Season two

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 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'm your host Sally Best, and throughout this series I'll be speaking with Manchester Cancer researchers about their innovations, discoveries and projects that are changing the landscape of cancer detection and treatment.

 

In this episode, we speak to Professor Matt Everson and patient Sally Hayton. A never smoker with ALK positive lung cancer. We focus on overcoming the barriers to early detection in symptomatic lung cancer patients, specifically never smokers spotlighting the Manchester self-referral chest X-ray service. We also hear Sally’s cancer stories, her experiences and the barriers she faced in receiving her diagnosis.

 

Sally Best

Hello, everybody. Welcome to another episode. It's actually our final episode of season two of one in two, which is really sad, but we've maybe saved the best until last. So season two obviously focussed on lung cancer and we've gone through quite a journey with it.  This episode I'm really excited about because we've got the wonderful Matt Everson and also a patient, and I think patients are so important and kind of tying everything together really, and understanding where this kind of research that we've spoken about is, you know, it can sometimes seem quite nebulous. And then we have the patient here and understanding the end the end goal, really.

 

So yeah. We've got another Sally as well actually, guys. So don’t get confused because it's Sally and Sally, but we'll do Sally B and Sally H maybe if we need to do direct stuff.

 

But today we're going to be focusing on overcoming barriers to symptomatic lung cancer diagnosis and focusing on never smokers. So I'm just going to come to Matt first, just so you give us a bit of kind of what's the word significance? Context is the word as to kind of why we're here today. So I'm wondering if you could introduce yourself, who you are, what you do.

 

And by the way, everybody, Matt's on call today. So if we lose him, that is why.

 

Matt Everson

So I'm a lung specialist, and, and my area of work is in lung cancer. So in the hospital setting, I see patients where there's a suspicion of lung cancer and oversee the diagnostic tests around that. And I'm the associate medical director for the Cancer Alliance. And I've had leadership roles in looking at innovations in lung cancer across the region over the last five or six years.

 

Sally Best

Amazing. And you went to uni here?

 

Matt Everson

Yes.

 

Sally Best

What did you do? What did you do? What did you study?

 

Matt Everson

Medicine.

 

Sally Best

Look at you go look. You might have been taught by my dad. Amazing. Well, you've got a lot on your plate there. And what you're saying is, so you, you work on kind of a lung care pathway board throughout the Greater Manchester area. Yeah. Amazing. And then Sally coming to you, I just wonder if you could introduce yourself and kind of give us a bit of information as to who you are and why you're here.

 

Sally Hayton

Yes, my name is Sally. I used to work as an occupational therapist and then worked in personnel in the NHS and then went back to working as an occupational therapist in the NHS and in social care and I never, ever thought that I would be advocating for never smoker lung cancer because it never crossed my mind that I would get that. And, and I think I've started to have a case in really because my consultant initially started to get me to tell my story to and all junior doctors and medical students, they were in her clinic and so yeah, that's where it all began. Also Greater Manchester cancer has patient voices and involves patients in decisions that are being made in relation to lung cancer and ask patients to comment on that. So I've become involved in this small lung community for Greater Manchester Cancer.

 

Sally Best

Amazing. Well, it's great to have a patient, as I've said previously, advocating for this, and we've done kind of previous episodes on never smokers, but we've never had that patient voice and it's something I'm striving for to have that representative. So thank you from the bottom of my heart, on the bottom of everybody's heart for taking the time, because I know it's not an easy thing to communicate and a dialogue to have. And it kind of must bring up a lot of things from previously that you're having to talk about. But, you know, showing strength in this area is so formidable of you. So you have my kind of sincere thanks.

 

Sally Hayton

Happy To raise awareness.

 

Sally Best

Amazing. And I'm just wondering, you know, it'd be great to hear from you about your kind of diagnosis. So I'm wondering if you could be able to tell us about, like when you were diagnosed with lung cancer and what type of lung cancer you have.

 

Sally Hayton

So I was diagnosed with stage four lung cancer in November 2013. And I've got is adenocarcinoma, a non-small cell lung cancer, adenocarcinoma. And I was tested for a mutation. And I've got this mutation called the ALK mutation, which is ALK, yeah, mutation. And I've only smoked less than less than ten cigarettes in my life when I was about 16 or 17. Yeah. And I think my understanding is that if you smoked less than 100 cigarettes, you're classed as a never smoker.

 

Sally Best

Yeah, quite a scary kind of thing to have faced I guess. And that ALK positive that you mentioned. We actually recorded with Fabia Gomez early on in the series on ALK positive lung cancer. So for anybody that wants to have a bit more of an insight into the kind of the science behind that, I'd say that would definitely be a good episode to look back on. And I'm just going to come to you, Matt, and ask if you could explain kind of the incidence of lung cancer as a whole and then this kind of percentile of lung cancers and never smokers, because I think again, for a lot of people, lung cancer and never smokers is quite a kind of enigma. So I'm just wondering if you've got any stats.

 

Matt Everson

yeah, lung cancers, a horrible, horrible disease. it is the commonest cause of cancer death across the world. So sadly, around 2 million people die from lung cancer across the world every year. So it's a major, major, health problem and challenge. In the UK. There's about 40,000 people that are diagnosed with lung cancer every year about 35,000 die every year from lung cancer, and approximately 6000 are in people that have never smoked. And that is completely correct. That definition we use, if you've smoked less than 100 cigarettes in your life, then you'd be classified as being a lifelong never smoker. So if you just look at it on its own, it would make it the eighth commonest cancer death.

 

Sally Best

Yeah. Across the country. So if that was considered as a kind of cancer on its own, yeah, it's crazy. And yeah. Seldom kind of talked about as well so it's.

 

Matt Everson

Why it's such an important topic.

 

Sally Best

So in terms of never smokers, what would be some of the symptoms that a never smoker with lung cancer might present with.

 

Matt Everson

So this is a massive challenge. in that there are certain symptoms and not just restricted to lung cancer, but certain symptoms that are red flags and very well-known red flags. So for me, from a lung perspective, if somebody coughs up blood, I think that's probably a relatively well, well understood that that should be looked at. And if that happens to someone quite frequently, they will seek, you know, they would go and see their GP or they would get that checked out. But actually that only happens in a very small proportion of people who have lung cancer. And the other the other symptoms are exceptionally common. So a cough, a cough is probably responsible I think for about 10% of all general practice sensations. So that volume is huge, absolutely huge. and actually lung cancer is a very, very rare cause of cough. So there's this the challenge of why I think what we will discuss is how do you ,from we all will suffer from a cough at some point we'll all get those symptoms. How do we investigate appropriately and diagnose appropriately at the earliest opportunity? So cough, breathlessness, pain, any way around the chest. And that includes, we've got to think about language when we say pain in the chest medically we may know what we think by that. But actually to somebody else that could just mean your chest is at the front.

 

Sally Best

Yeah.

 

Matt Everson

Now we could be talking about shoulder pain, back pain anywhere across the upper part, the torso. Yeah. So pain, breathlessness and cough. They're the kind of key common symptoms. I guess the centred around the chest. But equally there can be much more general symptoms. So you could lose weight, you could go off your food, you could feel rundown and tired. and really lung cancer can present in any way.

So it's a difficult diagnosis.

 

Sally Best

Yeah, completely.

 

Matt Everson

And that's, that's one of the reasons why suddenly it can present very late and sometimes it hasn't no symptoms.

 

Sally Best

Yeah. And I think it must be hard as well for patients to advocate for themselves because with such an array of symptoms, you kind of think, well this is, you know, this could be anything. Yeah, I mean, yeah, I, you know, type A person may experience fatigue and being run down on a cough and I don't know, but it might be easy to just kind of put it down to like, I've got seasonal flu or something, and I just keep on catching things over and over again so that, you know, consistent coughing, I think as well. You've spoken with was it on the GM podcast with Steve Bland about the message that, you know, you've got a cough, a three weeks, you go to your GP, Absolutely non-negotiable. That is just what you do and don't ever feel like you're kind of, you know, misusing the health service because that is the guidelines, right?

 

Matt Everson

Yeah.

 

Sally Best

Okay. Interesting. And then coming to you, Sally, I'm wondering if you could just give an overview of your journey from diagnosis to the treatment that you're receiving now, and also maybe just mentioning some of the symptoms that you are experiencing and are experiencing now. Just kind of raise awareness to the sort of things that you were looking out for.

 

Sally Hayton

So explaining how I was diagnosed, right? So I started with a cough and I went to my GP and within two weeks of starting the cough, I think I had it for about three weeks and went to my GP and he gave me some antibiotics and he said if your cough hasn't gone, come back in two weeks since my cough still hadn't gone. So I went back two weeks later and he gave me some different antibiotics and, and again said if you cough hasn't come, please come back in two weeks. So I went back two weeks later and he ordered a chest X-ray and, and then he phoned me and said I'm referring you under the two week rule to a lung cancer clinic, because something's showing up on your chest x ray. And at this time I was living just outside of Greater Manchester. And so I went to the lung cancer clinic, went through numerous tests on the day, and I thought, why am I going to a lung cancer clinic? You know, I've never smoked. And my parents didn't smoke. I've never lived with anybody who smoked. And yeah, so I, I couldn't really understand why I was going to a lung cancer clinic, but I thought, well, this is what my GP told me to do. I very rarely go to the doctor, so I will go to the lung cancer clinic. So on the day I went through numerous tests and then having gone through these different tests, I saw the consultant, respiratory and physician who said to me that I was an inappropriate referral so he wouldn't refer me direct for a CT scan now because, well, more urgent people coming through. But I would get a CT scan appointment in the future.

 

Sally Best

I'm sorry to hear that the inappropriate referral was down to the fact that you were a never smoker.

 

Sally Hayton

well, I think so, yeah.. He thought what I've got was a virus and he thought I had a virus and he said it can take up to 12 months for a cough to go.

 

Sally Best

Okay.

 

Sally Hayton

So I then went back and had the CT scan and numerous weeks later when the appointment came through and that showed that I'd got right middle lobe collapse and I had a letter from him to say that I had got right middle lobe collapse. The right middle lobe collapse was common in people in the late forties living in that area and, and he did say that they could do a bronchoscopy if I wanted it, but he didn't think that was appropriate. So and so I never saw him. I just got this letter. And so I went back to the GP and it did actually discuss with the GP and said, Do you think I need a bronchoscopy? And he said, Well, there's a lot of risks and you know, if they're saying you've got, you know, they don't feel you need it, I wouldn't do it. So and, and I, you know, not, nobody thought I needed it so I didn't have it. And then I went back to the GP because a cough was continuing and I was treated for acid reflux on two or three occasions and give him medication for that. Then I was treated for an asthma and given an inhaler. I mean, I wasn't breathless, I was coughing. I don't know whether asthma presents with coughing, but I wasn't definitely wasn't breathless and, and then I got really bad rib pain and the GP referred me and for chest x ray and that came back and it was reported as normal. So I assumed from that totally naively, that my right middle lobe would reinflate it for some reason and that my chest x ray was now normal because it hadn't been normal. When I first had it then I got shoulder pain and I was told I got a frozen shoulder and I went to physio and was given exercises for a frozen shoulder. And then I was treated with the hydro dilation technique for a frozen shoulder. And when I was having that, the radiologist said to me, we could, we, you know, we could, we need to do an x ray really. And I said, well I've just had one. Yeah, yeah. And it's come back as normal. And so now anybody says something is normal, I'm, you know, I'm ready to question. I never thought at the time, I just assumed what I was being told was right. And so then my shoulder, you know, resolved after that treatment and then probably about six weeks later, and I started to lose a sight in my right eye. And one evening I thought, this seems different. And we've got some friends rounds for a meal. And I couldn't see my partner's friend properly at the bottom of the table. It just felt different. Went to work the next day and didn't really think too much of it. And then on the way home from work I realised it was getting worse and called in an optician and they were just closing. Well, I went to explain what was happening. They said, Why didn’t you come sooner? Well I’ve been working I said.  So they looked at it and they thought that I got detached retina or they said I could have something more sinister.

 

Sally Best

Okay.

 

Sally Hayton

And so I asked if I could go. They said they could refer me to Rochdale or they could refer me to. And because now I was in Greater Manchester. Yeah. For this appointment. And I said, I think I prefer to go to Manchester eye Hospital. So they referred me to Manchester eye hospital and I went there that evening and by 9:30 at night I got a consultant holding my hand saying, I think you've got a tumour behind your eye. Can you come back and see the retinal specialist tomorrow? So when the consultant started holding my hand and having seen numerous doctors between sort of half six and half nine, I thought something's, something's going on here. And so then I was referred the following day to the ocular oncology people in Liverpool. And so as the Tuesday that I went to the eye  hospital, the Wednesday I saw the eye consultant. Then the following Monday I was seeing this professor in oncology at Liverpool and he said he thought it was a tumour and I, I sort of pushed him. And said do you think it's a primary tumour or a secondary tumour. He didn't want to say but when I really pushed him he said well if you really pushing me I will say I think it's a secondary tumour. So they did a biopsy on my eye the next day and when the results of that came through it showed that the primary was in my lung cancer.

 

Matt Everson

So Sally how long was the time from your cough starting?

 

Sally Hayton

11 months. So it was December 2012 that started with the cough and it was the 5th of November that I was at Manchester eye Hospital. Yeah. Yeah. So it was a few weeks after that that I got the biopsy results back.

 

Sally Best

I mean, it's. Yeah, it's quite a kind of treacherous tale and very difficult, I can imagine with repeated advice and, and different kind of scenarios and things. And was there any point at the start of that journey that you thought, you know, this could be lung cancer or did you just completely negate the fact that it could have been because you thought, you know, I've never smoked, I can't get lung cancer.

 

Sally Hayton

I never thought it was lung cancer. I never thought it was lung cancer at all? My partner said to me, you know, you can’t have lung cancer. A couple of people I knew said you won’t have lung cancer. Yeah. I never thought I got lung cancer yet. So I didn't. It just never, ever crossed my mind.

 

Sally Best

Yeah, it's crazy. And I mean Matt coming to you would you class that as a kind of a late diagnosis of, of lung cancer in a patient.

 

Matt Everson

Well yeah, there was. So there were clearly opportunities for an earlier diagnosis. It's a very harrowing story.

 

Sally Best

Yeah.

 

Matt Everson

For members of the public to hear that you know, those symptoms that we, everybody could relate to, a cough just won't go away. The thought my God, that could be lung cancer.

 

Sally Best

Yeah.

 

Matt Everson

From a health care professional. And that's even from a respiratory specialist. I think, you know, I see this all the time, see cough, you know, and I don't think this is lung cancer. And then fine, actually, this is lung cancer. So it's really harrowing. I think, on both sides. and it's the huge challenges. So 999 times out of a thousand, those symptoms like that will not be because of lung cancer, but one time they will be. And how do you make sure how do you do everything possible to not have 11 months of delay, you know, symptoms and to find that one? That's what we've got to try and address.

 

Sally Hayton

Yeah, I think I feel let down because I work for the NHS and social care. Yeah. I just automatically assumed that a consultant respiratory physician would know what he was talking about. So I totally took on board what he said. If I know what I know now, yeah, it will be quite different. And I know another consultant has actually said to me the only mistake you made was listening to a consultant. I must say, having said that, I haven't heard similar stories to myself where people have got to see a consultant respiratory physician. And have been misdiagnosed and people I've seen people have delays at the GP. And people not going to the GP. Yeah that so I think I do think my situation is a bit different and I'm, I hope it's a bit different. And yeah, I mean and I don't want to just put it down to the consultant respiratory physician because the chest radiologist had written benign. Yeah. And the clinical director of radiology had written needs bronchoscopy and the chest radiologist who was a consultant and put a line through that and just put benign. So I think I've just been really unfortunate. Yeah. There's, you know there is a human error. Yeah, but we didn't know anything. And when it's within the health service it's obviously impacts on people's lives. Yeah.

 

Sally Best

And I think there's an educational piece there as well to understand, you know, it's not just at the public level of you advocating for yourself and understanding that you only need lungs to get lung cancer. It's changing the mindset of people on the pathway as well. And I know you do work in that, so the, you know, consultants, clinicians can understand the referral routes for patients aren't so clean cut. If you don't fulfil one criteria, you get put on a completely different path.

 

Sally Hayton

Yeah, I think if I had, if I'd smoked, yeah, I would have got diagnosed earlier.

 

Sally Best

Which is really, really sad. and I'm sorry.

 

Sally Hayton

Yeah. Because there wasn't a red flag for never smokers. There was the red flag for smokers. Yeah.

 

Matt Everson

There's been some evidence published in the last 12 to 18 months or so that specifically looked at some of the, the barriers. If you've never smoked to the diagnosis of lung cancer and that is a very clear theme that, it's easier to be reassured that there's an alternative explanation for those symptoms and for, for vigilance to drop. If you've never smoked and that's being reassured by health care professionals more easily reassured by health care professionals, more easily reassured that those symptoms must be something else.

 

Sally Best

So I mean Matt you're kind of pioneering this, this diagnosis of lung cancer, an earlier stage in the symptomatic lung cancer with a focus on never smokers. Could you tell me a bit of an overview about the pilot that you've been running in self-referral chest x rays, because I know this kind of links into that more of a holistic approach in the early diagnosis piece.

