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Hello, everyone and welcome to our medical oncology, event, Medical oncology is part of our medical education program. Um, and we are delighted to have you today. I am joined by uh Caroline who is gonna be chatting about making progress in metastatic breast cancer. Um Caroline actually came across my path when she actually responded to an email that we sent out about prostate cancer and about um, er question banks and she, I don't know if she might think it was unfortunate that she did respond and said no, I'm, but if you have anything on breast cancer, I'd love to, you know, that's my thing. And so a conversation was started and I told her about medical education and about the, what it is we do here and, and thankfully, she has said she will come along and join us and give you a talk today. So at the end of this, we're gonna have uh a feedback form will be in your inbox. Please fill it out and I can pass all that on to Caroline throughout the talk if you have any questions whatsoever, put them in the chat. Um, for those of you that are regular on our medical education events. You will know I am not medical and I will not be able to probably ask any questions at all at the end. So please pop your questions in the chat and we'll get round to them at the end. So without any further ado, I am gonna hand you over to Caroline. Thank you. Thank you, Sue. And um hello, everyone. Um Thank you for asking me. I'm a consultant medical oncologist in Edinburgh and uh honorary clinical senior lecturer at the University of Edinburgh. And also I'm a research clinician and this is very good timing because actually it's breast cancer awareness Month is October. Um So I'm going to talk you through. It's a bit of a whistle stop tour of progress and metastatic breast cancer because there's been so much new data recently. Um But hopefully you'll find it interesting and not death by Kaplan Meyer Curve. So these are my disclosures. Uh This is the agenda I thought would cover a little bit a bit about the background of metastatic breast cancer where we were when I started out in oncology 20 years ago and where we are now um talk a bit about emerging therapies, the evidence for them and important toxicities and particularly if you work in community hospitals or somewhere where patients might be being admitted acutely, it's really important to be aware of those. Um I think something that's often forgotten about is brain metastases and we've really made quite a lot of progress here in particular. So we'll touch on that and I think it would be wrong for me not to talk about some of the global challenges. Um I know that actually more than, more than 50% of, of the group today are not from the UK. And II am gonna be talking about a lot of novel drugs. It's exciting science, but these drugs are very costly. So I do want to touch on that and a little bit about a bit about the future. So I'm sure this is not, this is a bit basic for but just to just cover as a starter who actually is cancer. And I think this is a really good um overall definition in the free dictionary. It's not just one disease, but it's a large group of diseases. And its two main characteristics are uncontrolled growth of the cells and the ability of these cells to migrate and spread to distant sites. And of course, it's often not where the primary is that that can result in death. It's because of that spread, that it causes obstruction or weakness of the patient or another complication like blood clots or sadly, some treatment related complications. So there's a multitude of complications once cancer spreads. So we're going to talk about breast cancer because certainly we tend to only really specialize in one or two tumor types at any one time. And that's partly because it's, each of them are diseases in their own cells and it's really hard to keep up to date with them because there's so much progress at the moment. For most of the tumor types, there are some that sadly are, are lagging a little bit behind. But I, I'm solely a breast oncologist. So, as you can see on the left hand side, actually, breast cancer doesn't kill as many people as actually, you know, in terms of new cases, you can see it right at the top there on the right hand side, but actually not that many people die from it, which is great news. And that's partly because of lots of research over the last 3040 years. Um and sort of mentioned that already about how does cancer cause death. So in 2000, just before I graduated autism, giving away my, when we talked about personalized therapy, which has been kind of a buzzword over the last 20 years. The only thing we really had in breast cancer was tamoxifen and that was for patients with estrogen receptor positive disease. But we still really didn't know who we should treat with preventative chemotherapy. We weren't sure why some cancers did come back even though they look quite small and not particularly nasty on the surface. And while other bigger ones didn't, and we only had a very small number of only modestly effective agents. And then time magazine often it does hit the spot quite a bit. But in 2001, just before I graduated, they mentioned this, there is a new ammunition in the war against cancer and these are the bullets and Gleevec was really one of the very first of the targeted treatments that have revolutionized cancer care since then. Um It was really the first proof of principle that by finding out what's driving a cancer, finding a drug that blocks it then and having good results. Um and that was really the, the very first of, of the targeted agents. And since then, and this is more about immunotherapy something we'll touch on later on, but actually been doing immunotherapy for years, actually came before quite a few lot of chemotherapies back interferon alpha back in the seventies. And then in the, in the nineties, the very first monoclonal antibody with trastuzumab or Herceptin and was started to come into clinical trials, but we didn't actually get access to that certainly in the UK until about 2004. So it took a while for it to filter through. And then 2010, we started getting the immune checkpoint inhibitors. And that's really what I think of as immunotherapy. Well, monoclonal antibodies are antibodies. They're not really immunotherapy in my mind is immunotherapy is about harnessing the power of the immune system to, to um see the cancer cell and then know how to attack it using the immune system. Um And the first immune checkpoint inhibitor was approved in 2011. And then more recently, they've been starting to do oncolytic viruses and then vaccines as well. So there's been a huge change over the, over the last 50 years. And um when I started oncology just after this, and we had this big chunky book called cancer and its management and it was kind of viable at the time. And if we look back to what it said back then about metastatic breast cancer with bone metastases, so cancer that spread to the bone, the the quote was the ultimate outcome for such patients is poor with a median survival of only about 12 to 15 months. Although some may survive for several years if sufficiently hormone responsive. And when it came to chemotherapy in metastatic breast cancer, it said despite some impressive response rates, any benefits are often short lived and the expected lifespan for patients with metastatic breast cancer has changed little if at all as a result of more widespread use of these treatments. So thankfully, that's not the situation we're in now and what really changed. It was really the biology. It was getting back to the science and trying to work out what is driving these cancers and how can we get better drugs that rather than chemotherapy, which is a bit of a, it's a bit of a stupid treatment. Really, it's a catch all about trying to target cells that are dividing more rapidly than normal cells. But of course, that's at the expense of significant toxicity. So it's been scientists that have helped drive forward progress and breast cancer. As I say, it's not a single disease. There