Season one

Sally Best:

Hello. You are listening to One in Two: a Manchester Cancer Research podcast, brought to you by The University of Manchester and the Manchester Cancer Research Centre. With one in two of us receiving a cancer diagnosis at some point in our lifetime, it has never been more important for our research to improve the outcomes for people affected by cancer. I am your host, Sally Best, and throughout this series I will be speaking with Manchester cancer researchers about their innovations, discoveries and projects that are changing the landscape of early detection.  In this episode, we speak to Professor Phil Crosbie and Professor Emma Crosbie about their research in the early detection of lung and womb cancer and their work on community screening and addressing health inequalities. With cancer incidence rising, especially amongst the most socially and economically disadvantaged communities, the need for early detection interventions has never been more important.

Phil and Emma Crosbie! Hello.  Thank you for joining me. How you doing today? 

Phil Crosbie:

Very well. 

Emma Crosbie:

Yeah. Really good. Thank you for asking us. 

Sally Best:

Oh, I'm great. Thanks for asking me. Oh, it's so great to have you both on. And, I mean, I'd like to get into the nitty gritty, but I mean, you're both a cancer research power couple. This is the term that we've coined, cancer research power couple. I love it, Phil’s shaking his head for those of you that can't see him. But I mean, we'll go with it. And I just like to start by asking how you both got involved in cancer research. And I'm going to come to the newly appointed professor Phil, kudos Phil. But yeah. How did you get involved? 

Phil Crosbie:

Well, I started from a clinical perspective, so I'm I started as a medical senior house officer doing post type ward rounds and seeing people come in as emergency cases. And the people with lung cancer were coming in with advanced disease. There was a shrug of the shoulders. We can't do much for them. Their life expectancy was days, weeks. And the messaging from senior doctors to junior doctors was this has been always the case. It's been like this for decades, and there's nothing we can do about it. And so then that represents a challenge and a challenge that I decided to try and address. So that was the journey for me. Um, I don't know about. 

Sally Best:

Yeah. 

Phil Crosbie:

Different from you. 

Emma Crosbie:

Yeah. Well, similar I guess. I was a junior doctor in training to become an obstetrician gynaecologist. And it was around about the time that, that scientists had realised that there was this very strong link between a virus and a cancer. And in my case it was human papillomavirus and cervical cancer. And I was fascinated by whether that represented any opportunities for early detection and prevention through vaccination. So this amazing opportunity came up to come and do a PhD here in Manchester with Professor Henry Kitchener and Peter Stern looking at HPV vaccination. And I just grasp it with both hands. 

Sally Best:

Oh, I love it. And is this is this how you guys met? 

Phil Crosbie:

No. 

Emma Crosbie:

Actually, in medical school together, we both went to University of Edinburgh Medical School. But I think when we first met. 

Sally Best:

Again, for the listeners, Phil’s shaking his head. 

Emma Crosbie:

I think, well, we worked, we were as medical students together in the same tutorial group. And I think Phil thought I was a bit square asking lots of questions at 4:00 on a Friday afternoon, and he wanted to get off and go and play rugby with his friends. So we didn't initially connect. But then when we became junior doctors together, we saw that we did actually get on quite well and I told him, it's up to you. 

Sally Best:

So I'm telling you it's great. We love it. We love that little insight. Phil doesn't love it so much, but there you go. You agreed to come on these things. Your life is open. So is it a coincidence you both ended up in prevention and early detection? 

Emma Crosbie:

I mean, yeah, I think probably so. I'm a gyno cancer surgeon, which essentially means that for me, the best outcomes for my patients is when we get the disease really early. And so looking at ways of preventing it from happening in the first place and detecting at its earliest treatable stage is an obvious way to improve outcomes for my patients. And I guess quite similar for you. 

Phil Crosbie:

Yeah. For me as a chest physician, you're involved in the sort of diagnosis and management of patients, not the oncological side in terms of chemotherapy. And the biggest impact I could have was on moving the diagnosis forward, and that was the area that I wanted to focus on to try to make the biggest difference. 

Sally Best:

Okay. And I'd like to pick up on that. So, I mean, would you be able to focus on the specific part of cancer prevention and early detection that you work in Phil? 

Phil Crosbie:

Yeah. So I mean, I had an opportunity to work at Wythenshawe Hospital to do cancer research and at that time there really wasn't any funding, any focus on lung cancer really as a disease at all because of its association with smoking. There was a sort of a blame culture. It's the individual's fault. All they have to do is give up. And that sort of fatalism had in a way, had gone through the whole of the sort of cancer community to mean that there wasn't any money or funding to try and make things better. But over the last few years, that has dramatically changed. I had the opportunity to get involved in an area where I thought actually that would make a big difference and therefore was able to complete a PhD in Manchester, which then gave me opportunities further down the line to have a role in cancer research and an increasing role in the sort of setting of screening and early detection. 

Sally Best:

And I'm wondering, like the, the emphasis was on early detection. And for my sake and for the listeners, would you be able to detail the importance of lung cancer, early detection? 

Phil Crosbie:

Yes, it's very straightforward. I mean, if you think of your lungs, they are to say two litres in size each. A lung cancer in its earliest stage. Maybe it's the size of a marble isn't going to cause any symptoms. There's a lot of area where it can grow and therefore for patients, by the time they develop symptoms, it's too late. The cancer has spread, they’re presenting the symptoms because it has spread to somewhere else say the bones or the liver and then it's an incurable disease. However, if you can detect a lung cancer early, it's curable. So if you identify, say, one centimetre lung cancer and if you have an operation, you have a 90% chance of a cure. Whereas the current state of play, because we're, you know, waiting for people to come to us with their symptoms, half of people, you know, die within a few months. At the moment. So you're completely shifting the disease through early detection from one that is often palliative to one that is completely curable. And that that intervention is really the only one that has such a dramatic impact. You need to find the disease early to cure it. 

Sally Best:

I'm very aware of kind of the landscape that you're working in, in the work that you're doing. But I mean, for the listeners, would you be able to explain the incentives that you're driving at the minute for detecting lung cancer early in certain deprived communities.

Phil Crosbie:

So the other thing with lung cancer is the close link with smoking. And smoking is the main driver of the development of cancer, lung cancer. In the UK smoking is also much more prevalent in more deprived communities. Um, so if you look at the distribution of lung cancer, the burden of lung cancer across society, there is a marked difference depending on where you live, whether your communities affluent, whether your community is more deprived. Um, and in our more deprived communities there is a huge amount more lung cancer. And that's especially the case in Manchester where we have some of the highest rates of lung cancer in the country. So the impact locally is huge and that's really the impetus to try and do something about it from our own local community. Um, so that association between smoking and deprivation is why you have the link between smoking and lung cancer, but you also have a link deprivation itself, the air pollution, occupational exposures.  There's a sort of a perfect storm of factors that come together. To me, lung cancer has a massively higher burden in more deprived areas. And therefore, any intervention you give, if you really want to make a difference, you have to be delivering that to the people who are affected most. 

Sally Best:

How are you delivering it, Phil? 

Phil Crosbie:

So well, in 2015, Macmillan came to Manchester and said, we want to make it. We want to do something, we want to make an impact on lung cancer. And so we sat around the table, a number of experts, patients, etc., around the table thinking about what is it, how do we make that difference? And then the concept, the design of the lung health chip. Then Kay was born and taken from scribbles on the back of envelopes in a committee meeting to actually designing a service where you implemented a screening service within deprived areas of Manchester. And the sort of design aspects of that were, well, we don't want people having to come to us, we want to take a service out to people so they're not having to worry about travel or parking or they don't have to come to hospital. We want to make our services accessible to everybody and especially to those who are in at most risk. And the intervention that actually saves lives for lung cancer is low dose CT scanning. So that's if you put someone at risk on a scanner, you've got a chance of detecting lung cancer and saving lives. And therefore, you have to take that's the intervention that you need.  And so you take that out to people and make it convenient, make it accessible. And that's what the lung health check approach is. The other side of it, of course, is you're not calling it lung cancer screening, you're calling it a lung health check to reduce any sort of perceived anxieties associated with lung cancer. So if you imagine if you live in a community where there's a lot of lung cancer, almost everybody you will know who was diagnosed with. Lung cancer has died of it. Therefore, the fatalism around that is also something you have to try and address. And hopefully as we do more and more screening, we can then inform people and say no laterally, this is a curable disease. We can do something about it. 

Sally Best:

Yeah, I mean, it sounds great and I think it's kind of detracting from the ignorance is bliss perspective that I think a lot of people may take with screening and things. And I mean, just to reiterate, so you're addressing the challenge of socio economically deprived communities that have high prevalence of kind of late stage diagnosis. And what you did was put kind of vans in car parks and deprived areas and then people would come for that long health check and you'd kind of do routine follow ups if there was any progression or kind of a late stage or early stage. Cancer is that right? 

Phil Crosbie:

So, well, what you're doing in the lung health check is, it's actually a bit more holistic than purely lung cancer screening. So the other things that we tagged on to it to make it more like a lung health check with things like a breathing test to look for COPD, which you get with smoking. We have smoking cessation practitioners on the truck again for prevention of not just cancer but diseases associated with smoking as well as an assessment of lung cancer risk. And then those individuals who are high risk are then there's a CT scanner immediately next door to where that lung health track takes place. And you go on and you have your scan and the whole thing takes 20 minutes. So that that part of the service is it's literally about 20 minutes. It's very quick for people, very convenient. And then the data, the information that's collected is then brought into the hospital where it's looked at by specialists. And then those CT scans are read by specialists. And if you have a lung cancer, then you are immediately brought into a hospital to have tests and diagnostics done. If you don't have lung cancer or a concerning finding, then that's the person's informed and then further scans are arranged. So that's the sort of set up.

Sally Best:

Great stuff.  And I mean, my next question will be, what's the success been of this so far? 

Phil Crosbie:

So, well, you can judge that in a couple of ways. One is in terms of lung cancer. So we've had a pilot about five years ago now where one in 23 people who stood on that truck and had a scan were diagnosed with lung cancer. 80% of those had early stage curable disease. Nine out of ten were offered curative treatment. And that's because they had stage one, stage two disease, whereas normally people are coming to us with stage three, stage four incurable disease. So just standing on a truck means that you completely change the stage of presentation of lung cancer. You change it from a terminal disease to a curable disease simply by something on a truck in a carpark. So that was a profound thing to see. And as a clinician sat in a clinic with a patient opposite me, I remember it distinctly looking at somebody and going through the questions you do for assessment, but thinking in my mind, if you hadn't stood on that truck, then we may have been seeing you one year later or two years later with I'm having a very different conversation, so it has a profound impact on you in terms of the other things that we, you know, offering people smoking cessation, early detection of COPD, etc.. They also come in with the service as well. So Manchester really drove this the innovation, the implementation of the lung health track started in Manchester and then from that it's been adopted nationally through NHS England. NHS England have backed it and said, right, we like this, we want to do more of it and funded a targeted health check programme initially at about ten sites, but now there's 29 sites or so. And indeed the UK National Screening Committee is deciding whether to roll it out nationally. So the impact from, you know, what we started here in Manchester could have a profound impact across country and indeed beyond. 

Sally Best:

And fingers crossed for that funding. I mean, it's great to hear about this work focussed on cancer outcomes and underserved communities because I think that's kind of a large area of poor health and it's great to hear that you're directly addressing in lung cancer specifically. I mean, Emma I'd like to come on to you and some of the amazing work you've been doing on HPV. I'm wondering if you've been able to talk about this specific part of cancer prevention and early detection around HPV and cervical pre-cancer? 

Emma Crosbie:

Yes. So we now know that cervical cancer is caused by persistent infection with high risk human papillomavirus, or HPV. And this is really exciting. This understanding, because it enables us to both prevent HPV associated cervical cancer by vaccination. So that is by vaccinating all teenage boys and girls with the HPV vaccine, which then prevents them from ever getting infected with the virus in the first place, and so effectively prevents them from developing cervical cancer in the future. But also because of this strong link and because it is so intimately associated with cervical cancer, we know that it is a really good biomarker for screening. And what we mean by that is that we find evidence of that virus before the patient goes on to develop cancer. So we see it just as an asymptomatic infection, we see it in people who've got cervical pre-cancer and we see it in people with cervical cancer. And the importance of that is that it's actually quite a long period between becoming infected and developing a cervical cancer. And if you can screen that person for HPV during those years of infection, you have the opportunity to find pre-cancer cells, which you can then treat and again effectively prevent the person from ever developing cancer. So it's understanding the biology underpinning this link between HPV and cervical cancer. That's so exciting because it does offer the opportunity to completely change outcomes with respect to cervical cancer. So in countries where they don't have organised screening programmes and immunisation programmes aren't universally funded, you know, they have a huge burden of cervical cancer, often affecting young women, women in their thirties, forties and fifties. And it's really a terrible disease when it's picked up in its later stages, you know, with often terrible numbers of deaths and illness from the cancer. So, you know, we're in a fantastic place here in the UK to be able to screen and prevent cervical cancer through understanding about HPV and the link. 

Sally Best:

Okay. And I know you've been working on alternate screening methods, and I'm wondering if you be able to tell the listeners a little bit more about that. 

Emma Crosbie:

Yes. So we as you know, cervical screening has traditionally been carried out by a woman going to see her nurse in the general practise and having a speculum examination and having a sample taken directly from the cervix. And in the past that was then looked at under the microscope to look for cervical pre-cancer cells. But now we've moved to testing that sample first for high risk HPV, and only if it's positive do we then look at it under the microscope to see that the person is genuinely at risk of cervical pre-cancer. And because we know that this HPV is so intimately associated with cervical cancer and also that, you know, skin cells are shed naturally during just normal life, the cervix sheds its cells and they contain HPV in them that you might be able to actually use a slightly less invasive method of picking up HPV from the lower genital tract. So initially there's been a lot of work looking at vaginal cell sampling, which is where the woman collects a vaginal sample using a swab in the privacy of her own home, which she then sends to the laboratory for testing for HPV. But here in Manchester, we've been interested in looking at whether urine could do the same. In other words, whether we could test a urine sample for high risk HPV, and if that would be as accurate as collecting a cervical sample and testing it for HPV. And so some work that we've been doing here in Manchester is looking at patients who we know to have an HPV infection when they come to the hospital to look for cervical pre-cancer and taking matched samples from the cervix alongside a urine sample. And just comparing the accuracy with which those two sample types detect HPV in those who've got cervical pre-cancer. And so far, the results are really, really exciting. To the extent that we think that a urine sample is not inferior to a clinician obtained cervical sample for the detection of HPV. And the reason why that's so exciting is because, of course, women don't really like having a speculum examination and having a routine cervical sample. The evidence suggests they're not really that keen on taking a vaginal self-sample either. But women are very used to collecting urine samples for all kinds of reasons, and we think that this might be a much more acceptable way of collecting a sample to find out if somebody is at risk of cervical pre-cancer. 

Sally Best:

I mean, it's amazing. Again, because it's the accessibility angle that both you and Phil pioneering here on. I mean, I want to ask again, in terms of socioeconomically deprived communities, do we see less take up of screening specifically in those communities? 

Emma Crosbie:

Yeah, absolutely we do. So on the one hand, people from socioeconomically deprived communities are at greater risk of cervical cancer because they are often smokers, but also because they are less likely to go for cervical screening. So as we spoke about before, there is a long time period between becoming infected with HPV and developing cervical cancer. And so if you are a person that goes routinely for cervical screening, then there are many opportunities to pick up that infection and those cervical cancer cells prior to the development of cervical cancer. But if a person doesn't go for cervical screening, then those pre-cancerous changes are not identified and they are not treated, which means that they are at risk of developing cervical cancer. So it's both the fact that they are often smokers, but also the fact that they are less likely to go for screening that puts people from socioeconomically deprived communities at increased risk of cervical cancer. 

Sally Best:

Okay. And I'd like to come on to that kind of two pronged approach in a bit. But I mean, can I just clarify that the challenge you're trying to solve in cervical cancer, early detection is kind of the same as Phil. So it's detecting early where outcomes and prognoses are improved. 

Emma Crosbie:

Absolutely. That's right. And specifically trying to address the barriers that we think are really important for marginalised groups that don't traditionally attend screening. 

Sally Best:

Okay. Fab, I mean a question for both of you. Again, it's what encouraged you both to focus on cancers in deprived communities. Was it kind of one of those things that it was just so happened that the cancers that you were focussing on did have the angle or was it specifically, Phil you've spoken about this before, but was it specifically I want to help in terms of health disparities, addressing health disparities? 

Phil Crosbie:

That's why it's both. I mean, but for lung cancer, the connection is so stark that if you don't, you don't make the big impacts that you need to do, but they go hand in hand. And so I suppose both from a clinical service perspective, you have to make sure your service delivers to people who need it most. But also from a research perspective, you still have to make sure your research is actually the results that you get from your research are generalisable to the people who also get lung cancer. So one of the factors that we're trying to do in Manchester is also take our research out into communities as well, because the barriers that exist for services in accessing screening of the same barriers and probably worse actually for research. So if you have a research that looks at, say, lung cancer screening and the majority of people taking part are not really representative of the people who get lung cancer in your community, then that means that the results are not necessarily as generalisable. So the push more recently has been to try and break down the barriers to research participation as well, because that's really important, because the results we get, we want it to be generalisable to people more broadly. 

Emma Crosbie:

Yeah. And for cervical screening, you know, we know that people who are from more affluent areas are much more likely to go for routine screening. They're much more likely to have been immunised as preteens. And therefore you have this situation whereby the worried well, who are those people who go for screening and vaccination programmes are doing extremely well from the services that are available here on the NHS, but those that have poorer access to those services just get a really bad deal in terms of much more likely to be diagnosed with cancer, much more likely to have bad outcomes. And so it is addressing that health disparity and trying to make it much more even for the whole population so that everybody can have good outcomes. 

Sally Best:

There's a lot of overlap between both your research areas in terms of prevention and early detection of cancer. And you both have this focus on addressing needs in underserved communities. It kind of makes me want to ask and I kind of know what the answer is going to be. But I mean, does the fact that you both work in the same environment make it easier for you to collaborate on projects? 

Emma Crosbie:

Yeah, I would think so. 

Sally Best:

Yeah. Is this dinner time talk? 

Phil Crosbie:

Yes, of course. 

Emma Crosbie:

Yes. And so, I mean, that is something that we probably going to talk about just now. But yes, I mean, noticing that the cancers that we're interested in do seem to affect a similar population demographic, it's clearly of interest to us because it was like, well, if you're tackling these disparities using your lung health check in socioeconomically deprived communities, is there a way that we could also harness that fantastic service to try and take cervical screening to the same community? So that was really a teatime discussion, I think. Yes. 

Sally Best:

Your dinners must be amazing. Solving world health issues blimey we just get on to the why have we got boiled potatoes and not roasted? I mean, but anyway, you've led me on Emma. So are there any projects you're both jointly working on? 

Emma Crosbie:

Funny you should ask that. 

Sally Best:

Funny, I thought. Yeah, as if I know.

Emma Crosbie:

Yes. No, we are. We've started an initiative called the Moped Initiative, which is the mobile cancer Prevention Early Detection Initiative, which is essentially, as Phil says, taking cancer research to the communities that need it most. And in the case of lung cancer and cervical cancer, that is communities from socioeconomically deprived backgrounds. And so because of the success of the lung health check, whereby people from those backgrounds are actually attending for lung health checks on lung cancer screening, we decided that that might be a really great opportunity to also look at whether we could offer our new urine HPV test to people attending that lung health check. So in other words, could we do a so-called one stop screening shop for both lung cancer and cervical cancer? And so that is a research initiative that we are very excited as just got started and it is using a kind of a research room at the back of the lung health check, which is the clinical service. 

Sally Best:

So is this just in Manchester at the minute? 

Emma Crosbie:

Yes, it is. 

Sally Best:

Okay. Paint me a picture of what is going on inside these trucks. We've got a CT scan for Phil’s stuff. Yeah, well, what else have we got? How many people are in there?

Phil Crosbie:

Well, it's quite a I mean it's quite an industry, but it all fits together with the logic of essentially trying to address things in a one stop shop model that are, you know, if you if we're sort of saying that we have underserved communities that aren't accessing services or getting the health benefits from the NHS or whatever, then trying to address that and, and doing so in a way that's acceptable. So we don't overburden people. But actually the feedback has been fantastic actually from everyone attending. When you go on the truck, the atmosphere is great and people do appreciate just having these various things checked. So you see there's a flow there's a flow to the truck where you have you see your lung health check nurse who describes what's going to happen. There's a room where you go, if you're a smoker, you go and see the smoking cessation practitioner. Then the research team is next. And it's not viewed as I think this is this is a great credit to the clinical service. Actually, research is not viewed as an added extra. This is fully integrated within the flow of the truck that you're going around these rooms. And obviously that has to go in each room. But these rooms are there. There's a flow and then you have your scan at the end and off you go in to your shopping if you wish to all go home. So the whole thing is very well integrated. It's a great atmosphere and, and the feedback we're getting is really good. But, but what we're trying to do is deliver all these potential health benefits to people in a convenient way and why not try look for the malignancies in the same way that we're trying to look, say, for COPD or indeed trying to help people with the smoking. So it's all part of that same package. 

Sally Best:

But where did you find your TARDIS?

Phil Crosbie:

Oh, there are there's two big trucks with the lung health check team in them and also a mobile C.T. scanner. So it is a big set up and the logistics of it are significant, but it's certainly worth it. 

Sally Best:

So Emma, where do you come in to this kind of flow? 

Emma Crosbie:

So in the research room, obviously, I'm really only interested in targeting people with a cervix, mostly women, and we are asking those women when they are, you know, if they're interested in taking part in research, whether or not they have routinely been for cervical screening in the past, and if they might be interested in having a cervical screening sample taken in the form of a urine test. And we are targeting women over the age of 65 who have exited the cervical screening programme. So we're not interfering with the NHS cervical screening programme. So this is really trying to identify those who haven't attended NHS cervical screening, and that's mostly because cervical cancer actually has the poorest outcomes in terms of contracting the disease and dying from the disease for women in their seventies. And currently we stopped screening at 65. But if people haven't been screened, as I said before, then they haven't had a cervical pre-cancer treated, which means that they are at risk. And so it's trying to find out whether those women who haven't been for routine screening, perhaps because they didn't want to have a speculum examination, might be interested instead in giving us a urine sample. It's just a very small urine sample collected using a little device called the Collip, which reliably collects the first fraction of urine that a woman passes, and then sending that to laboratory to be tested for HPV in the same way. So taking part in our study is actually quite a short thing, but we're hoping to get lots and lots of patients agreed to take part so that we can see whether or not this could be a successful initiative to be rolled out. 

Sally Best:

And I'd just like to emphasise to the listeners, this is in carparks, you would have never of thought it. Both of you, what's your hopes for the future of this incentive? Rolled out nationally?

Emma Crosbie:

So I think for me it's kind of reappraising the age at which we stopped screening. So other countries, for example, Australia, Denmark, some of the other Scandinavian countries, they actually stopped screening for cervical cancer at 79. But here, perhaps for historical reasons and perhaps because the test is uncomfortable in a postmenopausal woman, we stop at 65. So it's really sort of examining that and with fresh eyes and saying, should we be stopping at 65? Is there something we can do for women who are older than 65 and, you know, could urine be a reasonable alternative? Do women who haven't been screened before, particularly those from socioeconomically deprived communities, do they prefer to collect a urine sample for cervical screening and is a one stop screening shop something that they'd be interested in? 

Sally Best:

And I mean, are you kind of looking to integrate? I mean, it's already a TARDIS as it is but I mean, it seems never ending. So are you looking to integrate other cancers into this one stop screening shop? 

Emma Crosbie:

Yeah. 