 

Matt Everson

Yeah. so I guess it begins with the story about chest x rays because chest x rays have been around for a very long time. They get a bit of a bad name about their ability to diagnose things. There are some limitations, but equally there are some, some real advantages. So chest x rays are very, very accessible. They're very quick to do and we have resources within the health care system to deliver them really a much bigger scale than we do. and, and as I say, the big challenge is that there are many, many, many people who have the common symptoms of lung cancer for which the vast majority do not have lung cancer. So I guess one way to think about it is if there were a thousand people that have a cough or breathlessness or pain in their chest for three weeks or more, then ten of them maybe will have lung cancer. And a chest x ray will pick out eight of them. It will miss two. And that's a really key message that a normal chest x ray doesn't fully exclude lung cancer, but it's equally very reassuring because then the 990 normal chest x rays, all that show something else, are truly normal. So it is a, it's a test that's there and accessible and we could really utilise that to its maximum potential.

for, for the people that have these common symptoms and there will be that small number where actually the x rays abnormal, it needs further work, but there's a lot of people that where you could think actually that's quite reassuring and I might not do anything else unless the symptoms don't go away. I might have a little period of trying a treatment for something or always knowing that a normal x ray doesn't fully exclude lung cancer, though it is reassuring You kind of you take every individual case on its merit and you've got to have that awareness. So I think chest x rays are an important part of earlier diagnosis. When you have symptoms, it could be lung cancer. It's about getting that chest x ray. And there's lots of ways to do that. You've mentioned education already and that's on both for members of the public education for health care professionals, it's education. But I think one of the it's really clear and I guess really tragic that there are real barriers to accessing something like a chest x ray or accessing the health care system for someone who has those symptoms. that can be if you do smoke or you have smoked, you could feel that if you go to a doctor with a cough, then there could be a judgement of that. Yeah. if you haven't smoked, you could feel why you know, Why would I go with a cough? It's just a cough or I've had a cough before and it went away.

Why am I, why would I do something this time? Or I've been with a cough and they just told me it would go away. I just get told the same thing and it's some of the most tragic things we've kind of found in some of our insight work is the fear of, it's almost that that person isn't worthy of being seen and these symptoms aren't worthy. We get that the public get flooded by this messaging that the NHS is overrun. And so why would I go with this? I'm just coughing saying so there's lots and lots of barriers that could prevent somebody going to seek help. we know that, a person with, with a set of symptoms could go and see one health care professional and have a chest X-ray. They could go and see another health care professional and they wouldn't. That's kind then that's kind of human behaviour and assessment of symptoms. So there's some variation in access. So in that context, if somebody was concerned about their symptoms and in the right context. So if someone, we keep saying this message, if you've coughed for three weeks or more, it needs investigating, your breathing has changed for three weeks or more. Pain three weeks or more. Yeah. Needs investigating and generally that's over the age of 40. That's the kind of guidance we have nationally. Then you should have a chest X-ray. And if that person was able to just go and have one. Without going to see their GP necessarily, then the data we have suggests that there will definitely be a population of people that will have an X-ray that wouldn't otherwise. There’s still people who want to go and see their GP, want to talk those things through and that that's right there, there's not one or the other, but by providing an alternative route then the total number of people that should have an X-ray should go up. Yeah, that's the theory. so we've been running this in a few areas across Greater Manchester, and it's has very much played out like that. There's been very, very good uptake, so very high numbers, particularly when you compare it to other things that have been tried to try and increase the rate of X-rays. So there's been a very, very good attendance. you know, we're now into the thousands of people that have been x rays. Which is a real positive and they are people that need a chest X-ray. We know that because of the symptoms they've reported. They are in line with the guidance that we have, the people that should have an x ray and like we know 95% of them have a normal X-ray and they get a letter back, as does the GP, to say you've been for an X-ray. This is normal. That's very reassuring. But if there are some worrying symptoms, persistent symptoms and x rays and everything, you have to get those things checked out. And then in in 5%, the chest x rays isn't normal. So 3%. There's something else. There's another reason. And that x ray gets looked at by a chest specialist. And so sometimes that's just a case of, there's a chest problem that needs seeing in a chest clinic. It's not cancer, but it almost takes out some of those. That's not me that just straight into where you need to be. and in 2%, there's a suspicion of lung cancer, and it ultimately works out about, about half a percent. Just over half a percent have lung cancer.

 

Sally Best

so I'm just going to interject with a couple of questions here, because you've mentioned the kind of the criteria that people are adhering to, to be able to go for this chest x ray what are some of those criteria? is smoking within the criteria?

 

Matt Everson

No.

 

Sally Best

Okay. So that's great, first of all.

 

Matt Everson

Exactly. Yeah. And that is and that's a huge and it's got to be accompanied by this the education. So if you have lungs, you can get lung cancer, the chances are exceptionally small. They really are well, important. But as we said before, that one in a thousand is that that one, there must be the processes and systems in place so that one person gets access, gets a diagnosis quickly, as quick as can be, which will in turn give the very best chance of, of the best outcomes possible. so it's all symptom based. There is again, national guidance is about age, it's over 40 and then it's about symptoms. So three weeks or more cough, breathlessness, pain in the chest, back shoulders, fatigue, weight loss, loss of appetite. Those symptoms

Sally Best

and the my, my other question was, how are these scans interpreted? Because you're obviously going to receive you know, you've said that you've got thousands of patients that are being recruited and you're hopefully going to see that increase in. People are coming for chest X-rays. All I can think is who is going to be reading all of these and how are you dealing with the kind of sheer capacity of that?

 

Matt Everson

Yeah, it's a good question. And radiology in general is, it is in a crisis, the NHS. So, that's a consideration in, in any part of health care right now. I go back to say that chest x rays are quick and also quick to look at and reports much more so than other invasive other more detailed scans. Equally, when COVID hits, chest x rays dropped off completely. And it was there's been a horrible aftermath of COVID and lung cancer because everything we've just said, get a cough, get it checked early, early.

 

Sally Best

Get it away from everybody. Yeah, stay away

 

Matt Everson

Don't do anything. Stay at home. Yeah. And we have seen later presentation of lung cancer. and chest x rays just went and we're not back to where we were before. And, and that's got to be a key priority for us. so whenever you, whenever you pilot new services, you put mechanisms in place to ensure robust reporting, things like that. So within this programme there's a dedicated reporting resource. as part of the programme. And so the results are very fast and so someone can get reassurance very quickly. The vast majority of people can be reassured. It's very likely it saves GP appointments as well.

we know that could be in different ways. So someone may go and see their GP having had an X-ray. So that first appointment the GP has a benefit of you've got an x ray, I know what they expect. Sure, I'd have to send you for one and bring you back. We can make a decision now. What we do or having that x ray and reassurance and, and being reassured by that. As long as those people are appropriately safety netted. So just because you're x rays normal, you know, asthma doesn't show up on an x ray. If you've got symptoms that are worrying, they're not getting better. It has to be checked out, has to be. but you know, like I say 999 of the thousand, that cough will just go away. It will be viral. It will it be something just as we were just talking about? It will be and it will go away. But you've had the appropriate test to provide reassurance.

 

Sally Best

Yeah.

 

Matt Everson

And you select out those or you've to go and look into it further.

 

Sally Best

And within this pilot, was there any AI that was integrated in terms of stratifying kind of patient scans?

 

Matt Everson

So, there's a lot of interest in, in AI and chest x rays, particularly at the moment. So there's a lot of evaluation for it, and NICE, the national body has evaluated AI and chest x rays quite recently and is very much more work is needed to understand its role. So there is there's work going on in Greater Manchester and that's to try and understand does it improve diagnosis? We can miss things on an x ray, the human eye can miss things on an x ray. So if you have a human eye and a computer working together, does it improve diagnosis? And equally one we think one of the big things maybe that if you, if you do have thousands of X rays, how do you pick out those for you immediately and say that one's abnormal. So that person's got to get into a CT scan very quickly and AI might have a role in doing that. so it's all under, all under evaluation.

 

Sally Best

Yeah. Something to look forward to and hopefully and in terms of the sorry, just on the, the self-referral chest x ray, so what are the results looking like so far? Like have you seen, you've said that you've seen that stage shift and people being diagnosed early. Have you had any kind of feedback about people who, you know, have used the service or anything like that?

 

Matt Everson

Yes. okay. So stage shift will probably have to be a little careful in terminology, so.

 

Sally Best

Okay.

 

Matt Everson

lung cancer split into stages, stage one through to stage four. if wherever possible, if we can diagnose stage one lung cancer, if it's there and you can find it at stage one, the treatments are very, very good and have very good long term outcomes. They it's quite rare to have symptoms at stage one lung cancer.

 

Sally Best

Yeah.

 

Matt Everson

You don't have nerves in your lungs and you can't feel your lungs, you can't know something's there. and the real way to catch early stage lung cancer is through screening. So someone has no symptoms, but you find an at risk population and do a test that can pick it out. And that's a real stage shift because normally about half of all patients with lung cancer present at an advanced stage, whereas in lung cancer screening, about 80% found at stage one. So it's a huge stage shift. We're talking about symptomatic diagnosis.

 

Sally Best

Yes.

 

Matt Everson

And, it's very difficult to know whether that would cause a stage shift. But what it's very likely to do is cause it is lead to an earlier diagnosis, right? And that makes, it makes a massive difference. days can matter with lung cancer and somebody's health can deteriorate very quickly. And if someone's health is deteriorating, that then affects your ability to make a diagnosis or, be well enough to have a biopsy, which can mean you can't personalise someone's tumour and understand what the best treatments are.

Their health might not be sufficient enough for treatment. So an earlier diagnosis when someone has symptoms undoubtedly will mean, that there's a, there's an opportunity for better outcomes because we're finding it earlier when someone's fitter, whether it will cause a stage shift, I don't know.

 

Sally Best

Okay.

 

Matt Everson

But it's, there's been so much focus on lung cancer screening and rightly because it's, it's going to be, it will make huge, huge differences. But about one in four, one in five people with lung cancer will be found through screening, that's four in five, three and four. Four and five won't. And we know there are real delays in those in those path.

And it's that very first from the first symptoms I think everyone's in the lung cancer community is quite united that that's the that's the part that's the part where we still we've got so much improvements to make. And the self-referral actually is just one component of a bigger strategy. Yeah, but it does seem the biggest thing for me is that it brings people in that need an x ray. It overcomes those barriers and the actual prevalence of lung cancer within that cohort is really small as it is for all chest x rays. So we have to deliver this a really big scale to see to to really start to see benefits. So so far our day, our work has been demonstrating that it overcomes the barriers to attending and getting a chest x ray, which it really appears to do. And now it's about how do we expand and try and make sure it's available for as many people as possible.

 

Sally Best

So some of the people that are attending, would they have you know, have you got any reports that they wouldn't have attended the GP?

 

Matt Everson

Yeah, of everything. I think it's everything in there. We can show that there are some people that came for that x ray that have never contacted their GP and never would have, some that have contacted the GP and an X ray wasn't part of the outcome. so we're kind of all those barriers we talked about. It appears to overcome them all. And so for some people it provides that alternative route to where we need to get to while still maintaining everything else we've got and the education on both sides. you know how important it is to go and see if you've got that cough for three weeks  or more, that is still a really important message. We’re not saying that self-referral is the only route. It's not. just for some it might be.

 

Sally Best

Yeah. And I mean Sally, you've, you know been at this stage of diagnosis and I know you also work on kind of patient representative groups and communicating with them and understanding what's best for other never smokers. Would you and your cohort, you know, speaking on behalf of them, if you're comfortable to do you think some people would find this incentive helpful? And like, would it have been something that you were interested in in that stage of your diagnosis?

 

Sally Hayton

I think when I was when I was diagnosed, I was totally unaware that never smokers could get lung cancer.

 

Sally Best

Yeah.

 

Sally Hayton

So it wouldn't have been something that I really would have gone to. Yeah. Yeah. I mean, if I know now ten years down the line and what I know now, I would have definitely come to me because I'm, you know, I'm concerned, you know, I'm concerned like anybody about your health. I think the screening for any sort of cancers important and if I'd known that never smokers could get lung cancer, I would have I would definitely have gone and wanted it. And even if I'd continued to cough like, you know, even my situation, I'd have kept going back and saying, could I have never smoker lung cancer? Yeah, but I, I didn't know about it at all. And, and the thing that's interesting is when I'm a member of the ALK positive UK group and the World Wide ALK positive group, and within that there's like consultants without positive lung cancer, there's GP's, there's nurses, there's physios, there's OT’s, there's technical technicians and they didn't know about never smoker lung cancer. So I would imagine that a lot of people who haven't smoked wouldn't think that they're going to get it. So I did ask actually on the pages and said did you, did you know that never smokers can get lung cancer and there was this was on both the world wide site and the UK one and the there was over 80% of people said no and the ones who said yes related it to asbestos or radon or working in some sort of hazardous work environment. And one person said that although they knew about different causes of you know, never smoker lung cancer, they didn't realise that there could be an unknown cause for it, which I thought was quite interesting.

 

Sally Best

Yeah. So what I'm hearing there is that you kind of think this incentive would be absolutely, you know, buy off the hand for taking up with the self-referral of chest x rays. But there needs to be public awareness campaign to the fact, speaking to the fact you only need lungs to get lung cancer. And I mean.

 

Sally Hayton

I think unless people are aware that never smokers can get lung cancer you wouldn't really get them. So I mean I might be wrong. I don't know. Other people who've never smoked have been picked up via the current scheme or not. Have they?

 

Matt Everson

Yeah. And it's quite there's, there's such a big education piece, for, for everybody and that's about, you know, the saying we always have to appreciate that tobacco smoke is the leading risk factor for lung cancer that, you know, the single greatest thing that anybody can do if they smoke is, is to stop for their health. It's incredibly challenging, but there's loads of effective treatments out there to do that. And if they have symptoms like what we've talked about, cough, breathlessness, chest back, pain, three weeks or more, it has to be investigated. But at the same time, you know, if you have lungs, you can get lung cancer. The chances are incredibly small. They really are. But it's there. And there has to be a vigilance for symptoms that that aren't going away. Exactly the same rules that that three weeks rule needs an x ray, even if that x-ray is normal. There's got to be that vigilance that if things just aren't right not explains not getting better. It absolutely needs investigating further to find that one.

 

Sally Hayton

I think the profile of lung cancer is changing with it. So I sort of saw it as people who smoked, you know, a package of cigarettes a day for 20, 30 years. And then they got to the seventies and eighties and then they were diagnosed with stage four lung cancer. That was my sort of perception in my head then now, having been diagnosed with it with lung cancer and not fitting that group, I realised that like never smokers are a totally different group of people. And you know, I know somebody who was 17 when she was diagnosed and then went on to do a nurse training after she'd been diagnosed. And, you know, I know people in their twenties who've been diagnosed and people in their thirties, people who've been pregnant when the diagnosed, you know, people with very young children. And so there's people from that, the profile is changing. So it's actually getting that shift, I think, in health care professionals and the general public's read that any age, you know, Yeah, I mean seventeen's the youngest person that I've met. But yeah, so yeah, I don't work in that field, but just from the support group I'm in and yeah, you know, it's, it's covering a lot wider age range so.

 

Sally Best

And yeah, that's the thing I think and you had having the archetypal type-A smoker, I mean it's the what I grew up with and I think a lot of people did and it's not only I think what you've said there is correct, it's a two tiered approach. It's not one or the other. It's both health care professionals and the general public. The general public need to be endorsed and educated and the health care professionals need to be aware of this kind of profile of person that is eligible for these treatments. Because, I mean, it's you know, it's happened in the past kind of however many years. And it's yeah. So important for your group to be represented because like Matt said, if it was on its own, it would be classed as like the eighth most prevalent or.

 

Matt Everson

So the 8^th commonest cause of cancer.

 

Sally Best

Okay. So you know, having the understanding that it's that change of mindset is so important.

 

Sally Hayton

And people regularly post when they join the group and you get people who are like marathon runners and you know people who cycle you know, I don't know, a hundred mile long distances each week. People who do triathlons runs and there's people who've worked in cancer research who have no idea that it exists. But and then within me, obviously within the field of people working within that field, there's lots of developments going on. The treatments are changing. And and, you know, for me, at stage four, the treatments just changed as I was diagnosed, which was great. And I was given ten months to live. And because I've responded well to treatment, I'm still here. But now the stream is coming through because of genomics and genomic testing and biomarkers and yeah, there's treatments coming through for people at stage one, two, three who have never smoked lung cancer.

 

Sally Best

So yeah, it's great to her. And for those who haven't listened, definitely listen to the ALK positive episode with Fabio because it that kind of nods to some of those things that you've just talked about. So, I mean, coming to you Matt, what would be your hope for the diagnosis of kind of symptomatic lung cancer in not only Manchester, but kind of nationwide over the next ten years? Ten years is a good expanse to go by?

 

Matt Everson

Well I think the ambition is to never hear a story like that again.

 

Sally Best

Yeah.