are different ways of categorizing breast cancer but tend to think of it as four or five different types. So you've got your estrogen and progesterone receptor positive group. And that actually separates into two A NAS group called Luminal B and not, not as bad A cancer, Luminal her two positive. It's another protein we'll talk about soon and then something called triple negative breast cancer, which means it's negative for estrogen progesterone receptor and her two um some BRCA one and two mutation patient cancers associated with BRCA one and two mutations are a slightly different entity on their own. But there's a crossover and then there's some other breast cancers. Another important one is something called lobular. I'm not going to touch on that. So, clinical trials have really helped us work on the science and then test it in patients and find out what is it that's actually helping and improve outcomes. And you may know this but the different phases of clinical trials. So you might just mention this throughout the talk, but there's the preclinical phase which is when the scientists are working in the lab um in vitro studies. And then when they find something they think is theoretically helpful, it goes into phase one and phase one is the first in human studies and they tend to be really quite small. And the primary endpoint of these studies is about safety and tolerability and finding the right dose in humans. And it's often as crude as just looking at the lethal dose in a mouse or a rat and then dropping that lethal dose down to start a human. So a patient that goes into a very early part of a dose escalation study is probably unlikely to be getting anything that's even close to being biologically active. And so that's a real discussion that patients who go into these studies have to understand. So phase one is about safety and increasingly they do often do little subgroups to try and look for some data on efficacy or activity. But that's quite a novel approach. Then phase two is when you're looking to say, right, we think this drug is safe, we think we've got the right dose. Let's see if it works. And phase twos traditionally were non randomized, but that you often do get randomized. Phase twos trying to show maybe comparing two doses of one that goes against each other to measure the effect. You tend to be slightly bigger groups of patients, maybe 100 to 300 or so. Phase three are really the registration studies where you're, you're often comparing to what the current gold standard is. So it's often randomized and to what your normal treatment would be if you weren't on a study and they can be often huge studies, often multicenter internationals of several 1000 patients, particularly in breast cancer. And then phase four and is when we might do post marketing surveillance. So the drugs approved, but you're looking to gain more information on how does the drug really do? What the phase three study suggested? Are there any more important safety signals? And if you're thinking about clinical trials in your center, there are lots of arguments for them and lots of benefits for both the center and the patients. So for the center, we have need loads of supporting departments to run a clinical trial. So you need your pathologist, your radiology department, your potential radiotherapy or your surgeons all on site for your trial. And in a study, usually there's significant quality assurances that they will want for you to go into a study. So you have to be doing surgery the way that is considered the most optimal way in the moment or radiotherapy, for example. So there's an element of quality control and quality assurance for all the different departments. Now, if you're testing a study with a high cost drug, often that the the sponsor or the the pharmaceutical company will pay for that drug so it can offload your, your drug budget a bit. It increases your center profile which definitely improves clinician recruitment or retention. It might attract research funding. So it all becomes a virtuous cycle and from a clinical point of view, I know I really prefer when a new drug becomes approved. I've had some experience of it in a clinical trial setting because often you've got more time with these patients, there's lots of safety parameters for people on clinical trials. So you, you, you experience these drugs in a very controlled safe manner and then for patients, the obvious one is they might get earlier access to a novel agent or an improved technology or technique, whatever you're testing. I think a lot of our patients get potentially more personal or closer support because you should dedicated research nurses. And for some patients, they particularly in the phase one group that they may feel that they're giving something back. And for some people that is important, they want to give back because they feel that maybe had lots of treatment over the years. Um Some patients like to go into trials because there's more comprehensive follow up, there might be more follow up appointments or scans or blood tests. Some people might hate that idea and that's why they don't want to go into a study. But for some people, they like that. And I think there's no doubt there's better toxicity management because often research nurses are are really really detailed with the toxicities and clinical trials. And for rarer cancers, things like unusual sarcoma. For example, in oncology, it can be the only avenue to treatment. If there's no data, there's no evidence otherwise. So those are some of the arguments for clinical trials. So I'm gonna touch firstly on her two positive breast cancer. So her two is um uh it's a growth factor receptor, it's overexpressed in about 20% of breast cancers. About one in five women will have her two. And when it was first identified in the late nineties, it was thought to be a poor prognostic factor. And the patients who, if you compared a small, her two negative cancer to a small her two positive breast cancer, they had increased risk of relapse and worse survival. And this was one of the very first really important key studies and using chemotherapy and trastuzumab. So this monoclonal antibody against her two and for patients with metastatic breast cancer, and we actually put the patients in Edinburgh in this study, that's before my time. Um but the median overall survival for these patients who've just been diagnosed was only 20 months. So um isn't very long and that was really a landmark study. And then I have proof of principle. Again, we had Gleevec for the, the gi stromal tumors, but then this really was game changing. Um And that study that I mentioned, improved the progression free survival from about 4.5 to 7.5 months and it became available in about 2003. I've got a lady who's very funny who I look after and she went into into, it wasn't that study. It was, it was a trustee of access study. And around that time, and she'd been given a median survival of her around 12 months by, by the person that looking after her. Um, anyway, 21 years old, she's still alive and well and still and not at any second line treatment. Um, and she, she always says that the one thing she, she regrets is that she spent all her money and on them that she got for critical illness, which she thought that she had a really short, short time span. But actually, these new drugs really, particularly for some long survivors really change and change their outcome significantly. And then the Hero Study came out in 2005. And I remember the lady I was working for at the time, she was over in America where they're presenting the results. And this was the first time it really shown a monoclonal antibody improving the cure rate and the American Cancer conferences, about 30,000 people in this room that you can't even see the presenter. And um I think apparently people were literally on their feet, clapping, shouting and pooping because it was just incredible to show that they could reduce recurrence by by half and has a 0.54. So they reduced recurrence by by 46%. And this really was a huge seismic moment in