Sally Best:

Copyright on that by the way 

Emma Crosbie:

So, I mean, it's about targeting your screening to the right people. So, you know, obviously breast cancer screening is it tends to be in a slightly you know, it occurs in a different way. You know, you need mammography, you need ultrasound services, you need biopsy services and so on and so forth. And, you know, that's not really the same demographic of individuals that are at greatest risk of lung and cervical cancer. So it's about being smart about what screening bundle you offer. But there certainly are other cancers that are things that we should be considering. If this is successful. 

Sally Best:

Which I'm sure it will be, I have all the hope and a personal question again. But I mean, you're both cancer researchers and you both have kind of many hats that you wear. How do you how does it feel that you're in a fast paced environment? How do you deal? I mean, you've both got three kids and a dog and two cats. I'm sorry you all missed this preamble, but that's the bits that I love. How do you balance it all? How do you find that? Do you kind of feel like you're going to break down into a heap at some point? I mean Phil, you're very slow. Like not slow. You're very steady like the world. 

Phil Crosbie:

I think it's the same for every family, isn't it? You've always got time pressures too much to do when you just have to go do the best you can each day and every day. And actually it helps in a way to have being the same in sort of research environment, because the conversation we have a very you know, we have a debrief where we maybe walk the dog or whatever, having a chat about the day's events and then that just sort of is put to bed and then we deal with the day to day with the kids and what's needed. I don't think it's any different to any other busy family that particular. 

Emma Crosbie:

No, I think so. But we are both very, you know, driven. And I think if we weren't so passionate about what we did, you know, perhaps we wouldn't manage to balance it. But it's that it's that drive to really make a difference for our patients that's kind of fuelling this fast moving, exciting time in our lives. 

Sally Best:

Yeah, that dog must get over walked. You're discussing debrief from the day. Jeez, I feel. I really feel for him. It's like he'll be falling off by the end of it. I mean, it's it's another personal one, but how does it feel to know that you're both benefiting the lives of cancer patients and also kind of cancer patients that are from these economically and socioeconomically deprived communities? 

Phil Crosbie:

I mean, to deliver research that has an impact is it's I mean, it's a fantastic area to work in. It's motivating. I suppose you'd never satisfied that what you've done is good enough. And you always are looking for ways to keep making innovations and improvements. But when you do pause and think actually, yes, it has that impact is a really good feeling. But no you never you never sort of panic self on the back particularly and go great jobs done you then moving on to the next thing to go how do we get better or I mean you're constantly looking for ways to improve what you're doing. That's my angle anyway. 

Emma Crosbie:

Yeah. I mean, just totally driven by the desire to make a difference for our patients. And I'm constantly striving to tackle the next hurdle that we see. So it's, it's not a journey that has ended or feels like it's ending any time soon. It feels like a long, winding road that we are enjoying the journey of. But yeah, lots more challenges ahead I think. 

Sally Best:

Yes. I mean, there's so much more to come from you both. I am so sure we'll have you here in another month talking about something different. Have you got any titbits, any secrets, anything in the pipeline we can be looking forward to? Emma’s got a cheeky look on her face. 

Emma Crosbie:

Well, you know, are looking at the urine test in all kinds of different scenarios. So looking at different groups of people who may not have been for routine screening in the past. So that's exciting to see if there are ways of addressing more than just this socioeconomic deprivation issue. But, you know, perhaps we could appeal to other groups of people who perhaps haven't been screened before. So, yeah, definitely watch this space. 

Sally Best:

Phil, in terms of your mopeds, what do you want to come out of that? 

Phil Crosbie:

I think it's just for there to be an acknowledgement that research has to be representative of the people in our society. And we need to have because the results we generate, the data we generate has to be of benefit to everyone and not just to a select few. And I think that's an important, you know, whether it's by physically taking research into a car park or whether it's simply saying, actually, we need to try and be mindful of this issue and try and overcome it. And I'm sure there are various different ways of doing that, but it's just an important issue that we should be addressing. That's the key, I think, to it. 

Sally Best:

God, you've got the key and the secret if you got that reference. Honestly thank you so much, both of you, for speaking to me today. I know you've got absolutely hectic schedules and it's so appreciated because we get to speak about all this amazing stuff. And yeah, you're a cancer research power couple and there's there is no other term for you. Yeah, I might even have a picture of you on our wall at work. As the gods. But yeah, I hope as well I'll be speaking to you in the near future about this work because it's just it's incredible. And I think the pace that it's moving and people saying that it needs funding and things is incredible. But I mean. Yeah, just. Thanks again, guys.

Emma Crosbie:

Well, thanks for having us. Thank you for having me. It's been fun. 

Sally Best:

Oh, it has been fun, hasn't it? And thanks again for the listeners I’ll link Phil and Emma’s work in the blurb because there's a lot of stuff that we have written about because yeah again power couples, they need that air time so thank you for listening to us and yeah see you next time. If you have been affected by anything you've heard in this episode, please see the show notes for our list of charities and organisations that can help. 

One in two to was brought to you by The University of Manchester and the Manchester Cancer Research Centre. Listen to our next episode to hear from more of our researchers as they share the innovations, discoveries and projects that are changing the landscape of cancer prevention, early detection and treatment. To find out more about what you've heard today, please see the show notes for this episode, where you'll find a transcript and links to further information and research. 

Cancer is one of the University's five research beacons, showcasing the interdisciplinary collaborations and cross-sector partnerships that are tackling some of the biggest questions facing the planet. To hear more about Manchester's research in advanced materials, biotechnology, cancer, energy and global inequalities, go to Manchester.ac.uk/beacons.

Sally Best:

Hello. You are listening to One in Two, a Manchester Cancer Research podcast brought to you by The University of Manchester and the Manchester Cancer Research Centre. With one in two of us receiving a cancer diagnosis at some point in our lifetime, it's never been more important for our research to improve the outcomes for people affected by cancer. I am your host, Sally Best, and throughout this series I will be speaking with Manchester cancer researchers about their innovations, discoveries and projects that are changing the landscape of early detection. In this episode, we speak to Professor Gareth Evans about the importance of breast cancer screening, as well as the risk predictors of breast cancer as he answers the question, should all women be screened equally for breast cancer? So today I'm speaking to Gareth Evans. Would you be able to introduce yourself, Gareth?

Gareth Evans:

I'm Professor Gareth Evans. I'm a consultant in genomic medicine, but also I'm Chair of Cancer Epidemiology and Medical Genetics at The University of Manchester.

Sally:

Fab Thank you. So I guess we'll get started. So we've heard from that that you focussed on early detection of breast cancer as well as breast cancer risk factors. And I'm wondering if you could please start off by telling me and the audience why is it so important to screen for breast cancer?

Gareth:

Well, breast cancer screening is important because it's able to detect breast cancer at an earlier stage, where cure is more likely. And we know from a lot of information on breast cancer that the earlier the stage, the better the cure rates from those stages. So, for instance, stage one is below two centimetres in size with no involvement of the lymph nodes. And those patients detected at stage one do much better than those at stage two and those that where the cancer is spread beyond the breast itself. So the idea of breast screening is to detect breast cancer early. Now, no screening is perfect, so no screening will detect all cancer and have no false positives. In the UK we do three yearly screening from the age of 50 through to 69. In most other organised screening programmes, it's two yearly screening and sometimes that starts at 40 rather than 50. The reason that screening before 50 is more problematic is because the incidence is much lower, so only about 20% of breast cancer occurs before the age of 50 and the cancers grow faster and the breast tissue is more dense, which means that you have to actually do the screening more frequently. So from a health economics perspective, it's not cost effective to the NHS to do that screening on everyone below the age of 50.

Sally:

Okay, so you've said that there are occurrences of some women below 50, and I'm just wondering, would you be able to explain how some of these women are referred for early breast cancer screening?

Gareth:

Yes. So there is a facility for some women to get screening earlier if they meet certain criteria that are specified by NICE. That's the National Institute for Clinical Excellence. And that is if their family history of breast cancer is sufficient for them to have that early screening. And so a typical moderate risk woman would be someone who's got a mother or sister diagnosed under 40. And a typical high-risk woman would be someone who's got a mother and sister, both diagnosed before the age of 50. And in those situations, a moderate risk woman would get annual screening from 40 to 50 years of age and be considered for annual screening between 50 and 60. And a high-risk woman would get screened from 40 to 60 every year. Now there is an exceptional group and that is those that are proven to carry faults in the main high-risk genes, BRCA one and BRCA two. They have lifetime risks of up to 80%, eight in ten of getting breast cancer. And they qualify for the very high-risk screening programme, which is essentially annual screening from 30 to 70, but includes MRI scans of the breast, which are much more sensitive than mammograms, particularly where there are dense breast tissue present, which is typically the case in younger women. And they can sometimes even qualify for screening before the age of 30, depending upon other risk factors. So that is a tiny group. The high-risk group are based on the NICE criteria is only about 1% of the population, with about another 3% being in the moderate risk groups, a maximum of 4% of the population can present to their GP's with their family history and get earlier screening. In reality, less than half of those women actually do that.

Sally:

Okay, so you've mentioned the women that have the BRCA one and BRCA two. I'm just wondering if there are other genetic risk factors that increase your risk of developing breast cancer who aren't identified by these hereditary clinics?

Gareth:

Yes. So there are additional genes, although they contribute much less to the situation because they are rarer or are not high enough risk. So there are other high risk genes, including a gene called PLB2 and TP53, and they would also qualify for that very high risk screening. And then there is a group of moderate risk genes which roughly double to treble the risk giving you a rough 20 to 30% lifetime risk, they wouldn't qualify you for more than moderate risk screening without a significant family history. But additional to those, and much more important on a population level are what we call polygenic risk. So the individual genes, you just have a genetic fault in those that can increase your risk. But that is less than one and a half percent of the population. So less than one in 70 women in the general population carry one of those type of genetic faults. But many more of the population can carry common genetic variants which, when taken together, push your risk right up. So it's like a pack of cards. You get your single nucleotide polymorphisms, these common genetic changes, one set from your dad, one set from your mum. If you get the wrong deal of the cards, your risk can be high. If you get the right deal of the cards, your risk can be low. And about 50% of the population can get a meaningful change in their risk on the basis of a polygenic risk or from these common genetic variants, whereas actually on a population basis, only about 1.3, 1.4% of the population would get a meaningful result. In other words, a positive test result from a BRCA one or a BRCA two gene fault or one of the other rarer genes.

Sally:

And just for the benefit of our listeners, I'm wondering if you'd be able to describe what is a polygenic risk score and if you have any analogies that would be able to encompass a risk score for women for breast cancer.

Gareth:

So what we do in a polygenic risk score is we assess genetic changes called single nucleotide polymorphisms. So these are literally just a single letter change in the genetic code. And these may be in genes or they may actually be between genes. So they don't have to be an actual change in a gene. And at the moment, we're using scores of up to 313 of these genetic changes. Now, some of these changes may increase the likelihood of breast cancer slightly. Some may reduce them. So individually, they're of no real benefit. But when put them together, you can end up with a risk which is three times the average, or a risk which might even be three times less than the average. And it's a bit like, as I said, getting a deal of cards. You might get a fantastic handful of aces and kings. That means that in poker or in bridge or whist, you're going to win the hand. So you're not going to get breast cancer because you've got such a strong hand. You might get a terrible hand, which means that the likelihood of you getting breast cancer substantially increases. And every time you shuffle the pack, you will get a different deal from the two parents that have their children. And that means that the polygenic risk score can be substantially different from parent to child or even sister to sister. So, for instance, I've seen two sisters, one of whom had a twofold increased risk, doubling of her risk. The other sister had a halving of her risk. So those sisters had a fourfold difference in their risk of developing breast cancer, which is an enormous change. That isn't because one had BRCA one and one didn't. It's because their polygenic risk score was substantially difference between one and the other. The important thing about this is that we identify this very low risk group, which doing the standard gene testing for BRCA one and two doesn't give us. Being negative or having no fault in those genes does not really reduce your risk unless you've got an incredibly strong family history. So there is very little benefit of a negative test for all of the moderate and high risk genes. BRCA one, BRCA two, etc. But there can be huge benefits from doing a polygenic risk or in terms of identifying women at very low levels of risk.

Sally:

Yeah, it's really interesting how I mean, I'm quite surprised. I don't know if the listeners would also be surprised about that variability between family members and risk. I was under the impression that it was kind of a a continual spectrum of your mother was at high risk you're at high risk. Your sister's at high risk you're at high risk. And I guess it's interesting to hear, but I think it also highlights the importance of screening to differentiate between even family groups. So just kind of leading on from this genetic risk side of things, your research looking at saliva tests for breast cancer has recently been spotlighted in the Times and the Daily Mail and also in Julia Bradbury's documentary Breast Cancer and Me. And it's been described by Health Secretary Sajid Javid as promising new research. And I'll put the links in for the listeners that are interested, they're kind of very good reads. But I wonder if you'd be able to tell me more and tell the listeners more about this research and the results of this recent study.

Gareth:

So what this study does is it brings together all of the known risk factors. So what we call standard risk factors, those are things like when your periods start, when you have your first child, how many children you have, when you have your menopause, taking HRT, etc., your BMI. In other words, your weight and particular weight gain is the most important thing. And it takes together those standard risk factors that can put be put together in a risk tool with two actually much more predictive factors. And those are the polygenic risk score which I've just described. And breast density. And we now know that the bottom, you know, 10 to 15% of the population has a risk, 5 to 6 times less than the top 10 to 15% of the population based on assessing the density of the breast tissue on a mammogram. Now what we're looking for is on a mammogram, the white areas which represent the glandular breast tissue and fibrous tissue, and that is the risky tissue. So the less of that you have, the less risk there is, the more of a risk you have, the more risk there is. The other factor with breast density is that it can mask your breast cancer. So there are two elements to the risk. One, it's a higher risk that the mammograms won't pick up your cancer early, but also it's a higher risk overall that you'll get breast cancer. Now, we can now put all of those three factors together to come up with a ten year risk and a lifetime risk of getting breast cancer. So we can really accurately risk stratify the population into low risk groups, which have a very low risk of breast cancer and high risk groups which have a very high risk of breast cancer. Not only that, a higher risk of cancers that are likely to be later stage. So not so easy to pick up on screening, which means we need to do the screening more frequently. And so what we've shown in the study is that we can identify about 20% of the population who are in these moderate or high risk categories. That is a ten year risk of 5% or greater in the screening age group, 8% or greater for the high risk group. And those 20% develop nearly 50% of all the stage two cancers. So by identifying that group, we can potentially down stage half of all breast cancers, but also potentially prevent those breast cancers by those women taking medication or doing lifestyle factors which will help reduce their risk.

Sally:

I'd like to touch on that in a bit, but I know that you've been working on risk stratified screening and in particular cities such as PROCAS one and PROCAS two. And I'm wondering if you'd be able to provide a bit of a background to those studies, what they've been looking at and then how they differ to this one size fits all screening that we currently see in the NHS.

Gareth:

So what we've been doing is looking at really the whole totality of the risk and we know that for instance, lifestyle factors do affect the risk. In particular it's weight gain. So the more weight you put on from your sort of early adult weight at age 18,20, the more of that increases particularly your postmenopausal risk. So the risk after your menopause, which is typically 51, 52 years of age, when the periods have stopped, and that is the main period of risk. So over 80% of the breast cancers occur in postmenopausal women. And what we've been able to do is look at the risk factors, also look at, as I've said, breast density and the polygenic risk scores. And this allows us to really accurately divide up the risk, also to be able to advise women who are at most risk that they can reduce their risk, if they've gained weight, by losing that weight. We're not trying to get women to go back to weights below they were when they were 18 or 20 but if they can approach the weight when they were 18 or 20, that will very substantially reduce their risk if they put on a loss of weight and so these are factors that we can use in that. Now, in terms of the risk stratification at the moment, as we said, nearly every woman is offered screening only three yearly from the age of 50 and probably only about one and a half to 2% of the population come forward because of their family history and get more frequent screening before the age of 50. What we've shown is if we were to do a risk assessment at say age 30, we could detect 9% of the population at high risk and about 11% of the population at moderate risk. Who would qualify for that early screening. So we would increase the proportion of women eligible for that early screening by about tenfold, and we would have a much greater impact on picking up breast cancer early. Not only that, we would do more frequent screening for the women at high risk. So 9% of the population, one in 11, between 50 and 60 down staging potentially those cancers. There may even be a case for more frequent, maybe two yearly screening in the moderate risk women. And there may even be a case for reducing screening. May be starting it a bit later in women at very low levels of risk. So by combining all of these measures, we can very accurately risk stratify. And the important thing in the low risk group is that there is a much higher rate of effectively over diagnosis. So cancers that may never present clinically being a higher proportion of their overall cancers. But not only that, that their likelihood of developing a stage two cancer is much lower. So potentially the overdiagnosis, the overtreatment of these women, the fact that they're getting more biopsies when they haven't got cancer are things that are downsides of screening, which can potentially balance much better the risks and benefits. So more frequent screening in those at higher risk, maybe slightly less frequent screening in those at very low risk, but may be starting their screening a bit later. And these are things we're exploring with women themselves who are identified that they are at low risk.

Sally:

Okay. So you've talked about women that are identified at higher risk. They can take precautionary measures such as kind of looking at their BMI and then having this increased screening frequency. I'm just wondering if you'd be able to talk about the preventative medication side of things and how that links into some of the studies that you've done.

Gareth:

So there are now three medications that can be taken to reduce the risk of breast cancer, the most commonly used and commonly known is called Tamoxifen, and that is a treatment that's been used for over 40 years in women with breast cancer. It blocks the oestrogen receptor on the breast tissue, and that has been shown to significantly reduce the risk of breast cancer in women with breast cancer in their other breast, that unaffected breast. But also in clinical trials, it's reduced the risk of breast cancer by about 30 to 40% in women who don't have breast cancer in the first place. So it is now recommended for NICE, particularly for women before the menopause. After the menopause, there are two additional drugs that can be used, and these are Raloxifene, which is also a blocker of the oestrogen receptor, but has a few less side effects than Tamoxifen, but unfortunately isn't quite as effective at prevention. And then there is Anastrozole, which is an aromatase inhibitor, and that drug actually stops you producing oestrogen after the menopause. You do produce oestrogen from your fatty tissue and your adrenal glands, and it's able to reduce that level that's produced. So Anastrozole is even more effective and Tamoxifen, reduces the risk by about 50% and also has less side effects. The important side effects that Tamoxifen potentially has that make it less suitable after the menopause is it increases the risk slightly of getting cancer of the lining of the womb, whereas Anastrozole does not do that and there's a slight increased risk of blood clotting and Anastrozole has much less of an effect of that. So overall, although there are some side effects with these medications, they are very, very effective at reducing risk. And NICE recommends offering these treatments Tamoxifen to pre-menopausal women, Anastrozole to postmenopausal women who are at high risk and considering them for women at moderate risk. And NICE has shown in a health economic assessment that actually taking Anastrozole because it's so inexpensive, about two or three pence a day is actually cost saving to the health service because the treatment of cancer is so expensive that actually stopping those cancers occurring saves the health service a huge amount of money. But I think as importantly, if not more importantly, saves women the hassle of going through a diagnosis and all of the treatment that's involved in a breast cancer.

Sally:

Okay. And are any of the researchers that were involved in this that were from Manchester?

Gareth:

Yes. So, in fact, a lot of these trials were led from Manchester. The IBIS one trial was led by Professor Tony Howell as the lead clinician for the whole study, as was the IBIS two trial, which led the Anastrozole that assessed Anastrozole. So both of those trials were led from Manchester. And in fact, both myself, I was on the NICE guideline along with Sacha Howell, Tony Howells son, which came up with the final most recent guidance in 2017 recommending the use of these treatments and the important thing is you take the treatments for five years, but they actually give you protection for at least up to 20 years with Tamoxifen. So they continue to work after you've stopped taking the medications. And the really interesting thing that we haven't published yet, from our BC predict Study is that these are women who we've assessed in the last two years where we've given them their risk feedback immediately after they've had their mammogram. Once they're clear on their mammograms, about six weeks after they're given their risk and all of the women at high and moderate risk that have come forward to have a discussion, nearly 80% of the high-risk women have gone on to risk reducing medication, which is really, really an astonishing result, because typically we're only getting around 10% of women onto risk reducing medication through the family history clinics. And it may be that it's this fresh realisation of risk that prompts women to do something additional, whereas women that have been living with  the knowledge of their risk for so many years are perhaps less willing to consider risk reducing medication and in fact, women at high risk as a result of family history are much, much more likely to go down the route of risk reducing surgery, particularly if they carry a fault in BRCA one or BRCA two. About 50% of those women by about five or six years after their result, choose to have risk reducing surgery.

Sally:

So just kind of touching on the risk side of things. So your BC predicts and pro-can one and pro-can two looked into the potential of offering women this risk stratification of their risk of developing breast cancer in the next ten years. So I'm just wondering, what are some of the potential disadvantages of telling women they are both either at higher or lower risk of developing breast cancer.

Gareth:

So I guess the main potential disadvantage is I'm saying their potential because we think actually they're not such a disadvantage as our study is showing, is that women who are told they are high risk could become very anxious and have a great deal of cancer worry. And that might be actually something that is strangely a disincentive for them doing anything about it. They may feel that it's going to happen to me anyway. I just don't want to know. And the women at low risk might be falsely reassured that low risk means no risk and might detach themselves from any sort of monitoring, having any sort of mammograms. And we've found in PROCAS one, that those women actually do not detach themselves, that they're just as likely as average risk women to continue with their screening. And that has recently been published in the Breast Journal. But in PROCAS two, we've shown that there really is no significant increase in either breast cancer anxiety or risk concern in the moderate and high risk groups. And in fact, many of the women who were found to be high or moderate risk already had a perception that they might be at some increased risk of breast cancer. So their perception of risk was already higher, possibly due to family history and other risk factors that they knew about.

Sally:

Okay. I guess it's really interesting to actually look into that multidisciplinary side of the research and look at the health psychology as well as the actual science behind these diagnoses. And I guess leading on from that, I'd like to ask what your vision is for breast cancer screening by 2030. And we've heard about Sajid Javid's war on cancer. But I'm wondering personal to you what that vision would be for breast cancer screening.

Gareth:

So my vision would really be that all women are offered a risk assessment when they're 30 or around the age of 30 because breast cancer is vanishingly low before that point. And we can do a lot of the breast screening starting from 30 or at least 35. We've shown that screening is actually effective and reduces mortality in women between 35 and 39, for instance. And if we did that, we would identify about one in five women who would qualify for early screening. They would qualify potentially for taking Tamoxifen before the menopause. And we could substantially reduce the mortality from breast cancer in that group of women by that combination of taking preventive medication and early detection, and then women would be reassessed at the age of 50 when screening would normally start to assess what their screening would be going forward. From that point onwards, would it be every year if they were high risk as recommended by NICE? Would it be every two or three years or maybe even every four or five years if there were very low risk? And it might be that we would say, well, you know, your screen at 50 is fine, we will if you're low, very low risk bring you just back in in five years and reassess things. But give women the option if they feel they have developed an additional risk factor to have their risk reassessed. So, for instance, their family history change, a sister's diagnosed with breast cancer. That might affect their risk assessment, although going forward, the genetics is accounting for more and more of the inherited component. So eventually we may not even need family history to assess risk because we're assessing that already in all of the genetic testing that we're doing.

Sally:

Okay, so you've got PROCAS two that's in its review stage at the minute. What would be the next stages that you'd look at with that study to enable this progression to your vision of screening?