 

Matt Everson

through a, you know, a multifaceted strategy that does try to drive up public awareness about non smoking lung cancer, about the need for investigation and, persistent symptoms, through healthcare education, through new ways of, of delivering healthcare. like self-referral, that's just one of them, you know, maybe numerous of the things that work. And as I say, the focus is really now shining on this area, lots of areas across the country doing some, some really innovative work. So we try and learn which of these things work the best and is going to help us achieve that goal. So like a would you see the self refer x-ray is kind of one of many things that are going on, but that's just in Greater Manchester at the minute.

 

Sally Best

Would you like to see that rolled nationwide?

 

Matt Everson

Yeah, and there are, there are other services. yeah, and, and some that have run before the greater Manchester one. but I do really think that so that's a key part of it. And I think our results really show the, it's the uptake, particularly against other ways of increasing X-rays that have been tried before. I think it's a really powerful vehicle. One of others but and that's, you know, the Cancer Alliance in Greater Manchester, that's what it's charged with. It's charged with innovating and, understanding what interventions work well and then trying to make them, business as usual.

 

Sally Best

Yeah. And if you had a policy request for to address some of the barriers to these incentives being introduced, it's quite a hard question. But do you have a policy request that you'd kind of like to see implemented?

 

Matt Everson

I think I think it already is. I think it has the attention and the appropriate level of focus. you know, going right back to where we started the conversation about the horror of lung cancer, and, and the fact it terrorises communities, it really does. and so it rightly has the focus and there’s so many things happening about screening, about better treatments. This is the unmet need is that making sure somebody with symptoms gets the appropriate care that they need and knows what that appropriate care is and where they're empowered to get that care. so I think it has the attention. it's, I guess my plea would prefer for it to, to address every aspect of it. Yeah. Not just one. And I think that's really important, particularly what Sally said. Yeah. That it's on every angle. We've got to create almost a new persona of lung cancer because we have, you know, wrongly what you, if you say lung cancer, perhaps we could be guilty of thinking of a male in the sixties or seventies that smoked for a long time, often from, the communities that face the biggest, financial challenges. But that's, it's not the case particularly and never smoking lung cancer, which is younger people perhaps more common in females. Yeah, for more affluent communities, we've got to understand that there are different faces to lung cancer and recognise that.

 

Sally Best

And do you think maybe government or public health campaigns like, you know, kind of TV ads and the kind of billboards and things would help assist with that?

 

Matt Everson

Yeah, there has to be, there has to be good, media campaigns that raise awareness, and I think it's, it's a really, I think it's a really difficult balancing act. You've got to we have to listen to people that have been through this, and listen to how can we best get those messages across. it's really important for somebody to know that anybody can get lung cancer. I'd never want it to feel that it's for, The risk of lung cancer is a very powerful motivator for somebody to stop smoking. And for that person to hear a message you can get. It doesn't matter whether you smoke or not. You can get lung cancer. I would never want that to be interpreted as a message that doesn't support everything that is being done to stop smoking. So you've got to it's just you've got to get the balance correct and listen to every community to understand how do you best deliver those messages. We have to stop as many people as possible from smoking, from ever, ever smoking. If they do, to help them to stop, we have to make sure everyone knows that you could get lung cancer. You could. And to be vigilant and to be persistent and be empowered to act on those symptoms. So you say it's a challenge. There's not one solution. No. but I do think the focus is on it rightly, you know.

 

Sally Best

Amazing. And I guess that's why you come in Sally and the advocacy and patient groups that you're working with and communicating the messages that you find out for would have found helpful for the cohort that you represent. And so empowering and really, really beneficial as well.

 

Sally Hayton

Yeah, Yeah. I can see that. I mean, obviously I can see that awareness needs to be raised about and have a smoke lung cancer. And I can see the problem with people who've smoked and not wanting stop them going for screening. So I can definitely understand that. And I wondered if you wanted to if you could have like a campaign with like, you know, 85% of people who get lung cancer have smoked and then have pictures of them and then pictures next to them with the 15, 20% who you know, like somebody said the other day, you know, I was 26. They never thought I'd got lung cancer. Yeah. So if you see if you had obviously the bigger percentages, people who've smoked and, they need to get the right treatment equally as never smokers. But there needs to be some awareness that the age range is so different and the things like the screening programme only seeing people over 40. How do younger people get picked up. yeah, I think yeah.

 

Sally Best

I mean, Ruth Strauss Foundation actually did something with Rankin, the photographer. I'll put it in the bio for everybody that's interested. It's these patients holding up I think it's their CT or their X-ray scans, and it just shows the plethora of difference of what your archetypal lung cancer patient and inverted commas would be. So I'll put that in because that's so interesting. But for that to be that message to be disseminated to a greater extent would be.

 

Sally Hayton

Yeah, I mean that was a really good campaign. Yeah, it's really well, Andrew Strauss is actually set up this charity to raise money for never smoke lung cancer and to promote and raise awareness about it and it would be good if that campaign could be spread wider. Yeah. And the EGFR, which is a new mutation which is a lot more common than the ALK. Yeah. That that group was also involved in that. Yeah. And I know some people actually. Yeah. On those photographs so.

 

Sally Best

Well it's good. You've got a nice community as well, of the forums as well that are enabling you to kind of speak to all these different people.

 

Sally Hayton

Yeah, I think that's sort of developed since I was diagnosed. Yeah. Is the like the World Wide Group came about and then they. The UK group. Yeah. So that yeah, it is good. and they do try to raise awareness.

 

Sally Best

Yeah. So nice. Well thank you both so much for speaking with me today. I'm just wondering if you have kind of a leaving message, Sally, that you'd just like to say on, you know, why you kind of came. Just thought leaving message because it's been absolutely fabulous to hear your story. And I think, like Matt said, it's completely harrowing, but I'm really appreciative that you have got the kind of strength to tell about story because it's so beneficial in this conversation and other conversations and including that patient voice. And you've been fabulous. So honestly, thank you so much. But yeah, it was just.

 

Sally Hayton

I think you only need lungs to get lung cancer. Yeah. Is a big one and on about the changing profile. You know the profile for never smokers is totally different than for smokers. And there's a lot of research going on and treatments and people are living a lot longer. You know, I know people with my time from countries like for 16 years and everyone who's still alive after 16 years, some people aren't as fortunate as I am and I am very fortunate and some people are obviously a lot less fortunate than I am. And so genomics is sort of moved things forward an awful lot for never smoker lung cancer. And and I think screening and health education is just so important.

 

Sally Best

Yeah. Amazing. Thank you. So yeah, we've heard about Sally's story. We've heard about the self-referral chest x ray and the hopes to integrate AI into that, we've heard about kind of public campaigns that would be beneficial. And finally, hopes for the future and a little bit of a policy request. So thank you so much, everybody, for listening. Thank you Matt so much. Absolute hero. And I know GM cancer are doing amazing work and it's great hear about it. And unfortunately, we don't have the time to cover it all. But we also have to pick your brains for one of them. Massive, massive thank you to Sally. I'll include all the links in the show notes, but yeah, for now, I guess it's good bye.

 

Sally Best

Following the recording of this podcast, Sally Hatim recorded an additional message that she wished to include to contextualise her positive experience since her diagnosis and her treatment at the Christie in Manchester.

 

Sally Hayton

I must say, my experience before diagnosis has been very different than my experience after my diagnosis. And since my diagnosis as an inpatient now at the Christie for over ten years. And I feel very fortunate to be treated there. I have had excellent treatment from my oncologist and all the stuff they hear, the clinical expertise in treating never smoker lung cancer. I feel very fortunate to have been diagnosed just as cutting edge treatments were coming through. All of the medications that I had been treated with have been through clinical trials at the Christie.

 

Sally Best

If you have been affected by anything you've heard in this episode, please see the show notes for our list of charities and organizations 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 research shows 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 dot ac dot UK forward slash beacons.

 

Professor Matthew Evision

Professor Matthew Evison MD MRCP (Respiratory Medicine) MBChB qualified from Manchester University Medical School in 2004. He undertook specialist training in Respiratory Medicine in 2008-2014 including a two-year fellowship in Thoracic Oncology at Wythenshawe Hospital, Manchester University NHS Foundation Trust, completing an MD degree in lung cancer diagnostics. 

He was appointed as a Consultant in Respiratory Medicine (Thoracic Oncology) at Wythenshawe Hospital in 2014. He was clinical Director for Lung Cancer for Greater Manchester Cancer from 2017-2023 and Appointed as Associate Medical Director for the Greater Manchester Cancer Alliance in 2023.

Matt is the Clinical Lead for the Greater Manchester regional tobacco control programme ‘Making Smoking History’. He is a member of the British Thoracic Society Lung Cancer & Mesothelioma Specialist Advisory Group (SAG) & Member of the British Thoracic Oncology Group Steering Committee. He is also MASHC Honorary Clinical Chair, Faculty of Biology, Medicine & Health, The University of Manchester.

Sally Hayton

Patient Sally Hayton lives with Frank her partner. She has lived most of her life in Greater Manchester.

Sally is a never smoker and was diagnosed with stage 4 lung cancer in 2013 and biomarker testing showed an ALK mutation. She is now being treated at The Christie Hospital.

She has always worked in the public sector. After leaving school she trained and worked as an occupational therapist (OT). She then had a career change and worked within NHS Personnel for several years before realising that she wanted to return to her OT career. She has worked within both the NHS and social care, both of which she enjoyed.

She is a member of Greater Manchester Cancer Alliance Patient Voices’ and believes it is very important to raise awareness of never smoker lung cancer so that people are diagnosed at earlier stages and have access to the best treatment.

Professor Matt Evison’s profile

Non-small cell lung cancer information from Macmillan

The ALK project: A real-work national network and database

ALK Positive UK

ALK Positive Org

EGFR Positive UK

EGFR Registers

Ruth Strauss Foundation

Rankin shoots campaign to raise awareness of lung cancer in people who have never smoked

The ROS1ders

Roy Castle Lung Cancer Foundation

 

   

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

world, it's a fantastic feeling.

 

00:54:24:17 - 00:54:46:08

Unknown

Yeah, I can imagine. Oh, well, honestly, thank you so much. It's been a pleasure, an absolute pleasure and it's been really interesting to. Yeah. Talk about clinical trials because it's not we've never focused and episode on it and I found it really interesting myself. So I hope that everybody else has. But yeah, you're just amazing so keep doing what you do and can't wait to hear more.

 

00:54:46:16 - 00:55:18:09

Unknown

Look out for some press releases, maybe. Absolutely. But thank you so much, Sally. It was a pleasure to discuss clinical trials and rapid RT with you. And we'll link everything in. But yeah, have a great day, guys, and speak to you soon. Bye. If you've been affected by anything you've heard in this episode, please see the show notes for our list of charities and organizations that can help wanting One in two was brought to you by the University of Manchester and the Manchester Cancer Research Center.

 

00:55:18:22 - 00:55:38:21

Unknown

Listen to our next episode to hear from more of our researchers as they share the innovations and 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.

 

00:55:39:21 - 00:56:02:22

Unknown

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 and advance materials, biotechnology, cancer, energy and global inequalities, go to Manchester, the AC dot UK Forward slash beacons.

Corinne Faivre-Finn, FRCR, MD, PhD, is a Professor of Thoracic Radiation Oncology in the Division of Molecular and Cancer Sciences (University of Manchester) and Honorary Consultant Clinical Oncologist (The Christie NHS Foundation Trust) with a specialist interest in lung cancer. Prof Faivre-Finn trained in Paris before accepting a consultant post at The Christie in 2001. She has numerous professional roles including: Radiotherapy Research Lead and Radiotherapy Big Data Lead for Manchester Cancer Research Centre, Radiotherapy Research Lead for the CRUK Lung Cancer Centre of Excellence and Early NSCLC Chair of EORTC Lung Group. She is the co-lead of the Christie/Manchester Cancer Research Centre Patient Reported Outcome Group.

Professor Corinne Faivre-Finn research profile

RAPID RT press release

CRUK clinical trial research website

RAPID RT, The University of Manchester

Dr Gareth Price research profile

We are Vocal

Using real world data and rapid learning to drive improvements in lung cancer survival

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 and 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 of 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 lung cancer detection and treatment. Lung cancer is the leading cause of cancer death worldwide, causing 35,000 deaths in the UK each year alone. As such, it's one of CR UK's four cancers of unmet need. Of47,000 new lung cancer cases every year in the UK, 15% of those diagnosed are never smokers. here in Manchester, we have one of the worst lung cancer mortality rates in England.

So, we are striving to improve early detection and treatment of this cancer. Across these episodes, we explore lung cancer from the genetics and diagnoses to screening and treatment, talking to Manchester researchers who specialize in basic, translational and clinical lung cancer research. And remember, you only need lungs to get lung cancer.

 

Sally Best

Hello and welcome to another episode of One in Two, season two. I'm so excited. We've got with us the fabulous Fabio. I've been waiting all season to say that alliteration well, is that alliteration? But yeah, we've got Fabio Gomez. Is that how you pronounce your second name?

 

Fabio Gomez

Yeah, yeah. I mean it's, it's Gomes Gomes. Cause it's not a z at the end, it's an s so it, you just give it a slightly different accent.

 

Sally Best

My accent is not on point. And where are you from?

 

Fabio Gomez

Portugal.

 

Sally Best

Portugal. Blooming love Portugal been on holidays there before. It's an absolutely great place.

 

Fabio Gomez

Far, far away. Land with a lot of sun.

 

Sally Best

Yes, exactly. But we are, you know, it's sunny in England at the minute, so we're loving it. But I mean,

we'll get onto why the heck you left there for here, cause that is the question. But I mean, how are you doing? How's it all going?

 

Fabio Gomez

Yeah, yeah. He's going well, I'm busy. Yeah, there's a lot, there's a lot happening. Yeah,

 

Sally Best

I can imagine.

 

Fabio Gomez

Which is great, but that does keep you busy. I think it's one of those places that if you do have a lot of things that you're interested a lot of doors do open. And I think that's why, you know, I ended up getting involved in a lot more than I probably should. That I have time for.

 

Sally Best

You're a busy man

 

Fabio Gomez

But I enjoy it.

 

Sally Best

I'm sure you do. You always have a smile on your face. So today we're going to be speaking about lung cancer and never smokers. So, I think one of the rhetoric’s that we want to carry through this season is that you only need lungs to get lung cancer. And that's the message that we really want to kind of push. And I think it's something, the stat changes, but I'm going to say around 14% of lung cancer patients are never smokers. So, in this episode, I want to smoke focus on ALK, and the kind of, the things that you do. But I mean, I'm firstly wondering if you could give me a bit of background into you, who you are, what you do, and what your day to day looks like. Cause you're a busy man.

 

Fabio Gomez

Yeah, no, happy to. So, I'm a consultant medical oncologist. I work at the Christie, been there for seven years now. So I did all my training back in sunny Portugal, Lisbon. And then, uh, I went for a little while to the US cause I, I've been interested in, in research for a while. But then actually moving to the US as a medic is quite challenging cause you need to do tests again and exams to get recognized. So realized, oh, that's a lot of effort to do it again. So, so then I looked up in Europe and then I found Manchester has a good opportunity and moved to some research, but with the plan to, to go back to Lisbon at some point. But here I am. Seven years later. Uh, and, and yeah, so I, I specialize in, in lung cancer. So, I've been, I've been working in that area for quite a few years now. And that's, that's majority of my work. And that means, you know, the clinical side, seeing patients in clinics, going to the wards, MDTs, discussing new patients that got diagnosed, things like that. And then there are two other roles that I got involved over the years. One of them is looking at, so we have this clinical outcome unit at the Christie.  So that's pretty much thinking, you know, the day to day practice generates a lot of data. So how can we use all that real world data to really inform what's happening to our patients? Because, you know you can Google and find data from trials, but that doesn't necessarily mean that's what's happening on the ground. So, there's been a lot of interest in recent years about using more of that data. So, I took on that challenge to direct that the unit. And then another area of interest of mine is, is the care for older patients with cancer. So we are, we've launched recently another unit looking at how can we best support those patients throughout, through treatment when you are a little bit older and perhaps not as fit. How can we get you through?

 

Sally Best

And you work nine to nine, right?

 

Fabio Gomez

Yeah. It keeps me busy.

 

Sally Best

Yeah. That's amazing. And I mean, so you, yeah. You came to Manchester. I mean, what, what kept you here? Was it just that whole diaspora? I mean you've mentioned that you work within the Christie and NHS Foundation trust, like what, you know, you had plans to go back to Sunny Lisbon.

 

Fabio Gomez

Yeah. I think it's a long answer maybe because it's, it's not something that you think, oh, overnight or this is it. I think it built up to a moment that I realized, well actually why am I still thinking about it? Probably, probably I'm happy here. Yeah. Or maybe I am. Oh yes, I am. So, so why planning that. But I did, I did come with that plan that I would set up a research project and by the end of it I would go back, you know, as many research projects do. It got a little bit delayed. I said, oh, I'm going to stay a little bit longer. I want to see it through. Then I saw it through and then got involved with something else. And then one thing led to another. But I feel like overall it has been the number of doors that I've opened, I felt that it always nurtured my interests. It's not like someone, you know, opened all the doors for you, but I feel like you can see the opportunities and you can see, okay, I'm interested in this, and you can actually do something about it. And, and I felt that that kept me quite engaged and quite motivated. And I guess that's why I'm, I end up doing all the things that I'm doing because that environment was there to support it. And I think that was the main reason why I stayed. But it wasn’t overnight, but it was an overnight. It took me a little while to realize.