oncology. And everyone said that energy in the room is just so exciting because we realized that we were really on to something roll forward another few years in the cleopatra study. I'm going to show you in a minute. But then it starts to show that if we give chemotherapy with two anti her two antibodies, so you're really blocking this, her two, the median overall survival here is now 56 months. Do you remember that? Just, um, what's that? Just 11 years ago, the median overall survival was 20 months. You're now up at five years. Um And then in 2022 probably one of the, the biggest and new studies that came out in recent years was, was this other drug which is building on trastuzumab. It's called trastuzumab Diam. And we have never seen such a and the hazard ratio is 0.28. We've never seen such an impressive drug in, in, in breast oncology or probably in solitary oncology ever. And the 12 month overall survival was 94% and I'll show you that some of those studies in a minute. So there's been a huge change. Her two breast cancer has probably seen the most development over the last 20 years. So this is this cleopatra trials and this is the cap meyer curve. So you see on the top the green group, that median overall survival I mentioned at 56 months and the people who didn't have the additional antibodies. So which is a very well tolerated treatment, the overall survival was 40 months. So you've got a 16 month improvement in overall survival just by giving an extra antibody. And at that time, that was the longest improvement in overall survival we've ever seen. And then this came along with the antibody drug conjugates. And this is what the next drug I mentioned was Deam. And it's a really clever kind of technology and there's three parts to it. You've got your antibody, which is usually the first word in the name of the drug. And so trastuzumab, that's the the, it's the antibody that that's um binding to the cancer cell. And then what you've got is a really clever thing called a linker. And the linker only releases the chemotherapy, which is the red star once the antibody has bound to the cell and it then kind of internalizes the the drug into the cell. And there's also what's called a bystander effect where all the surrounding cells, even if they're not necessarily her two positive will also get um some of that chemotherapy really targeted to that area. So it's real targeted treatment. And there's a few in development at the European Oncology conference a few weeks ago, I think I heard there was something like 60 or so in developments in various phases of clinical trials. But, but the four that are in more widespread use, one is trustees. So in your chemotherapy, then there's trust of that can um and another one called s and so you can see that all got, there's a whole art the names and oncology that all the different drugs names give me some. So this was um another study we were involved in Edinburgh at this was the, the very, the breast cancer studies about with one of these antibody drug conjugates. And this group was a group of really heavily pretreated patients. It's very rare to have 1/7 line study. And if you're not familiar with me, study breast cancer, your first treatment you get for me disease is called first line. And you often on that until progression and then when it progresses, you go on to second line and third line et cetera. So the median number of prior lines of therapy was six, so hugely heavily pretreated group. But despite that, there was still a response rate of 60% and the progression free survival was 16 months. So this is a group of patients who, you know, these people didn't exist 20 years ago because didn't have that many treatments. So this was really important data and this is called a waterfall plot on the right hand side and it gives you a really nice visual of how much treatment is helping a patient. So anything on the on the, on the x axis that is zero and anything that falls below that is a response to treatment. And then in oncology, we use something called the resist criteria for assessing response to treatment. And a formal partial response is 30% improvement. And that's that dotted line just underneath it. Um So each of these lines represents a patient in the study. There are just over 200 people on this and you can see people going right down to 100% and that's your complete response rate. So quite a small number of it had a complete response 6% but almost everybody was, was um was responding. And then you just see these very small number of patients, only one actually progressed. Um And it makes you wonder whether they were her two positive at all because that in that sort of waterfall plot is something that we we've never really seen before to have that many people responding. So we knew this drug was really active. And then this is the study I mentioned that was probably the biggest one since in recent years. And I mean, the blue line is Dan and the gray line is, which was at the time, it was the best drug we'd ever seen. And you can almost drive a forklift truck through those cars. You can see there, you separate very early and they stay really nicely separate and, and the median progression free survival for people on um was, was about seven months and they didn't even have a medium because people 50% hadn't gone down there. And if you look at the 12 month progression free survival, 34% were still well and not progressed on and, and 76% on. And this is just nothing that we've seen before in oncology. And these are these waterfall plots again, I see. It's quite a nice, gives you an immediate visual of how these drugs are working. You can see you're getting a lot more complete responses that the bottom flat line and with Dan versus in tans and you can definitely see more people progressing there. So it just gives you a real sense that this drug is highly active. Excuse me, we all want to know, you know, our survival. That's really the gold standard. But all these patients are doing so well. They all that there's more treatment options ahead. So the the the first interim analysis a couple of years ago of overall survival in that study is really immature. We're not even close to getting down to. So we need to wait for a while for that data. And this is a drug that is being tested in a what's called the Destiny Breast cancer trial program. And um if you look on the right hand side, this is how we do drug development. You tend to start in later line therapies. So you can see that Destiny Breast or one that first one there, then you start to bring it forward. And the study I just showed you was second line metastatic disease. And there's a study that. Um Again, we're part of in Edinburgh called Destiny Breast Nine, which is looking to see, well, when people are first diagnosed with metastatic disease, is this more active than the already really good drug we have for the 56 months overall survival? So we'll wait for those data. And then once you see, you've got an active drug and metastatic disease. The next question is, can we start to cure more cancers? And their studies are going as you can see that I've highlighted in red in the adjuvant and neoadjuvant setting trying to find out if we can cure more people. That's ultimately what we want to do. Yes, we want people to live well and longer with metastatic disease, but we really want to cure more people. But sadly, and it doesn't come at the expense of no side effects. And plus of Dean does unfortunately have a significant risk of um, interstitial lung disease or ILD pneumonitis. All means the same thing. And you can see these quite sick looking lungs with what's usually described as ground glass appearances. Um And um, unfortunately, this, it was highlighted in Destiny brest one study and it's been an issue although the company been great at trying to keep um doing lots of patient and clinician education, but undoubtedly this is a significant side effect and it's about a 15% risk across all patients being treated with the drug. But there has been one or 2% mortality across the differing trials. So it's something that