Gareth:

So we have a study that's in set up at the moment, which is a young women study, where we are going to offer a low dose mammogram, about a 10th of the dose of a normal mammogram to assess the breast density and to do the polygenic risk score and potentially the test for the other genes, as well as using the standard risk factor. So this would be a study that would potentially legitimise the idea of doing a much earlier screen to determine risk. And I think, you know, going forward, we would hopefully, there is other research which will be coming out from the My Pep study, which is doing actual risk stratified screening at changing the risk, changing the interval of screening to one yearly in the very high risk and the high risk staying at two yearly for the average risk and then going to four yearly for the low risk and the Wisdom study which is similar in the States and going to the national screening programme assuming that the data continue to back up this risk stratification and saying, look, we need to be doing this and going forward, that would be, I think, an initial assessment, you know, as we say, around 30 years of age and then a second assessment at around 50 years of age. So women who were already approaching 50 would get that first assessment in that 50 age group, women who were in their thirties. I think we would have to work through that population slowly to make sure that eventually we got to the situation where every woman had been offered that risk stratified approach, at least up until 60 years of age. And that we then just did those two main assessments, one at 30, one at 50, potentially one more at 60. But again, the research will tell us if that is the right way to go forward. And we would have a fully not one size fits all where we can we can offer this screening. And importantly, and I've just looked at this data, the idea that, you know, you need a family history to be high risk of all of the breast cancers we've picked up when we use all of the risk factors together, half of the women who develop breast cancer, who we classify as high risk, have no family history of breast cancer at all in either first or second degree relatives. So it's really important that women don't think they can't be at high risk because they don't have a family history. There are many other ways they can get there. The genetic factors may not have shown themselves in other people because it's a deal of the cards. It might be different in you to your previous relatives and your mammographic density may be different or your relatives just may have been lucky. So for instance, we know you can carry a fault in BRCA one or BRCA two and there be no family history. So again, no family history is not immunity from risk. It just means overall, the likelihood of your risk is to be lower than someone who does have a family history.

Sally:

Okay. Finally, to summarise, I guess we've kind of covered it, but it's to get that kind of 2 second snippet of should we screen all women for breast cancer?

Gareth:

So I guess the standard answer is, yes, we need to screen women for their risk first. So that's the screening test. I think there may come a time where we will identify women at such low risk that those women may decide themselves that it's not worth them having the screening, you know, it's a little bit uncomfortable. The chances of false positives will be so much higher than the chances of getting cancer that they just decide, nope, no, I'm not going to I'm not going to have it. Maybe they'll be a better test, like a blood test that that doesn't have the same false positivity that mammograms have. So at the moment, yes, every woman should be screened or be offered screening. We can't force women to obviously get breast screening. But the evidence suggests that risk stratified screening is much better at balancing the benefits and the dis-benefits of what screening does. And that may mean that we do less screening, that we start screening later in those women at lower levels of risk. And it may eventually mean there'll be a group of women at such low levels of risk that we just stop screening altogether for them.

Sally:

Okay, fabulous. I'd like to ask what's made you curious about breast cancer and breast cancer research?

Gareth:

So I guess sometimes it's where you end up rather than what you necessarily had in mind. So I was a paediatrician and I became very interested in genetics. I was interested in genetics at medical school, didn't realise there was an actual profession in genetics. So while I was a paediatrician, I discovered that you could be a clinical geneticist. So I then looked around for jobs. I was actually in the army at the time as a, as a paediatrician, and I went for a job interview in Manchester for a clinical research fellow, and the job of that clinical research fellow was to set up cancer genetics services in the northwest of England. So my remit was essentially to develop services for people who were at increased risk of developing cancer. So there are syndromic cancers, but by far the biggest demand was from women who were worried about their risk of breast cancer. I started this in 1990, and in that year the BRCA one gene was identified as being on chromosome 17. The TP53 gene was a cause of Leigh Fraumeni syndrome and they have the highest risk of breast cancer with TP53 gene faults up until the age of about 50. And I was really fascinated to work with women to understand how women perceived risk, how they understood risk, because I was talking to them about risk. And that's really how it all started. And I've worked on breast cancer and breast cancer risk since the 1990s, initially just on women with a breast cancer family history. But from 2009, we decided that we would look at this on a population basis, and that's how the PROCAS study was started that I put in an application to the NIHR and we got a five year programme grant which is PROCAS predicting the risk of cancer at screening. And it's that study which recruited 58,000 women that has really given us huge information. That's the study that shown us what proportion of people are moderate and or high risk and what proportion of cancers we can pick up. It's shown us what happens to the screening going forwards. It's shown us about the weight gain issue. These are all factors that have been born out of that. But really, as soon as I had the opportunity to work in the breast cancer field and to develop the services for breast cancer in the Northwest, I was hooked and I wanted to help women who have that risk going forward since 1990.

Sally:

What an answer. And I think I mean, listening to that and listening to all the work that you've done, it's a lifetime worth of work and there's a lot kind of behind it. And I guess my kind of final question would be what continues to inspire you in breast cancer research?

Gareth:

What inspires me is the women themselves that the women who come forward and want to know about their risk, what they can do about their risk, the women that go out there and raise the money, that allows me to do a lot of the research that I do. But it's also that discovery factor. It's looking at the data and saying, gosh, I've just found something that's going to be important going forward. So I'm inspired by being able to identify things that are important, identify risk factors, and identify things that we can do. The more and more we can do, the more we have in our armamentarium to try and prevent deaths from cancer. And preventing deaths from breast cancer is about prevention, but it's also about early detection. And so working with those two together, I think we can make a fantastic contribution to reducing the 11 and a half thousand deaths per year from breast cancer, especially if we can get in and do this do this assessment earlier in the early thirties, that is the stage where women are losing more life years they're dying when they have young children. We should be trying to prevent those breast cancers because that's really where the most is lost.

Sally:

Great stuff. I mean, I want to say thank you so much for speaking to me today. It's been enlightening for me and I hope for the listeners as well, and I'll link all the references that we've made in this discussion. But honestly, you, Gareth, very inspirational and it's pretty great chatting to you.

Gareth:

It's a pleasure. Thank you.

Sally:

If you've been affected by anything you've heard in this episode, please see the show next for our list of charities and organisations that can help.

Speaker 3:

One in two was brought to you by The University of Manchester and the Manchester Cancer Research Centre. Listen to our next episode to hear from more of our researchers as they share the innovations, discoveries and projects that are changing the landscape of cancer prevention, early detection and treatment. To find out more about what you've heard today, please see the show notes for this episode, where you'll find a transcript and links to further information and research. Cancer is one of the university's five research beacons, showcasing the interdisciplinary collaborations and cross-sector partnerships that are tackling some of the biggest questions facing the planet. To hear more about Manchester's research in advanced materials, biotechnology, cancer, energy and global inequalities go to Manchester.ac.uk/beacons.

 

Sally Best:

Hello. You are listening to One in Two a Manchester Cancer Research podcast brought to you by the University of Manchester and the Manchester Cancer Research Centre. With one in two of us receiving a cancer diagnosis at some point in our lifetime, it has never been more important for our research to improve the outcomes for people affected by cancer. I am your host, Sally Best, and throughout this series I will be speaking with Manchester cancer researchers about their innovations, discoveries and projects that are changing the landscape of early detection. In this episode, we speak to Dr. Jen Davies Oliveira and Professor Emma Crosby about their research into womb cancer and human papillomavirus, commonly known as HPV. We also discuss one of their research projects developing alternative cell sampling methods for HPV, with lower cervical screening uptake in communities such as the LGBTQIA+ community. We explore how addressing barriers to screening can be achieved through greater engagement with these groups and the importance of developing an inclusive approach to screening. Jen and Emma hello! Thank you for joining me. How are you both doing?

Emma Crosby:

Hello. Thank you for inviting us.

Jen Oliveira:

Fantastic.

Sally Best:

Not too warm?

Emma Crosby:

It is quite warm today.

Sally Best:

Is it.

Jen Oliveira:

It’s heat wavy.

Sally Best:

It is heat wavy. But it's fine. We will ride the wave, as it were. So to start with, would you be able to introduce yourselves and what it is you do? Emma, I'll come to you first.

Emma Crosby:

So I'm Emma Crosby. I'm a professor of gynaecological oncology at the University of Manchester. And essentially that means that I've got the best job in the world because I spend half my week looking after patients with gynaecological cancers and half my week doing cancer research.

Sally Best:

And Jen.

Jen Oliveira:

My name is Jen Davis Oliveira, and I'm a PhD student with Emma's lab at St Mary's Hospital. And I have taken time out of my clinical training. I am an OBS and gynae trainee and I absolutely love being a PhD student in Emma's lab, mainly because of Emma, but also because I have a fantastic project which you're going to hear all about.

Sally Best:

So Emma, I'm wondering if you would be able to provide us with an initial overview of cervical cancer incidence and causes.

Emma Crosby:

So cervical cancer is caused by high risk human papillomavirus infection. So this is a really common sexually transmitted infection that affects around 80% of us. And this virus causes infections that can persist and become pre-cancerous lesions. And then with time, in a rare group of people can become cancer. So essentially, it's a really, really common virus, but a very, very rare consequence of infection with that virus. And this understanding of the biology underpinning cervical cancer has allowed us to develop screening and prevention programs.

Sally Best:

Okay. And I'd like to kind of touch on some of those screening and prevention programs. Just something that I read the other day was that 99% of cervical cancers are caused by HPV. Is that right?

Emma Crosby:

Yes, that's right.

Sally Best:

That's a really high statistic. And then what is the other 1% is there is that is like just kind of general genetic.

Emma Crosby:

Yeah, probably.

Sally Best:

Interesting. Okay. So I personally know that you've worked on HPV in Manchester, and I'm wondering if you'd be able to explain what this work has involved in the past on the outcomes that we've seen from it.

Emma Crosby:

When I was a PhD student here in Manchester, I was working on the HPV vaccine, which as you know, has now been rolled out to school age girls in the UK and more latterly two school aged boys. And this vaccine protects against HPV infection. So the reason that we give it to young adolescents is that we want to give it to people before they have been naturally infected with the virus, because that is the population in whom it's likely to work best. So when I was doing my PhD, I was looking at the HPV vaccine and we were applying it to people with another condition called vulvar intraepithelial neoplasia, which is essentially when the pre-cancerous changes affect the vulva instead of the cervix. And that was the nature of my PhD. I was looking for immunological responses to the vaccine and looking to see whether or not people with VIN cleared that disease when they were vaccinated.

Sally Best:

Okay. So 14 is the base age, right? So that's like pre kind of sexual what would you call it?

Emma Crosby:

Sexual debut.

Sally Best:

Sexual debut? We’ll go with sexual debut. And I mean, I personally remember when I was 14 having that, I don't even think I really knew what it was for. I don't think it was explained that much. It was just you were administered HPV vaccine and it was kind of you rather than the boys and things. And I'm just wondering, because I can't remember. But when was it routinely rolled out? What year was that?

Emma Crosby:

And so in 2008, the government started to give it to girls aged between sort of 12 and 13, but they had a catch up program where they offered it to girls up to the age of 18 because they didn't want people to miss out. You know, for it just to be because of their age that they had missed out on this really important opportunity for cervical cancer prevention. So since 2008, we've been offering it in a schools based immunization program to girls. And then just last year we introduced it to boys as well. So it's now a gender neutral HPV vaccination program. And essentially the whole idea behind this is to try and prevent anybody from developing an HPV infection in the first place. And if we can prevent the infection from happening, then the idea is that we will prevent the consequences of that infection, which is the pre-cancerous changes that I've been talking about, and also, of course, cervical cancer.

Sally Best:

Okay. So it makes sense as well for the fact that boys are receiving it because I kind of think that they'd be a conduit and pass it onto girls as well. And I'm just wondering, so this vaccine was rolled out in 2008. Would you be able to explain a bit more detail into that vaccine and there's been any development since and changes in that vaccine.

Emma Crosby:

Yes. So the vaccine that was given in 2008 was a bivalent vaccine, which means that it protects against two of the most important high risk HPV types, HPV 16 and 18, and together, these two HPV types are responsible for around 70% of cases of cervical cancer across the world. And so this was the vaccine that was initially used. And then around three years later, the government decided to instead introduce a quadrivalent vaccine called Gardasil. And this also protects as well as HPV, 16 and 18. It also protects against HPV six and 11, which are two low risk HPV types that cause genital warts. And although, of course, genital warts are nothing to do with cervical cancer, they are a cause of great. You know, there are really unpleasant thing to have, really difficult to treat. And so by getting rid of genital warts, that would seem to be an added benefit of vaccinating our children against HPV. And then this year and 2022, we have actually swapped to an even better vaccine that protects against more HPV types, and this is called Gardasil nine. So in addition to protecting against the low risk types, HPV 6 and 11, that cause genital warts and the very important HPV types, HPV 16 and 18 that together are responsible for about 70% of cervical cancers. The new vaccine protects against an additional what would it be five? An additional five high risk HPV types. So in theory this new vaccine should prevent around 85% of cervical cancers around the world.

Sally Best:

So you've talked about this kind of the effects of the vaccine and having a real preventative effect in terms of development on cervical cancer. And I'm just wondering if it's been administered since 2008, why do people need to be screened if they've had this vaccine?

Emma Crosby:

So the whole idea is that you're vaccinating people before they've ever been exposed to it naturally. So we're vaccinating girls age 12 to 13, but of course, and now boys as well. But of course, those girls don't become of screening age until they're 25. And so although they've we have vaccinated quite a lot of young people now, they're only just starting to become of screening age. And so the vast majority of people who are in the screening program have already been exposed, naturally exposed to HPV and remain at risk of cervical cancer. So there's just, you know, the new cohort of people, if you like, coming through that have been vaccinated. And of course, in the early days they were vaccinated with Cervarix, which only protected against HPV 16 and 18. So that means that there were still around 30% of the of the cervical cancers that would not be protected by cervarix and actually the profile of HPV types in pre-cancer and in cervical cancer are a little bit different. So actually we do see other HPV types causing pre-cancer of the cervix that the vaccine does not protect against. And we don't know whether or not, if left for long enough, these would be equally as likely to become cervical cancer, because in the past, the whole picture has been dominated by HPV 16 and 18. So people still need to be screened because they still may carry HPV infection that causes cancer and pre-cancer.

Sally Best:

Yeah, it's really interesting because I wouldn't have thought about the prevalence of other strains of HPV that would be cancer causing, and that would be the reason that you need to get screened. So it's a good message for people to still get screened really.

Emma Crosby:

And of course, not everybody was vaccinated. So particularly in the early days, the uptake of the vaccine wasn't perhaps as good as it is now. And we've had dips associated with the COVID pandemic that have meant that, you know, far fewer people than we would have hoped have been vaccinated. And actually, the way that it seems to work is that those who are at greatest risk of cervical cancer tend to be the girls who are less likely to be vaccinated.

So they've done some studies where they have looked at mothers and their daughters, and it looks as if mothers who are themselves not going for cervical screening are least likely to consent for their daughters to be vaccinated against HPV. So you get into a situation where some girls are vaccinated and then religiously go for their for their screening and other girls don't get vaccinated and then are still less likely to go for screening. And so, you know, we tend to offer screening for everybody because we don't know what group each individual will fall into.

Sally Best:

Yeah, it's really interesting to think about that compound. The fact of unvaccinated and then not screened. Yeah. Kind of puts you more at risk, I guess. I'm just wondering as well in terms of the catch up program, so is the vaccine as effective if you've already had that HPV exposure?

Emma Crosby:

Yeah, so we don't think so. We think it needs to be before you have any exposure. And the reason for that is that the way that it works is that it produces antibodies that neutralize the virus and prevent it from ever infecting the cervix. So if you have already been exposed to HPV and already have accumulated it in your cervix, so it's sort of lying in the cervical cells, then the antibodies that you produce from vaccination are unlikely to be able to clear the virus because it's already inside the cells and antibodies work by preventing access to the cells, if that makes sense. So you need a different kind of immunity once you've been infected to one that prevents infections.

Sally Best:

Okay. And we talked before as well about this new cohort of people coming through that are those that we saw in 2008 received the vaccine. Are we seeing the drop in incidence and prevalence of HPV?

Emma Crosby:

So we're seeing a reduction in the proportion of people coming with cervical cancer. So it's definitely making a difference. So a recent study published in The Lancet, I believe this year by Peter Cassini and his team from King's College London showed that the vaccine has resulted in a 90% reduction in cervical cancer cases in women coming of age of screening age.

Emma Crosby:

But we are still seeing women coming to clinic with HPV associated diseases. And it could be, as we discussed, because the uptake of the vaccine wasn't perfect, particularly in the catch up groups. So it was pretty good in the 12 and 13 year olds, but less good as girls became older up to age 18, but also could be due to the emergence of other different HPV types causing these cervical pre-cancers.

Emma Crosby:

So Jen, I think you had to look at this in the literature and you found some quite interesting results.

Jen Oliveira:

Yeah, well, I had a look at it actually in the research that we've done, so I'm sure we'll be talking about it. But interestingly, those with high grade disease that needed treatment, so high grade pre-cancerous cervical disease, we saw that in fact, 99% of those had other types of HPV that weren't associated with the vaccine. So certainly there's a change there's a change in the type that's causing the issue.

Emma Crosby:

Yeah. So we're still seeing people coming through. Hopefully the numbers are less, but the proportion of the different HPV types seems to be changing.

Sally Best:

And do you know of any research groups that would be looking into developing new vaccines for these different HPV strains?

Emma Crosby:

So I think at the moment we are stuck with Gardasil 9. I'm not aware of any that are going to prevent other types of HPV, but there are 13 high risk HPV types, so we're only covering seven of those with the current vaccine. So there is room for developing even bigger and better vaccines, if you like. But at the moment, I think we're stuck with Gardasil 9.

Sally Best:

Cool and just as an aside, I'm interested in this concept of a vaccine against cancer, and I'm wondering if this vaccination protects against other kinds of cancer.

Emma Crosby:

Yeah, so that's a really interesting question. So HPV causes other cancers, not just cervical cancer. That's the one that we have been developing it for, of course, because it causes such problems, particularly in low and middle income countries, where it affects young women who are often the main breadwinner and have families. And it's you know, it's a devastating disease, particularly in those countries where they don't have screening programs. But it also causes other types of cancers. So it causes cancers of the anus, of the penis, of the vulva and the vagina and also cancers of the head and neck known as oropharyngeal cancers. And all of these types of cancers are associated with HPV. And although the studies done so far have all been centred around cervical cancer, we absolutely expect that the prevalence of these other cancer types associated with HPV to drop as vaccination becomes much more common in our young people.

Sally Best:

Yeah, and especially boys as well. I mean, there's a lot of cancers there that are not gendered. So yeah, kind of sounds very important for boys to get vaccinated, really?

Emma Crosby:

Yes, I think so. And I think in the past we thought it was it was better to vaccinate more girls, more cost effective and more effective at preventing cervical cancer than it was to be gender neutral and vaccinate boys as well. But in the interests of fairness and the fact that boys do develop HPV associated cancers that policy has been sort of turned on its head, if you like. And so that's the reason why we now have a gender neutral vaccination policy, because we want to be fair.

Sally Best:

Yeah, it's a really nice progression and I guess we've heard about the prevention of cervical cancer through HPV vaccination from you either. So I'd like to move on to the early detection of cervical cancer. And Emma know in 2020 you received funding from the NIHR, which is the National Institute for Health Research for a five year advance fellowship to investigate whether urine testing can be used to screen women at risk of cervical cancer. And Jen, I know you're working on this project with Emma, so I'd like to come to you and I'm wondering firstly if you'd be able to explain the importance of cervical screening. And I know we've touched on it with Emma, but I'm just yeah.

Jen Oliveira:

Just an overview. So screening came about in the sort of late seventies, eighties in the UK and we know from big studies that it's reduced the number of those dying from cervical cancer by up to 70%. So it’s definitely made a difference. So that's the importance of it. And we also know that in high income countries where we have screening programs such as what we have here luckily, we certainly have lower numbers than in low to middle income countries where people just aren't being screened. So it definitely makes a difference and is important.

Sally Best:

Okay. And I've read that only 70% of people eligible for cervical screening attend their appointment here. Is that in the UK or England?

Jen Oliveira:

That's the whole of the UK.

Sally Best:

I'm wondering if you could explain the current screening methods and some of the barriers to cervical screening that currently exist.

Jen Oliveira:

So the way that we screen is the same way that we've always screened pretty much. So you

have to have a speculum examination to visualize the cervix and then a brush is taken. A brush of the surface of the cervix is taken with some of the cells taken in that sample. And then what's recently changed and is in 2019, we started to test that sample just for the virus, HPV. So the high risk types and whereas before we used to look just at the cells, but we found the virus to be effective, to look for the virus more effective than just looking at the cells. And then if you're positive for the virus, a high risk strain of the virus, then you are then, the sample is then looked at from the cellular perspective to see if there were any abnormalities. And then based on that, you may be having further investigation. So that's the way that screening works currently. Essentially, that obviously requires you to go to your GP practice to make an appointment, to then obviously take time off work. Often, you know, the screening program is for younger people. So between 25 and 65 they'd have to take time off work, go to the GP practice. So that's one of the big barriers is access or making that appointment and finding time. And then the other barriers are understandably going to be the embarrassment of having that examination, an intimate examination like that. And also the discomfort or sometimes the pain that that some people experience having that examination.

Sally Best:

I'm wondering if you'll be able to tell the listeners about some of the research activities that you're currently doing that are taking place to address these barriers.

Jen Oliveira:

Yes. So my project with Emma is looking at whether we can get rid of the access barriers so people can do a test at home and whether we can also get rid of that examination. And that would be through a self sampling method. And we're specifically interested in looking at urine testing. Urine is something that the people generally have no issue giving a urine sample. It's quite straightforward. And we're investigating whether that urine sample can actually pick up the high risk HPV, if that individual has it, and whether that could be done potentially at home and then sent in and then tested for.

Sally Best:

Jen, what is ACES?

Jen Oliveira:

So ACES stands for alternative cervical screening. And one of the first tasks that I was tasked with by Emma was to come up with a good name for this urine HPV testing study. So we did come up with ACES.

Sally Best:

Okay, so there's the kind of looking and seeing if this urine sample can be used. And is it as effective as the previous screening method? What would you call that screening method?

Jen Oliveira:

Well, no cervical sampling.

Sally Best:

Cervical sampling, wow.

Jen Oliveira:

Bit more of a mouthful

Sally Best:

But yeah we’ll go with it, bit cumbersome. so that's the number one kind of prong of this research. And then I know so I had the great opportunity to attend an event with you last week and that was looking at access for all and the LGBTQIA+ community and I'm wondering if you'd be able to explain the kind of acceptability parameters that you've been investigating, because it's a really great study. I've loved hearing about it and it's one of those things that every kind of single update, I get excited about it. So please, can you just tell people about it because it's, it's fab.

Jen Oliveira:

So that's great. I'm really pleased that you like it. And I do too.

Sally Best:

I’m glad you do

Jen Oliveira:

But essentially, I mean, we're looking at an alternative test to see if we can get more people tested and potentially also get testing started in places where, you know, it's too expensive to have the kind of testing that we're doing currently, so in low to middle income countries. So that's sort of what we want to do. But the thing is we need to know that it's actually going to increase the numbers of people being screened because there's no point in looking into it if it's not going to do that. So the acceptability bit of it is really to see whether people think this is a good idea and whether it is likely to increase the numbers of those going for screening. And we look to the LGBTQIA+ community because there's no research being done in this community within Manchester in early cancer or prevention. And also it's a really important group to look at with regards to cervical screening and especially those individuals who identify as transgender. It's really important because we know that the likelihood is this community is not going for screening as much as other people. So that's why we looked at it.

Sally Best:

Yeah. I mean, I found it really interesting that we talked about barriers to screening in the community and specific and even just things such as gendered waiting rooms. And if you're a trans man sitting in a female gendered waiting room could be very stressful. So then the acceptability side of things of saying, okay, well if you don't have to go through that because unfortunately sometimes society isn't as accepting to people as you want it to be. If we did give you this at home urine test, you could use that and just send it in and kind of eradicate the need for going into the GP, which I think I mean, I know you've spoke about the results looking really positive, it's a great pathway for people that feel discomfort associations with all kind of current health care system.

Jen Oliveira:

Absolutely. The only thing is, is it can't replace us looking at those barriers because these individuals also need to feel comfortable accessing their GP and care for other things. So we need to be careful that it doesn't completely replace that or is a way of making people not look at these other things which are also really important. But I think awareness is key here. But if it can increase the number of people being screened, then that's got to be a positive.