 

Sally Best

Yeah, maybe the sun in Lisbon isn't so great. You just need to not go back and not remind yourself of how nice it is. Yeah. So, I mean specifically can we focus on the non-small cell lung cancer component of your research and ALK positive. And I'm wondering, you know, could you provide me some background detail on the non-small cell lung cancer side of things and what an ALK positive mutation is just for our, audiences? Cause it, it can be quite complex in describing, but I'm sure you've got a very succinct way of describing it. Don't look, don’t look so stressed about that.

 

Fabio Gomez

All right. I'll be succinct. Yeah, so, so we, we classify lung cancer in two big groups. So you have non-small cell and small cell. And non-small cell will be about 85% of patients. Which is good because the small cell is, is much worse. In terms of, you know, the chances of responding to treatment, prognosis, et cetera. So, it gets very resistant to our treatments. Non-small cell is less aggressive, and it has a higher chance though you can get, you know, the cancer control for many years gets even rid of it. Uh, which with small cell is, is, is not that likely. So non-small cell, it is the most common, most patients with lung cancer as a whole would, would have a smoking history. But you may have non-small cell without ever smoking, as you were saying before. And then we, we subdivide non-small cell in different, so you know, there's adenocarcinoma, squamous, those are two main ones. But over the years we've been looking at, because this is pretty much morphology. So, over the years we've been looking more and more into the molecular side of it. So, if you have specific genomic abnormalities and that, you know, can have a gene fusion, which is the case with ALK, and that allowed us to personalize the treatments even more. So, we, we obviously can diagnose the cancer at different stages. So, you might find someone, you know, with an early-stage cancer and they potentially can go for surgery with a curative intent and try to get rid of it altogether. But then a lot of the patients would be diagnosed a little bit later on. And, and that is a challenge. And although know the, the last time we've done, cause we, we do the, the, the lung cancer national audit and we, when we looked at age or the median age of diagnosis of non-small cell in the UK is about 73 years old. So, people tend to be much older but then there is that subgroup of patients that actually potentially never smoked or smoked very little and they still have lung cancer, which is really hard for those patients to accept as well, but that leads often to delays in diagnosis. And ALK, bridging to, to the topic, ALK is one of those where you have population that is a little bit different than that average. And you know, it has good things, uh, and I'll tell you about the good things as well. Because if you think about an overall non-small cell, you know, these patients, if they are picked up with a more advanced stage, and that's a lot of what I do at the Christie on average, now these patients might be living up to two years. Some patients obviously will live longer, others would say they live less. But once you start finding those molecular subtypes that have those genomic abnormalities that you can target and personalize the treatment to them, those patients tend to live longer. Yeah. So, it is really important that we look for them.

 

Sally Best

For sure. And I'd like to come on to the kind of the barriers that both, I guess clinicians and patients both face in terms of the diagnosis of never smokers. Cause I, we've got that rhetoric that's, you know, it's been since the 1940s where cancer, where smoking was identified as a carcinogen and that rhetoric that, you know, smoking causes cancer and it's kind of, it's sometimes seen that, you know, the only reason that you'd ever have lung cancer is from smoking. So, from a patient point of view, I can understand that need to correct people and say I've got lung cancer and I've never smoked before. And understanding, you know, the barriers that are faced there, but also the barriers that are faced clinically. But we'll come onto that, because I want to ask first about the kind of specifics behind what kind of mutation ALK is. So, it's an ALK positive mutation. Right, so yeah. What kind of mutation is that?

 

Fabio Gomez

Yeah, so, so you're absolutely right. And just to touch on what you were saying before, it's the whole system isn't it? You're not used to think about lung cancer in someone that never smokes. So, it's the whole system from the patient to a GP all the way, uh, along the pathway. So, it is a challenge, but basically what it is, so there are different types of genomic abnormalities, and what happens with the ALK is that, and this isn't exclusive to lung, but basically, it's a fusion between two genes. So you have two genes that, you know, would function in a penalty and there's a fusion and gets them together. And pretty much what that happens is it changes the way the signalling within the cell works. So once that fusion happens, that does drive the cancer and does drive those cells because it's giving the constant sign to divide and replicate. Yeah. And, and, and that's where the problem arises because you might have as by default, by definition even cancer is an accumulation of mutations and genomic abnormalities. It's not normal. But that doesn't mean all the mutations have the same meaning. A lot of the mutations are passengers so they will be there, they might influence to a degree the behaviour of the cancer, but they don't necessarily drive it. So if you target those mutations, the cancer may still continue growing. But with ALK, we’ve realized that's one of the driver mutations. That if you do block that, you block the main pathway. And you can, you know, can't get rid of the cancer by doing that, but you can really shrink it and paralyze it. Yeah. Pretty much after that.

 

Sally Best

And I know we spoke in a previous episode with Colin Lindsay about oncogenic drivers. So it's one of those oncogenic drivers. And also this is quite interesting, I've read that its, so a gene, the ALK gene is switched on in embryos in utero.  And that's for the kind of the protein synthesis and the growth of the embryo and then it switches off before the embryo or then the baby is born and then in some cases it switches back on and that's where you get that kind of fusion. Is it with the EML, is that right?

 

Fabio Gomez

The EML four and ALK fuse. Exactly.

 

Sally Best

And then exactly that causes the proliferation and then the, the cancer driver, and I thought that was so interesting cause it's, yeah, it's a weird mechanism, but also another thing is it's not hereditary, is it?

 

Fabio Gomez

It isn't. No. So you won't pass that on to your children. You know, it wasn't your parents' fault, you know. It just, it just happened.

 

Sally Best

And I can imagine, you know, with understanding hereditary mutations, it, you know, it's distressing for say your children to find out that, you know, they might have a one in four risk of their parent passing them something on or something. But it also, it's a great indictor, and it's a great kind of mechanism to go through early detection and for people to have this, this kind of continual screening whereas if it's not a hereditary mutation, you would never go to a screening. You just, so I can understand that there's, you know, a lot of problems there. And I mean, just to clarify, so the percentage of non-small cell cancers that are ALK positive, is that around 5%?

 

Fabio Gomez

Probably lower than that, but up to five.

 

Sally Best

Yeah. And does that vary population to population? Like is that just a figure here in the UK or?

 

Fabio Gomez

Yeah, so what we know is that, Asians tend to have a higher prevalence of it. So it is more common there. So if for example, we have a patient here that has an Asian background, we know that they have a higher chance. So there are a few characteristics that we know are a little bit more common. So it's a bit more common in women. It's a bit more common in younger patients and in Asian background. And then obviously people that never smoked. Or have a very light smoking history. So if we see someone that, got diagnosed recently with lung cancer that never smoked and fits, you know, some of the, this profile and it's obviously it's not a, is not a perfect profile. There will be people outside of this that still have if. It’s just more common then we, we tend to test for because there's a big chance they might have it. Although as you said, it isn't that common. So if you think that the ALK, rearrangement is more common, and essentially we only see it on adenocarcinoma. Well adenocarcinoma is a subtype of non-small cell, which is a subtype of lung cancer. So you can see we start narrowing this down and it's, yeah. It’s quite a small population and we don't really know how many patients we have in the UK with an ALK mutation, because we don't necessarily test everyone. Especially when they are diagnosed at an early stage, things are changing. But that's why we don't really have very accurate figures. We just know that in Asia it's a little bit more prevalent than it is around here.

 

Sally Best

Interesting. And I mean, you mentioned a few of the demographics so that are kind of, that have this ALK positive. So, you've got, the under 50, women, never smokers and things. Do we have any indication as to why those demographics, it might be particularly in those demographics? Or is that one of the research questions that's kind of continuing to find out why it's these particular demographics that are presenting with this mutation?

 

Fabio Gomez

I mean, short answer is I don't know. And I don't know if, if we have very good evidence on the reasoning For that. But that's an interesting point and I, I think one of the challenges is because it's not something you screen the large groups of people to be able to really understand the distribution makes it a little bit harsh. You could always say there's some bias potentially in some of that, but definitely yeah. There, there are groups there. The reasoning we still, I don't think we know.

 

Sally Best

And I mean does the ALK as well, you kind of mentioned that it's not any lung cancer, does it put you at risk of developing other cancers as well?

 

Fabio Gomez

So, so actually, so the, the ALK and that gene does play a big role in lymphoma, for example. Even the name ALK comes from it. So, it's anaplastic lymphoma kinase. Yeah. So, it came from that. So you can find that in other tumours, but if you have, you have that specific rearrangement in the lung, then it's very unlikely going to develop the lung and the lymphoma, et cetera. Yeah. Because you know, you've, you've already developed that, that tumour, but it is common. Yeah. It is seen in other tumours as well. Yeah.

 

Sally Best

God, it's crazy, isn't it? The number of people that are diagnosed. With never smoking lung cancer is kind of on the rise at the minute and there's, proportionally, and I think that's because, you know, there's this dissemination that smoking's bad and I think the marketing is kind of working for that and the proportion therefore is shifting. So never smokers becoming a more representative percentage of that cohort of lung cancer patients. And I mean, I guess what my, one of my questions would be what would we classify as this never smoker within that kind of demographic?

 

Fabio Gomez

Yeah, I mean you can use different definitions, but the most widely used is someone that smoked less than a hundred cigarettes in their life. And they aren't currently smoking. So that is, that would be definition of a never smoker. But I would argue that even someone that is a very light smoker, which more than a hundred, still has the impact. I'm not saying it's all fine until a hundred cigarettes.  And then 101 there's a problem. So obviously that's not the case. But even light smokers, we would still think of them, well actually you're quite a light smoker and you have this advanced lung cancer. We still follow that same rationale of testing. Prioritizing for those patients to get tested as well. Because for example, we do test quite widely for adenocarcinomas, but not necessarily for squamous. But if you see someone with a squamous that, you know, it's very unlikely they'll have a target mutation. But if they've never smoked, they're very light smokers, we would test.

 

Sally Best

Okay. And what, what stage along the diagnosis is that testing pathway? Like when does that happen? Is that kind of when there, I mean, Identified as a non-small cell lung cancer or?

 

Fabio Gomez

Yeah, so, so, so the first step we'll try to get some histology so the patients will get a biopsy, we'll see what, you know, what type of cancer it is, we know it's lung and then if we know it's non-small cell, then if it's adeno we, we would test for them. If it's not adeno and it's squamous, we don't necessarily test for everyone. But things are changing, and we are testing more and more. But definitely if they would be, never smokers or light smokers, we would, we would test for everyone following what I've just said. If you have a diagnosis of, advanced lung cancer. So you have a stage four, you’re coming most likely to the Christie or Wythenshawe for example, are the two main ones that will get patients, uh, in the region, uh, we would test for those patients. But if you are diagnosed at an earlier stage, then we may not do that test because they may not, that may not necessarily change what we could offer to that patient. Because the treatments targeting the ALK that are currently approved are for advanced metastatic stage. So if you are diagnosed at a stage one and you get a surgery knowing you have that ALK mutation or it's important useful information but doesn't really affect your care at that stage. But it might affect your care later on if your cancer comes back.

 

Sally Best

Yeah. And I mean I've read that I think it's around 90% of people without positive lung cancer are diagnosed at stage four. So that's a big cohort. Right, and what's the treatment options for those people when they are presenting at stage four with ALK positive?

 

Fabio Gomez

Yeah, let me go back just on one thing you just said. Because that's really relevant fact isn't it, that the majority of those patients are diagnosed later on. But you can see why that is the case because probably this is, that group that is younger is fitter, probably never smoked, has been having some symptoms for a while. But no one is really thinking, not even, no, not the person or, or the GP thinking about might be lung cancer. And I think that contributes quite a lot for the fact that you get diagnosis done a bit later when the cancer is more advanced as well. So it's not necessarily that the cancer will be more aggressive because you have that. It's just because there's that delay in diagnosis. Because you just don't fit the profile of someone with lung cancer and that, that makes it really challenging.

 

Sally Best

I'd like to touch on that later. Just a sneak peek, but yeah the treatment options.

 

Fabio Gomez

So basically we, as I was mentioning before, we developed treatments, that would target that. So basically what we want is to target that pathway. What I often describe to patients is think of this as, you know, this is, this is a subway and you want to go from station A to B and you know, the signals are passing within a cancer cell and there are multiple, there are multiple lines within the cancer cells, well within any cell to send signals around. And you may sometimes block one pathway, but you can use another one to get the message. But if you do have one of those driver mutations, that is that pathway that is being used primarily. So, what you do with the treatments is that we are going to target, and that's why we call them the targetable treatments. That we target that pathway, we target that mutation and we pretty much, we block that. But the reason why this isn't going to get rid of the cancer is at some point you'll develop resistance mechanism, or the cancer will, and we'll find a way for the, the message to get to the destination. But just using another line on that subway. And that's why I think one of the things that is really, really important is this is really tough for someone that, you know, just been diagnosed and all the implications that that might have in their life and the treatment, which might be really good. And I would say it’s really good and we have a few of them and I'll tell you about that, only goes so far. Yeah. You can't really get rid of the cancer is very unlikely you, the cancer would just disappear because at some point you'll develop those resistance mechanisms, and you can just bypass that primary line and use a secondary line to get to that destination so the message gets there, but that might take years. And that is, that is the good thing among all of this is that a lot of these patients might live a lot longer. So if I was saying before that, you know, on average someone with advanced lung cancer, non-small cell might be looking at two years. This patient might be looking at six, seven years. So, it does change things quite a bit. And we do have, so we have uh, thine kinase inhibitors, they're pretty much blocking that pathway. And we came a long way. So, we have more and more drugs available. So we try as best as we can once one failed, try to switch to another one. But, and these are tablets, so the patients would take them home with them and take them every day. They tend to be very well tolerated for most patients. So and that's, you know what, what, as an oncologist, that's what I like to see cause what I want to see is someone that is doing their medication, not impacting their life too much. For most patients, the vast majority will have a benefit, so the tumour tends to shrink. So, if they had symptoms, they tend to improve and then they can have that long lasting benefit. And then at some point, yeah. At some point and prepared patients for that, that treatment will fail at some point, but things evolve so, so quickly. I remember when I, when I started  , at the Christie, uh, we had one drug and that was that one drug. Now you have second and third and so we have so many drugs now available. You know, it's really encouraging and sometimes it's hard to tell patients what we have cause obviously you want to know what happens when this fails. And I said because it might take a while for this to fail. I don't know what I'll have available then. Because I may have more than what I have now and that's really, really good for us. Makes it a lot, a lot better. But for patients gives them a lot of options.

 

Sally Best

I can imagine. So are they, are they ALK inhibitors? The drugs? So, they bind to the ALK and then stop the reproduction of the cancer cells? But they don't necessarily diminish the size of the tumour.

 

Fabio Gomez

So, they tend to shrink but they tend to reach a plateau where yeah.  It doesn't shrink anymore and then, and then stabilizes there. Okay, and then we keep an eye. So, we do regular scans. So, every three months patients are having scans and then they can stay on that plateau where the cancer is, is quiet. Isn't changing much and we just carry on with the treatment. And then at some point, one of the areas that we already knew had cancer, restart growing or something new, start popping somewhere else. And then, then we'll see something has changed. But sometimes not all of the sites with cancer change because you might develop some resistance in one area but not on the other areas. So you may have, you know, other parts of your tumour stable, but some parts start growing and that's when you realize I think we are starting to lose control with this treatment.

 

Sally Best

And is that what you are referring to? Is that like first line treatment, second line treatment, third line treatment? Yeah. And that's how you progressed on the pathway?

 

Fabio Gomez

Yeah, exactly.

 

Sally Best

And that's either through increasing the dose of the primary drug that you're giving or introducing another drug?

 

Fabio Gomez

So, we wouldn't increase the dose. So, we, we start with optimal dose. We might reduce if the patient has side effects, okay. We’ll start with optimal dose. And with these treatments, you know, it’s not like cause chemotherapy for example, we calculate the dose based on the height, the weight, so we can calculate the body surface. How well your kidneys work, do not cleanse your body from it. But with this type of drugs, no. You know, it’s like almost if you think about, no blood pressure tablet.  That you start to that medication unless you have side effects, then we reduce, but everyone pretty much gets the same upfront. So, it's the same with this. And if you realize that at some point, you know, the cancer seems to be growing, there’s something new that treatment is failing, we switch. So we switch for something else, we don't necessarily add something on top of its. Or increase the dose, we just switch.

 

Sally Best

Yeah. And I mean it's so exciting to think that if a patient say kind of that a drug is working to the first line treatment is working for three years, the second line treatment is working for three years and then, you know, by the time seven years is elapse, there might be those new options that are kind of circulating in the UK. And it's just, it's so exciting to think of that because the, the kind of the option list just grows.