really isn't really important to be aware of. And they have done a pooled analysis of lots of the Destiny studies as I see the overall incidence about 15%. Um And so there is advice to do regular CT scanning to try to identify asymptomatic or grade one side effects. But, but six weekly CT scanning is not always practical. Um It's a huge resource. So, and there's a lot of work ongoing at the moment, working at how is the best way to manage and identify patients more at risk of ILD. And these are some of the risk factors. Um history of pneumonitis or disease, poor overall health, smoking, more advanced age, the Japanese and African American ethnicity seem to be more at risk males or prior extensive treatments. So these are some of the things that help us to try to select patients for or not for these, these drugs. And then after that, we've got another new drug which is, it's not so much monoclonal antibody, but it's a tine kinase inhibitor called and this is what we also have in combination for metastatic breast cancer and different countries will have different ways of of when you can use these drugs. Everything is done as per in the clinical trials. But this particular study and was given to patients who've had prior treatment with the, the cleopatra regimen and the, the TDM One trust in third line. Um and actually about half the patients have brain metastases at baseline and her two positive disease is something unfortunate. It's more associated with um with brain metastases. Um And there's been a dearth of data for years. Patients were often excluded from clinical trials who had um brain metastases. But there's been a real move over the last five years to start including these patients and the overall survival in her two cli was 22 months and this is the third line treatment. So this is another drug we have in our armor. Now thinking about response in the brain. Um One of the the challenges we've had and one of the theories is that because of the blood brain barrier, the cancer cells can get across the blood brain barrier and find a home like a sanctuary. It's called a sanctuary site. So unfortunately, we are seeing um probably about half the patients now that relapse after primary chemotherapy and anti her two therapy or her two positive breast cancer when they relapse, about 50% have disease in the brain either on its own or in combination with a disease elsewhere in the body. So it's a really important challenge. And this is just presented at the European Cancer Conference a couple of weeks ago and published at the same time. And this was the Sin 12 study, which is one of these phase four studies looking to get a bit more information about outcomes. They had 500 patients in it. Over 50% with CNS disease involvement, 60% had, had previous brain radiotherapy. And you can see that even though they had brain metastases, the 12 month progression free survival was, was over 60%. And again, you can see that waterfall plot of improvements in, in, in disease. So there's no doubt we are able to get these drugs across the blood brain barrier and we'll talk a bit more later on about an issue around the world. But when these new drugs become available, it often takes quite a long time for them to become available to patients and particularly in countries who may not be able to afford these, these drugs. And they are very high cost drugs and it's extremely emotive. It's really difficult for clinicians, it's difficult for patients to know that something is out there that they maybe don't have access to. So we can't underestimate how difficult this is in, in many countries. It's hard to know that there's something there that could help you, but you can't get access to it. Ok. So that's like downer, we'll move on to er positive her two negative breast cancer, which is one of the most common types of breast cancer. And it's really a very heterogenous group of, of um cancers. So I mentioned earlier, Luminal A tends to be AAA less aggressive form and Luminal b tends to be progesterone receptor negative and often behaves in a little bit more of an aggressive fashion. The bone is often the, the first site of metastatic disease. Um about 40% of patients. Um but in er, positive breast cancer, it's uh the most common site of metastatic disease in about 55 to 70%. A lobular breast cancer is usually er positive and her two negative unless it's a particular uh a more unusual type called pleomorphic and it's usually er positive and her two negative. So I'm going to just give you a case and I like to have a think how many people have actually worked in oncology before. But about this lady and what you think her, her prognosis might be as we go through. So this is that this was a real patient. She's 54 she's working full time in the postal service, got a busy job. Um and back in 2015, she was diagnosed with metastatic er positive, her two negative breast cancer and she's got multiple bone metastases and in a variety of ribs and spine and she was on letrozole, which is a um it's an aromatase inhibitor, it blocks estrogen and because she was premenopausal at diagnosis, she was on or Z which is ovarian suppression and she was on Zoledronic acid for her bone disease to try to prevent um skeletal events like a fracture. Now, rolling through to June 2020 she's still on that first line treatment and she'd had a stable CT scan. But as we all know what happened in 2020 she was admitted in July and unwell with a fever and breathlessness. And on admission, her SATS were 75% on air and she had high suspicion of COVID, which was the case. So when we looked at the notes, the me junior doctor for medicine immediately said not for intensive care discussed DNA CPR in the registrar for medicine said not for ICU escalation of view of metastatic cancer, which I know we were dealing with things differently during COVID. And then the post take consultant says has the escalation, DNA CPR and discussion been discussed. Let's have a chat with oncology. So I just want you to have a think um things up. But what do you think her prognosis might be if you got metastatic breast cancer or bone disease? And she's been on treatment for about five years. So do you think it's less than six months, 6 to 12 months, 1 to 1 to 2 years, 2 to 34 to 5 or much longer? 5 to 10 or um more than 10? So estimating prognosis is really complex. So this particular lady, there are lots of really positive factors about her case. So she's already, you already know she's got endocrine sensitive disease because she's been progression free for five years on actually was not our best treatment. Now we've got these new treatments to talk about, but because she was diagnosed in 2015. She wasn't even on them. So she's on pretty basic hormone therapy and still alive and well at five years. So she has lots of different treatment options ahead of her. And no, um she's still actually fine and hasn't progressed. So even that first line therapy, she's now nearly at 10 years. So there are some patients that do extremely well and it's really difficult to estimate prognosis. It does depend on her type subtype. It is. And if that person's disease actually responds to treatment because until you actually treat one cancer with a treatment, you don't know if they're going to respond, you can give people uh 60% response rate or 30 based on the data, you don't really know what's gonna happen to them, their prior treatment responses and what we think of as their disease free interval or if it's me disease, the progression free interval is really important and it tells you a bit about their individual tumor biology. So the story of that person's cancer is really helpful to think about. Then of course, there's the patient factors. Are they fit, what's their performance status? Do they have comorbidities? The bottom line is, are they fit for these treatments? Um And then what is the burden of their disease? So she's actually got a really low volume bone only disease and actually she was diagnosed what we called de Novo. So when someone's diagnosed with breast cancer if they have metastatic disease