Sally Best:

Yeah, definitely. And I know you spoke about this at the event, but for the benefit of the listeners, would you? So urine is really useful. We use it for STI tests and kind of various tests look at kidney function, liver function, etc., etc.. And I think one of the things with cancer is and I know you kind of look at this with Phil Emma, on teaming up and looking at multiple cancers rather than one, because if you've got kind of a patient in one location, you might as well test for everything while they're there. Do you envisage the development of that test to not only look at HPV but maybe even integrate some STI tests and into the sampling?

Jen Oliveira:

Absolutely. That's definitely something that can be done. That would require, I guess, a concerted effort from industry as well, because obviously the testing is done by companies who have their own platforms for testing. So it would be really important to work with them and potentially across the industry to try and come up with a test like that. But I think urine is definitely looking positive as a method of screening for potentially lots of different cancers and also other infections.

Sally Best:

Urine is the future then.

Jen Oliveira:

Absolutely.

Sally Best:

Oh, yeah. If we can minimize the number of wees in pots and use them the best that we can, I'm sure that would be great.

Jen Oliveira:

Although there's generally plenty of urine to go around. Yeah.

Emma Crosby:

That's one of its benefits, isn't it?

Sally Best:

Yeah. And if you run out, you can just produce more. Fab. Okay, well, I'm just wondering, this is kind of looking to the future with you both. Utopian environment. It's, you know, Jen you’re laughing, but it's going to be utopia, don't you worry.

Jen Oliveira:

A urine utopia has a ring to it.

Sally Best:

Well, coin the urine utopia.

Jen Oliveira:

Crosby's urine utopia.

Emma Crosby:

Now I like it even better.

Jen Oliveira:

Although now we have to say Emma Crosby's.

Sally Best:

It's true. It's got a ring to it. I love it. The Golden Era

Jen Oliveira:

I'm taking it too far.

Sally Best:

All right. Okay, so Manchester has a large and engaged LGBTQIA+ community. And is this one of the reasons, why this trial or the survey component is being conducted here.

Jen Oliveira:

I think it really it came from individuals within the Christie sort of came together and said we should be doing something. This urine the urine study looks interesting and we should be looking also at being more inclusive in our research because we knew that this community is not very engaged with research, unfortunately, for various reasons. So that's why it came about. And of course, Manchester is a big hub for the LGBTQIA+  community, so it was a perfect place for us to address this issue and with also looking at larger numbers as well. But because it was an online survey, we actually got a lot of data, as well from London, which you'd expect and some other the places in the UK as well, but less so.

Sally Best:

And can I just ask about the results of those of that survey as well? So am I right in thinking you had 550 responses?

Jen Oliveira:

Yeah, 503.

Sally Best:

Oh close, 47 off. But I'm going to take that as a win. And what was the composition? So you went out to the LGBTQIA+ community. You said, Please, can you fill in the survey on acceptability? And what were the responses like?

Jen Oliveira:

So we so first of all, it was interesting because we did get a high number of individuals who identify as transgender, which is fantastic because you know, obviously there are less numbers of people who identify in that way than there are, for example, lesbian or bisexual individuals. So that was fantastic. And essentially it showed that there would be a high acceptability. And obviously we're talking about acceptability. When people just hear about the test, they haven't actually undergone the test obviously yet, but when they hear about the test. But there was a really high number that were very happy to do screening in the future with urine. And we also asked them about vaginal sampling as well, because that's another method of self sampling and that was also a lot more accepted then obviously cervical sampling, which requires you to have someone else do that test for you.

Sally Best:

And has a vaginal sampling been tested for efficacy?

Jen Oliveira:

Yes, it has. It's a bit more forward in terms of it's it's done a lot more progression than urine sampling. But yes, it's just as good at picking up HPV as the cervical sampling. So and there are two big studies happening in Manchester and also in London in the general screening population to see whether we can do vaginal sampling in the future. And I think, you know, it's safe to say that the likelihood is that will be available in the coming few years in the UK. It's available already in nine countries in the world as their primary cervical screening method.

Sally Best:

Really, what countries do you know?

Jen Oliveira:

One is at least Sweden. I know probably all the Scandinavian countries. I'm pretty sure they're pretty forward thinking with these things are.

Sally Best:

Progressive.

Emma Crosby:

But the reason that we thought that urine would be even better is that the studies so far suggests that although vaginal self sampling is acceptable to some people who don't go for cervical screening, it by no means, you know, gets over all the different barriers. So some studies in the UK have looked at specifically targeting people who haven't gone for screening with vaginal self sampling and had a really bad response rate. So you know, the majority, you know, the best they could get was about 20% response rate. So that means that isn't addressing the barriers for the other 80% of non-attenders. And we think that that's probably because it still requires an intimate examination and you know, there might be personal and embarrassment and cultural reasons why that isn't acceptable to some people. But as Jen said before, you know, people are familiar with taking a urine sample and hopefully that will help us to develop a test that's even more acceptable to people. And I guess ultimately the plan is that if we can offer choice to people. So, you know, it might be that some people prefer to go for cervical sampling because that's what they're used to. They perhaps have abnormalities in the past and they feel safe. Continuing with physician collected cervical samples, there are some who, you know, are very comfortable with taking a vaginal sample and that might be their preferred method. But there will be others for whom urine would have more acceptability. And so the idea is that we want to give choice stop.

Sally Best:

And Jen, just back to kind of your work ACES work. So you want to have you been to Somaliland or you hope.

Jen Oliveira:

It's not part of ACES. It may be in the future.

Emma Crosby:

I mean, ultimately, we want this test to be useful not just in the UK where we already have 70% of people going for screening. We want it to be useful in other countries where they perhaps don't have a screening program and where there are even greater barriers to screening, like the cultural things that we were talking about. And so I think you had aspirations, didn't you, to go and try it in way like Somaliland or Kenya or, you know, some low middle income country where there isn't any, you know, an established screening program to see how well urine sampling would perform.

Jen Oliveira:

I guess the other thing, there are other issues with going to a place where there's no screening program in place and that's the infrastructure. So what do you do with a positive test? So those are the big questions and the big barriers, I guess for us researching is to make sure that it's adding benefit to that population and not just finding out if people have HPV or not and then not being able to do anything about it. So that's really important.

Emma Crosby:

Yeah. I mean, ethically, it's, it wouldn't feel right to go and find a whole lot of people with high risk HPV infections. And then there was no opportunity for them to be, you know, have further investigations and treatment. And we know that that is a problem in some of the countries that we're talking about. So, you know, that needs to be more than just a new sampling method. But, you know, this could be one small step that helps the other things fall into place.

Jen Oliveira:

Watch this step.

Sally Best:

Watch this space. I'm saying you could go worldwide.

Jen Oliveira:

Global urine utopia.

Sally Best:

Wee everywhere, don't wee everywhere.

Sally Best:

I mean coming back to the UK, I mean we'll talk about the global utopia in a bit, but coming from the UK, what are you're next steps Jen.

Jen Oliveira:

Oh gosh, we have looked at. So the main thing that I've been doing with Emma is looking at whether urine tested for HPV is picking up people with high grade cervical disease so that pre-cancer that that need treatment because they're at risk of developing cervical cancer. So we've looked at a group at St Mary's, so I've collected a lot of urine, so I'm very well versed in that now. And so hopefully we will be able to share those results in the near future. And we are also the ACES research is also continuing into the screening population. So we are currently undergoing the primary care arm with the study.

Emma Crosby:

And then yeah, I mean, I mean, those two things are really important and they say, first all, it must pick up the high grade disease. We need to be seeing those women and offering them treatment. But it also needs to safely reassure people who don't have the HPV. So you need to look at a kind of an enriched population who've got the pre-cancer to check on the first thing. But then you need to look at a low risk population, a general population, to look at the second. And so it's this combination of the two settings in the Colposcopy Clinic where there's lots of pre-cancer and in the general population where there isn't that will help us to see actually is urine good enough you're also testing it in people who've undergone treatment for pre-cancer?

Jen Oliveira:

Yeah. So six months after a treatment, you have a cervical sample taken to see whether you've cleared the virus. And if you have cleared it, then that's, that's essentially means the treatment, which is it was a success. So we're also collecting urine in that group of women to see if the test works just as well in that population and whether also it would be acceptable to people who have had a treatment for abnormalities to then have a urine test instead of cervical sample as you know, as their test of cure, so to speak.

Emma Crosby:

And then after all of this, once we know that it actually works, the plan is to see whether it helps people who haven't attended for screening to actually go for screening. So the plan will be to find people who have not attended routine screening and send them a self sampling kit to the home address and ask them to return a urine sample to the lab. And then we will be able to see whether it's appealing to them, whether it helps people who haven't been screening be screened, because we're also going to be directly comparing response rates with vaginal self sampling in that group we’ll be able to directly compare how well urine is working compared to a vaginal self sample, compared to doing nothing at all and allowing people to just, you know, eventually turn up for routine screening if they wish to. So that's really quite an exciting study. We're going to look about 10,000 people and that'll be in the year 2024, I think. But yeah, that'll be really exciting. But clearly it's only worth doing that if we know that the test genuinely works. So watch this space again.

Sally Best:

You guys are so busy, do you sleep?

Emma Crosby:

No, she's not allowed to sleep. She's doing a PhD.

Sally Best:

Fair, fair enough I'll do some sleeping for you. Jen, You're from Wales.

Jen Oliveira:

I am.

Sally Best:

What’s brought you here?

Jen Oliveira:

Emma, that's all I need to say. One word.

Emma Crosby:

I think Jen could see that this was a great opportunity because it was on the back of the NIHR fellowship that I had received. So we had money to do, you know, a really good study. And yeah, I mean, just just very, very exciting. The general public were really sort of buzzed by the idea of a urine alternative to routine screening. So it was just riding that wave, wasn't it, of wow, this this looks exciting. Let's, let's study it further.

Jen Oliveira:

Yeah, there's a lot of positivity.

Sally Best:

Yeah. Well, personally, I kind of met your research group and god, the gang is just amazing.

Emma Crosby:

They are.

Sally Best:

Makes you want to be part of the gang.

Emma Crosby:

Oh, well, you're part it.

Jen Oliveira:

You’re very welcome. A PHD opportunity is coming up.

Sally Best:

I'd like to look into the future with you both. And the World Health Organization wants to eliminate cervical cancer by 2030. And I'd like to put the question to you both. What are your ambitions for cervical screening by then?

Jen Oliveira:

I mean, there's only eight years until then.

Emma Crosby:

It's not long, is it? I mean, to be honest, the UK is doing pretty well. It's about increasing uptake of screening, it's about making sure we continue to vaccinate all the young people that are eligible and it's about there being access to treatment. So we are doing really, really well in the UK. There are strict targets that we have to meet but I don't think we're far off them. The issue isn't here, the issue is other countries where just none of that stuff is in place. So there is nothing to protect people who've already been exposed to HPV from cervical cancer. Those who develop cervical cancer often therefore develop it at a more advanced stage where treatments aren't as effective and sadly aren't as available, you know, so they just don't have the, the, the opportunity to treat women with advanced disease in the way that we have here. And, you know, the vaccination programs are starting, but it's it hasn't been in place for as long as it has in this country. So they are significantly behind. And I guess for both of us, the you know, the ultimate ambition is to try and correct some of those global disparities. You know, it's all very well to you to make screening a little bit better in the UK, but we're already doing quite well. It's how do we reach those other countries where women have no access? And I suppose that's my ambition. I think it might be yours as well.

Jen Oliveira:

Yeah, sounds familiar. Yeah, I think I think it goes beyond those screening, you know, looking more at the disparities and the services that people have in low to middle income countries. Unfortunately, you know, even if we as I said, even if we find HPV or if we find high grade diseases, then the treatment to that and the follow up of that, you know, it requires a complete overhaul of systems that are probably already not in place because potentially a lack of lack of well, definitely a lack of funding and also a lack of, you know, political will. And just the fact that people in their life, they live very different lives. You know, a lot of it is about survival, you know, and putting food on the table rather than thinking about going for screening and making sure that, you know, developing cervical cancer, but nonetheless really important. And if we can, you know, if we can change that will make it a bit easier and at least start that process or ball rolling. Maybe that will then lead to some change.

Sally Best:

I'm sure it. Well, you're making great leaping steps. Thank you so, so much for coming on with me. It’s been an absolute delight. I love hearing about your research and what you guys are doing because it's always amazing. Maybe I'll join the team on day, who knows.

Jen Oliveira:

Yeah. We'd love to have you.

Sally Best:

Thank you as well to our listeners and I'll tag both of your Twitters if that's okay. Yes. And of course, you know, Jen loves a selfie and Emma loves Twitter also.

Jen Oliveira:

So I'd never heard of Twitter before I met Emma. So I was like, my world has changed.

Emma Crosby:

So I was like, you need to get in my world.

Jen Oliveira:

I find out about the next projects I'm doing from Twitter.

Sally Best:

Yeah, we want food updates as well. Everything, everything that we can get. But yeah we’ll link all tags because they're kind of amazing. We've got a lot of links and a lot of MCRC blogs as well. But yeah, thank you for listening and thank you guys and have a great day.

One in two to was brought to you by The University of Manchester and the Manchester Cancer Research Centre. Listen to our next episode to hear from more of our researchers as they share the innovations, discoveries and projects that are changing the landscape of cancer prevention, early detection and treatment. To find out more about what you've heard today, please see the show notes for this episode, where you'll find a transcript and links to further information and research. 

Cancer is one of the University's five research beacons, showcasing the interdisciplinary collaborations and cross-sector partnerships that are tackling some of the biggest questions facing the planet. To hear more about Manchester's research in advanced materials, biotechnology, cancer, energy and global inequalities, go to Manchester.ac.uk/beacons.

Sally Best:

Hello. You are listening to One in Two, a Manchester Cancer Research podcast brought to you by the University of Manchester and the Manchester Cancer Research Centre. With one in two of us receiving a cancer diagnosis at some point in our lifetime, it has never been more important for our research to improve the outcomes for people affected by cancer. I am your host, Sally Best, and throughout this series I will be speaking with Manchester cancer researchers about their innovations, discoveries and projects that are changing the landscape of early detection. In this episode we speak to Professor Katherine Payne about health economics, what it is, it’s importance in cancer treatment and early detection strategies, and the crucial role it plays in changing healthcare policy. We discuss Kathryn’s work evaluating the health and economic benefits of banning sunbeds in England and the effect that a policy intervention would have in reducing the burden of skin cancer on the NHS. Hi, Kathryn, thank you for joining me today. How are you doing?

Katherine Payne:

No problem. Good, thanks.

Sally Best:

I'm just wondering if you'd be able to introduce yourself for us on what it is that you do in your job?

Katherine Payne:

Absolutely. So my name's Katherine, and I am a professor of health economics based at the University of Manchester. And I work with a number of health economists in my centre, and I also have the role as lead for the Manchester Centre for Health Economics.

Sally Best:

So I think I'd like to start off this episode by asking firstly, what made you interested in health economics?

Katherine Payne:

Yeah, interesting. I've had an interesting route into health economics. Yeah, most health economists came into the topic having done degrees in economics. I was part of a family who'd never been to university, so I didn't really have any parents to sort offind out what it's like being at university. So I relied very heavily on careers advice. And so when I was 12, a long time ago, I went to this talk by a pharmacist and they were for me at the age of 12, they seemed ancient. They weren’t actually that old, but they seemed really old. And I was just amazed about how still vibrant they were and excited about their career as a pharmacist. And I thought, being honest, I'm really squeamish. So I thought, no way I could be a medic because I would be a medic on the floor. So I thought, right, that's what I'm going to do. I'm going to be a pharmacist. So that's what I set my sights on and that's what I ended up doing. So I qualified as a pharmacist and started work in the Queen Elizabeth Hospital in Birmingham. And after about two years, I thought, Do you know what? I can't do this for the rest of my life. I really cannot. So I started  thinking about, well, what else could I do? And I started being interested in research and thinking. So I'd done research projects as part of my undergraduate degree, and I trained and done some clinical pharmacy training as well on top of my degree. And so I thought, yeah, I like this research thing. I didn't really know what it was. And at the same time I was put into a new post for the Haematology Directorate and back then we were starting to use some really expensive medicines. So intravenous immunoglobulins are one of the ones that I still remember and my job was to try and stop people using them inappropriately. I had no real training on this. And so I ended up being called the penny pincher on the wards. And that really hurt because obviously I wanted to be a pharmacist to train my whole life. And they started to think all I was about is sort of saving cash. So then aligned with this idea that I wanted to do some research, I applied for this fellowship that the Department of Health had set up to move pharmacists into academic careers. And as part of that, I ended up talking to people. It was in the 1990s. We didn't have, you know, the power of the Internet. It was the phone. And so I ended up talking to my line manager and another health economist who is really famous called Martin Buxton. And he really inspired me. And I, I got some money to do a master's, I'd applied for a PhD, was not successful in the Ph.D., but they said, do a masters. And I thought, oh great, but what in. So that is literally how I ended up being a health economist because I talked to Martin Buxton and he said, do this course at the University of York. And that is what I did. And I thought I would go back and be a pharmacist afterwards, but I went and did this masters. Could no way could I go back to working on the wards after doing that, because it completely changed my thinking. It moved me away from thinking about individual patients that you try to care for on a day to day basis, to thinking about people being part of a larger population and how we get the best out of things for that larger population. So yeah, quite a long winded story, but that's how I ended up becoming a health economist.

Sally Best:

No. It's really interesting. I loved listening to the kind of chance interactions that have meant people have ended up where they have ended up and not ended up where they thought they were going to end up. Yeah, that's the way that works. But I think just that change of insight and the change of perspective is so interesting and I’d definitely like to come onto that later on. I'm just wondering if you'd be able to explain more about what health economics is?

Katherine Payne:

I will try. Health economics is a discipline and so it is massive. A lot of people, I suppose, now think about health economics in the context of the National Institute for Health and Care Excellence. So NICE is the decision making body that gets on the front of the Daily Mail because they've said no to a particular medicine and basically all hell breaks loose. So NICE uses something called cost effectiveness analysis, which allows you to think about the impact on the NHS budget but also capture the benefits to patients in terms of the effectiveness of treatments for patients. But health economics is part is a subdiscipline of economics and economics is a behavioural science, so it's interested in behaviour at the population but also at the individual level. And it's there to produce information so that people can make good decisions about how to use scarce or finite resources. So one example of a finite resource is the health care budget. So because health economics is a behavioural science, it means it can work at the macro level. So at the sort of policy level or at the micro level, which is where we get into evaluation type methods that we're used to seeing, used by NICE. But other things that health economists can do is we're interested in defining core concepts. For example, what is health and what is health care and how might we measure health? For example, we're also interested in supply and demand. So how do we best supply health care to meet the demand for the services? And we're also interested in using methods to understand what people think about health care. So this might be preference type work. So I could talk forever about what is health economics, but the main thing that we should remember is this core concept called opportunity cost and what that tells us is if we spend some money on one thing, then we're not spending money on something else for another portion of the population. So there's a cost for investment in that one particular item, be it a medicine for breast cancer or a hip replacement. So what this does is encourageous to think at the population level about if we spend money on one group of the population, what are the potential benefits to that population? What benefits are we may be missing from someone else in the population that isn't immediately in front of us. So I don't know whether that was clear.

Sally Best:

No, great. Absolutely great. I mean, I understand. And I'm not in the realm of health economics at all. So yeah, very, very vast. But interesting overview. And I'm wondering with this understanding why health economics is relevant to cancer research, because I guess that's kind of why people are listening to this podcast and why it's, it's of interest to them. So yeah, I'm just wondering about that cancer research hook of health economics.

Katherine Payne:

Yeah. And I think again, going back to thinking about the work of NICE, if you look at the number of and type of medicines that NICE appraises of part of their technology appraisal programmes. I think the majority are medicines for cancer. And so again, everybody might think, well, health economics then is just all about saying whether or not patients can have this new cancer medicine. And indeed, there is a use before that. You know, it has a vital role in understanding whether a new medicine coming online is worth how much the NHS would have to pay for it, and worth in the sense that patients, given this medicine, how much benefit they would get from it and what harms this medicine might cause. But also, if we think about cancer research with Manchester, we've got an interest in early detection and prevention. And so you can think about using health economics there to say, is it worth investing in this new early detection mechanism? Is it worth investing in prevention programmes or screening programmes? And the behavioural side is interesting as well because we can think about looking at interventions to reduce obesity in a population and economics has a role there as well. And as you know, obesity is an important factor in causing cancer. So there are many different areas where it's relevant to cancer research, but not only in terms of evaluation of new cancer related interventions. It's also important to think about people's behaviour and an uptake of cancer interventions such as screening programmes. And that's where a lot of the preference work that we do in Manchester is important because we can try and start to predict, if we design a new cancer screening programme such as the lung health check, for example, we could start to say if we designed it in this way, what type of people might use it and what might the uptake be? Because you need you need good uptake for these programmes to be effective and realise the benefits that they promise.

Sally Best:

Great. Yeah. I'd like to touch on some of those points in a bit, but I'm just wondering why the health economic side of cancer research for you, was that something that just you just happened upon, was a kind of project that you were placed on?

Katherine Payne:

Yeah, I could be trite and say, well, it's the funding, isn't it? Because you can only do what you want to do if someone's prepared to pay you for it. But no, I think drawing back on my career as a hospital pharmacist, I used to spend hours in aseptic suite, drawing up medicines, chemotherapy used to be very labour intensive, very hot as well. You think we're hot now, you’re very hot when you're in one of those and also seeing people with cancer on the wards. As I said, I work for a haematology directorate. So, a lot of blood cancers and so that, that's always been there and there's always been this belief that medicines, although I was a pharmacist, so medicines were always important to me, but medicines weren't always the only solution. And particularly now when they getting so expensive and yes, offering people some gain in health but not massive, you know, teeny tiny amounts. And so starting to think, is it is it worth it? Is it worth putting a person through this medicine that might give them harms might be toxic as well? Yes, there might be benefits. And, you know, everyone as an individual is right to, you know, try medicine. But I see my role is as giving the evidence to people to say, well, if you do invest in this medicine, this is really what you're going to get out of it compared with other alternative treatment options available to people. So there's that pharmacy link, but then there's the stronger link about trying to prevent cancer. And I think that that is highly relevant. And I now see there's a role for health economics in there.

Sally Best:

Yeah, definitely. I think prevention is a massive thing, especially in Manchester and leading on, I'm just wondering what specific studies you've focussed on that are kind of related to cancer research that you've done here?

Katherine Payne:

It's really drawing on my memory here, so I don't know whether there's a good or a bad thing. I've now been at Manchester for 27 years, so two years ago I got my, 25 years prize for being here. Yeah, it wasn't very big, but anyway. So yeah, I'm trying to think of some more recent ones. So I worked on with a colleague called Cheryl Jones. We worked on a project evaluating the cancer vanguards that were rolled out. And there's a couple of examples of new services that are rolled out across Greater Manchester. And we looked at trying to understand what the cost implications of rolling out these services might be. I've worked with Stuart Wright on a project where we looked at moving beyond cost effectiveness to think about the impact of implementation of mutation testing for targeting treatments for lung cancer. So those specific types of treatments for lung cancer that need the tumour to have a particular genetic makeup. And so that requires having a test, the patient having a test, evolving the tumour sample to see if they're going to respond to a particular medicine or not. And NICE had said, you know, roll out these new medicines. What they've not thought about is how the NHS could cope with the roll out of the required genetic testing to support that. So what Stuart did is look at what factors might influence the ability for the NHS to deliver these genetic testing for treatments for lung cancer, how that affects the cost effectiveness of the service and what might be done to try and improve it. So going forward you could start to predict if a new genetic test came out, how to better roll it out across the NHS. I think you've spoken to Gareth Evans as well as part of this series and I've worked with Gareth on evaluating his risk based breast screening programmes as well. So looking at the economic impact of that and also worked on a project looking at quite a sensitive area. We’re thinking about removing some beds from the high street. And so thinking about the impact of saying to people at a younger age, you know what, using a sunbed frequently is perhaps not a good thing. So that perhaps is the most recent project that I've worked on.