 

Fabio Gomez

Yeah. It has grown tremendously over the past few years. And then you have clinical trials as well. So the drug might not yet approve but you know, it, it may never be but at least it's in development and you can have trial to offer to patients and then, you know, and when all that fails you still have more the traditional chemotherapy as a potential option. Yeah. Obviously, it's a very different type of treatment, uh,

you know, and the patients might want it or, or not. But we'd also have that option as, as more that that classic treatment. It's still an option. But that’s, that was all we had a few years ago and you can see how we completed, we, we flipped this. So, we, we are targeting so we can personalize that and once all that fails. And, and we no longer have options, then we, we revert back to what we had before, which was the chemo.

 

Sally Best

And do you ever do them simultaneously? Like would a patient ever have an ALK inhibitor at the same time as radiotherapy or chemotherapy? Or is it usually you try the kind of the different inhibitor drugs that you have and then revert back? Is it always that order?

 

Fabio Gomez

Yeah, so different things. So, for example the chemo, yes. So, we, we don't do it together. So we would do it afterwards. So, we would be last resort in this context. Radiotherapy you could, and sometimes we do radiotherapy if you imagine, the cancer spread to a bone. And is really painful. Uh, we may think about doing some radiotherapy. It’s a little bit less common with patients because if they do respond to the treatment that pain should be getting better. So, it is unlikely you're going to be thinking about some radiotherapy to alleviate the pain because the tablets should do that for, for the patient. But that could be an option. Or you may have for example, a brain mat. And you might think about doing some radiotherapy, but again the ALK inhibitors tend to penetrate. And tend to work on the brain as well. So you may not, so in theory, yes you could do the radiotherapy to palliate some symptoms, but the chances are if the treatment is going to work, it’s going to improve those symptoms. So yeah. In theory yes. But we probably don't use it as much.

 

Sally Best

Okay. Got that nifty little thing

 

Fabio Gomez

Got everywhere.

 

Sally Best

Yeah, so I mean like just looking at ALK positive lung cancer, would you be able to kind of go through some of the symptoms that never smoker might expect from that type of lung cancer? Yeah.

 

Fabio Gomez

It would be the same. So, so it would be the general symptoms. So, you may have, you know, a cough that doesn't go away. And that often you might get an antibiotic, thinking it's a chest infection that doesn't really clear and the cough continues. So, a cough is, is an important sign, then sometimes you might start feeling a little bit more breathless. That is another important sign their pain might happen. It’s not perhaps as common cause it depends where the tumour is growing because if it’s growing the centre of your chest, you don't really feel anything. But it’s, if it's growing close to your rib cage, then then you can feel pain in that area. So you can feel that discomfort growing that doesn't really go away. That sometimes it'd be worse at night. So that type of pattern of pain, but it's perhaps not as common as the other two. And then there's the obvious that people get very frightened as if they cough some blood. So, if there's any blood there, something is, something is wrong. It doesn't mean that, you know, if someone coughs a blood equals cancer. But obviously that is an alert sign and I think people are quite an aware of that. I think people get very scared with that. But a cough that is lingering, perhaps you pay less attention if, you know if you're told probably just a chest infection. And sometimes, you know, sometimes six weeks for someone to completely get rid of a cough after they had a chest infection.  So, you know, but if that cough continues and you know, four weeks have passed, eight weeks have passed, clearly that isn't normal if you know, if you are a healthy person. But it, it can be easy to ignore. If you think, well I'm young, I've never smoked, now I went to the GP, got some antibiotics and it might have given you a false sense of even an improvement, but it just doesn't go away. But that's when you should, that's when you should. And I think it's more about that awareness that actually as you were saying, you only need lungs to get lung cancer. Yeah. So, if something isn't adding up, even if you've never smoked, you should be considering.

 

Sally Best

And going to the GP, that's the thing I, you know, I had a cough throughout pretty much all of uni and you'd just never consider it. And, I think that's probably, you know, one of the barriers for a lot of people is, I mean, especially with covid as well, right? You were kind of advised not to go into GPs if you had a persistent cough. Whereas, you know, that's a indicative sign of lung cancer and it’s, it’s quite imperative that you are seen by the GP pretty quickly. So, it’s, it’s a weird, weird kind of thing to work with, I guess.

 

Fabio Gomez

it's challenging, isn't it? Cause if you put yourself even on the GP shoes, no you're definitely not thinking you have cough equals cancer and you don't go, you know, into screening programs or you don't go in having all scans because of that. And, and you as a, as a person might go there once because you have that cough it didn't really clear, but you may not go again. So no, I can see how it is almost a little bit unfair as well and challenging for the GP you have a snapshot of that person and say, well you don't fit the profile. You don't have any risk factors. So, so their decision isn't wrong sometimes of not investigating. So, I do think it goes both ways. Totally. You need to say, well, you know, I know myself well, you know, something is off. So, and then, and then having that conversation with your GP to get things going.

 

Sally Best

Yeah. Having that autonomy in your own body.

 

Fabio Gomez

Yeah. And obviously, you know, you may have cough for a long time. Yeah. And you know, you may have other health problems, you know, you may, you may find out actually have asthma or something else, you know. There are other things. So, and that’s, that’s when it gets a bit trickier.

 

Sally Best

Yeah, I can imagine. And I mean we've kind of talked about some of the barriers that never smoker patients find in seeking treatment and a diagnosis, but I'm wondering if you could expand on that a bit more, in terms of those kind of ALK positive or even just any of the never smoker, patient barriers that you could perceive a patient might experience.

 

Fabio Gomez

So, barriers to the patient getting diagnosed?

 

Sally Best

Yeah. And I guess barriers that the patient might experience. So, I, I'd say kind of yeah. Understanding,

not understanding that, you only need lungs to get lung cancer might be one of them or yeah.

 

Fabio Gomez

Yeah. I mean I think the biggest barrier is perhaps the lack of awareness. That that could be the case. Most likely it isn't because in all of this is really an uncommon But there is that risk and I think that should always be something that should be considered. So, I do think that lack of awareness is, is a problem. Yeah. Because if you, you know, you may identify these mutations in someone, you know, that fits the, fits the profile where you have someone, you know, older that smoked and older rest, those, you know, are easier to spot and they may still have the mutations, but those that never smoke, those are the really tough ones. So, I do feel that, you know, that awareness from the general public. But then that awareness at primary care as well and, at the Christie with good collaborations, you know, the Gateway-C. Doing a lot of training and education in that space as well so people understand that that might be the case. You know, all those things are important. So, education is a big big thing that I think is needed and that awareness is needed early on. Early on in that, in that pathway. So you can find those patients and hopefully one day we're going to have more of those patients being picked up at an earlier stage where we can offer them, uh, treatments that could potentially get rid of their cancer. But as you said, most of them sadly are picked up much later. And I think it's that, that delay at diagnosis, that is a big, big, big challenge.

 

Sally Best

And I want to come onto the education side cause that's obviously what you're working on, but I mean another thing to flag is, there was just talking about public campaigns, the Ruth Strauss Foundation. So, have you heard of it?

 

Fabio Gomez

Yeah. Yeah.

 

Sally Best

So, it was Sarah and Andrew Strauss I want to say founded on behalf of his wife, Ruth Strauss. And she was a never smoker and had ALK positive lung cancer and sadly died of that. And he set up this foundation in her memory and to kind of raise public awareness and things. And, Rankin the photographer has done a campaign with never smokers and their kind of CT scans and stuff and it looks amazing, but it’s, it’s understanding the benefit of work like that in relaying that message that you only need lungs to get lung cancer. You, it is, you, you need some autonomy in terms of your healthcare and pushing forward on that. But understanding your symptoms could be other things rather than just kind of your immediate response of, oh, maybe it's pneumonia, maybe it's a chest infection so, you know, we'll come onto our work as well cause it's all incredible. But that, that's some really good work that I just, I think is incredible as well, so I mean, in terms of a patient that's a never smoker versus a patient that's a smoker, what would be the current difference in their care pathway if they went to the GP and they presented with exactly the same symptoms and they both reported, you know, I've got fatigue, I'm coughing blood, I've got chest pain, I've got persistent cough, what would that kind of, I don't want to say it as in it, it would be every pathway would happen like this. But I mean, what would be the general difference in the pathway that each of those two people would go down. Just from the one factor that one of them smokes and one of them doesn't smoke.

 

Fabio Gomez

Yeah. I mean it's not an exact science, but I would argue that if, if you go and, and you've smoked or you you're currently smoking, that would be a risk factor. So you are perhaps more likely to be identified as at a higher risk of having cancer and you more quickly could get onto the, the two week pathway of, of trying to ident do the diagnosis. You get fast, you can potentially get more easily fast tracked because you might be more easily identified as at a higher risk of having cancer and therefore getting, you know, getting your x-rays done and, and all the rest a little bit quicker. If, you know, if you have no other risk factor and you are particularly young, the chances are it might take a little bit longer. For you to get onto those quick diagnostic pathways. So there that, that is the reason why there might potentially be a bit of a delay.

 

Sally Best

Yeah. So, you wouldn't necessarily be referred straight away for that low dose CT scan of your chest.

 

Fabio Gomez

Potentially not, but I guess it all depends on, you know, is this something that you've been to your GP multiple times? Is this something that hasn't cleared? Then you know, then it'll be the GPs judgment as well assessing. So, we wouldn't be an algorithm there. You know, you tick the box here, here and there, and then, uh, then the referral is sent. So, there will be that judgment if it's the first time the GP is seeing you, you don't fit any of that criterion. You could argue it's not necessarily wrong of the GP not to immediately send everyone to, to do no screening for lung cancer. But if you do fit in, then yes. So, if you're a little bit older and if you have a smoking history, if you have a heavy smoker,

then you can imagine that it's much more reasonable. That you get the referral a little bit earlier on.  So, I do, I do feel that it's, it goes both ways. And it's so important that the public in general is thinking about that as well to say, well actually this has been ongoing for quiet, for quite a while, although I only came to you now. Or if it doesn't go away, you go back to your GP and say, well actually didn't clear. I think that needs to go both ways. To aid that, that decision making etching on the right pathway as soon as.

 

Sally Best

Yeah. And it can sometimes be disparaging, but I think yeah. Understanding your own health and knowing when something isn't quite right, and trusting in that instinct as well is a real big thing. And you know, you can't rely on a GP to understand when something doesn't feel right for you. So, it's, it's really important to have that, that drive to kind of. Get yourself seen and get yourself into the system.

 

Fabio Gomez

Yeah. Cause you know, I think we can easily put a lot of expectation and pressure on the GPs, but if you, you, if the GP sees you once, you know how, how realistic is it that you can expect that to be done, you know, in one go, you know, you don't fit any of those risk factors. It, it is unlikely that in one, that one contact and you fit none of those risk factors. The GP will say you might have lung cancer, I'm going to send you that. You know, you can appreciate why that may not happen in, in the first go. And that's why I say it's so important that this goes both ways that, that people in general are thinking, well as you were saying, I know myself, well this hasn't happened before, this isn't going away and maybe I need to go back to my GP.

 

Sally Best

Yeah, yeah. For sure. Great stuff. And I mean coming onto you specifically, could you tell me a bit about your work on the UK ALK project?

 

Fabio Gomez

Yeah, yeah, yeah. So, so a few years ago, so this is, so this has probably like two phases. So, a few years ago we've set up an ALK project that was pretty much a bit of a national database because we realized that things were changing so quickly, you know, more treatments were getting available, more patients were coming through our doors, how are we ensuring that all of this knowledge and all the access to these trials and new drugs is, you know, is happening across the country. Because, you know, the Christie is a big centre. We end up, although this is relatively unusual, this type of, of lung cancer, we end up seeing reasonable numbers because of the sheer size of, of the hospital. But if you think of some smaller centres, you may have colleagues who have never treated someone with, with an ALK lung cancer. So, we felt, well let's engage with oncologists across the UK in this, you know, beyond England, and get data in. And it was really, really interesting to see and you know, people were really eager because I think I might have mentioned before, you know, we do that national lung cancer audit, but we don't really have the granularity. Of the ALK specific outcomes, et cetera. So, it's, it's everyone as a whole, we just separate non-small cell from small cell pretty much. Yeah. So,  people are really eager to understand what was happening. So, so we've started there, collected a lot of data, realized that, you know, as we suspected in a good way, these patients were living a lot longer than what we were used to see before. But we also realized that perhaps there was a lot of, the care might be a little bit different Yeah. Where perhaps some drugs were available at that stage, but perhaps they, they weren't aware of some of those drugs, or they just had been approved or maybe there was a trial that is open on one site that is not open on another site. They could have been a good opportunity, but we don't know even if the patient would travel for that. But we realized that perhaps he was a bit disjointed. Because it was a landscape that was changing very quickly, and it wasn't a very common landscape. So, people may not be entirely aware. And this was, this was quite a few years ago. But at that highlighted that need. And I do think things improved quite a bit now. Because ALK became a very, interesting topic and, you know, the more and more treatments that available, I think it became much more popular in that sense. So, I do, I do think the awareness has increased quite a lot within, within oncology. But it flagged that actually there were issues with you know the late diagnosis. There were issues sometimes in making sure that even more specialist teams were aware of all the developments. So, so more recently on the back of that, we felt that we should invest in education. So, we got a good collaboration going on between know colleagues from the MCRC, School of Oncology, myself, the Christie, and we've put a grant together and secured some funding with the Pfizer support to develop a whole educational program. That would be tailored, you know, not just, you know, at the, at the specialized oncology teams, but also thinking about the GP, thinking about patients, and that's why as part of that, we are partnering now with the, with the national patient, the ALK UK. So, it's a patient advocate group, it's really important that they have a voice there as well and it helps shape the program. So, it's something we are just about to start, but it's really exciting and I think it, it grew from that. That we realized we needed to get that platform of education, uh, out there.

 

Sally Best

Fab. And I'll link out positive UK because I think that's what you referenced, that UK ALK project. That then led to this fruition of the ALK educational program. And that's the Christie School of Oncology, the Christie and the MCRC, which is Manchester Cancer Research Centre. Yeah. And so, you are the clinical lead for that?

 

Fabio Gomez

Yeah.

 

Sally Best

And there's other educational kind of components. So, I mean, what does the educational component of that project involve more specifically? Like how, who, who is it targeted at? What, who are those kinds of discreet groups and how is it going to kind of I be implemented, I guess?

 

Fabio Gomez

Yeah, yeah. So there are a lot of things we still don't know cause we're going to be working on that over time. But we've already agreed that we want three layers. We want the layer that is, that is tailored and targeted at, at the patient. And then there is the layer that is targeted at the, at the GPs primarily. So primary care. And then the third layer is the more specialized layer that is targeted at essentially oncology teams. Not just the medics, but the whole of the multidisciplinary team, the nurses, et cetera. Uh, so those are the three layers and those are the three targets. And we keen to have one single platform that depending on who you are, then you can access the layer that is more relevant to you. So, the level of information would be tailored to that, and the focus would be tailored to, to you as well. Yeah, and then the way that we're going to deliver that, I think a lot of that we're still discussing and seeing what, what is the most efficient way and I think it very hybrid model probably will work best. Where we have some more, more traditional, uh, here I am talking about a topic, or you can have something a bit more interactive as well. So we still don't know all the specifics. So, we, we are now building, so we've built the skeleton of the topics we want to cover, agreed on who the target is. Now we're defining how best deliver this in a way that, you know, we've managed to keep that up to date as much as possible. We've managed to get, you know, a good reach with the content, and you know, and we get the right people involved. Yeah, so we are inviting our other clinicians to get in on board as well. Uh, so I'll be one of them by getting more clinicians involved. Getting patients involved. Yeah. I think that's really, really essential. Yeah. And I do think, and we all agree within the project, that having the patient voice there to help shape the content, not just the content that is targeted the patient, but the content that is targeted at the GP or targeted at the specialized oncology teams. Getting that voice is really important.

 

Sally Best

Yeah. And I think especially understanding from the patient's perspective what barriers they experienced. So I mean, even in terms of, I think there's kind of a, a commonality whereby if somebody is diagnosed, with lung cancer as a never smoker, their first port of call is to say to somebody, oh, I never smoked. Well, the first question is from kind of Joe, Joe public, did you smoke? Yeah, and it’s, it’s understanding removing that and removing the stigma and understanding as a GP or an oncologist that people do experience, barriers. And some of them may be in the form of a stigma and just having a patient to communicate that and the kind of the importance to them of breaking down those barriers is just. It's incredible. And having those kind of three groups working together, you know, your patients, your oncologist, your GPs is really, really powerful. It's like a tripartite of greatness.