at diagnosis, it's quite unusual but they do tend to have better outcomes partly because those cancers have not been exposed to treatment before. And therefore they've not been able to adapt and mutate and respond to their treatment. So you need to look at the, how much disease do they have, where are the metastases and you know, liver, kidney function, those sort of things and also what future lines of therapy are available. So, if I'm thinking about that lady, she might be one of these people who's got so more than 10 years to live. So she did actually go to it um as you can imagine and she's, she's well now, but it's really important that not to write people off just because you see metastatic disease because things are changing quite quickly. And of course, some people do badly, but there, there are lots of factors and it's really important to always speak to an oncology team if you're not sure. So what really changed in this type of breast cancer. And we've had access to these drugs since about 2018, they're called the CDK 46 inhibitors. So, and Cyclin Dependent Kinase, the CDK four and six, there are three different drugs made by different companies, all very well tolerated for most patients. There are some key side effects you have to be aware of. Um but essentially each company did very similar first line studies for these patients and they all had very similar progression free survival outcomes. So it gives you a sense that this is a class effect. And on average, the delay use of chemotherapy by around a year. But again, there's some people that are on these drugs for years. And one of the studies recently for ABEM showed that at six years, I think 20% of people were still on first line therapy. I'm not gonna go through all the studies. But basically all these first line studies were similar to this. It was patients who are newly diagnosed with metastatic er positive her two negative disease and they were randomized to um endocrine therapy like letrozole also with the placebo or letrozole and the the new drug. And you can see that those curves are nicely separate and the median progression free survival went from just over a year for letrozole alone to just over two years. Um Now, in this study that over 50% of the patients had visceral or liver and lung metastases and about 50 45% had three or more separate sites of disease. So these were by no means like my lady, I mentioned with really low volume bone only disease. These were people with a a significant burden of disease in the viscera and, and you can see their outcomes are significantly better with combination therapy in terms of overall survival. Um RC three does have the best overall survival data. Um So, um the, you can see in the red, that's the rib plus letrozole. And the median overall survival now is, is 64 months versus placebo of 50 months. So, the median overall survival now exceeds five years. Um, and that's something just to be reminder if you're coming across these patients. And I think this is a really, really helpful study, a helpful slide that I've got permission to share and there's a huge spectrum of er positive her two negative disease. So just like that heat map all very different, lots of different types. We see that in practice in patients. So you've got your, you're highly sensitive. Like my lady I mentioned in the case de novo metastatic or a very long treatment, free interval and group. And you've got maybe just only disease, maybe a little bit of nodal disease or something, not very symptomatic. They tend to do really well with endocrine highly sensitive, then the slightly less good group but still likely endocrine sensitive. They've often had a long disease free interval. For example, more than two years after completion of the postoperative tamoxifen or letrozole, maybe not quite as much and maybe a bit more disease, minimal symptoms. Then we got the moderately sensitive groups. So they might have relapse quite short shortly after their endocrine therapy for primary breast cancer might have more visceral disease, a few symptoms. And then the group, you start to get a bit worried about people who are progressing on the adjuvant endocrine therapy and after a few years, so that tells you those cancers are probably mutated and they found a survival mechanism to progress. These patients may have more extensive visceral disease or be quite symptomatic. And then there's a slightly resistant group who they relapse early on adjuvant endocrine therapy. They've got fast progression of life threatening disease, often very symptomatic and they're often not sensitive to an estrogen based approach and they often need more chemotherapy. There's this newer, her two low concept that has come out in years, which is when you're looking at that her two, are you positive or negative? You used to just be called one or the other. But essentially you're looking at immunohistochemistry. So her 20 is it's not showing up in immuno chemistry. One plus is either weak staining in lots of cells and it's usually one plus two plus is moderate staining or high staining in not that many cells or there's three plus three plus is considered positive for her two. And so they decided that when they saw that it was amazing results for the her two positive patients with the um uh the Trustees drug. They said, well, why don't we try it in people who've only got a little bit of her two around their themselves. So the, the the two groups in between. So not the zeros and not the three pluses, but the her 21 or two. And that's called the, the her two low group. And it could be, er, positive or negative. And another Destiny study. And they were randomizing patients to either trust me or TPC, which is treatment of physician's choice. So, their oncologist got to choose which of the standard treatments of which they could choose. Five chemotherapies, they could choose, the majority were actually, er, positive and you can see that the progression free survival was increased from 5.4 months for standard treatment up to 10 months with of oxicam. And in the er positive group, the oral survival was increased by about six months and this is approved in Scotland. Now, the triple negative breast cancer is a different entity. It's characterized as I mentioned by being E RPR and her two negative, about 15% of breast cancers are TNBC and the more likely to be BRCA one mutation carriers in this group. And unfortunately, disproportionately affects younger women and women of black origin, but three fold increase and there is a nasty cancer. Unfortunately, there's a propensity for visceral brain brain disease, less bone metastases and typically early relapse within the first three years. So the hormone positive group, actually the risk of relapse goes on even beyond your 10. You often hear in the media people talking about maybe a celebrity who's got the five year all clear and, and actually, if you're talking about er positive, her two negative breast cancer. Yes, it's great to get to your five. But actually the risk goes on well beyond that now, for triple negative breast cancer. Unfortunately, it's got a bit of a bad press and I always tell patients not to look things up on the internet because there's a lot of quite outdated data. A lot of frightening data about it. And the median overall survival for metastatic disease historically has been about 12 to 18 months. So quite a lot less than the other groups. Now, this was the management in 2018, I'm not going to focus on that, but just to show you that even in the last five years, we've gone from a few drugs, largely chemotherapy because we can't use endocrine therapy, we can't use anti her two therapy. Um to actually quite a lot of different options. There's lots more intensive options in the preoperative setting as well to try to reduce outcomes because it's quite an area of unmet need. So, immunotherapy, lots of other other cancers types have really adopted immunotherapy over the last decade and have revolutionized outcomes. And breast cancer is often at the forefront of lots of developments. But actually, it's