Sally Best:

Yeah. And I think that's what I'd like to pick up on. I've worked with you previously on developing blogs for this. And I think it's an interesting area because number one, there's the prong of UV exposure and being linked to melanomas and other types of skin cancers. And it's that kind of okay, if you're banning somebody, you're therefore saving lives. And then I think there's the interesting kind of part of the model that you looked into, which was more on the health economic side of things. And I mean, I've got some of the articles in front of me actually, so I'll link these for people that are interested. I know you're not a massive fan of the press, so we can, you know, just kind of breeze over them. The Sun has actually written about it. Quite ironic. Dying for a tan. Urgent calls to ban some beds to save thousands of lives. And then specifically, I'd kind of like to talk about the BBC and Guardian ones which are, ban on sunbeds could save lives from skin Cancer that's the BBC. And then the Guardian is, ban on sunbeds in England would save hundreds of lives from skin cancer study finds. And I mean this focuses on the life saving side of things but I mean the BBC say researchers applied the same model. So the one that we’ll kind of go on to talk about, in England suggesting it could save the NHS £700,000. So I'm just wondering about that kind of health economics side of things. And if you would be able to discuss, first of all, how you and your team formed to set up this model, and then I'd kind of like to go on to other aspects.

Katherine Payne:

Okay. So this is one of the sort of cold calls, if you like, from from an email from Adele Green. Adele is an epidemiologist based in Australia, but she's also got a position link with the Manchester Cancer Research Centre. And Adele had been successful in being awarded some money from the Research Town Hall SEED grant and as part of that she wanted to look at perhaps making a case for removing sunbeds from the high street. This would be building on work that she'd done with her colleague Luisa Gordon, based in Australia. And so she wanted to look at this from the Greater Manchester angle, but also from sort of a wider English angle as well. I have to be honest, when she approached me, I was quite cautious because it's, you know, people's decisions to use sunbeds or not, that's their own decision. It's an individual level decision. And who am I to say, you know, you shouldn't be doing that? But as I said at the beginning of this conversation that we're just having, I'm not really that interested in what happens at the individual level. I'm interested what happens to populations of people and presenting the evidence in a way that's clear and transparent and say, you do this, this is what will happen. And so that is why I was perhaps minded to work with Adele and Paul Lonergan on this project. And so I had to find a team of health economists that were willing to work with me. So Martin Eden and Rob Hainsworth both worked with me on this. They're based in the Manchester Centre for Health Economics and Louisa was heavily involved as well because of obviously her previous work in Australia. So we set out to look at building a mathematical model that would tell you what would happen if you looked at a starting group of people aged 18 years of age. So, it's obviously we’ve got a defined population of people and say, right, if we follow them through their lives, what happens if they have exposure to sunbeds? What happens if they don't have exposure to sunbeds? And this is using sort of published data to inform the input numbers into this into this mathematical model. Now, to do that, we were were also aware of it's not a case of just banning sunbeds. That's not a sensible thing to do. You need to support that with some public  health campaign. So something like, we've heard of Movember and Stoptober, things like that. And so we would say, right, let's see how much we could invest in a public health campaign paid for by the NHS and at the same time remove sun beds from the high street for 18 year olds. So, that's what we did. So as part of that we had to try and understand what the relevant population size of 18 year olds is in England. And so we can use Office for National Statistics data on that. And that's where we come up with our about 620,018 year olds were living in England in 2019, which was our year of focus. And then we also had to try and estimate how many some bed premises are out there and how many sunbed units are out there. That was really hard. There actually are no published records of how many sunbed premises are out there and units, and I find that myself actually quite interesting because you'd think these premises should be at least monitored in some way. So at least we know how many there are. So we did some estimates based on a really basic method looking round Google basically to estimate how many premises were in a particular area and then rolling that out to an England wide estimate. So that would be my first recommendation that if nothing else happens, can we at least know how many sunbed premises are out there that are sort of, you know, less than 101 from this? And then we moved on to try and think about how we might design this public health campaign. And so we worked with Tracey Epton, who's a psychologist based at Manchester, and she did a lot of qualitative work around this understanding why people continue to use sunbeds. We probably all know that sunbeds aren't good for us, but there are some of us who still feel that there are some benefits from using sunbeds. And so we needed to understand that to try and think about what we would need to do to design a public health campaign. And the obvious thing is to talk about is be clear about what sunbeds do to you, your skin and your eyes, but also say, look, there are other things you can do, there are other alternatives. And so maybe think about these, there options available to you.

Sally Best:

I’m personally a fan of Bondi Sands fake tan. You know I've got to do it. Gotta have that gradual tan but I think there's a lot of dissemination of fake news actually around sunbeds and people, I’ve kind of read online you know and I think it references that in the BBC article actually this girl called Sasha where she went on sunbeds because she thought that they gave her a base tan and yeah, this kind of vitamin D diatribe, yeah. I think the kind of public health campaign side of things is so, so important to stop that dissemination of fake news. Because I mean, once it proliferates, it's there and it's there for good. And yeah.

Katherine Payne:

Yeah. There is also a side of it though, that, you know, people just like using sunbeds, it makes them feel good. They like that time, you know, lying down, making themselves bright. They like that. And so we we did look at this in a mathematical model as well. And so we looked at, well, what would happen then if we sort of factored in this anxiety level from taking away some beds from people, which is potentially what it might cause, even if we took account of that on balance, it was still a good thing to do. And so again, at the individual level, those people would need support. If you take in a way their sunbeds, that they like using, you can't just leave them, you know, they've got to have some support. But I still think it's yeah, if you look at the numbers, it's a good thing. The other people involved in this obviously are the people who provide the sunbeds and their business is their business. And I and I understand that it'd be quite difficult to think about sort of repurposing some of those businesses, but it can happen. And with support, I think that is something that is possible. And I understand again, people who make the sunbeds would be very worried about this. But I think we have to think about the long term health of our population.

Sally Best:

Yeah, I also think it's great to see that it encapsulates this kind of wide landscape of sunbed use, you know, it's not just you looking at the public health side, it's looking at people's livelihoods that might kind of rely on this income and saying, well, actually, yes, we might have to take that away from you, but we're saving lives and yeah, just on that, I'd like to talk more about this cost saving element of the model. And I mean, do you have any estimates of how much that would save the NHS?

Katherine Payne:

Yeah. So the first thing to be clear about is when you build this model, you have to be clear about what viewpoint you're taking. So we did not take the viewpoint of a societal level. So that means we didn't include the impact on sunbed premises as part of our main analysis. So we very much focussed on the NHS point of view. So if the NHS was prepared to invest in £1 million for a public health campaign, that would be targeted to 18 year olds. It would be a one off, you know, lets target, 18 year olds, let's spend £1million. And we, we think about having the population of 18 year olds being of the order of 620,000 people, then that would save the NHS and around £700,000. So you can, you can tell it's about a pound per person if you want to look at it in that way. So that might not sound very much, but alongside that you're also accruing these benefits in terms of avoiding cases of melanoma, fewer melanoma deaths and improving the health of the population as well. So in some ways it's a no brainer. You're saving some money, albeit not a lot, but you're also accruing these benefits to the population. And I feel that's the that's the important side of things.

Sally Best:

And this is a term I've heard of. It's QALY, which if I'm right in understanding that’s quality adjusted life years. Was that put into your model?

Katherine Payne:

So that's one of the things that we like to measure. So when we're thinking, um, remember at the beginning we're talking about the scope of health economics. So one of the things I said, we, we've tried or done our best is to understand this thing called health, what is health? And there's many different ways of measuring health. Health is a broad concept, but if we want to start to do these analyses where we say, right, what are the costs to the NHS and what's the impact on the health of the population. We need a we need a ruler, we need something to measure it with. So that's what the quality adjusted life year is. It's, it's our way of trying to measure this thing called health. So that means, we have to go back to basics and think about, well, what is the QALY? So the first thing is, is it captures the effect on the number of life years you have. So remember an opportunity cost as well. So we have to compare. So in this analysis for sun beds, we compare people who've had access to some beds for their life and people have not had access to sun beds for their life. What's the difference in the number of life years? And that becomes subtracted life years gained, so how many extra years of life do you get? Now some of those extra life years might not be perfect. So there are, you know, things that happen to people as they age. And if people need treatments and things like that, those additional years of life might not be 100%. So you can quality adjust them. So that basically means downgrading your year at perfect health into a year. At not so perfect health. And again, we need some way of measuring that. And so we have this thing called utility where we place it on a scale to allow us to compare between different treatments. So our scale is anchored at one for perfect health. So if you're in perfect health, you get a score of one. So if you have one extra year of life and it's that perfect health that gives you one quality adjusted life year because it's a perfect health for an extra year .If you are not so good and say your quality of life is less than one. So let's say it's at 0.7 because we are on this scale from 0 to 1. So then you would say your QALY would be for one year would be point seven times one year. So point seven of a quality adjusted life year. So you see if you start to then compare between treatments, you can work out how many extra life years you're gaining, but also what's the difference in these quality adjustments made to those extra life years? So you might be living longer, not at perfect health, but it's still better off than the alternative which is being dead. Yeah. So, so yeah. So that's, that's the basic idea between this behind this QALY. And then we have to have tools that we can actually measure the quality of life. So health economists have designed these health measurement tools and the one that NICE says is perhaps the easiest one to use and the most common one to use is something called the EQ5D. And that is a very simple measure that has five questions, and you get people to complete those five questions. And then health economists work their mathematical magic and turn that into a utility value so that that's where the core basis for this quality adjusted life year comes from. Because if you give someone a new one of these targeted medicines, yep they might give you a few extra years of life, but they're highly unlikely to be at perfect health. Then you have to make this judgement. You know, whether those extra years of life, how low does your quality of life have to be before it starts getting perhaps? I don't know. Not a good thing to do, you know.

Sally Best:

And who makes those decisions?

Katherine Payne:

Yeah. So the individual must make it for themselves with with that, with their doctor. So if, if they're in a position of having awful position of a diagnosis of cancer, they should have, on an individual level, have a discussion with their doctor and and maybe pharmacist and specialist nurses about the the benefits and the risks of this particular treatment for them. And what they, you know, what their the beliefs are about their their life and things like that. So that is definitely down to the individual. But a population level you can say, well, if the NHS invests in this new medicine, this is how many extra years of life you're going to get and this is how many extra quality adjusted years of life you're going to get. And then we need some criteria to say, well then is it worth it? And this is where this thing called the threshold comes in that you've probably come across as well. So NICE talks about this threshold of £20,000 for an extra quality adjusted life year. What that is saying is that decision makers, taking on the role of making these value judgements for how to spend the NHS budget is saying on balance we think if you're paying less than £20,000 to gain one additional quality adjusted life year, then on balance that's a good thing to do. Now other things come into that as well. So the, the quality of the evidence that is going into those decisions, the quality of the trial data and also the level of uncertainty about those data. No data are perfect. And so when NICE are making these decisions about new medicines, they're looking at the mathematical numbers, but they're also thinking about making judgements about the quality of the data and the uncertainty in the data as well.

Sally Best:

It’s a controversial question. And I think you've kind of answered it, but would it be valid to say that, I mean, of one life year that is quality adjusted and it's kind of worth living for a person in this country would be £20,000. That's what the life year would be worth?

Katherine Payne:

No.

Sally Best:

Okay.

Katherine Payne:

No. So there is work that has been done in the transport environment and that does look at the value of a statistical life. And what that does is saying, okay, how much are we willing to pay to avoid a death effectively? And they generated some numbers in the context of making everybody wear seatbelts in their car and asking people on an individual level, which they added up to make it a population level, how much they'd be willing to pay to avoid, basically dying. And so that basically turned into the value of a statistical life. That is not the same as the £20,000 per quality adjusted life year, the £20,000 for quality adjusted life year is something to help people put the numbers that get pulled out of a mathematical model into some context. So it's I mean, that threshold could be any number. It doesn't have to be £20,000. But on balance, what NICE did is look over their past decisions and their past experiences and said, right, this feels like it's a good number to use. And in some instances, they do change that threshold. So they've they introduced a few years ago now something called the end of life criteria. So that meant that if people were very poorly, had very relevant populations, so a specific population size and had fewer than six months to live, then they would invoke another threshold that would be higher. So they'd be more likely to say yes. So that threshold was set at £50,000, per quality adjusted life year. But again, this is population level. Within our population is the NHS willing to pay this amount of money to gain this much extra health but slightly different concept to the value of a statistical life, which is how much should we pay to save someone's life? Slightly different.

Sally Best:

Yeah, I can see the nuance there. So thank you for me and for the listeners because yeah, that's clarified a lot and leading on from there. So you've explained about how you model a health intervention such as the banning of sunbeds from England. And in this specific study has been shown that it's both life saving and cost saving. So the next question would be how much is health economics such as this needed to make policy changes and NICE guideline changes.

Katherine Payne:

So it's a piece of information is another piece of the jigsaw, if you like. So if you're deciding, so keep going back to NICE. But, it has such clear processes about how it uses evidence. So NICE, has many different heads. Some might say it's a multi-headed monster, but let's talk about it in a positive way. So it has lots of different programmes and as part of that it produces guidance but also guidelines. So guidance might be very about very specific medicine or intervention, and guidelines tends to be about sort of pathways of care. And so looking at someone with a particular condition from diagnosis through to end of life care, for example, that might be more about guidelines. And so within that, they'll use evidence from epidemiological studies, clinical studies, both randomised trials, also observational trials as well, observational data. So economic evidence sort of feeds into that. And then all those data are put together into a report which is then read, digested and talked about by a committee so that committee then makes deliberations about whether they trust the numbers, what the numbers might mean to the NHS and also more importantly, patients with the condition and clinicians who treat patients with the condition are also involved in those committee processes so they can feed in a committee level about how good or how relevant these data are, but also it can get sent out to the wider, the wider population. And then people, stakeholders can make comments about these these documents and a wider level. So then, you know, health economics is just one little bit of the jigsaw. I think the challenge is that quite often it's viewed as a black box and it's perhaps not explained very well. And, and, and so it can, it can feel a bit like I know, cooking up the numbers almost. And so I think that's part of the reason why I agreed to do this, this chat really, because I think the more health economists can get out there and try and explain the methods that we use. It's really hard because when you think when you're talking about things in the abstract without showing someone the actual model and taking them through it and say, look, this is what we this is what we did here, this is what we meant here. It's really hard, but it's at a sort of on average level. I think we should be better explaining. It's not just about saving money. It's about using resources better. And so going back to opportunity cost, if we spend the money on this group of patients who have lung cancer, as distasteful as it sounds, that means people with mental health problems don't get the money from the NHS because the NHS isn't a bottomless pit of money. So we have to move money around the system where we get the most value from it, value being benefit to patients. And so we as health economists can only provide that information. We don't make the decision. We give people information that's hopefully clear and transparent enough that they can understand what we did and why we did it and what it means.

Sally Best:

So, honestly, thank you. Because I think in my job, I speak to cancer researchers kind of all day and health economics comes up and it's coming up more and more. And I think as you've kind of described, it's a what's the expression a sword in the armoury. I don't know.I hope some of you know it there's something in the armoury. We’ll, go with it. But yes. it's kind of that case building exercise of, okay, you've shown that this drug is effective or that this implementation is effective, but what next? Yeah, and you're kind of you're backing people in and thank you for being so transparent and brilliant about talking about everything that you do, because I think it's just great for people to and I'm under the impression that in cancer research, health economics will become more and more prevalent in terms of people wanting to do things. You know, or  need support. That that sort of thing. I'm, I want to make a kind of utopian Katherine world, there's wine everywhere, maybe a bit cooler outside than it is today. But I mean, what is your hope for the use of sunbeds by 2030 in this utopia

Katherine Payne:

Okay well at least a minimum, know how many are out there. That's first thing. And I don't I don't like taking away things from people when they see value of them at an individual level. But personally, I hope that we don't see them on the high street anymore. I think there are other things we can do to make ourselves either look better or feel better. And I think reliance on sunbeds is perhaps not the best thing. So I'd like to say goodbye to them, really put them into a room 101.

Sally Best:

Room 101. That's your room 101. Yeah. I mean great answer. I can roll with that definitely, definitely get on board. Like I've said before, there’s tanning options. This is a question that really intrigues me and I kind of like it from the cancer research perspective as well. But the way that I personally think of people saving lives is the general nurse doctor clinician route. And it's like when you're a kid, you know, who saves lives, well doctors save lives, but there's jobs out there such as being a health economics where you can benefit and save the lives of many patients and people and even prevent the kind of root cause. And I'm wondering, how does it feel that knowing that you have this impact on the lives of the population?

Katherine Payne:

Oh, interesting. Do I know I have this impact? I don't know. Because all I do is I produce information for people. I can't make people read that information and I can't make people act on that information. And that's for somebody else to do with more power than I will ever have. But I hope. Yeah, because I could still I could do with the jobs. I don't have to carry on working as a health economist. So there must be something that drives me somewhere to believe that at some point, you know, people will listen and also understand that we're not about being money pinchers. You know, we're not about cutting costs. We're about trying to use what we've got in a better way. That's what we want to try and achieve. And so yeah, my hope is that people do read the work of health economists and that they act on it. That's all I can hope for.

Sally Best:

Yeah. There's a power in changing people's minds. A great power. Okay, and leading on, Last but not least, a lovely question. What continues to inspire you?

Katherine Payne:

And I'm very good at deflecting away from myself here, and I'll do that. What inspires me is working with other health economists and specifically, people who are new to health economics, persuading people to get into health economics. So coming in from different backgrounds and you know, I supervise PhD students and so turning them into people that hopefully will grow into grown up researches and have an impact themselves. So it's about the early career researchers and keeping them engaged in the topic, providing them with opportunities to use their own skills. I now work with people that are so technically clever they can do such amazing things that my job is just to be a sort of a conduit to allow their brilliance to come through. So that's what keeps me going. It's these early career researchers. And, you know, you spoke earlier about the cancer research needing more and more health economists, well health economists are a rarity as well, there's not many of us. And so at the minute we have to decide where we spend our time. And so by trying to build this, the future, you know, future health economists, hopefully some of them will spill over and start working in the area of cancer, early detection and prevention, and that's where they'll have their impact as well.

Sally Best:

Well, any budding health economists, get over to cancer and early detection. We need you. Well, thanks so much for speaking with me. I know that. Yeah. One of those things that some people don't like, but honestly, I think the listeners would agree as much as I would. You've been brilliant. You've given a great insight into health economics. I've learnt things, which is great because my brain is sometimes not so sponge like. And as I said, I'll link everything we've discussed in the blurb, but that's it for now and catch you all again next time.

Katherine Payne:

Bye everyone

Sally Best:

One in two to was brought to you by The University of Manchester and the Manchester Cancer Research Centre. Listen to our next episode to hear from more of our researchers as they share the innovations, discoveries and projects that are changing the landscape of cancer prevention, early detection and treatment. To find out more about what you've heard today, please see the show notes for this episode, where you'll find a transcript and links to further information and research. 

Cancer is one of the University's five research beacons, showcasing the interdisciplinary collaborations and cross-sector partnerships that are tackling some of the biggest questions facing the planet. To hear more about Manchester's research in advanced materials, biotechnology, cancer, energy and global inequalities, go to Manchester.ac.uk/beacons.

Sally Best:

Hello. You are listening to One in Two, a Manchester Cancer Research podcast brought to you by the University of Manchester and the Manchester Cancer Research Centre. With one in two of us receiving a cancer diagnosis at some point in our lifetime, it has never been more important for our research to improve the outcomes for people affected by cancer. I am your host, Sally Best, and throughout this series I will be speaking with Manchester cancer researchers about their innovations, discoveries and projects that are changing the landscape of early detection. In this episode, we speak to Dr. Marilena Hadjimetriou about her research on Nano-omics, which aims to integrate nanotechnology to the world of omics as well as proteomic biomarker discovery. We find out how Nano omics is being used to isolate molecular biomarkers that highlight the early stages of cancer in patients making earlier cancer detection possible. Marilena hello. Thank you so much for joining me. How you doing?

Marilena Hadjimetriou:

I'm very well, thank you.

Sally Best:

Well, I'm wondering if, for the sake of our listeners, you'd be able to just introduce yourself, what it is that you do, who you are.

Marilena Hadjimetriou:

So my name is Marilena Hadjimetriou, and I am a lecturer at the University of Manchester leading the nano omics team.

Sally Best:

Oh, well done. And I'm so glad you pronounced your second name. Not me. That would have been absolute carnage. So you currently work with Nano omics and it's your team that introduced this term. Would you be able to just explain what it is for me and the listeners?

Marilena Hadjimetriou:

Yes, of course. So Nano omics aims to integrate nano technology to the world of omics. It can be defined as the nanotechnology enable isolation of molecular biomarkers from blood or other biological fluids for their subsequent omic analysis. And this could be the analysis of proteins, lipids or genes. In other words, nanoparticles. And these are materials that have at least one dimension in the nano scales of between 1 to 100 nanometres, are utilised as scavenging platforms to capture and reach and isolate novel disease specific biomarkers from biological fluids. For example, we have developed a nano mixed pipeline for protein biomarker discovery, which allows us to see deeper into the blood proteome. And this is the entire set of proteins that are present in blood. This is extremely important for the discovery of novel blood based biomarkers.

Sally Best:

Okay. So just to clarify, absolutely tiny things in your blood that you're then kind of you're pulling out of the blood, maybe amplifying and you trace them. So it might be lipids, proteins, genes. And you're looking for cancer signatures.

Marilena Hadjimetriou:

Yes, exactly. So blood contains a treasure trove of information which allows me to find ways to access this information.

Sally Best:

Okay, cool. Just trying to work it out in my head. But I mean, it sounds very complex, but we're going to, you know, go into it more and work it out. So, I mean, at this point, please could you explain what a biomarker is? Because I know you've mentioned that before and a lot of our audience might not be aware of that.

Marilena Hadjimetriou:

So the term cancer biomarker covers a range of biological molecules that are present in blood or other biological fluids, including proteins, genes and lipids. These are molecules that can be objectively measured in order to diagnose or guide treatment of various diseases, including cancer.

Sally Best:

Okay. So basically cancer signatures is a way to snippet. And you've mentioned this nano omics proteomic pipeline. Do not get me to ever say that again. Ever. But I mean, it sounds very impressive. And again, could you just like explain a bit more in detail what this is and how it works?

Marilena Hadjimetriou:

So proteins are the most commonly used blood biomarkers, although a number of protein biomarkers are used clinically to monitor cancer progression. Currently, there are no biomarkers used for cancer early detection. And one of the biggest problems in protein biomarker discovery is that highly abundant proteins such as albumin that are blood circulating are masking the identification of these smaller and lower concentration proteins, some of which are secreted by cancer cells or in response to cancer progression. And so due to this masking effect, the identification of these smaller and rarer proteins is extremely difficult. So we cannot obtain high resolution protein signatures like that. In nano mix, we employ nanoparticles as scavenging agents to pick up these blood circulating protein molecules of low concentration. These allows us to detect subtle differences in the blood proteome of cancer patients, which could be further developing into a blood test for either early detection or disease monitoring.

Sally Best:

Okay. So basically we've got a big ball pit, we've got massive balls and then we've got tiny balls. Can't find the tiny balls. And we're going to use the analogy that the proteins, that the cancer cells produce, they're the tiny balls. And then you've got these big ones that are just circulating in your blood. Am I right?

Marilena Hadjimetriou:

Exactly.

Sally Best:

Okay. Next thing, a small child, we're going to call that a nano net.

Marilena Hadjimetriou:

All right.

Sally Best:

The Nano net goes in and collects up and amplifies all the tiny little balls. And that is our thing that gives us the signature of whether there's that cancer present or not.