 

Fabio Gomez

Yeah. Yeah. No, I agree. And, and we, we had a meeting, maybe a month ago and, uh, one of the, the patient advocates was talking about no, the things you don't really reflect, but if you, if you are diagnosed with, with cancer earlier on in your life, the, the impact is different than if you're diagnosed later on in your life.  So, you know, it might affect your, it will affect your chance of, for example, you know, getting a loan, getting a mortgage. So, it paralyzes a lot of aspects of your life. And, you know, it's quite significant. One of my, one of my patients, his life's passion to play clarinet. So, it's something that, is really, really is something that not only he loves. But also, he teach, he was teaching kids and that was a source of income as well. And then suddenly you couldn't breathe that well. So, so you not only stop doing something you love, but you also stop doing something that provides you an income. And I remember we started, uh, started the patient on the treatment, you know, and there was an improvement over time. And then there was one day that I got an invite to go to his concert, and that was his first concert since he had been diagnosed. You know, that was so significant. And I felt like, oh, you know, I didn't tell him that I was going because I felt that I imagine something happens and then I don't show up that, that, that would be terrible. So, I didn't say anything, but I, I went to his first concert, and he spotted me in the crowd. And then he came to me, you know, and just, just so happy that I went there, but he was so happy that he was able to play again. And not only, you know, he managed to get back doing the things he loves doing, but also know that give, provide him an income. So, he managed to get his life back. And I, I know, and this isn't to say that, you know, if you are old than, you know, a diagnosis has less of an impact, but it has a different impact. Because you are at different times in, in your life. And, and you know, at that, that point made by, by that patient saying, you know, you are a young family, and you can't get a mortgage, you know. All those things, because we might say, but it's okay. No, you can live for many years with this treatment. But still your life can be paralyzed. And, and if the cancer, for example, had spread to your brain, you can't drive for at least a year, which might have huge implications for your line of work, et cetera. So absolutely getting the patients involved in that voice provides a perspective. That is really, really important. Yeah.

 

Sally Best

And I mean, as well, I, I guess the, the family aspect as well, you're more likely to have a kind of dependence when you are, you know, that age and having dependence is so stressful because, you know,

they're completely reliant on you and your, your kind of financial stability. You have that ripped out from under you and you don't know where to go from there. So, I can understand it's a completely different landscape that people are navigating. Like you say, it's not saying that one's lesser than the other, or less stressful, it's just a completely different stage in your life that you're in. And understanding those younger patient groups must be really helpful for those patients as well. And looking at likewise people in a room where you are kind of, you're, the thing that's drawing you together is that, you know, you've all been diagnosed with cancer, and it might be this ALK positive cancer at a very young age. It's not hereditary, it came from late diagnosis, and you're trying to deal with it and having that community group must be so, so important.

 

Fabio Gomez

Yeah. Absolutely. Absolutely.

 

Sally Best

And I mean, I guess you learn a lot from your patients as well, don't you?

 

Fabio Gomez

Yeah. And you know, it, for us, it, it makes it all worth it as well. Yeah. Because obviously some, sometimes it can be quite challenging. But seeing, and, and I think, you know, seeing that these treatments, sadly they don't work for everyone for, but the vast majority, they will work and seeing that benefit, seeing how you can sort of get your life back on track. Yeah, you know, it may not be forever and ever, but that ability of giving you more time. That is, that is brilliant. And seeing your patients getting back to their, to their normal lives. That's, that makes it all worth it.

 

Sally Best

And you see quite often that people switch that mount tells, you know, I've known people with cancer and family members as kind of everyone does with the, the way that it is, like one in two, but the mentality switches to that. Well, in my experience, every day is a bonus. So then when you're presenting somebody with a treatment strategy that's, you know, promising them kind of so many years, it's, you know, such a relief for them that it's not this death sentence straight away. Yeah. Which is I bet so lovely for you. Yeah.

 

Fabio Gomez

And just, yeah, oncologists, try as much as possible. Avoid promises. But, but yeah. But patients do have a good chance. Yeah. So that, and that's important that they know as well upfront that there's a good chance. Yeah. But we need to get started to see now is is this going to work? But there's a good chance you will, so, yeah.

 

Sally Best

Sorry, I'm a junior. I can't promise anything. And I mean, previously you mentioned Gateway C so that's an educational component of the Christie, is it the school of oncology that it's within? Could you tell me a little bit more about that and if you envisage this, the kind of outputs from this ALK education program being fed into that?

 

Fabio Gomez

I mean, that's a really good question. And, uh, I don't think we've, we've determined everything about the program yet. We've just secured the funding and we, we are working to, to get things going. We're definitely very keen to use the machinery around Gateway C Yeah. Because there's a lot of know-how already there on how best to deliver a lot of this, I don't think we've agreed necessarily is this going to sit within Gateway C is, it's going to be linked somehow with it. I don't think we came to that, to that decision just yet. But, really, really keen what we want is for that to be, you know, as accessible as possible. Reaching the right people. So very happy for that to happen, if that is the best way. Or having that into different routes of access. All of that to, to me and I guess to all the others, we are very flexible about it. But definitely there is a, there is a skill set and a know-how and a whole platform that we really want to tackle into. And so, Gateway C definitely is very key for us to be able to develop this. The whole machinery around, around it. Uh, I don't think we just decided just yet where, where do we make it all available.

 

Sally Best

Yeah. And what's like, how long do you envisage that program running for?

 

Fabio Gomez

So, so we, we planned that over the next year we'll be developing all the content. Putting it all, uh, out there and available. So, for example, in September there's going to be, the UK ALK the patient group. There's going to be a conference. So, we're very keen to bring that there, get that engagement going to them, hopefully showcasing and announcing of the platform. Although necessarily, I don't think we're going to have all the contents there for sure by September. But getting, getting that, those comms and that engagement, uh, going then and then over one year developing all the content, uh, and this is phase one. We haven't really well planned, how do we keep this, you know, up to date . Because all we want is obviously something that would hopefully continue. But one, one step at a time. So, we we're at the stage where, yep, we've secured the funding we have, we plan one year to develop all the content and get everything up and running. Hopefully we'll succeed with that. Reaching out the groups we want to reach out, partnering, you know, with the different charities as you've mentioned as well, patient groups, Gateway C, once we get that well linked and getting that, hopefully reaching the right people, then we need to think about phase two is where do we go from here? Cause what we don't want is obviously developing all of that. And then, you know, in a few years all of that is out of date, at least in terms of treatments. And then, and then the platform is no longer useful, but, uh, still, still on phase one. Yeah. We'll get, we'll get to phase two.

 

Sally Best

So, you've said in terms of the content, and that would be like a kind of hybrid- esque sort of thing. What would that look like for an oncologist? Would that be educational materials for them that would be looking out for certain symptoms and , the kind of care pathway?

 

Fabio Gomez

So, I think there, there'll be different things, but, I think for the, for the more specialized oncology teams, a lot of it could be around the decision making in certain circumstances that are a little bit trickier. So, for example, sometimes patients develop upfront brain metastasis or a little bit later on how to tackle this, you know, the radiotherapy to the brain we've discussed before, switching the treatment that has better penetration in the brain. So, all those considerations I think. Can be quite challenging.

So, a focus on that decision making on what could be the best options on the table for the patients, particularly in very special circumstances. I think that will be a big focus. Another could be on managing some of the side effects of, of some of these treatments. Could be another area that we're focusing.

And then there's an element of how this is perhaps impacting the patients and bring more awareness from the patient's side on that. So there, there will be, there will be different layers. But for example, you can imagine that, you know, that decision making content is less relevant or is not relevant for the GPs because they wouldn't be engaging, you know, at that level. Because no, they wouldn't be making that decision. So that's why the content needs to be tailored so that you are tailoring the content for the right audience.

 

Sally Best

Yeah. And then for the GP, would that be more of the identifying these symptoms in never smokers

 

Fabio Gomez

And understanding the pathway as well. Because I think it's important to understand that yeah, that patient may have, may end up having a lung cancer, but if you have a lung cancer with one of this, no, if it's ALK positive, that's a very different type of, you know, prognosis treatment pathway. Et cetera, et cetera. That the more traditional lung cancer, uh, patients would face. So having them understand as well that that is a very different pathway and that, you know, in five years it changed, you know. Dramatically, that, that message is important to come across as well.

 

Sally Best

I can imagine. And I think with GPS as well, there's such a vast expanse for them to cover. That, you know, you won't necessarily identify everything that comes into your clinic. And also, you won't necessarily have the materials to identify everything that comes into your clinic cause things are updating every year or so. And if you've qualified 10 years prior, you're not going to know the kind of the new things to look out for and the things that are kind of coming up, more frequently.

 

Fabio Gomez

Yeah. I mean the GPs, any of us would have, you know, ongoing training to get updated. But I completely agree that, you know, it's a lot to cover, you know, even within oncology, if suddenly you ask me something about breast cancer, I'll be like, oh, it's been a few years now. So, I prefer not to answer because I probably, I may not know, but I, so I do think it's, it, the pressure on GPS is really high. Yeah. Because, you know, obviously you, you, you want to know until a level until a degree, but there is a lot to cover. So, it can be quite tricky. But I did think they do a great job. And I, and I think it’s that getting that awareness and getting that no two-way communication. That's why, I think we all have a responsibility. We can't transfer that responsibility all to the GPs. So, we have a responsibility as well to say something is wrong, something isn't getting better. And you go and discuss, uh, because you can imagine if you see someone once and you don't see them again, and you don't fit, you know, if it's not that clear. There's a chance, you know, the GP rightfully may not be able to identify  that, but if you come again and then you have that conversation, then you are the increase might the chance my increase that you'll find it. So, I, it, both ways, I think it does go both ways.

 

Sally Best

Yeah. For sure. For sure. And I mean, what are your hopes for the future of this and its outcomes? Is that to shift the 90% that are diagnosed at stage four kind of into the earlier stages?

 

Fabio Gomez

Yeah. Yeah. There will be different things. So that would be the dream, isn't it? That yeah. You find these patients at an earlier stage, and you can offer them, they don't even need me. And then you can get hopefully surgery and other treatments and that would be, that would be great. So that, that, yes, for sure.

But then the other is ensuring that if you do get diagnosed at a later stage, you and everyone along the pathway is doing the best we can for, for this patient. They aren't very common but and have very different circumstances and that we are aware of them and we're providing the best care we can. And that on the back of all of this, we're thinking about, you know, what are the outcome, the, the outcomes for these patients in the real world. And that's why I was, in a way when I've introduced myself in the beginning and I was talking about, you know, my role around, you know, the use of real-world data . Understanding the outcomes of our patients, that is so key that we are capturing that data. And we are seeing, okay, on paper, yes, we have this drug, then on paper they do this and that. But what is happening on the ground to a lot of these patients and getting those, those data sets, getting those out outcomes out there is really important. And, and that was really the beginning of this journey. So, we're now focusing on this educational packaging program. Because it came on the back of that dataset. So, you know, should we be developing more tailored dataset, so we know what's happening to those patients? I think we should because they don't fit the bill when we are thinking about the wider lung cancer population. They're quite specific. So, for being so specific, we need to understand their specific outcomes as well. So, I do think there's an area that I would be very keen that we do more. And I hope that this would raise that.

 

Sally Best

And do you see it as kind of a good exemplar that could be translated to other disease groups, this educational program? Cause I mean, it could be useful for countless, like even different hereditary cancers and things like that.

 

Fabio Gomez

Yeah, I, I do. I do feel that when you have a tumour or a subtype of tumour that is a little bit rarer. Yeah. It gets really challenging. Yeah, not just, you know, because, you know, I may have something in my trust from a trial that the other trust may not have. And now we have better platforms to find out about trials across, across the UK.  That, you know, may not be open in your, in your hospital. But more than that is are we can say for sure that we are on top of all the developments in that area? Which is quite rare and you, we may not see as many of those patients, and that doesn't mean all those patients need to be referred every time to a specialist centre. Sometimes, you know, they can be seen at their, at their more local hospitals. Which a lot of patients would prefer instead of having to travel a long way.

 

Sally Best

Yeah.

 

Fabio Gomez

How can you empower those teams as well to feel confident and having access that information considering how busy everyone is as well. So, I do feel that specifically for, you know, rare tumours or rare subtypes of tumours, that that would have a lot of potential.

 

Sally Best

Yeah. And I think that was kind of like leading onto my other question that was how is Manchester suited to this research? And I guess it would kind of lean onto this patient populations. So, we do have, we have the labs, we have the patients,

 

Fabio Gomez

We have the hospital, and we have the staff. So, I do think we have all, all we need, and the profile has been raised. I would, I would say for ALK over the years, you know, I would even say that the patient group had made a brilliant job at raising profile as well for themselves. So, it's, it's getting all these people together with a, with a joint project or a joint focus and, sometimes there are pots of money here and there and if you start pulling this together, I, no, there's a lot that can be done. And obviously this is a very vague answer because you know, you could apply that to anything. But I do feel that we already have a lot here and we do have the patient group and I’d say, you know, a lot of these patients are really engaged. So, I tend, whenever I have a patient I say, well, are you aware of them? There's this patient group, they tend to engage and maybe because they're a little bit younger they engage a little bit more in some of these things. So, we definitely have the patients there as our allies. And you definitely have the numbers. So now we just need to get a little bit more working together. And I do find that there are funding opportunities out there. Just need to tap into them.

 

Sally Best

Great stuff, and I mean, I think kind of going on next, it's a question that I like to ask everyone, and it's how does it feel to work within this kind of like sector of cancer research and know that you are benefiting the lives of your patients?

 

Fabio Gomez

Oh, I should have prepared for that question.

 

Sally Best

Everyone always freezes. They're like, well.

 

Fabio Gomez

Yeah. Oh, it's, it's hard to answer. I, I really enjoy what I'm doing. And I do feel that as I was saying the beginning, that there is a lot of, there is a lot of know-how around, and I know I feel like, you know, I, I’m, I feel confident in certain elements of it, but, you know, yeah. There are elements of the research that I wouldn't be very no, you don't, you don't put me in the lab and I would just find it all very interesting, but I wouldn't know what to do there. So there is a lot of different know-how already there and I think Manchester does provide you that support and that opportunity to do things in this space. So, I think there is probably a lot more that I could be doing that we could be doing. But, I think the sum of the little steps is, is, is a big thing. And I can see a lot happening in this space. So, I don't know if I'm answering your question, but uh

 

Sally Best

You're answering a question. That's okay.  I mean it's incredible work and I'm so impressed and it's so great that you've got this funding and that you're pushing forward with this educational component. Cause I think that is one of the most integral things. You can do the research, you can, you know, do the clinical trials, but if it's not communicated to the public, the clinicians, the GPs, then it’s, you know, sitting dead in the water. So, it's so important to have that, to facilitate the new conversations and have that group of the tripartite that communicate and trans translate each other's messages.

 

Fabio Gomez

And getting the right people around you because, you know. In all fairness, and that's really important to acknowledge that, you know, we got that funding and we have this plan. But now, although I may come with the, so the, the clinician hat on for this, you know, it, it's really only possible it's only moving forward because, you know, we have the director for School of oncology, at the Christie that is really supportive and behind this. And then we have leads in education like Rachel Chown that is really driving this as well. So, you, you get the right people around you cause you if would be me, I would just say, uh, we should talk more about this, we should do something. But then, then the whole delivering of an educational program, you know, is way beyond, you know. What I'm feel more confident and comfortable. So, you really need to get the right people around you to support that. And that's the key thing. And that's the key thing is not just finding the funding. Is finding the funding and the right people around you.

 

Sally Best

Yeah, for sure.

 

Fabio Gomez

And I think that's perhaps what I, I know I've said that a couple times, but that's what I like about Manchester is that you end up having, you get the link, with the university just up the road and then you have the link with MCRC and then you have, and you have all these different people, uh, with very different skill sets that can quickly get together and, and, and get a project up and running. And that's brilliant.

 

Sally Best

Like the diaspora of people here is just incredible. You only have to get talking for a bit and you have looped into some of the Pullman projects, and you've mentioned the uni. Were you a student at the uni?

 

Fabio Gomez

So, I did research, so I did, I did a master's in MRes. I did an MRes in the uni, uh, on experimental cancer medicine. So, I did that, but I, I did my training in my PHD back, back in Lisbon. So, uh, but yeah, but I got that link and uh, yeah. And then beyond that as a, as for some time, as a student as well, is all the links you build on your professional side. Yeah. Because we, we end up collaborating because you know, no one, someone knows someone and then suddenly you are engaging with that person, with that person. I think perhaps the majority of my links with university came outside of that student, uh, yeah. Sphere perhaps and different interactions along, along the years but there's always been a really good collaboration and good interaction. So, I think that it, it builds Yeah. And, and grew from that. Yeah.

 

Sally Best

Oh, great stuff. And do you know of any, other oncogenic drivers that drive non-small cell lung cancers?

 

Fabio Gomez

There are quite a few now. Oh gosh. So yeah, things are changing

 

Sally Best

So never smoking non-small cell lung cancers. Sorry.

 

Fabio Gomez

Well, it doesn't have to be. You know, I think I, you can look at its different ways. I would argue that, you know, if someone never smoked, they have a higher chance of having no, if they didn't smoke, why do they have lung cancer? They probably have one of those driver mutations that, and that is the reason why they have it. There are a lot of those that we just don't know about them, so we can't test for them. And there might be some that no, we test for, and we find, but we still don't have a treatment for. So, so it, it is what it is. But there are a few that, uh, beyond ALK that we test routinely for. So, EGFR we test routinely for,

we have RAS- one, we have B-Raf. So there, there have been more and more that we have treatments for and that we test routinely. ALK is definitely one of them. And perhaps ALK has that, that cohort of patients that are a little bit younger. Yeah. But all of this are common in people that never smoked. But again,

it doesn't mean that no. If you have a smoking history, we are not going to test.

 

Sally Best

Yeah. Yeah.

 

Fabio Gomez

So, we will, and we'll find people that smoked and have one of this positive hits. On the tests. Think the argument is if someone never smoked, uh, or is very light smoker, we definitely should be testing

because you know, if they weren't exposed to tobacco, then why, why did they, why did they develop?