been kind of at the back for immunotherapy. And partly that's because breast cancer is not thought to be that driven by the immune system. Um but triple negative breast cancer was the group that people thought, well, maybe that is a bit more immune driven. We can see tumor infiltrating lymphocytes in this group and, and there's such an unmet need. Let's try immunotherapy in this group. So, immunotherapy is different i therapy and it's trying to unleash the power of the patient's own immune system to identify the cancer cell and then um and kill it that way. Whereas traditional chemotherapy uh treatments cause more healthy cell death because it's just looking for, for the, the more rapidly dividing cells. And immunotherapy again is another thing that's really exploded in recent times, which I won't go through this. But there are maybe not all but a lot of solid tumors now have immunotherapy as part of their treatment package. So, keynote studies, they're all using pembrolizumab and this was in metastatic triple negative breast cancer when patients were having chemotherapy, but some got placebo and some got pembrolizumab as well. And that was continued until progression or toxicity or completion of two years of treatment. Now, 841 patients went into the study 2 to 1 patient. So you're more likely to get, get the immunotherapy and they're also testing how immune are these cancers. So PDL one is um is the test that we would do to see. Um if we, it's a program cell death like and one is what it's called and the higher the score, the more likely you might be to respond to immunotherapy. Um So the top circles, this is the group that's CPS 1 to 9. So not very positive. And the placebo group was 5.6 months overall survival. So that's very poor versus 13.9 for the, for the people who had immunotherapy. Then the next circle down is the comparison between patients who had a CPS score of 10 to 19 and it was 7.5 months versus 20 months. And if you had a high p one score of over 20 it was 5.4 months versus 24 months. So this was a study that PAB was approved in breast cancer. But again, that like T DX D or drugs that can, there's significant toxicity need to be aware of. And the problem with immunotherapy is that it can stimulate your immune system into almost anything that, that mimics an autoimmune disease. So, um almost any part of the body can become inflamed. So anything itis hepatitis nephritis, pneumonitis and interesting ones, particular hypophysitis. So, and you can get hypothyroidism and low cortisol level. It can be quite serious and but there's a whole variety of different side effects. And the thing to be aware of, particularly if you're in acute setting is that the timing of side effect is less predictable when you finish chemotherapy. Most of the side effects except things like neuropathy and things are reversible, we finish quite quickly. But if someone's had immunotherapy in the last year, then they're still at risk of immune related side effects. So often they should be carrying a card around with them. And awareness is the most important thing for immune driven side effects. So patients hopefully are telling you I had immunotherapy, just be alert to immune driven side effects. And to see there's expanding scope, this is actually quite old. 2016. We find a good recent um whole body uh diagram just as showing you that all the different subtypes of cancer that are being treated with immunotherapy. And then we have another of these ADCS in triple negative breast cancer covi um this is similar to patients were, were allowed, the clinicians were allowed to choose normal chemo standard chemotherapy or elvy. And so they were randomized and this is a group who are, who are third line treatment. And you can see that the median overall survival was um six months versus 12. So you're talking about a year um in the third line. And if you remember, I said at the beginning that the median overall survival is 12 to 18 months from diagnosis, you're seeing that we are starting to change the natural history when people are living the brain metastases. And it is often a very devastating diagnosis and it often really changes your your potential um overall survival. So second case again, a real, a real life case that I know a fit and well 47 year old is brought by ambulance to the emergency department following a first tonic clinic seizure. And when going through the notes you see, there's a past history of at two and one, positive, her two positive breast cancer from just a few years ago, but she does have a complete response to neoadjuvant therapy and had surgery and was on Tamoxifen. So she was in that curative setting. Um, however, uh, the notes also, you can see that her left arm has been weak for a few months and she's been seeing a variety of doctors and waiting tests. And as I mentioned, her two positive breast cancers do unfortunately have a propensity to spread to the brain. So she has a CT scan with contrast that shows a large lesion in the right frontal lobe, extensive edema midline shift. And also also comment on the CT that there's meningeal enhancement suspicious for leptomeningeal disease and a body scan which shows no breast cancer anywhere else. And I said this is an increasingly common situation. So what do you think is her likely prognosis here? So she's got, she's got midline shift. Lots of edema, potentially got leptomeningeal disease. What do you think her prognosis is less than six months, 6 to 1212 to 18 months, maybe a few years. You can think more than four years. What's really important here is that CT s underestimate the amount of disease in the brain? I think it's about uh it misses about 25 to 30% of small lesions in the brain. Um But it's also not very good for looking at the left meninges. So an MRI is really important. And actually this patient's MRI showed no le meningeal disease and it showed it was a solitary cancer, a solitary lesion and and times have really changed with breast cancer related brain metastases. So, whereas before whole brain radiotherapy was kind of the standard and to come to here a minute and we think about surgical resection and for selected patients, it has to be carefully individualized. But we know that patients have a survival advantage if you can resect the disease. And you would do that for somebody who has a more favorable cancer like breast cancer, it's solitary or it's a small number of areas, it's an area you can operate on. Um So this patient actually her prognosis, I hope might be in that four year plus category. I don't know that. Um but she's had surgical resection and a good resection and managed to get it all out and she'll have some systemic therapy, possibly some postoperative radiotherapy as well. And I've got four or five patients in this situation who several a few years down the line and they're still in remission in the brain. So like the lady from 20 years ago who, who had the liver metastases that still well and hoping these patients might be a group that will do much better in the future. So thinking about brain metastases, it's devastating. It's often very feared by patients and it's increasingly common as we're able to deal with more systemic disease with better drugs. We see more brain disease popping up and we see about 15% of patients. It's more common in triple negative and her two positive breast cancer. And the risk is shown to be higher with younger age positive nodal status, visceral metastases, particularly lung grade three disease. And what's really important is just to, to think about what subtype of breast cancer because on, on the right, you'll see the overall survival from the diagnosis and you can see that the people in orange for the triple negative patients do really quite badly. Their median survival is only about six months. But then you've got a purple, it's the er positive, her two negative group and then you've got your two, her two positives, the green is uh er negative and the blue is er positive. So she would be in that group. So the median overall survival as of 2019 was looking at this is about 20 months. But