Marilena Hadjimetriou:

Yes. So when you fish, you can either collect buckets of water hoping you will catch this small and rare fish or you can throw it in nets. In the same way we use nanoparticles as our nano nets, we immerse them into the blood sample and then we allow them to interact with the blood circulating proteins. We then lift this nano net and analyse only the proteins that are here onto them.

Sally Best:

That analogy was a lot better than mine fab. I mean. Okay. So that was a really good analogy. And I can really picture it clearly and I think it's one of those things that is important for our listeners, because a lot of us might not function on this kind of sub molecular level. So understanding things that that kind of bigger picture of a trawler, and large fish, and the tiny little ones that we want to know about because they are that cancer signatures. So I'm just wondering, just to clarify, the only proteins that adhere onto these nano nets are the ones that are secreted by cancerous cells.

Marilena Hadjimetriou:

Now, many different types of blood proteins interact with the surface of nanoparticles. There is no specificity towards cancer secreted molecules. However, by analysing this subset of blood proteins absorbed onto the nanoparticle surface and by purifying any unbound proteins, we're able to search deeper into the blood protein and identify more in low, abundant proteins, some of which are secreted by cancer cells. By then, comparing the blood samples at healthy and disease states, we can identify those proteins that are either upregulated or downregulated in response to the disease. And these are the potential biomarker proteins.

Sally Best:

Okay, so there's a lot of post work that you have to do post the kind of nano, net retrieval. I mean, we focussed in the season on the early detection of cancers and I'm wondering specific to this work, what is the role of Nano omics in the early detection of cancer?

Marilena Hadjimetriou:

Well, we know that detecting cancer early increases the chances of of survival. And so nano omics ultimate goal is to use nanotechnology in order to uncover biomarkers in blood that can be used for early cancer detection. This could allow patients with cancer to receive effective treatment before the burden becomes incurable.

Sally Best:

Okay, so, yeah, detecting early from blood samples, I mean, as well, it's not kind of as invasive as a lot of the tests that you might use. And in general kind of cancer detection.

Marilena Hadjimetriou:

And exactly. It's much less invasive than tumour biopsy, for example.

Sally Best:

Yeah. And a biopsy, just to clarify, is cutting out of internal and then monitoring and looking into it.

Marilena Hadjimetriou:

Yes, exactly.

Sally Best:

And I mean, this all sounds incredible. Do you have a real world example of this? And like a key project that you're working on that we can kind of tell to the listeners. So they get an idea for, you know, what, what sort of things you're working on in the background.

Marilena Hadjimetriou:

We're currently privileged to be working with Professor Caroline Dive and Dr. Phil Crosbie and looking into nano omics and biomarkers in lung cancer. We know that when lung cancer is found at an early stage, patients can often be cured through early intervention. However, when lung cancer is found at the metastatic stage, and this is where it has already spread throughout the body, the prognosis is often poor. And so in this project, we use nanoparticles. These are lipid based nanoparticles. We call them liposomes as our scavengers to look for early detection biomarkers. Our aim is to utilise the nano omics pipeline to analyse pre and post surgery blood samples collected within Manchester community based screening project. And by doing that, we hope we will be able to extract information from blood that in the future can aid in early lung cancer detection and this is monitoring.

Sally Best:

Amazing I mean I've had the pleasure of speaking to Phil earlier in the season about lung health checks so it's amazing to hear about, you know, these other projects that he's working on and he must never sleep because he's just always doing things. And I'd like to take a few steps back because it's something that I've kind of asked everybody else. What led you into this field of nano omics and cancer?

Marilena Hadjimetriou:

So the nano omics idea was generated during my PHD project, and this was like ten years ago. And the main goal of my PHD. was to understand the interaction of nanoparticles with blood proteins. And this is a spontaneous interaction that happens as soon as nanoparticles are exposed to a biological fluid, also known in the nanoscience community as protein coronal formation. So during the last year of my Ph.D., I worked in collaboration with the Manchester Cancer Research Centre and the Chris's Biobank team, and we were able to recover and characterise nanoparticles from the blood circulation of ovarian carcinoma patients. We covered a nanoparticle based chemotherapy drug that these administered in patients with recurrent ovarian cancer. And this was the first investigation of the interaction of nanoparticles with blood proteins in human patients. So we isolated and purified the nanoparticles from the blood of ovarian cancer patients and analysed the corona that was form around them. And what we observed was that nanoparticles were able to pick up ovarian cancer specific blood circulating proteins, which indicates that the composition of protein corona around the nanoparticles reflects the ongoing pathology. These reinforce the idea of utilising nanoparticles in order to surface capture and amplify cancer specific biomarker proteins of low abundance. And then during my postdoc, I further developed these into a pipeline for protein biomarker discovery ex vivo. So when nanoparticles are incubated in a tube with samples, plasma samples obtained from cancer patients. And we are now working to further develop this technology for the multi-omic analysis of blood.

Sally Best:

Okay. So just to clarify, in this ovarian cancer specific project, your nanoparticle was kind of, it was in the blood circulation and it was trying to pick up proteins that were kind of released by ovarian cancer cells. And the early detection angle is because when you first start developing cancer, there's only very low levels of that protein. So then you have to amplify that to higher levels and look at them in more detail, kind of outside of the body.

Marilena Hadjimetriou:

Exactly, exactly. You got it right. So this is an enrichment step for those very low concentration proteins. So nanoparticles are fishing these proteins. And is a discovery tool. So you use it to identify those proteins, but then you have to develop it into a blood test that will be clinically used.

Sally Best:

Okay. And then would that just be like general screening that we'd use that test? So would it be people that would come into the clinic and have screening for, say, lung and ovarian cancer, through blood tests?

Marilena Hadjimetriou:

It could be that or it could be a companion diagnostic.

Sally Best:

Okay. And that would just be kind of, that just be a healthy population of people or would that be people that had kind of experienced family hereditary links? I know you're not a clinician, so it's kind of a difficult question to ask.

Marilena Hadjimetriou:

Well, I think it could be both.

Sally Best:

Okay. Another question, I'm just very interested in this, so you've got really low levels at this early stage. Would you then see kind of a massive increase in those levels of biomarkers as you get to stage four so that you don't require that kind of amplification level.

Marilena Hadjimetriou:

You could either see a massive increase or a massive decrease. So a biomarker that would be upregulated or downregulated in response to cancer.

Sally Best:

Got it. So interesting. God, look at you. Amazing honestly. I mean, just moving on again. You're Cypriot as we can all hear what wonderful accent.

Marilena Hadjimetriou:

Yes, that's correct.

Sally Best:

I am so jealous of both the accent and where you're from. But I mean, what the heck encouraged you to come across here? I mean, I'm kind of presuming that was your research that that gave you that, not the weather.

Marilena Hadjimetriou:

So a pharmacist by training and I obtained my first degree in Athens I already knew from the first year that I wanted to do research that was a five year programme. And during the fourth year of the course, I attended a lecture on nanotechnology and I was immediately fascinated by cancer nanotechnology and the use of nanoparticles for drug delivery purposes. So after the completion of my studies, I decided to move to London to UCL School of Pharmacy to obtain a masters degree on carbon based nanomaterials. This is where I met my Ph.D. supervisor who was about to move from London to Manchester to explore the use of graphene based materials for biomedical applications. And this is how I ended up in Manchester.

Sally Best:

Yeah, and of course you've got a massive graphene centre here and you're going to stay aren’t you.

Marilena Hadjimetriou:

I hope so.

Sally Best:

Keep funding. Come on. So you've mentioned you're now going to develop this tech for the Multi omic blood Analysis tool. Would you be able to explain what a multi omic tool is and the work you're carrying out on Multi-Omics?

Marilena Hadjimetriou:

So we know that a single biomarker cannot provide the sensitivity and specificity needed for early detection. Instead, we need panels of biomarkers consisting of multiple molecular classes, including proteins, lipids and genes. Currently, there is no other technology that is able to offer multi-omic analysis of blood with a single enrichment step. And this is the blood analysis gap we seek to fill. So what we've realised over the last couple of years is that nanoparticles not only interact with proteins when incubated in blood, but can also interact with other biological molecules such as cell free DNA and lipids. And therefore what we're trying to do is to develop a nanoparticle platform that will simultaneously enrich the cancer specific proteomic lipidomic genomic information with a single nanoparticle enrichment step. This not only will significantly minimise the volume of blood we need for our analysis, but it will also result in the discovery of integrative multi-omics biomarker panels.

Sally Best:

Okay, so it's a very, very, very selective net that kind of picks out and amplifies very, very selective proteins and biomarkers and lipids and genes and.

Marilena Hadjimetriou:

It selects a combination of biomarkers.

Sally Best:

Wow the things that you guys are doing. Please, could you give me an example of where you're using Multi-Omics?

Marilena Hadjimetriou:

So an example of a project we're currently working on is funded by Cancer Research UK and the International Alliance for Cancer Early Detection, and this is in collaboration with the Cancer Centre at Stanford University and so what we're aiming to develop is an integrative blood biomarker discovery at the genomic platform. This means you integrate proteomics with genomics for the early detection of non-small cell lung cancer.

Sally Best:

So you're working with AIST and Stanford. I mean, how does this collaboration come about? What are Aist kind of doing with you or Stanford doing with you? What's the partnership look like?

Marilena Hadjimetriou:

So what we're trying to develop here in Manchester is, is the nanotechnology platform that will integrate the product genomic information in the blood of non-small cell lung cancer patients and our collaborators at Stanford will then use this information to develop integrative bioinformatic analysis platforms.

Sally Best:

Okay. And then AIST what's contributing to that?

Marilena Hadjimetriou:

AIST is this funding, this project. For us to build new connections with Stanford University.

Sally Best:

Oh, wow. And Stanford as well. I'd like to look at this and approach it from more of a patient angle. So, I mean, what does this mean for patient treatments and outcomes of these cancer patients?

Marilena Hadjimetriou:

So such multi-omics early detection approaches hold great potential in providing precise information on the localisation and the size of the tumour. We hope that this novel panel of biomarkers discovered will be translated into simple blood test that will enable cancer early detection monitoring and will facilitate the design of personalised therapies without the needs of invasive tumour biopsies.

Sally Best:

Okay. So it's I mean, it's amazing that it can it has the specificity to both kind of know the staging and the location of tumours as well as the fact that it negates the need for tumour biopsies, which is again massively kind of invasive like you've said and can be. That can be a bit of recovery and distressing and things.

Marilena Hadjimetriou:

Exactly.

Sally Best:

Doing great work. And I mean, it's a question I'd like to ask all of our guests. Some of them don't like it, but I love it. So it's why you passionate about your research?

Marilena Hadjimetriou:

I'm passionate mostly because of the multidisciplinary nature of nano omics. We use advanced materials and nanotechnology to address pressing clinical needs, even though we are based at the main university campus, we work closely with the Manchester Cancer Research Centre and the Christie hospital, and this allows us to integrate technology development with clinical research. Manchester brings together a very rich ecosystem of cancer research and creates this unique opportunity of clinically translating our technology innovations for personalised medicine.

Sally Best:

You came to England and you spoke about for the podcast, you know, the environment of Manchester and why you've chosen Manchester to build your research portfolio following your PHD. And I'm wondering if you could just expand on that, give these listeners a little tit bit about what you kind of told us about, you know, that integration and the landscape of Manchester sort of thing.

Marilena Hadjimetriou:

I think Manchester is a great city for cancer research and the reason for this is a collaboration between technology development and clinical research. So it becomes very easy for us to get access to clinical samples and collaborate with clinicians. And this is a unique opportunity to see our technologies being translated.

Sally Best:

And I mean, yeah, you've said you've been given opportunities to move elsewhere. I won't say where because you're not going. What's keeping you here? What’s that kind of drive to want to keep your research here?

Marilena Hadjimetriou:

I think because the nano omics was generated during my Ph.D., I wanted to see how nano omics will further be developed into clinical research and cancer research.

Sally Best:

Finally, it's been such a nice conversation with you and there’s so much to go into, but unfortunately we don't have the time. What are your hopes for the future, like your personal future, I mean, as well as the future of nano omics.

Marilena Hadjimetriou:

So I hope to see some of these newly discovered biomarkers clinically used. The discovery phase of biomarker development is often initiated in academic labs and frequently results in the identification of multiple biomarker candidates. Translating these discoveries into clinical tests requires tremendous resources for analytical and clinical validation, and this, of course, requires collaboration with industrial partners. I believe we have not yet fully explored nano omics, as this is a new area of research and nano omics can be applied across a range of clinical needs in biomarker applications, including early detection, minimal residual disease monitoring and patient stratification. But what is even more interesting is to explore the application of nano omics in understanding the molecular pathways that are involved in cancer progression. And this could potentially lead to new treatment approaches.

Sally Best:

New treatment approaches. A Manchester pioneering is stuff that we love to hear honestly. Thank you so, so much for taking the time to speak with me today. Absolutely killing it in this research area and can't wait to find out about all the project updates.

Marilena Hadjimetriou:

Thank you so much, Sally.

Sally Best:

Keep us updated, please come back again. I mean, as usual for the listeners, I’ll link everything related to Marilena's work in the blurb. But yeah, thank you for listening and hope you can all join us next time. Bye.

One in two to was brought to you by The University of Manchester and the Manchester Cancer Research Centre. Listen to our next episode to hear from more of our researchers as they share the innovations, discoveries and projects that are changing the landscape of cancer prevention, early detection and treatment. To find out more about what you've heard today, please see the show notes for this episode, where you'll find a transcript and links to further information and research. 

Cancer is one of the University's five research beacons, showcasing the interdisciplinary collaborations and cross-sector partnerships that are tackling some of the biggest questions facing the planet. To hear more about Manchester's research in advanced materials, biotechnology, cancer, energy and global inequalities, go to Manchester.ac.uk/beacons.

Sally Best:

Hello. You are listening to One in Two, a Manchester Cancer Research podcast brought to you by the University of Manchester and the Manchester Cancer Research Centre. With one in two of us receiving a cancer diagnosis at some point in our lifetime, it has never been more important for our research to improve the outcomes for people affected by cancer. I am your host, Sally Best, and throughout this series I will be speaking with Manchester cancer researchers about their innovations, discoveries and projects that are changing the landscape of early detection. In this episode we speak to Professor Emma Crosbie about her research on womb cancer and the breakthrough she made in discovering a link between Lynch syndrome and womb cancer. We discussed the steps Emma and her team took to change NICE guidance on testing for Lynch Syndrome for women with womb cancer. And what this now means for the many women and their families with this disease. Hi, Emma. Thank you for joining me today.

Emma Crosbie:

Thank you for having me.

Sally Best:

I'm wondering if you could first introduce yourself and provide an overview of your research into womb cancer.

Emma Crosbie:

So, yes, I'm Emma Crosbie. I'm a professor of gynaecological oncology here at the University of Manchester. And my research interests really focus on screening, prevention and early detection of womb cancer.

Sally Best:

Okay. And you're a clinical academic. That's right. So what is that, what does that kind of entail? And what made you choose that route?

Emma Crosbie:

So, yes, I am a clinical academic. And essentially that means I spend half my week looking after patients with gynaecological cancer. I'm a surgeon, so that means that I am involved in their surgical care. And the other half of my week is involved in doing cancer research. And so that's a really, really rewarding career because the clinical side allows you to see the unanswered questions in your speciality, to see where particular tests might not be very effective, where treatments might have bad side effects, where cancers might come back and allows you to ask the kinds of questions that might enable you to make things better. So being a clinical academic gives you the opportunity to make a big difference, not just for the patient that you're caring for that day in clinic or in surgery, but really for populations of patients. So patients of the future in terms of making the management, their management strategies better, more research based and you know, really trying to really trying to innovate and improve their lives.

Sally Best:

So, I mean, I'm getting from that that you not only treat individuals at a kind of individual level, but also a population level that isn't kind of just the patient in front of you. Do you feel like that's very beneficial to the line of work that you're in?

Emma Crosbie:

Yeah, because I'm really interested in screening, which is essentially a public health intervention. So it's not about an individual patient in that case. It's about screening a whole population of individuals at risk in order to find those that are at increased risk of cancer, for example. So it's you know, it is useful to be able to do research that thinks about the whole population rather than an individual patient.

Sally Best:

So, Emma, you do a lot of work around gynaecological cancers and personally I'd love to cover all, but we don't have time for that. And so I'd like to use this time for you to focus on your research into womb cancer, and particularly a genetic condition you've worked on called Lynch Syndrome. Please could you tell me in the listeners what Lynch Syndrome is and its connection to certain types of cancer?

Emma Crosbie:

Yes, sure. So Lynch syndrome is the most common inherited cancer predisposition syndrome that's thought to affect around one in 300 of the general population. Yet only 5% are aware of that diagnosis. It is caused by an inherited mutation or called a pathogenic variant affecting one of the four mismatch repair genes called MLH one, MSH two, MSH six and PMS two. And essentially altogether, those four genes are involved in making sure that when DNA replicates, it does so faithfully. And so a defect in one of those four genes causes an increased risk of certain types of cancer. And those are bowel cancer, womb cancer, ovarian cancer, and some more rare cancer types. But the reason why I'm interested in Lynch syndrome is because womb cancer is often the first cancer in women with Lynch Syndrome, and therefore it offers a really unique diagnostic opportunity because if we can identify women as having Lynch syndrome, then they can protect themselves and their family members from future cancers by taking an aspirin every day and being involved in bowel cancer screening.

And these two things have been shown to save lives in Lynch syndrome. And so when I first started looking at Lynch Syndrome and womb cancer, I realised that there was just a massive disparity in care in terms of what was available for people with bowel cancer and Lynch syndrome and what was available for people with womb cancer and Lynch Syndrome. So for bowel cancer, it was already recommended that everybody be screened for Lynch Syndrome. There was an established Lynch syndrome testing pathway in place. There were national and international clinical guidelines and also evidence based cancer surveillance. But none of this was true for womb cancer. And so I wanted to do something about that.

Sally Best:

Okay. So you mention Lynch syndrome is linked to both the development of bowel cancer and womb cancer. And there was a big difference in those being screened for Lynch syndrome and those with bowel cancer versus those with womb cancer. I'm just wondering how you got a handle on how big that difference was and also why do you think that was?

Emma Crosbie:

So we noticed that here in Manchester there was a very kind of ad hoc way of screening people with womb cancer for Lynch Syndrome. So we kind of did it if they were particularly young when they got womb cancer or if they were known to have a strong family history. And we wanted to know whether that was the case elsewhere or whether there were guidelines in place for who we should be screening. And so we teamed up with the patient support group called Lynch Syndrome UK, and we asked patients with Lynch Syndrome. So about 300 patients and the clinicians who care for them. So gynaecologists and pathologists, what the current practise was like in the UK and essentially what we found was that there's a real postcode lottery with a complete lack of services in some places, and this real inconsistency of care that seemed to be underpinned by a lack of evidence and a lack of clinical guidelines. So essentially clinicians were just doing what they thought was best because there were no protocols to tell them what they should be doing.

Sally Best:

Okay. So you noticed these disparities, and the fact that there was this absence of screening and basically kind of meant that women and their families were more at risk. I'm just wondering, what were the next steps in terms of other evidence gathering and finding this link and proving it, between Lynch Syndrome and womb cancer.

Emma Crosbie:

So what we did next was we convened a meeting in Manchester called the Manchester International Consensus Group meeting, and we invited experts from across the UK, from Europe and North America to come and tell us all about Lynch syndrome and womb cancer. So we wanted to know what the kind of state of the art was, if you like, from the real experts in the field. So on the first day we heard from them and we had an audience full of all kinds of people that would be important for such an event. So we had patients, patient support groups, we had gynaecologists, nurses, medical oncologist, geneticists, pathologists, gastroenterologists and so on, and so those experts told us what the state of the art was. And then the next day we had four different working groups where delegates rotated through and we debated topics until we reached a consensus. And essentially, that process enabled us to find some important research questions that were unanswered. And these were particularly for women with womb cancer, who we should be screening for Lynch syndrome and how we should be doing it.

Sally Best:

So you showed almost 3% of womb cancers are linked to Lynch syndrome and that there wasn't screening in women with womb cancer for the syndrome. So, I mean, theoretically, that policy gap was leaving 3% of women with womb cancer in the dark about a genetic condition they carried. And I was wondering, what are the next steps to ensure this difference was shown and the evidence that you were gathering?

Emma Crosbie:

Yeah. So you're exactly right. We, first of all, carried out a systematic review. So we looked at all the published studies that had previously measured the prevalence of Lynch syndrome in womb cancer. And although these studies were not particularly good quality, we were able to show that around 3% of womb cancers are associated with Lynch syndrome, and that is very similar to the case of bowel cancer. So we know that 3% of bowel cancers are caused by Lynch syndrome and our systematic review suggested fairly similar levels. And so because the studies that we had found in that systematic review were of poor quality. And by that, I mean they were small studies, they didn't test all eligible patients, they didn't compare testing strategies, and they were usually based in private health care settings, which meant that only around half of the eligible women had actually taken part in the study because there were financial implications for finding out that they had Lynch syndrome in terms of their insurance policies. So this inspired us to do the PETAL study. So the Petal study was the proportion of endometrial tumours associated with Lynch Syndrome, which was the first UK prospective study that looked at every single patient coming through St Mary's Hospital in Manchester with womb cancer and testing them all for Lynch Syndrome and testing them using all the different types of testing strategies in order to directly compare those testing strategies and find out which was the best one for finding Lynch Syndrome in womb cancer. So this study formed the basis of my PhD students PHD’s. So that was Dr. Neil Ryan. He was an MRC funded clinical research fellow at the time, and it was also done in conjunction with Professor Gareth Evans, who is a clinical geneticist here in Manchester, and Professor Rae McMahon, who is a pathologist who with a particular interest in this area here in Manchester and essentially that study showed again that 3% of womb cancers are caused by Lynch syndrome. But it also showed us exactly how we should be testing those patients in order to find those cases most efficiently.

Sally Best:

So how many women did you test, Emma?

Emma Crosbie:

500.

Sally Best:

Okay. And they were from St Mary's? And I'm wondering, I mean, you've mentioned that that was kind of that side of things where in America people didn't consent to being tested because of finding out that they had a genetic condition. And I'm kind of presuming that that's to do with the fact that, you know, health care and health insurance prices go up. Right. And we don't have that here. But I'm wondering, in kind of this country did all of these women agree to take part in the study? So, did you ask 500 women and they all said yes or where there kind of 600 that you asked and 100 said no. And I mean, were there any women that were worried of finding out that they had a genetic condition?

Emma Crosbie:

So that's a really great question. And actually, that was a really important thing where we were devising the study. We were very worried that women actually wouldn't want to know and that that would then indeed prevent us from doing a good study because we would again have some sort of selection bias. So we would only be testing a proportion of those that were eligible to be tested. But actually what we found was over 99% of women wanted to take part. So we asked 502 and 500 consented to take part. And those two that declined to take part were quite elderly women and didn't have any family members who might be at risk. So there was no benefit to them or that's how they saw it, to find out that they had Lynch syndrome. But everybody else wanted to take part. You know, they often had been you know, they'd just been diagnosed with womb cancer. And they often were asking questions about why this had happened to them. That is something that patients do tend to ask a lot. And the fact that it could have been due to a genetic condition, that they might then, that might then put them at risk of other cancers was something they definitely wanted to rule out.

Sally Best:

Okay. So it sounds like there's quite a protective aspect in terms of protecting family members. But then there's also, you know, the fact that these women might then go on to develop bowel cancer. And I'm wondering, out of these 500 women, whether around 3% with Lynch syndrome in this cohort.

Emma Crosbie:

Yes.

Sally Best:

And what what did you kind of go on to provide them with? Was there any support because I mean, it's quite a large kind of thing to be diagnosed with them and it’s a big conversation that you've then got to have with your family and preventative measures and things.