So, we really need to do the best we can to run tests. And we can do some of those tests and blood samples and tissue cause sometimes when we have tissue, we may not have enough to run all the tests. Yeah. Sometimes we re-biopsy and you have a stronger argument to try to do as best as you can to run the full panel in patients that never smoked. But yet, but they are more, more targets and pretty sure that the number of targetable targets will, will increase over the years.

 

Sally Best

Yeah. God, just more knowledge. Well thank you so much for speaking with me today. It's honestly been a pleasure.

 

Fabio Gomez

Oh, thanks for having me.

 

Sally Best

I really appreciate you taking time out of the clinic, to speak with me cause it's just yeah, it's great. I love it. Oh, been fun. And yeah, it’s nice to shift that perception of lung cancer as a smoking disease and

working with you on this. And I can't wait to hear more. There's going to be more.

 

Fabio Gomez

Don't you worry, I'll tell you as as we get more out there.

 

Sally Best

So go and have a blooming fabulous day. Thank you. Hope it's sunny and it reminds you of Portugal,

but doesn't make you want to go back. So, thank you so much to the fabulous Fabio.

 

Fabio Gomez

Oh, thanks

 

If you have been affected by anything you've heard in this episode, please see the show notes for a list of charities and organizations 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 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.

Dr Fabio Gomes is a Consultant Medical Oncologist who specialises in the care of patients with lung cancer, focusing specifically on the ALK positive mutation in Non-small-cell lung cancer (NSCLC). He also has a special interest in the care of senior adults with cancer and is the Clinical Director of the multidisciplinary senior adult oncology service launched at the Christie Hospital in 2022.

Fabio also works with digital services where he directs the clinical outcomes unit. This unit focuses on the use of clinical data generated as part of the daily practice across the hospital to identify the outcomes of groups of patients and promote improvements.

He is an elected board member of the International Society of Geriatric Oncology (SIOG). He is also a Clinical Research Training Fellow alum at The University of Manchester.

Dr Fabio Gomes’ research profile 

Non-small cell lung cancer information from Macmillan

The ALK project: A real-work national network and database

ALK Positive UK 

ALK Positive Org

Ruth Strauss Foundation

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 and 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 of 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 lung cancer detection and treatment. Lung cancer is the leading cause of cancer death worldwide, causing 35,000 deaths in the UK each year alone. As such, it's one of CR UK's four cancers of unmet need. Of 47,000 new lung cancer cases every year in the UK, 15% of those diagnosed are never smokers. here in Manchester, we have one of the worst lung cancer mortality rates in England.

So, we are striving to improve early detection and treatment of this cancer. Across these episodes, we explore lung cancer from the genetics and diagnoses to screening and treatment, talking to Manchester researchers who specialize in basic, translational and clinical lung cancer research. And remember, you only need lungs to get lung cancer.

 Sally Best

Hello! Caroline Dive. We've got you’re here. Finally.

 

Caroline Dive

Good. Well, it's a pleasure to be here.

 

Sally Best

I'm so glad to see we've got another episode of season two today. Season two is focusing on lung cancer. So, we're going everything from the basic biology through to treatment, diagnosis, and then kind of to the pathway, which will be some of our later episodes. But we've got you on today to talk about I think it's quite a complex subject, so we will start at the beginning I think is obviously always the best place to start, but you're very good at talking about this, so I am so very sure we are on safe hands, in safe hands for this. So, I mean, how are you doing first of all?

 

Caroline Dive

Oh, we're thrilled because, you know, we've just moved from Alderley Park. The fire to the Patterson Institute. In 2017. So, we've been in exile in Cheshire, in wonderful accommodation, I have to say, and oddly part, but not close to the Christie hospital. So, we've just moved back into the most extraordinary research facility. In the Christie Hospital site with all our colleagues who do cancer research from the faculty. It's brilliant to be there. It's brilliant to be back and all the sort of collaborative research that I do is done best right where we are now.

 

Sally Best

Yeah, it's fab and for those of you that don't know the Patterson burnt down, as Caroline said in 2017, and there's now a flagship build, which was a 150 mil build and it's incredible. It's right on Wilmslow Road and I got a little tour of the biomarker centre which we'll talk about, and it was incredible. I was like an energised puppy looking around all the labs. It's a great space and like you say, there are so many different teams in there because it's got the CRUKMI, some of the Christie, some of the MCRC, some of the uni. So, it's just this massive collaborative space which we’ll come on to talk about the benefits of that and the benefits of that close proximity research. But I mean, just to get started, are you okay to tell our listeners a little bit about you, what you do, your responsibilities?

 

Caroline Dive

Sure. I mean, I started my career as a pharmacist. I trained in London in pharmacy. I then decided after being fully trained that actually I wanted to do cancer research. And the sort of motivations for that is personal, as it is with many people. Cancer touches most families lives sooner or later. For my family, my maternal grandfather died of a brain cancer just a few weeks before I was born. Had a devastating impact on my mother and I did think at the time when I when I just finished my pharmacy training that I actually wanted to go and do something about it. So, I went into cancer research. I did my PhD in Cambridge with Paul Workman, but when really working on drug resistance, cancer drug resistance, and then I took a career path which was a little bit unconventional, I completely missed the postdoc piece. I went from being a PhD student to a principal investigator. That was very stressful. I can imagine. That's when I decided perhaps, I should swim. I studied apoptosis or programmed cell death, as it was then called, and that was quite a new subject area at the time. So, I spent more than a decade doing really fundamental curiosity-based research. Moved to Manchester 1990 I think and continued to do that for some time. And then Nick Jones, who was then director of the then Paterson Institute here at the Christie Hospital site, asked me if I would like to join the institute. So, I stopped being a division chair in what was then the Division of Pharmacology, Physiology and Toxicology. Completely restructured of course, the faculty now and I moved over to the institute and one of the things that Nick wanted me to do was to work with the phase one trials unit at the Christie Hospital. He knew I'd been a pharmacist in the past. He knew that I was used to working with clinicians, that I'd done that in my training, and he wanted to me to work on a Friday afternoon to do pharmacokinetics, to look at clinical trials, to find out how long drugs stayed in bodies and whether they worked and do that kind of research. So, I came with a basic science research programme but gradually realised and it didn't take long to realise that once I was here, Patterson Institute on the Christie Hospital site personalised cancer treatment was just coming over the horizon at that time. Back then in the early, well late nineties, early, early, 2000s and we didn't really have what I would call that much biomarker research going on in the institute. So there was incredible opportunity to build a cancer biomarker centre. and that really started to get going in about 2005. So, I've been doing that for quite a long time. It's been it's been my life's work pretty much. And we are where we are today in a brand-new cancer biomarker centre in a new building. And yeah, so that's a quick tour of how I got to where I am

 

Sally Best

I love that little synopsis of Caroline Dive’s life and I mean; did you plan on staying here this long in Manchester?

 

Caroline Dive

I come from Sussex, and you know, it's a lovely place. Yeah, I didn't I thought I would come to Manchester for three years. And three years has become well, I came in 1990

 

Sally Best

So, we can do the maths. Yeah.

 

Caroline Dive

Yeah. I think, you know, I love it here. Best place to do what I do. I truly believe that in the country, I think to do the work that I do. The University of Manchester, its medical school and the Christie Hospital with the Cancer Research UK, Manchester, you put all that together and it's the very best place for me to do what I do and that's why I'm still up here in the north. But I still can't have gravy with chips

 

Sally Best

Oh, God, Caroline, come on, you can't. Cheese on top. It's got to be. Well, so you've mentioned the cancer biomarker centre. Can you tell me a little bit more about that? And also, maybe kind of a brief overview of what exactly a biomarker is for those people that aren't too sure?

 

Caroline Dive

It's a pretty much a catch all term. And I think most people would think about biomarkers when they think about that. They would think about it's just a test. Yeah, so it's just a molecule of molecules measured objectively, usually in a clinical sample, but it could be in a preclinical model. That tell us a little bit about whether a patient is healthy or has a disease. Doesn't have to be cancer biomarkers for all sorts of diseases. It tells us how that patient might do their prognosis. It may tell us what type of therapy they will respond to. It might tell us whether they're at risk of a toxic side effect. It might help us to diagnose cancer early. Yeah, early biomarker, early detection biomarkers. So, biomarkers are a whole range of things. But essentially molecules, a molecule measured in a clinical sample usually that help us support the management of a patient.

 

Sally Best

Okay, so go on. Tell us about the CBC.

 

Caroline Dive

So, the CBC has just grown and grown. So, when I first arrived and I was supposed to be doing that pharmacokinetics for the Phase one trial unit on a Friday afternoon, it did become clear very quickly that there was this massive opportunity to develop cancer biomarker sciences here in Manchester. We started by thinking we would get tumour biopsies, bits of patient’s tumour to study, to try and understand the biology of each patient's tumour, and then to try and figure out perhaps what the best drug would be for example, one of many things we thought we would be able to do and actually it became very clear quite quickly that we didn't get tumour biopsies very often.

 

Sally Best

Yeah.

 

Caroline Dive

So then that sort of pragmatically led us to start thinking about measuring biomarkers or tests in blood. And everyone's heard of prostate specific antigen or PSA. Yeah, it's a classic example of a blood-based biomarker. We now call them liquid biopsies. Yeah. So not tissue biopsies, but liquid biopsies. And this whole field has just exploded. In cancer research. And I think, you know, it's been a long time coming, but we were somewhat one of the earliest groups that set up labs to develop liquid biopsy, to predict responses, to measure responses is a patient responding or not? And difficult to do that if you don't get not just one biopsy at the beginning, but then another one as they go through their treatment. But of course, you can much more easily get over and over a sample of their blood to study. So that's what we've done a lot since the beginning of the biomarker centre. We've tried to develop an expertise in this liquid biopsy approach and the two major types of measurement we make in blood are circulating tumour cells. Or circulating free tumour DNA. Okay, so this is DNA that's been shared from a patient's tumour as a result of the proliferation and cell death that goes on in tumours that that DNA shed into the bloodstream where we can find it. It's tricky because we have to make sure it's tumour DNA. And it's still a very vanishingly small amount of the DNA that's in the blood. So we have to have sensitive methods to find it and measure it and that can tell us what type of mutations a particular patient's cancer has. And that in turn can help us determine what type of therapy might be best for that patient.

 

Sally Best

Okay. So, you've said about the circulating free tumour DNA, so why is there a higher level of that in the blood? why do tumours release DNA into the bloodstream? Is it known?

 

Caroline Dive

Well, it's a good question. It's not precisely known. Yeah, and I think a lot more research is needed to find out more about how and why tumour DNA shed into the bloodstream. It's thought that it happens when tumour cells die, but the amount of tumour growth is a balance between how rapidly the tumours proliferate. And how many of those tumour cells are dying and both proliferation and death and the balance of those two probably important parameters for how much circulating tumour DNA there is in a patient's bloodstream. And it varies depending on what type of tumour they have, because some tumours are good at shedding circulating tumour DNA into the blood and other tumours less good. So, it may or may not be the answer to everybody's tumour. But I think for many tumour types now all over the world people are measuring circulating tumour DNA to monitor how well a patient's responding to therapy. So, do the levels drop?  If the therapy is working, do the levels come back up again? If the tumour, becomes resistant. And it starts to come back. So, on a simplest level, elements of circulating tumour DNA measurement can just tell us perhaps the reflection of how much tumour burden the patient is carrying. but also, by sequencing that DNA, it can tell us, well, these were the mutations they had at the beginning and that's why we gave them a certain type of targeted therapy. But now as they become resistant, there are different mutations potentially. So, it's a way of tracking how a tumour changes over time though therapy.

 

Sally Best

And I can imagine that's very, very useful to know in terms of the specifics of the treatment that you're allocating. And we'll come onto lung cancer.

 

Caroline Dive

But it’s even more exciting than that. It’s when to stop treating with a drug and start treating with another one. So, you know, there are lots of ways now that liquid biopsies are being used. The one that's very much in the public eye at the moment is Grail., a liquid biopsy for early detection of cancer. You know, and I think we all sign up to the I'm sure it's completely true that if we find cancer early, we have a much better chance of that patients seeing cure.

So that's probably one of the most important utilities. And developments in the liquid biopsy fields for sure.

 

Sally Best

And I've just got a couple more questions about liquid biopsies in particular. So, I'm just wondering what is the sample size that you'd have to take? Does that adjust and how long does it take to process that sample? Because I mean, if a patient comes in and I guess it's kind of beneficial if it’s processed within a short space of time so that treatment can alter or whatever with in that short space of time, I don't know the specifics.

 

Caroline Dive

The field is maturing, so a lot of the research that goes on with liquid biopsy is in clinical trial activities to actually try and test to see whether this new liquid biopsy is going to be useful in routine use in the NHS, for example, in this country. So, we have to do an enormous number of experiments in a lot of patients to be sure the test does what it says on the tin. Yeah, we can't just use you know, a lot of the work is in research mode, and you know, a lot of biotech companies are also developing liquid biopsies and we work with some of them. And the idea is to do enough testing of the new test. to make sure that new test is going to be clinically useful. So, for the last, you know, in the early detection space, the last thing you want to do is tell someone they have a cancer and actually they don't.  And your test is Not accurate. So, there's a lot of work that needs to go in. It's called validation. We have to set up big, well-designed clinical trials to actually prove the liquid biopsy does what you want it to do accurately, robustly, reliably. Reproducibly ground truth.

 

Sally Best

Yeah, exactly. Exactly. A lot of work and just going back to your research area of expertise. So, you're in small cell lung cancer, which is around, if I'm right, 10 to 15% of the lung cancer population. And is it the most aggressive type?

 

Caroline Dive

It is. I mean, the biomarker centre works across all tumour types. But yeah, part of my research group is very focussed on small cell lung cancer. And we got to that almost by some sort of lucky happen chance because I worked very closely with Professor Fiona Blackwell Yeah. Who is the most incredible thoracic oncologist who has a real deep understanding of lung cancer biology, as well as the clinical application and the treatment of patients. So, she and I got together in about 2006, I think if I remember correctly, okay, I was getting the biomarker centre going and she'd come back from Toronto where she'd been doing training in cancer research, lung cancer research, not just the clinical part. The laboratory part too. So, she's one of those clever people that can do everything. And she and I got together, and we were interested in, we just bought a new technology at the time it was called Cell Search, and it was a technology that allowed you to find and count circulating tumour cells from a sample of a cancer patients blood. And the very first sample that we ran through this new technology, back then just happened to be one of Fiona's patients who had small cell lung cancer. And what we discovered is, you know, we all knew that circulating tumour cells were going to be vanishingly rare. So, zillions of blood cells in a blood sample because that's where they live. And occasionally a rare circulating tumour cell. So, we were quite surprised in some of our first samples from small cell lung cancer patients that actually there were quite a large number of circulating tumour cells. So, we shouldn't have been so surprised because we know this, as you said, the most aggressive of lung cancers. It is metastatic very early. Yeah. So, most patients who present to the clinic have already got metastases. So maybe it's not such a surprise that we found quite a lot of circulating tumour cells because that's how the tumour that starts in the lung moves around the body against other sites. So maybe it wasn't such a surprise, but it was, it was perhaps quite lucky because we then went on to sort of count them, realised that the number of these circulating tumour cells was related to how, how long a patient will live. Yeah, we, we found out that the number of these circulating cells disappeared when you gave the patient their first cycle of chemotherapy because most patients respond quite well at first. And then we discovered that those circulating tumour cells went up in number again as the patient starts to become resistant to the chemotherapy, which almost all patients with small cell lung cancer do. So that was the sort of basics of well circulating tumour cells, a barometer, if you will of how a patient with small cell lung cancer is responding to that treatment. And we've got much more elegant with our study since then. And I guess the biggest breakthrough that we made the team with Fiona's team and our lab-based team, as we really started thinking about what more can we learn from these circulating tumour cells? And because small cell is the disease, it is, it's very aggressive and it's very hard to get tissue biopsies. You know, it's not so much like breast cancer where a tissue biopsy is a lot easier. These are deep seated in the lung, and you can't really keep going deep seated into the lung and taking a piece of tissue. And even if you do, it’s very small. And they're quite necrotic. So, they're difficult for a researcher to work with. And doing it over and over again is not really an option. because we know that patients respond to the chemotherapy and until very recently that was all that was really available for them. Immunotherapy is making some impact, but not a huge impact. So going in and taking tissue biopsies isn't really ethical even. It’s really what you would do is as a routine in small cell lung cancer. But the fact there are so many of these circulating tumour cells made us think, well, how do we get to study the biology of small cell lung cancer? How can we do that when we don't get tissue biopsies hardly ever. So, what we did is we, we found the circulating tumour cells, we tried, we did some experiments to remove as many of the blood cells from the blood tube that we can. So, we try and rich would find as many circulating tumour cells and as few blood cells. It's not perfect, but then we take that enriched circulating tumour cell sample and we put that into a mouse, and we grow what effectively looks exactly like the patient's tumour. In a mouse model that we can then study. So, one of the other things that's it's really, really, really challenging in the clinic for small cell lung cancer patients is many of them get metastases to the brain.  we're getting a biopsy out of the brain. The human brain. Really hard, so. And it's devastating. You know, it's a really big unmet medical need, as is the treatment of small cell post piece. But what we can do now is we have models where we can get those brain metastases in the mouse. We can study the biology. And only by understanding the biology of any cancer can you really, truly get new therapies that have a good chance of being effective. So, I think the landmark change for us was understanding that there were lots of circulating tumour cells compared with any other cancer type that we'd studied and that we could get more out of this finding than just counting them. You could actually make new models with them. And really begin to much better understand the biology of this really aggressive disease. What I'm really pleased to say is, you know, this methodology that we do, these models that we call CDX, everybody thinks they stand for Caroline Dive Xenograft, they stand for circulating tumour cell patient explants. Anyway, that's beside the point. This new methodology for making these CDX models from circulating tumour cells is now, you know, being developed across the world. So, I was really proud of that discovery. I think the team that put all of that together wasn't just me, it was a big team. Yeah, you know, I think we have made a step change in understanding the study of small cell lung cancer. Yeah, and we have, I think, some of the unique brain metastasis models now, and we're very, very busy in the lab trying to understand what does a tumour cell have to do to get to the brain to stay there, to survive there, and then to grow there? So, what changes in the biology has to happen for a brain metastasis to grow? And it's absolutely fascinating. I won't talk about it in detail today, but we're beginning to understand, what those processes are, and you know, and the hope will be that one day we'll understand it well enough to figure out how to slow it down. Or stop it.