um you know, that's before we were doing all the new things we do now. So I hope she will do better than that. One final thing to me, that disease is the pattern of progression surprises you. If you find somebody who you think should really respond, say de novo metastatic, you are positive breast cancer, you might want to, they don't respond to the CDK 46 inhibitors. You might want to to rebiopsy. And see, because sometimes you can have diseases are changing as a response to treatment. So, going from er, positive to er, negative um and we are doing that increasingly frequently now, particularly because we have some drugs like TRV, um which are only approved for triple negative breast cancer. So if you have an er, positive, her two negative um disease that then starts progressing. If you biopsy it, you're more likely and not more likely. But you're, we're increasingly aware that more cancers are adapting to that therapy and you can see the er falling and then, and that's when you, you're on your own treatment. So I think in summary about the newer treatments, they're more effective, they are more personalized or targeted and they can more often be given until progression until the disease gets worse. Generally, they're easier to tolerate, but most of them have really important side effects to be aware of. And across the board, we've got more lines of therapy and for all the different breast cancer subtypes, but it's still always that careful discussion with a patient, particularly if they're older or frailer or lots of comorbidities. And what is the risk and what is the benefit? And there's this elephant in the room that I mentioned at the beginning and it's the cost and they are hugely expensive and some of that is because of the amount of research and development that the companies have had to, to put in to make these drugs and run these enormous trials that cost millions of pounds. But the reality is that most novel anticancer agents are over $100,000 per year per patient. Some of them, a lot more than that and looking at specifics of things I spoke about today 13 week cycle of, of Deans and it works out to about 7000 lbs for an average 80 kg patient. It's the cost will depend on the weight. That's 100 and 30,000 lbs a year rib, one of the CDK 46 inhibitors that we're using for you. Commonly for one of the most common types of breast cancer. It's about 3000 lbs for um for a month and that's for the slightly lower dose and the starting dose. So these are really highly expensive drugs. And this is the challenge and I am aware this is difficult for me to talk about all these very exciting new drugs that perhaps some of you wouldn't have access to. And I think there is more of a conversation happening about the barriers and access. And there really is a global crisis because we know that actually more of the world is in the low middle income countries than the Western world. And Comprehensive Cancer Services are only reported in less than 15% of LMS, low middle income countries versus 90% of high income countries. And even the basic essential medicines list for wh o less than half are available to patients in these countries. And even thinking about key pain medication, um actually, 80% of the world's population don't have access. So this is an enormous issue. And II personally think that the pharmaceutical industry has a real duty of care to do what they can, to try to. And we're not just focusing on the high cost on the countries that can afford it. And the other thing I'm not mentioned is radiotherapy. I'm a medical oncologist, so I give drugs, but radiotherapy is an absolutely key part of management of breast cancer, both in the early setting and in management of pain or other symptoms from in metastatic disease. And radiotherapy access across the world is as important a challenge. And you can see this um this map of the world where the green countries have um have much better access to a radiotherapy machine or a linear accelerator. And so really dark green is um per linear accelerator is serving less than 100,000 patients. And you see only a few countries have that. Um It basically maps out the world based on an income, doesn't it? So this is a real challenge. There's a really interesting paper which this is a bit too wordy here, but it's worthwhile reading this paper. It's a discussion about it from different oncologists around the world about what the possible barriers are in the different countries and they talk about. Some of the solutions are meant to be transparent, evidence based drug pricing, trying to really improve availability and participation in clinical trials to patients all around the world because we need to know if they're safe if they work in these countries. And also it's as a means for those patients to access to some of these drugs. And then a friend of mine, her and she grew up in Hong Kong and she had had a nanny many years ago and her nanny now lives in the Philippines. And actually she was in one of the trials recently that, that we're we're involved in. So she's been able to get access to some of the new drugs. So trials really are a way to try to get some of these new drugs to people around the world and involvement of all stakeholders in negotiation and thinking about regulatory reform and how we, how we liaise with the pharmaceutical industry. The other major challenge in the UK is about the resource. So we're very lucky we can have access to quite a lot of these drugs. But you can see this is in my unit here. So on the left here in 2019, we had just under 10,000 Oncology Day unit attendances within three years, up at nearly 18, 18,000. So that's just in a very short space of time. And that's because a lot of these drugs are not just stopped after six or eight cycles or whatever it used to be, they're given until progression and we have a lot more different options. And these are some of, I think for some of the outstanding research he's mentioned triple negative breast cancer, there's probably lots of very small percentages of patients within this other heterogeneous group have, have drug targets. But getting trials in very small and populations of people who just have a very particular drug and disease mutation is challenging and better biomarkers. Thinking about the use of liquid biopsies which where we take blood and do whole genome sequencing, for example, and lobular breast cancer is often really forgotten about. I haven't mentioned that much today but I think there's more research in that group and more research in brain me and leptomeningeal disease. Thinking about how do we overcome endocrine resistance. Lots of lab research going on there and also the management of these really important side effects. There's nothing worse than giving somebody a drug, but actually, they're extremely unwell because of a side effect. And uh we're also trying to even treat small volume metastatic disease with radiotherapy or even local interventions. So, so the the boundaries are being pushed in a, a number of different ways and it is a hugely exciting time to working in Bristol. And the bottom line is this nice graph last year from the BMG. And for most women diagnosed with breast cancer and the five year risk of death is not less than 3%. And you can see 1993 to 99 4004, 2005, 2009. And so, and that's part because of everyone's hard work. It would be better surgery, better staging with the radiologist, um, better drugs, better radiotherapy. So all these things come together to, to show better out come. And if anyone was keen to learn more about a career oncology, I've listed a few things that I think are make it really good, especially to be, to be involved in and it's not going away. It's a rapidly going specialty. And I think it's quite flexible for less than full time training, many opportunities for teaching management, even political strategy research. And, and it was really unparalleled opportunities for, for going around the world to be involved in different studies or, or going to conferences. And the bottom line, the thing I love most about it is it is very