another theory. So our understanding of biology, uh, is constantly changing. And our understanding of cancer genomes and cancer biology is constantly changing. So maybe AI will help, but maybe just good old fashioned common sense with a bit of AI will help. But, uh, I think the biggest challenge that we'll have with OMI in general is just our, our understanding of where we are. Thank you so much. I'll hand back over to Martin to close the session. Thank you. Pleasure. Thank, thanks both of you. Uh, it's a very thorough, I was gonna say scan, but that's kind of understating what you've done. Hugely complicated. Feel beautifully presented. Thank you very much. And Nicole, thank you, real privilege to have you here. Thank you very much and please join me in thanking Sanjay.