Emma Crosbie:

Yes, it is. It is a big deal to find out that you have a genetic condition that could increase your risk of future cancers and also put your family members potentially at risk. And if we look at it, there were 500 women that we tested and 3% of that is 16. So 16 women who found out that they had Lynch syndrome, actually, three of them already knew. So it was 13 new diagnoses of Lynch syndrome. And all of those women were referred to the clinical genetics department where they had genetic counselling, which essentially involves finding out which members of their family would be eligible for testing. So that's something called cascade testing, where you find an index case of a genetic condition and then you roll out testing to their at risk family members in order to find healthy people with Lynch Syndrome, in whom you could prevent future cancers. So all of those women were offered cascade testing and they were then enrolled in the appropriate prevention programme so that is they were either enrolled in a clinical trial to find out which dose of aspirin they should take to prevent future cancers, or they were started on a low dose aspirin, depending on when they were recruited to the study, because that trial wasn't for the whole duration and they were also enrolled in bowel cancer screening. So that is when people with no symptoms who have Lynch syndrome have a camera test called a colonoscopy to look inside the bowel and check for any polyps that could be removed. That could be dysplastic polyps, which means that they are pre-cancer and therefore removing them can effectively prevent bowel cancer. So that kind of comprehensive package of care was organised through the clinical genetics department.

Sally Best:

And I guess there's the side of things that is better in terms of early diagnosis of that syndrome, because, I mean, correct me if I'm wrong, but early diagnosis would kind of mean increased patient outcomes.

Emma Crosbie:

Yeah. I mean, that's, that's the whole thing is that we can if we can prevent cancer, that's brilliant. But even if we can catch cancer at an early stage, then we know that patient outcomes are better because usually they are cured with their first treatment, and that might be treatment that causes less problems to them because for example, it's just surgery than if they needed more advanced treatments, more aggressive treatments for more advanced cancer. So yes, early diagnosis is key to improving outcomes from cancer.

Sally Best:

And presumably, I mean, if a woman has Lynch syndrome and kind of is un-symptomatic and has no symptoms of bowel cancer, but actually turns out to have bowel cancer that would be the early detection side of things. And then in her children, I mean, am I right in thinking it's both boys and girls? That would be.

Emma Crosbie:

Yeah. So Lynch syndrome is an autosomal dominant condition, which essentially means that a parent passes it onto approximately half of her children, whether they be boys or girls.

Sally Best:

And then for them, it would be the preventative measures and the preventative side of things.

Emma Crosbie:

Yeah, absolutely. And of course, some of them will be girls who have not had womb cancer. So, you know, in this case, the index case has had womb cancer. And she's had treatment for it. But her family members may not have had womb cancer. And therefore, there are things that we can recommend to reduce their risk of womb cancer in the future as well.

Sally Best:

God, it's good stuff, isn't it? It is good stuff. So just back to the original study, the PETAL study. So within this area we've talked about health economics and we've talked about it comprehensively in a few of the episodes that we've covered. But I'm just wondering if there's any health economics portion of this PETAL study.

Emma Crosbie:

So we teamed up with Professor Katherine Payne, who's a health economist here in Manchester, and we carried out something called a micro costing study, which essentially calculated the exact costs to the NHS of doing the Lynch syndrome testing. So we compared four different testing strategies and worked out how much each of those would cost in terms of diagnosing the patients with Lynch syndrome. So if you think about it, you know, it doesn't sound as if it's going to be cost effective to screen everybody with womb cancer to find the 3% that have Lynch syndrome. But that's really an important piece of information for the NHS to know in order to make it policy that we should be screening everyone with womb cancer for Lynch syndrome. And so it was important for us to gather the costs so that we could understand whether or not it could be cost effective. So that portion of the research was finding the costs. And then we teamed up with Dr. Tristan Snowsill from the University of Exeter to do a formal health economics modelling exercise. And essentially by putting in the costs that we had gathered in our micro costing study and all the information that we had got from the PETAL study, we were able to show that screening or offering screening for Lynch Syndrome to everybody with womb cancer is indeed cost effective for NHS.

Sally Best:

Okay. So you mentioned as well, you've you tested four methods of screening for Lynch Syndrome. Which one did you settle on?

Emma Crosbie:

So we settled on the one that was most clinically effective. So the one that showed found all 16 Lynch syndrome cases and that was essentially examining the tumour tissue for the presence of these mismatch repair proteins that I talked about, using something called immunohistochemistry, which essentially staining the tissue and looking to see whether it's stains brown, you know, on a very basic level. And then those that don't stain brown are at risk of Lynch syndrome and they go on to have a blood test, which is the proper test, if you like, for Lynch syndrome. So we could just take a blood test and do genetic testing of all our womb cancer patients. But that's extremely expensive and also, you know, very time consuming and requires a lot you know, it takes a long time to get a result, whereas this tumour test is very, very quick. It can be done at the time of, you know, diagnosis and treatment for womb cancer without causing, you know, much backlog in terms of workload. And it effectively reduces the number of it needs to have this genetic test.

Sally Best:

So, Emma, this is a question that you'll have had before. With this blood test, is there a multi-pronged approach that we can take? Could we test for multiple cancers at once? Because, I mean, if it's expensive, you might as well kind of do multiple while you're there. Am I right?

Emma Crosbie:

You are absolutely right. But however, in this particular case, we are just looking for Lynch syndrome. So if you increase the panel, in other words, you look for more mutations or defects in other genes, then that increases the cost and it increases the workload and the time to get the results. So because in this particular workflow, if you like, we're simply looking for Lynch syndrome because that is the genetic condition that predisposes to womb cancer, then expanding the panel to other genes isn't that cost effective. Because it's very uncommon that those will be affected in these patients, if that makes sense.

Sally Best:

Makes complete sense. So just moving on to my next question is looking back on all these findings, how have they been appointed to NICE and what was the process of this?

Emma Crosbie:

So right at the very beginning of this, we thought we really want to do research that makes a difference. We want to do research that changes how we care for our patients. And so we approached NICE and said, Why is there no guideline to say we should be screening our womb cancer patients for Lynch Syndrome? And they said there's no evidence for it. There isn't any good quality research that allows us to create a guideline like that. And so we asked them, well, what, what research would you need? And they said, Well, we need the results of your PETAL study. We also need health economics modelling. We need to know that patients want to be tested. And so that kind of informed how we did our research because we sort of started with the end in mind. We knew what the what we wanted to achieve through the research and we knew what NICE needed us to show. And so that is how we did our research. And so at the end of that process, when we had done all the work and got the results through, we were then able to approach NICE again and say, you know, the evidence you asked for? Well, here it is. And if we hadn't done the research that we had done, there would still not be enough evidence for them to say we should be offering screening for Lynch Syndrome in womb cancer. So we really started with the end in mind.

Sally Best:

Absolutely brilliant approach there, nailed it and realised that I mean a lot of people might not know what NICE is. So for the benefit of our listeners who might not have heard of it, would you be able to just give a quick overview of the role of NICE and how it plays into clinical practise changes?

Emma Crosbie:

Yes. So NICE is the National Institute for Health and Care Excellence, and essentially they are the body that oversees new guidelines for all clinical trusts in the UK would want to abide by. Because these are such high quality guidelines that are informed by the best evidence and NICE is impartial. So it doesn't, you know, write a guideline because it has a friend that does this particular type of research or has asked for this clinical new test to be brought into clinical care. It's very impartial. It's got a transparent processes whereby it looks at the evidence in a very impartial way, in an objective way, and it sort of engages a team of independent experts to appraise the evidence and decide whether or not the evidence is strong enough to be recommending a change in clinical care for our patients here in the UK. So it's really the best way to introduce a change in clinical care, is to go through NICE because the quality of their guidelines is such that most clinical trusts will then want to roll them out.

Sally Best:

So I mean it's quite comprehensive and I guess I think that reiterates the integrity that your research has to have. So I mean, from my perspective, I applaud you for that and it's just amazing. So I'm wondering with regards to NICE, what specific guidance is now in place for womb cancer patients and what does that mean for the future of patients now and in the future?

Emma Crosbie:

Yeah. So the research that we did directly fed into the NICE process and in October 2020 they released new guidance that said that we should be offering screening for Lynch syndrome to all patients with womb cancer, using the approach that Manchester showed to be most clinically and cost effective. And so essentially what that means is that the UK has now got a mission to start screening all of its womb cancer patients for Lynch Syndrome and this is being rolled out. So it's already happening here in Manchester. It's happening for most of the large cancer centres that deal with womb cancer and it's being rolled out to the peripheral centres, the cancer units as well. And so it really has changed what we do and now it's just part of routine care that we do that tumour test that tells us whether or not a patient's at risk of Lynch syndrome, and then we ask patients if they'd like to have the blood test if they're at risk. And this has basically meant that we are now able to understand better who is at risk of future cancers and enrol them in the right screening programmes for bowel cancer prevention, start them on aspirin, find their family members that might be at risk as well. And essentially it's just this sort of cascade, too, of identifying people at risk and helping them to mitigate that risk.

Sally Best:

Yeah, and I guess, as we've mentioned before, identifying those at risk as part of the prevention and early detection work, which as we know, is the kind of the route that we want to take if we're going to kind of tackle cancer at the source. For want of a better way to put it. So am I right in thinking that's diagnostic guideline 42.

Emma Crosbie:

You are absolutely right. How did you do know that?

Sally Best:

Can you tell I've done my reading?

Emma Crosbie:

I'm very impressed here it is.

Sally Best:

So I'm wondering, the mission. So you're saying it's a mission to roll out. Are there any timelines with that?

Emma Crosbie:

So it's happening. So I think this year, next year, I mean, it's about gathering resources. So, you know, pathology departments are hugely under-resourced and understaffed and it's about trying to introduce it into work streams. So there is a will, everybody wants to do it. It's just about finding the ability to do it by working out how best to introduce it at each local place.

Sally Best:

And I'd like to know about why were you so passionate about getting this evidence and research into NICE guidance? Because I mean,  it's an arduous task. And I know it's taken you years and years, and it is now your life's work and I mean, it's not the only thing you're known for, which is crazy. Absolutely crazy. But yeah. Where did your passion come from?

Emma Crosbie:

I think I just saw this big difference for bowel cancer and womb cancer and thought, well, that's not fair. Partly because, as I said before, women with Lynch syndrome are much more likely to get womb cancer first than they are to get bowel cancer. And so if we could find that they had Lynch syndrome, then we could potentially prevent them from getting the bowel cancer that let's face it, has often a much worse prognosis. So womb cancer, you know, we do tend to diagnose early and often cure it. But my view was, well, there's no point in doing that if we're going to leave this poor woman to subsequently develop a bowel cancer that ultimately kills her. So we need to be doing something now and we need to be correcting this disparity. It felt like women were getting a bad deal and I wasn't happy about that.

Sally Best:

I guess that's the thing as well. Like if you're going through one cancer and cancer treatment, it's a hell of a lot for your body to go through. And I mean, presumably going through the next is just kind of another knock.

Emma Crosbie:

Absolutely. And, you know, the women that took part in our study were very clear that it was partly about preventing future cancers for themselves. That's why they wanted to take part. But it was really, quite a lot of it was about protecting their children and their other family members. And there was that real altruistic, you know, nurturing side to them that was like, well, if this thing has been caused by a genetic condition and I can help my family member by enabling them to get involved in cancer prevention interventions, then why wouldn't I?

Sally Best:

Yeah, completely. I completely understand that. I mean, knowledge is power.

Emma Crosbie:

Yes, it is.

Sally Best:

Emma, what would be your advice to a researcher who wants their research to be adopted into NICE guidelines and don't say coffee?

Emma Crosbie:

I think.

Sally Best:

Yeah.

Emma Crosbie:

I mean, I think it is to do what we did. So essentially you need to identify an area of unmet need. So you need to find an area that really needs some work where there is a real clinical problem, a conundrum if you like. But there is just a lack of evidence to support a change in clinical practise. And you need to gather the evidence and present it to NICE and ask them to look at it in a formal way so that they can create a new guideline. So it's essentially, as I said before, it's about starting with the end in mind. What is it you're wanting to achieve? What do you need to put in place to achieve that? And essentially working together with NICE to make sure that there the research you're doing is going to be effective in that sense.

Sally Best:

Ever thought of motivational speaking? There’s a new career path for you there but don't leave gynae cancer. For God sakes, we’d all be ruined. I mean, the next kind of point I'd like to look into is through research you've continued to positively benefit the lives of women, and that's women with Lynch Syndrome, as well as their family members. And I'm wondering, how does it feel to know that your work is positively changing the lives of all these people? I mean, I think, you know, in terms of being a medickand a doctor, you're benefiting kind of lives on the ward and, you know, like saving through A&E and things. But I think looking at this clinically, this is a population level of people that you're helping. And I'd just like to know, you know, how it feels that, number one, you are benefiting lives and number two, that it's women. And number three, that it's such a vast population level.

Emma Crosbie:

I mean, it's amazing. I mean, that is essentially why we do what we do. We do it to make a difference. And, you know, to have seen the patients being diagnosed and being grateful that they found out that they have this condition, is very rewarding to listen to the patient support groups and you know that the patients themselves to say, you know, this is so important, it's made a real massive difference to our lives to know about this condition. You know, that that is essentially why we do what we do, it’s to benefit not just the patient in front of us, but groups of patients, populations of patients. And to make a real positive change for the future.

Sally Best:

Yeah. I mean, to say, you know, all the kind of the kids as well that you're pre-emptively helping. So I mean, there's a hell of a lot of people down the lineage as well. Emma, you're always somebody looking to the future. You've got a lot of foresight. What's the future of your research? And you know, what do you want to be the next stages of this work?

Emma Crosbie:

So obviously we are identifying people who have got womb cancer and it's caused by Lynch syndrome. But through cascade testing of their family members, we're finding women in their family who have not had womb cancer, but who are at risk of it. And as I said before, we have bowel cancer screening programmes in place to reduce the risk of bowel cancer and prevent bowel cancer in people with Lynch. But there isn't anything that is effective or known to be effective for womb cancer. So again, you know, the clinical service is patchy. Some people are offered annual gynaecological surveillance. It's in the form of an ultrasound scan, a hysteroscopy, which is a camera test inside the womb and a biopsy. And other people are offered nothing. And the people who are offered testing, you know, the testing isn't really fit for purpose because it's invasive. It hurts people. Some people find it quite painful. It's expensive, and we don't really know how often we should be offering it. So there is a lot of work that needs to be done in terms of finding a new womb cancer early detection tool. So a screening tool, if you like, that can help us to identify which women need invasive diagnostic testing and which women can be reassured that there is no pre-cancer or cancer sitting there that needs to be looked at.

And so we've been looking at this and trying to develop a non-invasive detection tool. And the thing that we're working on at the moment is the possibility of a urine test. So we've had a look in urine and we've been able to show that you can actually see womb cancer cells in a urine sample of a person who's got womb cancer.

And you don't see similar cells in a urine sample from a person who doesn't. And this is quite an exciting finding. Essentially, all it involves is taking a sample that the woman has collected at the toilet and then spinning it down onto a slide and looking at it under the microscope. So it's a very, very simple test, but it actually does work. And we've done it in a small number of people. And we're now rolling out into a much larger, larger study of 2000 women, of whom about 100 will have womb cancer. And seeing whether or not the urine tests can actually identify those women, because we think that this could be the future. This could be, you know, a urine test that could be done at home that a woman with Lynch syndrome could simply send into the lab every year. And we could say the womb, you know, the urine samples clear, you don't have womb cancer, you can be completely reassured. Or actually, we do see some cells and you need to come in for those invasive tests. I think that would completely transform what we currently do to screen for womb cancer in Lynch Syndrome.

Sally Best:

Yeah, I mean, it's a scary thing. A cancer diagnosis. And I think for a lot of people, you know, ignorance is bliss. And if you kind of get over that ignorance is bliss phase and want to kind of be screened and things, the painful aspect of things and the invasive aspect of things can be an additional scare.  A real barrier. So I'm guessing, you know, giving women the kind of urine sample just the ease of it would encourage more women to come forward as well.

Emma Crosbie:

Yes. That's the plan.

Sally Best:

Which, you know, again, early detection. We love it. We do. And I mean, I've spoken to you and Jen about this. Can we use that urine for anything else? The great power of urine.

Emma Crosbie:

Yeah, I mean, we're as you know, we're very excited about the power of urine because we are also looking into the possibility that it could be an alternative way of screening for cervical cancer. And indeed, Jen's work has shown that we can find the HPV virus in urine samples of people who've got cervical pre-cancer. And so actually a urine test might be good to diagnose or to identify people at risk of both cervical cancer and womb cancer. And ultimately, if we could find a biomarker in people with ovarian cancer, then we might be able to actually create a pan gynae cancer screening tool, which is urine based. And this is something that I find really exciting. This is this is the area that I'm really interested in at the moment.

Sally Best:

You're a gynae goddess. Gynaecological goddess. That's what we'll have to call you. Change your Twitter handle now. Well, in America, you have witness that women don't come forward for screening of Lynch syndrome because it would increase that kind of health insurance premium.

Emma Crosbie:

That's right.

Sally Best:

How would you get around that?

Emma Crosbie:

I mean, it's really challenging, isn't it? So I mean, the whole paying for your health care thing is is very, very difficult. And, you know, there are repeated studies from America showing that even when a person is identified with Lynch syndrome, their family members don't want to be tested for the exact same reason. So they really are at risk because their family member has it and they don't want to be tested. And I think it's a massive challenge. You know, we are so lucky in the UK to have the national health system. A national health service sorry, is absolutely amazing because it takes care of all of us and we don't have to worry about how much things costs when deciding what's best for our health. And I think that it is a real shame that that same way of thinking isn't transparent in America because it is private health care. So, you know, the rich can have and the poor cannot and that that's just seems wrong to me.

Sally Best:

Yeah. It's a very sad way that the world works. I mean, in terms of other countries is, the testing being rolled out?

Emma Crosbie:

So it is in Europe. And yes, so our work has actually made it into European guidelines now.

Sally Best:

That she goes, she doesn’t stop.

Emma Crosbie:

So there are now yeah. The sort of European guidelines for the management of womb cancer are all saying we should be screening for Lynch Syndrome using the Manchester approach. So, you know, we're in Europe and whether we can get into America. Yeah, I mean that's the challenge, isn't it. And also, of course, in low and middle income countries where health care resources are very slim, I think this might not be seen as a priority, understandably. But, you know, we have hope that we will be able to do some big stuff in at least in Europe.

Sally Best:

Yeah. Keep pushing forward. Yeah. And I love that, Manny on the map. Well, thanks Emma so much for talking to me today.

Emma Crosbie:

Well, thank you for having me. It's been a pleasure.

Sally Best:

As always. A pleasure. You're honestly a wealth of knowledge and honestly, thank you so much for just talking to me about another one of your kind of life's work, your children, as it were.

Emma Crosbie:

Thank you for having me.

Sally Best:

Yeah. So great to talk about pioneer of early detection and another meaning of ped, prevention and early detection, the pioneer of early detection we love it right. Well, I mean thank you everyone for listening. I'll link Emma’s work in the blurb and I'll put in her Twitter handle. Follow her on there, keep up with her movements, keep up with the team because they're all doing great stuff and yeah, everything will be linked. So just keep, keep reading. She's great, but thanks for listening and see you all next time. Not see you all, listen to you all, speak to you all. Thank you very much. And we're out.

If you've been affected by anything you've heard in this episode, please see the show notes for our list of charities and organisations that can help. One in two was brought to you by The University of Manchester and the Manchester Cancer Research Centre. Listen to our next episode to hear from more of our researchers as they share the innovations, discoveries and projects that are changing the landscape of cancer prevention, early detection and treatment. To find out more about what you've heard today, please see the show notes for this episode, where you'll find a transcript and links to further information and research. Cancer is one of the university's five research beacons, showcasing the interdisciplinary collaborations and cross-sector partnerships that are tackling some of the biggest questions facing the planet. To hear more about Manchester's research in advanced materials, biotechnology, cancer, energy and global inequalities go to Manchester.ac.uk/beacons.

 

Sally Best:

Hello. You are listening to One in Two, a Manchester Cancer Research podcast brought to you by The University of Manchester and the Manchester Cancer Research Centre. With one in two of us receiving a cancer diagnosis at some point in our lifetime, it's never been more important for our research to improve the outcomes for people affected by cancer. I am your host, Sally Best, and throughout this series I will be speaking with Manchester cancer researchers about their innovations, discoveries and projects that are changing the landscape of early detection. In this episode, we speak to Professor Sarah Cartmell on her work in bioengineering and ex- vivo modelling, which involves studying cancer cells outside of an organism. Specifically, we talk about her team's work developing these models that can analyse in three dimensions

how non-cancerous lung cancer cells develop into tumours and what the findings from this work could mean for improving patient outcomes. Hello, Sarah Cartmell, thank you so much for joining me. How have you been?

Sarah Cartmell:

I'm good, thanks. Yes, pleasure to be here.

Sally Best:

Pleasure to have you here. Absolutely loving your presence. Sarah's in a lovely dress today. I am very jealous. I am, of course, dressed in black because what else for this Manchester weather. But you know, so I'm wondering to start off with if you be able to tell me and the audience a little bit about yourself and what it is that you do.

Sarah Cartmell:

Yeah, sure. So my name, as you just heard, is Sara Cartmell. I'm a professor of bioengineering at the University of Manchester. I'm also the head of the Department of Materials in the Faculty of Science and Engineering here at the University. My labs are located in the National Royce Institute of materials, also based here in Manchester.

Sally Best:

Okay, and for the benefits of the audience we can put a map on because the Manchester campus is very broad and has a lot of different buildings. So it would be helpful for you guys to look at that. But I mean, I'm intrigued to ask, what does your day to day look like?

Sarah Cartmell:

So typically it's a lot of emails, a lot of meetings. I do have quite a large research group, so I've got about 20 researchers, PhDs, postdocs, project managers within my group. So they're normally in the lab going through collecting the data and we sit down and go through the data. So there's a lot of exciting kind of project discovery and sitting down and coming up with new hypotheses based on the data that we've gathered.

Sally Best:

Just to kind of go back, you're a professor in bioengineering. We've had quite a few different people on here that aren't your kind of standard cancer research. But I'm wondering, what's your research journey into engineering?

Sarah Cartmell:

Sure. So I began my academic career at the University of Liverpool in 1993. I studied chemical engineering of material science there, and that was a Bachelor of Engineering degree, but that was perfect marriage for me. So that combined my engineering passion as well as my passion for medicine. I carried on at Liverpool to do a Ph.D. and I studied the degradable phosphate based glass and its use for urinary stress incontinence and tissue engineering purposes. 2000, I moved to Georgia Tech in Atlanta in the States for a couple of years, and I was in the mechanical engineering school there, so I keep moving from different faculties, very interdisciplinary work. Here, I really began my interest in orthopaedic tissue engineering, which is kind of these 3D tissue models that we'll be talking about today. I moved back to the UK in 2002 when I started work in Keele University for eight years, and then I moved to Manchester in 2010.

Sally Best:

Can I just say Sara does not look like she's lived this much life? 2002 I think I was 4. Goodness me, it’s a lot. And I mean, it's so interesting to hear about. You work as the head of the Department of Materials at the University of Manchester. Is that right?

Sarah Cartmell:

That's right.

Sally Best:

Okay. Your bio is right online. And I'm wondering within this role, how many different fields do you work across so you've kind of mentioned health care and medicine and things, but like what's the kind of plethora of roles?

Sarah Cartmell:

So I have obviously a couple of different roles. One is the head of the materials department. The materials department itself is, is very broad in its disciplines. So Manchester is a cotton trading town. It initially came from technical textiles so university in 1824, nearly 200 years, we've been going as built up from that technical textiles and we carry that on in our department. So we actually have material science as you would imagine it in terms of, as I mentioned, textile technology, corrosion and composites, biomaterials, which is my field and imaging and characterisation. But also we have a large body of research and teaching in fashion business technology. So there's a lot of kind of humanities business and obviously arts within the department as well. Myself in terms of my research and I work in biomaterials, so I work across the faculty of Biology, Medicine and health and the Faculty of Science and engineering and sometimes humanities as well. Because what we're doing affects society, as you can imagine.