rewarding. The patients are all lovely. We're so thankful for what we do and you really get to know your patients and their families as well, which is slightly more unusual in medicine these days. And this is Edinburgh. So on that note, I will finish. Sorry if I go on time over Tuesday. That was great. Thank you very much Caroline. Even I listened to this one. Everyone who uh all our delegates, if you have some questions, please, please, please do pop them in the chat. Um, I won't really have questions but I'll chat with Caroline for a few minutes whilst you pop your questions in the chat. Um, that was amazing Caroline. And it is that research and everyone working together. And I remember watching a film where I can't even remember what it was. It might have been bucket list or something like that where these people were, these old guys were, they had cancer and chemotherapy was just absolutely awful. And then now it's not as bad as it was. You know, the progression of treatment has just come along so much, hasn't it? Yeah, it has. And this is because of lots of different people's inputs. It's not just because of the drugs by any means. Um, and I know there's a bit of a focus on drugs just because that's what I do. But no, it's really exciting. I see a difference in the patients that we used to treat when I was a junior junior registrar in 2004. We used to see these young women with her two positive breast cancer with lots of really complex brain disease, spinal cord disease, often very high dose of steroids in our ward for sometimes even months. And we just don't see these people anymore. It's great because, you know, it just doesn't happen and, and people still get, get metastatic disease, but it just, we have such better drugs now. And, yeah, that was always quite a sad part of our war, these women for so long and we just don't see it. So I really feel like we are making a difference, which is great. Yeah. Yeah. It's incredible to see, you know, just that progression of cancer isn't, I don't know if I can say this, you know, in the past cancer was like a death sentence, wasn't it? Whereas now it's not, there's more people that are being cured and helped and, you know, living with cancer even, you know, for sure. Yeah, absolutely. And obviously there's still some very groups but yeah, I think that's really the message to, to get to the public is that, um, you know, it's not as bad as it used to be and our drugs are not as bad on them as it used to be. Yeah. Yeah, I do have one question, Nicola, I really do appreciate you popping a question in there. Can you see that question? Ok, Caroline. Oh yes, I can. Yeah. No, that's a good question. Um, so it was quite a bamboozling overview trying to get as much in as possible. So again, as a spectrum of, er, so we use the all red score from 0 to 8 where it actually starts being positive at three. I won't go into the sign a bit of it but three and four low, er, five and six are moderate, er, and seven and eight are high. Er, So, um, if you've got a seven or an eight for, er, and pr you're that Luminal a or that group that probably going to respond well to, to endocrine therapy, I don't tend to treat many patients with metastatic disease. You've got, er, 34 or five with an endocrine based approach. I wouldn't really do it. So. No, it's definitely a spectrum there too. Um, so there is, er, low. Perfect Nicola. Did that answer the question? Ok. And I have to wait for people to type in now. Perfect, thanks. You're welcome. Does anyone else have any other questions now? Is your time to ask them? And this is an open space. Any question will do. You've heard me chatting. I know nothing about uh cancer. Um So please, I hope it was interesting sometimes. No question me is not very interesting, but sometimes it, it's ii think you covered so much in that. It was really, and like I said, I don't have a medical background, but I found it really interesting too because that's what it's meant to be. Yeah. Sorry, I've got dogs walking around at this end. So everyone, if there's perfect, we have another question. Let me put that up and we'll go to the next question. Ah, someone I know. There you go. Absolutely. That's really one of my key things. Petro is definitely um I do these talks around the so that you keep general medics and different hospitals safe. Please always discuss with us because prognosis is changing all the time. And there are some groups that do do really badly and you might not know that and you might think, well, actually we won't put that person a ventilator, but equally more common things, people sometimes underestimate someone's progress because of just the fact things are changing so quickly. So even for lung cancer, I've been a consultant since 2012. And when, when I was on call, I just get really nervous that patients with lung cancer because I know there's so many new treatments now. And in the past, we would have said, oh, it's quite palliative and maybe their survival is not gonna be so good, but it's all changed. They've got all these different new subtypes, new different drugs. So even as oncologist, we know when I did a study of an oncologist or around the UK and gave them a whole lot of scenarios of which the first lady was in them. And I compared the outcomes of oncologists versus people who were noncancer physicians. So junior doctors, consultant, surgeons, people working in GP as well. And you can see that on average, the noncancer clinicians did significantly underestimate the prognosis. But then when you look even at the oncology, consultants, we asked them which groups they subspecialized in. And if it wasn't your subspecialty, you were underestimating the prognosis. So it's really important. But we should also as oncologists understand that if someone's really, really sick, they don't necessarily have the survival that was in the phase three trial. And those emergency physicians who are looking after the patients and it's helpful to guide them, but they have the patient in front of them. And actually, if someone's got saturations of 60% and they're trying to work out whether to ventilate them or not, then they have to also sometimes use their clinical judgment. And I think sometimes oncologists get a bad name for saying yes, but their survival might be. So it's again a joint discussion. But what we can advise that the clinicians can help with them, their decision making. So the bottom line is always called the oncologist. If you're, if you're sitting, not sure, you know about to escalate care with someone who's sick or not, who has a cancer. It's really important to ask the oncology. Wonderful. That's brilliant. Yeah, that everyone had, everyone in the chat is saying. Yep, great. Really interesting. It was perfect. Very informative. So what I'm gonna ask our delegates to do, you will get a feedback form in your inbox. I would love for you to fill that out. Um There's a lot about um Caroline's teaching how, you know, the questions. Was it informative? Was it that we really want that I'll, I'll be passing all this on to Caroline. And also if there's any additional teaching you would like, especially within this subject, this is medical oncology. So if there's any more teaching, you would like within this topic, we would love to know a Medic Caroline or one of our colleagues might come back and do some teaching for us. Because honestly, when everyone works together, that is how we progress with this, isn't it? It's everyone, like you said, many times when you talk, everyone working together, it's not just one person, it's everyone working together. So no matter where you are in the world, let's let's see what we can do. So if you can fill out the feedback form, after you fill out the feedback form, your tenant certificate will be on your medal account. Ok? So without further ado, there's lots of thank yous without any further ado uh Caroline and I will say goodbye and hopefully we will see you again at another either medical oncology event or one of our other events on the platform. Ok? Thank you very much for coming along. Thank you.