Sally Best:

It’s a massive plethora of work. And I really want to focus on cancer early detection because that's what this podcast is about. I mean, just to get a full idea of what you spend your time doing, do you have any examples of a project outside of cancer that you work on that you'd like to kind of briefly highlight just to give us a little titbit into the life of Sarah Cartmell.

Sarah Cartmell:

Sure. So last year I started my own spin off company called V Tendon Ltd. That's been translating some of the tendon repair products that I've been developing in my laboratory over the last ten years. And we've got a couple of products that are made from a degradable plastic, called polycaprolactone and one of these products is to augment tendon suture repair and therefore improve the functionality of the wound healing and the time needed for the repair to shorten that. And the other product is a novel tendon retrieval and attachment device. I've also got a portfolio of research in wound care products and I also investigate the effects of applying electrical regimes and mechanical forces to cells and tissues in order to influence their activity. So we can either get them to grow more, to proliferate or to differentiate, which means turns into different cell types or produce more extracellular matrix, Making more tissue, if you like.

Sally Best:

God what don’t you do? Tendon repair. That's insane. I love that. I need to talk to you more about that another time. I'd like to kind of get to the nitty gritty, but I mean, how long have you been here in Manchester? So since when did you say you moved over 2002?

Sarah Cartmell:

2010 at University of Manchester. But I'm from Manchester myself. I'm from sale from South Manchester.

Sally Best:

I'm from Stockport. Two different ends of the world. But Manchester through and through. We love it. So you came back?

Sarah Cartmell:

I did.

Sally Best:

Yeah, you came back. So you've been here what year 2022? I accidently wrote 2020 earlier. So that’s 12 years.  I mean, compared to other places you worked, what was it like to work across this kind of broad research landscape as Manchester? Because I mean, it's massive. It's, you know, there's so many different counterparts of the Manchester campus. And I'm just wondering, what was that like?

Sarah Cartmell:

Yeah, it's really exciting. So the depth and the breadth of the research activity that we have at Manchester is one of the reasons why I came here to work. The opportunities are really vast, you know, and the expertise and the resources that all here on our doorstep as so you know, we're in a really great position to translate our research through its inception all the way through to the clinic.

Sally Best:

And do you find it easy to collaborate here because there's so many different teams? Like, has that made your research easier?

Sarah Cartmell:

It definitely has. And if anything, it's probably because everyone is very enthusiastic about different projects. Probably too easy to collaborate. I have to make sure that I'm not taking on too much, you know, because it's. That's the only thing.

Sally Best:

Yeah, I understand. I get very excitable, but, you know, sometimes it's the way of the world. And I mean, coming back to what I'd like to talk to you about today, firstly, I like to ask when and how did you get into working within cancer early detection?

Sarah Cartmell:

Yeah. So there's a guy called Rob Bristow and he joined the University of Manchester in 2017 as the director of Manchester Cancer Research Centre. So he began to bring together different expertise across the university, such as biomaterials that could be a benefit to cancer research field. And he held a variety of different workshops, and some of those I went to in order to mix with different cancer research academics I hadn't previously collaborated with. I then began translating the 3D tissue engineering models that I've been developing all through my career for cancer early detection models when we secured our first grant in 2019, and that gave us the resource to fund an excellent Ph.D. student who's with is now called Emmanuelle Amita. A big shout out for Emmanuelle. She’s worked with myself and Andrew Gilmore and Angeliki Mullery, who are at Manchester University as well in the Cancer Research Centre. And Emmanuelle is looking to create a lung cancer early detection model. And since that project that's ongoing I've also been working with a lung oncologist, academic clinician Sean Knight and cancer biologist Katie Finnegan, who were also working on lung cancer. And we've just been awarded a couple of research grants that we just starting now.

Sally Best:

This is fab. I love it. Loads of people. So I mean just really quickly biomaterial, that's a biological material just for the sake of the audiences.

Sarah Cartmell:

Yes. Just to clarify. So when I say biomaterial, I mean a material that's going to be in contact with a cell. So it doesn't necessarily mean sometimes you can read in the literature, biomaterial is a naturally occurring material. When I say biomaterial, I talk about and it could be a naturally occurring materials, which is collagen and or it could be a synthetic material. It could be something that we've made in the lab from different chemicals. But the purpose is biological.

Sally Best:

Okay. And in terms of, say, just back to your tandem work, it would have to be a material that wouldn't negatively interact with the cells in your body.

Sarah Cartmell:

Typically, yes. So normally we want it to be biocompatible and non cytotoxic. It depends on its application. You might want a biomaterial to create an adverse effect. So if you wanted it to kill cancer cells, for example.

Sally Best:

Okay, interesting. I mean, back to this kind of modelling, how would you do it? So you've said that Emmanuelle, she develops these lung cancer models and I know you're going to kind of go on to this, but I mean, how is that done? Is that done in the lab? What do they look like?

Sarah Cartmell:

Sure. So we do we do have a lot of different rooms in all laboratories for all the different purposes. So one of them is like a wet chemistry lab where we're able to manufacture the different materials that we want to use. And we call them tools that we're developing scaffolds and we create those materials, as I mentioned, so that typically for this purpose they're biocompatible and also they've got the similar shape, the size, the chemistry, the mechanical properties that we need for the particular tissue type that's in our body. We then take healthy cells so non-cancerous cell at that point and grow them and place them. We call them seeding, put those onto the scaffolds. And what we tend to do in the cancer early detection is we, in half of those samples were able to keep those as controls, if you like, and keep those healthy non-cancerous and in the other half we're able to create like a cancerous tumour. So we’re able to genetically alter those cells using a process called transfection so we can create cancerous tumour. And as such we're able then to analyse those very early changes in cancerous versus non-cancerous cells in a 3D environment, in a developing tissue rather than just on the bottom of a plastic dish, which is essentially the process that's happening now. So it's a lot more kind of biomimicry mimicking the biological environment that we have right now. The materials that we use hugely vary depending on what environment you want to create. So it might be gel that we want to encapsulate the cells fully or it might be fibrous mat where we place the cells directly on top of them. And then we can then apply different types of stimulus to the samples which are just mechanical forces for a breathing action, for example.

Sally Best:

And can I just ask, where are these healthy and cancerous cells? Where did you get them from?

Sarah Cartmell:

So again, it depends on your research question. So we have, you can use something called a primary cell, which is where we take a biopsy of cells of tissue and then we isolate those cells. We digest them out. And typically, I'm very interested in that clinical translation. So typically we would use biopsy, obviously we have ethics in place, ethical forms and approval in place, typically human samples to make that clinically relevant. A research question might be comparing some of the data to literature that's already out there, and that might be from a mouse model, for example. So it might be that we need to take, you know, a skin sample or a blood sample from a mouse or you might be using a cell line, which is something that's already established, have been established many, many years ago by a different researcher.

Sally Best:

Okay. And I mean, so are these what we call ex vivo models?

Sarah Cartmell:

So the terminology of ex vivo and in vitro does change from field to field, and which is something I've had to be aware of when I've started very much with this interdisciplinary working. And when I do talk to the cancer biologists, then when they say ex vivo, they're talking about something that I mean, in vitro. So for me, ex vivo means when you've taken a piece of tissue, maybe a piece of skin, and we work with that piece of tissue in the lab. So we haven't isolated any cells from that, but it's still an intact piece of tissue if you like. It's ex vivo its out of body. so and we can then perfused that with blood and keep it viable for another 24 hours and keep that going. So that's an experiment in itself. The work that I do tends to be with 3D in vitro models, and which is when we use single cells, we see those onto those 3D scaffolds that I mentioned earlier. And then we build up the 3D tissue. So we create that 3D tissue by growing them in containers that we call bioreactors. And those bioreactors then control the environment that's needed to grow that tissue, essentially the different gases nitrogen, oxygen, carbon dioxide and all the different nutrients, you know, the salts and the sugars that we need for those tissues to develop different proteins and different, you know, stimuli such as mechanical forces or electric regimes that the tissues need to grow. I have an example. So Emmanuelle that I mentioned earlier Emmanuelle Amita who's our PhD student, She's working with a type of scaffold which is made from a biocompatible rubber. It's called polyurethane. And she's created these different fibrous mats out of this polyurethane using a technique called electro spinning. So they're very, very fine, kind of randomly aligned fibres. And she's then taken these mats and grown lung epithelial cells on those, and she either taking these healthy cells or genetically manipulated cells, as I mentioned earlier. And she's growing that in a bioreactive system. So the cells are in an air liquid interface. Obviously with your lungs you have obviously this there's fluid there, but there's also air there's also a gaseous presence. So Emmanuelle is currently at the stage where we're now incorporating magnetic particles into these polyurethane fibres and by doing this, we can then apply an external magnet and then move the rubber mat, if you like, and stretch and apply a physical strain to the cell that is seeded onto the fibres in a way. Then it mimics the motion of a lung alveolar, so it mimics that breathing action. And in this way we're able to analyse the samples that as the cancer tissue and the healthy tissue grow in comparison to each other in this lung alveolar mimic in the lab.

Sally Best:

And I mean, just for the audience that don't necessarily know lung physiology, could you just explain briefly what an epithelial cells is and what an alveolar or alveoli are?

Sarah Cartmell:

Sure. So if you like, I guess if you look at a tree where you have the main trunk and that might be your main trachea, your airway, and then it goes off and it branches off. Those branches get smaller and smaller and smaller and kind of at the end of those at twigs, if you like, there's this little circular sack. And obviously it's like a bag when you breathe in is expanding and when you're breathing out, it's decompresses. And so you've got your negative and positive pressure going on in the lungs, the outflow of these tiny little sacs right at the end of the those branches of the tree, if you like. So they’re very small individual and spaces, but, they're very important in terms of increasing the surface area of your lung. As cancer develops, that gets blocked, that obviously has an impact with the exchange of the oxygen. You asked me about epithelial cells within your and within your skin, within your lungs. You have different types of cells. And epithelial cells is one of those cells which is on the surface, layering on the inside of your lungs. And obviously would be if you had lung cancer, sometimes those epithelial cells, those surface cells on the inside of the lung will be contributing to the tumour growth.

Sally Best:

Okay. So what I've heard so far is that you're doing these this kind of modelling type and one is having your control group which is looking at non-cancerous cells and the other is having a non control group which is looking at cancerous cells. How is that being applied in early detection? Are you looking at different cancer markers at different stages of development? Like what's the what's the process behind that?

Sarah Cartmell:

So what we're trying to do is, as you can see, we're able to then develop the cancer from a very early stage all the way through. If we can detect distinctive biomarkers that are emitted, if you like, by those cells. So the cells will have a different genetic profile, different proteins that they're producing as well. And our hypothesis is that there's a signature, if you like. So it's not just I don't think it would be just one bite might be, but only would be just one protein that we can then say, oh, this protein is being expressed, therefore the cancer has developed. I think it will be a signature. So I think it might be 12 different proteins, for example, that would be upregulated, that would go, oh, that's unusual. That wouldn't happen in a healthy tissue. with the hypothesis Then if we have that signature profile, we could then possibly take, for example, a blood sample from somebody who's more at risk. So that might be somebody who's genetically predisposed to getting particular lung cancer or it might be somebody who's smoking heavily, and that might need regular checks to see if that signature if that starts going up, then that again, that's the hypothesis and what we're trying to do.

Sally Best:

Okay. So you're saying that you're looking out for these biomarkers, which I'm assuming are cancer markers as a kind of lay term, and then they might be things such as proteins that are regulated, i.e. overproduced, and they signature the start of a cancer that you wouldn't then see in a healthy patient with non cancer cells.

Sarah Cartmell:

Exactly.

Sally Best:

Okay. I mean, that that's amazing. And I mean, it's great to see like why we're using these sorts of models in early detection and also that clinical application of blood sampling and being able to test the early stages and look at people that are at risk. Cause I think that's a major thing in terms of risk factors. I know that kind of catching it at that stage. One, which is why you're saying would be these kind of starting upregulated and regulating of these biomarkers is just amazing because I guess it kind of means that your treatment options are more kind of a better and more varied and less kind of invasive as well.

Sarah Cartmell:

Absolutely. And the outcome, obviously, the success then of that treatment would be, you know, hugely increased.

Sally Best:

Okay. I mean, it's great. And just taking a step back here, this is kind of a biological question, but I'm wondering if you'd be able to explain how a cell goes from being non-cancerous to cancerous.

Sarah Cartmell:

Yes. So our bodies are made up of trillions of different cells and they're grouped, obviously, as I mentioned before, into different tissues and different organs. And there are genes inside the nucleus of each of those cells. And those genes tell them, tell the cells when to grow and when to work, when to divide and when to die. And normally our cells follow these instructions and we stay healthy. But when there's a change in our DNA or damage to it, a gene can mutate. mutated genes, They don't work properly because the instructions in their DNA gets mixed up. This can cause the cells that should be resting to divide and grow out of control, which can lead to cancer. When the genes aren't working properly, they tell the cells when it's the right time to grow and divide. And when the cells divide, they make exact copies of themselves. So one cell divides into two identical cells, two goes into four and so on. In adults, the cells normally grow and divides make more cells only when the body needs them such as to replace ageing or damage cells. There's not a huge, apart from stem cells, There's not a huge amount of division that's going on, but cancer cells are different. So cancer cells have gene mutations in them that turn the normal cell into a cancer cell. These genes, these gene mutations, they might be inherited, they might develop over time as we get older and excuse me, the genes wear out or they might develop if we're around something that damages genes, such as cigarette smoke or alcohol or UV light. And a cancer cell doesn't act like a normal cell. As we as we discussed earlier, it starts to grow and divide that that gets out of control instead of dying in the way it should. And they also don't mature as much as normal cells, so they stay immature and although there are many different types of cancer, they all start because the cells are growing abnormally and out-of-control and they can start any cell in the body.

Sally Best:

Okay. And I mean, I'm guessing in terms of the difference between these cancerous and lung cancer cells in your models for early detection, that's kind of the start point. Are you using lots of different kind of cancerous cells, like are they from different places? Do you witness different levels of growth mutations and different cells from different areas?

Sarah Cartmell:

So there's lots of different researchers working in this area. So I myself only just as I say, started working in the lung  field and we're doing that by the transfection and then causing that cancer. So I do work with all the researchers that have, as you've described, you know, how all these different stages and different types of cells are cancerous and growing in that way. But again, what I'm doing is initiating that transfection and starting that cancer in the lab. And that's what we're observing.

Sally Best:

So  do you like watching it?

Sarah Cartmell:

It depends what you mean by watching it. I like looking at the data. I think if I just stood looking down the microscope at the cells, that's a bit like watching paint dry. It’d be tough to watch, you’d have to speed through it. Yeah and then that's pretty cool. Yeah.

Sally Best:

How much would you have to speed it up by?

Sarah Cartmell:

Well, that's a good question. So the cells in a typical cell might double, you know in 24 hours. Cancerous cells And again, if it's a younger patient, that that can be quicker or it could be longer. So if you take it like a healthy cells, for example, if you took a bone marrow stromal cell from a 19 year old male, then you'd be looking at 24. You know, hour turn around in terms of doubling of cell number, if you took that from a post-menopausal female, for example, you're probably looking at 72 hours.

Sally Best:

So cool. Get me in the lab looking down these microscopes. I love a microscope. I mean, so you've mentioned that you've while you've started to develop these models and lung cancer, have you developed these and any other cancers, are you hoping to develop them in any of the cancers?

Sarah Cartmell:

Well, that's the plan. I think what we have is a plethora of different materials and 3D bioreactors I mentioned those environments that really we can apply to a whole variety of different tissues. So we're talking now with our researchers in the Manchester Cancer Research Centre and also through ACED the Alliance for cancer early detection. And to talk about what we can do, you know, do they need that hydrogel that I mentioned before. Do they need that 3D environment? Do they need to control hypoxia, which is essentially how much oxygen is getting to the cells and control that permeability? Because that's important, obviously as tumour develops, do they need to alter the mechanical environment? So you might get a breast tissue, for example, that gets more fibrous and gets very stiff. And a lot of the models that are used right now wouldn't counter for that change in mechanics, but that could be key.

Sally Best:

Okay. So there's a lot of kind of trial and error behind it that's really interesting. So aside from the tissue sampling that's being used, do these models vary between, say, the work taking place and lung cancer or breast cancer?

Sarah Cartmell:

So they would they would change quite a bit, yes. Because the different tissue obviously the different cell types are going to be different. And the way the cancer develops in terms of the tumour and is going to be different and the mechanics that I mentioned is different. So we would probably use a different scaffold if that makes sense. And so I know that one of my colleagues at the University of Manchester Alberto Saiani they're developing this kind of peptide based hydrogel, and they are encapsulating some of those breast cancer cells in there and seeing how that develops as well.

Sally Best:

Okay. And just to confirm, peptide is basically protein.

Sarah Cartmell:

That's right it's like the building block of a protein.

Sally Best:

Building block of a protein. Can we have biology lessons with Sarah Cartmell, please? That should be a new podcast series. I mean, you've mentioned AIST, which is International Alliance for Cancer Early Detection, and I know quite a few of the people on here have done work with AIST- great group. But I'd like to know, number one, so is the project that you've specifically been working on with AIST, this development of the lung cancer model?

Sarah Cartmell:

That's what I've been doing so far, yes.

Sally Best:

Okay. And I mean, how did the partnership form?

Sarah Cartmell:

And so again, it was led the initial collaboration and introductions. Rob Bristow again is key. So he knows a lot of the people, obviously that I wouldn't know when he's putting us in contact. And we also have within Manchester and it's kind of a network this advancement materials and medicine network and we also have the Royce Institute I mentioned before. So that's already linking us with different materials expertise that we might not already have in the team, but we know that we need and we already have connections with University College London, for example. So we've been working with Umber Cheema and one of the lung cancer projects that's just about to start that I mentioned with Katie Finnegan and Sean Knight. And but essentially they start with, you know, getting people together and presenting the research they write this is the unmet clinical need. This is where we are. This is the state of the art. This this is what's going to be big science. This would give us a breakthrough. And then we can go off and sit down and go well we could approach it through this, you know, particular technique. And whether or not that is a new 3D model that I mentioned before and inclusion of mechanics or it could be, you know, in our faculty, we have lots of really cool new analytical equipment like microscopes or spectroscopy that are cutting edge that wouldn't normally get to other the fields, maybe for 15 years. Right, because they're so state of the art that it wouldn't be a common tool in the lab, if you like. So that's how we can through those conversations, we can find out that research needs get to the specific research question and then come up with some solutions.

Sally Best:

So I mean, within the AIST project, do you work with partners in the US on this project? Is it just partners in this country?

Sarah Cartmell:

Right now we're only working with Umber Cheema at UCL, but it doesn't mean that because we don't want to. We just as I say, I've only just started a couple of years ago in the field and getting some data. We're going to be presenting those at conferences soon. So Emmanuelle, who's my Ph.D. student I mentioned, is going over to Portland, Oregon, in a couple of months I'm going to present the data. We're hoping some new collaboration is going to come from that as well.

Sally Best:

And in terms of the clinical need for this project, was that just like lung cancer diagnosis?

Sarah Cartmell:

Again, it's going to initially that the collaborations that were formed so the and the research that I've been working with Andrew Gilmore and Angelili and you know, really are saying this is what's needed, this is where we are right now and this is what would make a big difference. So yes, they are working in lung cancer. Obviously Andrew works in breast cancer as well. But this particular model was working in lung but the same would be the same for any tissue.

Sally Best:

Yeah. And I guess in Manchester you know there is massive unmet clinical need just because of the vast rates of lung cancer in this population.

Sarah Cartmell:

That's why it's a huge, huge. On a graph. Yes.

Sally Best:

Yeah. I think it's something like that there is kind of that massive need to address that. And the work that you're doing is obviously really contributing towards that. So I mean, what do you hope that the development of models such as these will mean for patient outcomes?

Sarah Cartmell:

So obviously we want to improve the patient outcomes. We want to be able to have a fast and easy, a reproducible way of detecting these cancers as early as possible. That would then mean that we have better treatments, better outcomes. We want to really get to a place where we can move to a world where cancer isn’t a scary world, where it, you know.

Sally Best:

Yeah, I think that's the thing. And like this podcast name one in two and it's yes, one in two people will be diagnosed with cancer. But I think it's something like one in two die from cancer that are diagnosed. And it’s those rates that we're really looking to improve. So even if it is the one in two that are still diagnosed in 20, 30, 40, 50 years time, it shouldn't be seen as the same death sentence that it has been in the past, because it's all about the early detection side of things and the improved prognosis. And it's just amazing kind of speaking to people about the work that they're doing because it is removing that death sentence from the word and making it a less scary cancer, you know, so I mean, Sarah, what makes you passionate about your research and specifically cancer research?

Sarah Cartmell:

Well, obviously, just what you've just said, right. The impact. So obviously, I love doing what I do. I find it really interesting. But actually having that impact at the end really is what motivates me. And I love coming up with solutions. So people coming to me and say, this is the problem I've got, you know what? What can we do? And then go right well we could solve it this way, this way, this way, and then coming together as a team. So again, I really like working with people from other disciplines. So clinicians, industry, mathematicians, biologists, you know, material scientists, engineers, all sorts that is such a stimulating environment. Everyone's coming from a different viewpoint and I'm learning so much every day as well as contributing. Right. So it's is very exciting.

Sally Best:

Yeah, I guess that's the thing having external people coming in, you do, you do think in a different way and you are forced to, but you also force them to think in a different way and it's just yeah, it's amazing. I love I love the research kind of landscape here in Manchester because it is just so vast. There's so many different groups and it's so, so easy to collaborate here because there's just so much going on and like all of like minded people like you who have that drive for change and yeah. Wanting to kind of make a difference. Have you got anything in the woodwork? Anything coming up? Any new projects doesn't have to be cancer related.

Sarah Cartmell:

I think the things we’re translating right now, obviously is the tendon which is quite new with the new spin off company. And I briefly mentioned some of the work I was doing in electrical stimulation and cells. So this is really exciting in that, you know, our body has electrical regimes associated with it and most people will be familiar, you know, with the heart maybe taking an ECG or the nerves, whether it was electrical sign up. But each of our tissues and our cells has a electrical regime associated with it. So what we're doing in my lab is applying to is specifically targeted electrical regimes to stem cells. So music how much stem cells that we take from people's bone marrow and we're able to apply the right regime and turn them into different tissue type. So able to turn into bone or were able to push it towards chondrogenesis and things like that instead, which is really exciting.

Sally Best:

And just to confirm, stem cells are the kind of the first cell that you'd have in terms of a division or pattern of a cell. So it's what you start with. It's the flower to the cake.

Sarah Cartmell:

So that we kind of the baby cells that grow and mature into you know your muscle , your fat, your bone.

Sally Best:

And they can be anything they want to be but they are fiercely directed towards specific cells. My analogies are getting out of hand. I mean, I ask this to everybody, but I think it's a really important question. And like looking to the future, what are your hopes for this modelling and yeah, how do you see it progressing in your dream world?

Sarah Cartmell:

So as I mentioned before, we're very interdisciplinary and I just really hope that all the biologists and engineers really continue to work together to grow in our understanding which of these fields and create even more synergy. We've really got such potential to create relevant testing models in the lab. We also have increasing expertise and ability, as I mentioned before, to analyse the samples from an engineering perspective. And in these ways I really hope that we improve our understanding but also increase the rate of gaining data and therefore the solutions faster. So we can again move to that that will world I mentioned before. That's cancer isn't that scary world.

Sally Best:

But oh great stuff. I mean, thank you so, so much for taking time out of your day to speak to me. It's honestly just oh great. So appreciated. And I learnt a lot from this as well as hopefully the listeners. But I mean, yeah, as usual, I'll link Sarah's work in the blurb and kind of put on a few diagrams as well just so you can see that whole cancer research landscape. But yeah, thank you so much.

Sarah Cartmell:

Thank you for having me, Sally. Thank you.

Sally Best:

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