 

Sally Best

Yeah, well, you say that I was thinking this before our talk. I was like, what can I talk to Caroline Drive about that will fit within an hour slot. And it's, you know, you've got to really blooming pick. And we've chosen to focus on lung cancer, but maybe it'll be something else on another episode.

 

Caroline Dive

But yes, there’s more actually, because, you know, the big discovery in small cell lung cancer worldwide is when we think about, well, actually let me change tack a bit. When we think about breast cancer or even non-small cell lung cancer. If you think of a pie chart, we can say that a patient's tumour fits somewhere in a segment of that pie chart. So, there are different types of breast cancer. There are different types of non-small cell lung cancer. But we just had one pie charts for small cell without any segments. Just small cell and everybody got chemotherapy. Like I say, patients, some patients respond to immunotherapy, but not the vast majority of small cell lung cancer patients. So, we had no segments of the pie. And we do now. So just recently the whole field is it's a very tight knit group across the world that study small cell lung cancer because it's a really difficult, really difficult topic. And we've all got together and collectively we've come up with a new classification of stem cell lung cancer, which was published in Nature Reviews recently. But they're based on what's called transcription factors. So not based on mutations, based on transcription factors, and there are at least four or maybe five subtypes. And the hope is, and the studies are beginning to suggest that different subtypes will respond to different types of drugs differently. So now there's a chance that we could stratify or pick the right patient for the right drug for the first time in small cell lung cancer. We're not there yet, but it's coming. For the first time in 30 decades, there's been a step change in the way we think about the treatment of small cell lung cancer. So, what we decided to think about then was, well, we need a blood test because of all the problems with getting tissue biopsies. We need a blood test that tells us what subtype they are. So, the very recent publication from our group, we've achieved it. We've managed to do that from the blood. So, we and this is going back now, not to the circulating tumour cells this year, going back to the T DNA yet. So, what we can do now is not just measure, is it there, is it not there or what mutations are present. We can actually measure molecules which alter the profile of that circulating tumour DNA. So, it's called methylation. Methylation groups or molecules onto DNA, that changes how we recognise that DNA. and that's important for lots of reasons. One is it tells us where in the body that circulating tumour DNA comes from. In this case from the lung. But more than that, we now have developed these profiles of the circulating tumour DNA that tell us which subtype it is. so, working with pharma, working with biotech, new trials will be coming forward where when we fully validated this test. So, we just, we've just started on a journey with this. So, we've got lots of new samples coming in from around the world, from clinical trials in small cell lung cancer. Where we now can test all tests. Yeah, and if that works out, the next step will be a new clinical trial going forward where we take the blood, we say it's this particular subtype and therefore this might be the best drugs for that patient. For the first time in the history of small cell lung cancer. So, this is not just my group, obviously. This is a global effort. Yeah, but I'd like to think we've made an important step forward in it.

 

Sally Best

You really blooming have and just, just a kind of simplification of that. So, we've got our circulating tumour DNA, which is just DNA, the instruction manual of a tumour cell, and within that we've got the, the bases which is a A, G, C and T, I don't know how far people go back. You might have learnt that in GCSE biology and the methyl groups that you mentioned, so they will attach to the DNA.

 

Caroline Dive

and they, they instruct gene expressions. Whether a gene is on or off. And whether a gene is on or off tells you a little bit about which tissue it’s in. We can use this in lots of ways. So, I'm telling you about how we might subtype small cell lung cancer, but there's another tumour type where this is going to be really, I think, important. And that's called cancer of unknown primary. So, we're working with our colleagues in the Christie. Natalie Cook is leading from the clinic and we trained a clinical fellow in the lab called Alicia Conway, and together with the team in the cancer biomarker centre, Dominic Rothwell, Simon Pearce, lots of people with lots of different skills came together to develop a new test, and that is to use this circulating free DNA methylation that we were talking about to find out where ,so the patient presents with a metastasis, but no one knows where the original tumour came from. and to know how to treat the metastases, it's really important to know where the original tumour came from. And now because these methylation on CFDNA and they give us a postcode, we can infer where that metastasis came from. So, we can say it was a colon or it was a prostate. it was a breast. Because once you know that and you know the mutation landscape through the mutations in the circulating tumour DNA, you can now say, well, if this was a cancer of unknown primary from the colon with this particular mutation, the best therapy would be, it’s that approach that we've developed as well. So, the nice thing about becoming so focussed on liquid biopsies is you start to think about all the different clinical utility. So, whilst we focus on small cell lung cancer biology. And liquid biopsies for small cell lung cancer treatment, what we learnt there helped us develop a different test for a different clinical question. So, we try and go for the really difficult clinical questions that really need an answer usually.

 

Sally Best

Yeah, it's amazing. And I think looking into small cell lung cancer as that thing that was treated with platinum-based chemotherapy and like you say, you know, the prognosis for it has been poor in the past and it's looking to the future and looking at specialising because as soon as you know, the subtypes of a type of cancer, your treatment changes and that is the precision medicine.

 

Caroline Dive

that's the anticipation. We have to do the experiments clinically and pre- clinically. To get there. It’s hope where there wasn't very much. Yeah. The last 30 years that treatment will change small cell for sure.

 

Sally Best

And just looking back at the CDX model so that was in 2014 was it.

 

Caroline Dive

That's when we first started. So that first eureka moment where you grew, we were just so excited that we developed these new models

 

Sally Best

and you were the first group ever to do that.

 

Caroline Dive

We were the first group to do it in small cell lung cancer. There had been a group in Germany that had done it for breast cancer. But we made hundreds of attempts to make one model because the circulating tumour cell count in breast cancer is much lower. And those cells don't appear to be quite as tumour genic in the mouse model says that small cell lung cancer. So, we can, we can go down to just five cells back into the mouse and they'll grow the tumour. So, they are really, really aggressive in the small cell.

 

Sally Best

And is that higher in small cell because of the high metastatic rate?

 

Caroline Dive

I think I think that's the clear indication. I think, you know, when we think about these, these cells, they're neuroendocrine and they undergo quite a lot of plasticity changes. And what I mean by that is if you think about caterpillars and butterflies, yeah, their genes don't change, their mutations, nothing changes at the DNA level. But the post DNA level, everything changes. And a caterpillar looks nothing like a butterfly. And we think the small cell lung cancer cells are very good at going from caterpillars to butterflies, if you will. They can mimic for example, one of our other discoveries is that they can mimic endothelial cells. So, they start off as neuroendocrine type of cell, and then they can undergo a switch to non-neuroendocrine. And when they're non neuroendocrine and different, they behave like the cells that make blood vessels. So, we think they can make their own vessels inside tumour to get nutrients and oxygen to help the tumour grow and that's an example of what I would call functional plasticity. So that's the tumour cell mimicking another cell type. For a particular function. That's to the benefit of the tumour. So, we're pretty excited about that, you know. But, but these, these small cell lung cancers, this is why it's difficult to treat. Because it's a moving target. We have to think of combinations. So, what would they be, what would be the drug that would treat it when it's neuroendocrine it might be a different therapy When it switched to non-neuroendocrine. And if the tumour is composed of both of those phenotypes, then we might need a combination therapy that hits both. You know, so there's lots to think about once you start understanding the biology, you can start thinking about how do you treat this tumour? and that's very much, I think, completely important because you know, the CRUK Manchester Institute does really fundamental biology research, cancer biology research as well as the biomarker centre that's much more translational. Sitting in between that basic science and the clinic, and that's where we come back to the new building. Because that's the synergy that we now have in that new building between the folks doing curiosity driven, fundamental basic science. someone like myself that sits in the middle on the bridge to the clinicians. And it's that backwards and forwards between clinical, translational and basic research going in both directions that I think generates progress.

 

Sally Best

Bench to bedside then bedside to bench

 

Caroline Dive

both directions.

 

Sally Best

Could you just explain a little about what a neuroendocrine cell is?

 

Caroline Dive

It depends on where the cell originated. So, for small cell lung cancer, the main cell of origin is called a neuro endocrine cell body in the lung. So that's a specialist type of cell that's in the normal lung. And it's there where the first, if you will, mutagenic events take place that drive small cell lung cancer.

 

Sally Best

Okay. Interesting. Cool. And then just CTCs again. Sorry, I know we are jumping around, but it's fine. The case study that I'd like to focus on is CTC’s post tumour resection. So, did you do a paper was on small cell lung cancer where you monitored CTC since circulating tumour cells post resection of the tumour in the lung?

 

Caroline Dive

that was in the preclinical model. so that's how we ended up trying. It's how got to the point where we can really study brain the brain metastases, okay, so you can grow the tumour and the tumour gets to a certain size, you can take it off the mouse, the mouse stays alive, but that mouse already is seeing circulating tumour cells move around. And you wait. And then that mouse may develop a brain metastasis or a liver metastasis. that gives you a really interesting question that you can start to study, which is what is it special about the tumour cells that go to the brain and are they different from the tumour cells that go to the liver? And is the adaptation to the brain environment clearly different from the environment of the liver? So what do those tumour cells have to do to grow in the brain that's different from what they have to do to grow in the liver. So again, all of those questions are hard to address. So, what we do is we have our preclinical models that we can study and do function testing experiments in. So, one of our subtype molecules we can knock out in the mouse model and say, do those cells still go to the liver? And the answer is no. So that says that that very important molecule has a role to play in liver metastasis. So, there's lots of ways where we can have the preclinical models and the collection of clinical samples, and we go backwards and forwards between the preclinical model and the clinical samples. Is what we see in the preclinical model relevant to what's happening in a patient because that's what we're striving for., you know, and what we see in the patients’ samples is that there's a brilliant protocol nationwide. I'd run from the Crick and UCL within the Lung Cancer Centre of Excellence with us in Manchester by Charlie Swanson and Mariam al-Hasani, working with Fiona Blackwell and myself called Peace. They’re there when folks past sadly passed away, they've given permission for autopsy or for an autopsy. that's the only chance we've got of getting a brain metastasis from a human being. Yeah, but does that brain metastases from a human being look like the brain metastases that we've developed in our model? So, it's a way of validating preclinical models to make sure that patient relevant, if that all makes sense. Obviously, we don't want to use the mouse models that are not relevant to the patient. I'm sure that's the piece that we need to get right. It really is incredible stuff. And you think about yeah, 2014 that the inception of this in small cell lung cancer and then I guess it is a signifier for prognosis of that you know the high levels of CTC’s post resection and maybe if you've got a brain and liver metastasis, I guess we don't know that because most patients who have small cell lung cancer don't have surgery. When they’re diagnosed, it too late for surgery. So that's the that's why and again, we don't get very often resected material from a patient to study. So that's the challenge and that's why these circulating tumour cell models are, I think, a step change in understanding that biology that we wouldn't otherwise have the challenge of the opportunity to study. We can put tumour cells in plastic dishes, we can grow them in the lab, but the plastic dish doesn't really look much like a patient. So, you know, we can do certain things with cell lines in plastic tissues, but I think we want to have a more elegant model than that

 

Sally Best

It's amazing. So, I mean, you've talked about the use of biomarkers here, so we've specifically focussed on CTC’s. And I'm wondering what are the current barriers that you envisage to getting those liquid biopsies into the clinic and used in a more routine manner that could be, for instance, a patient having early detection or the tracking of their prognosis, the tracking of how that treatment is going. What do you envisage as the barriers?

 

Caroline Dive

I mean, it's quite a hard and long road because as I said, you have to test the test. So, you have to design really good clinical trials to test the test and you have to show that the test works because otherwise you can't. Why would you use a test that you're not sure about routinely? So, you know, it is it's a bit like drug discovery. You know, you start off with lots of possibilities and you end up with very few that make it all the way to the clinic. Because it's a difficult road. And the same is true of these liquid biopsies. We have to validate them when we have to make sure that they're accurate. So, so those are and sometimes take years to do the early detection experiment. So, there are many companies around the globe, including GRAIL and the gallery test in the NHS. Thousands and thousands of participants in that in that experiment. To find out does that test detect cancer early? How many cancer types does it detect early and how early does it detect them and how often does it detect them early? all of those questions will come out of that huge experiment. it will take a lot of money and a lot of time and a lot of people participating to get there.

 

Sally Best

Yeah, and I think we've spoken to people before that have got that, you know, research into clinical practice or change guidelines and things and the actual process behind is arduous and so, so convoluted in the sense that if you're you know, working with NICE or NIHR and all to implement in the NHS, you need your evidence basis you need your economic modelling and things such as that take years

 

Caroline Dive

Not my areas of expertise at all.

 

Sally Best

No. And they wouldn't because you've got loads of other areas of expertise.

 

Caroline Dive

But that's, that's the route there is a road map. But it's a hard long road. we just have to keep, keep plugging away until we get to the point where we're confident and we've proven with evidence that the test works.

 

Sally Best

And I mean, what are your kind of future hopes of a CBC? Like, what is this road map that you speak of?

 

Caroline Dive

Well, I think I think, you know, we have about 100 staff at the moment. And what I'd like to see in the coming five, ten years is that we become will be more populous. We want to increase the number of folks that we've trained to be specialists in cancer biomarker sciences. We want to think a little bit more about a wider scope, the types of molecules that we measure. We haven't even thought about the microbiome. So, the influence of bacteria and so forth on, on tumour at the institute who is beginning to get into that space. the basic science has to give us enough information to understand how we might develop biomarkers in that space. And I think that will be very challenging. There's a whole new area of cancer metabolism. So how cancer cells change their metabolism to their own advantage to grow and to invade and to metastasise. And I think there will be biomarkers in that space that haven't been developed for clinic yet. And that's something we would like to expand into as the basic science evolves and we get more information so that we can really, you know, we don't want to be plucking biomarkers out of the air. We want to know evidence based. So, so that's another area. And I think what we want to do is increase the number of collaborations that we do. so, we're very collaborative already. I think I can't even tell you how many clinicians at the Christie we've worked with over the years. but we'd like to work with more folks with different areas of expertise and really expand our scope. So yeah, capacity and scope, new areas for biomarker development and it's all predicated on what is needed in the clinic. and that again is why having a biomarker centre at the same place as the Christie hospitals is ideal. because we have that constant connection with the clinic. So more and better is the simple answer to your question. But listening to the clinical needs, listening to our clinical colleagues, what do they need, what will clinical questions all the most important clinical. That need biomarker solutions. And being much more nationally engaged. So yeah, with most of the Cancer Research UK experimental cancer medicine centres. But again, to really be fundamentally working across that network across the country as well.

 

Sally Best

Yeah. And we've mentioned collaborations that the one that's come to mind is Tracer X because this has been in the news quite a bit and I know you work very closely with Charlie Swanton. Could you tell me a bit about the small cell cancer work that you did within that Tracer X consortium?

 

Caroline Dive

We worked with Charlie on non-small cell lung cancer predominantly. although the Lung Cancer Centre of Excellence that he and I direct between London and Manchester does of almost all types of lung cancer. But in Tracer X we sort of used our expertise in circulating tumour cells and I think one of the studies we did together with Charlie's teams and a huge national effort really was we asked whether, could you look at circulating tumour cells in early-stage disease, were they there. So everyone's, you know, in, in the past this would have been a thought that metastasis was a late event. Yeah, but actually it's quite clear now that circulating tumour cells are out and about quite early. So even in the earliest stages of non-small cell lung cancer and rather than taking the blood sample from blood samples from the arm, where we didn’t find very many. We took it from the pulmonary draining vein of when patients were having their tumour resected from the lung. this is, I think what you were referring to was so. So, when a patient has a tumour resected. just before the tumour comes out of the lung, surgeons busy, which we take some blood from the pulmonary draining veins. That's, that's the lung that drains the cancerous lung. This is the vein drains the cancerous lung. And we look at for circulating tumour cells there and we found them and when we found them the number that we found seemed to predict whether that patient's tumour after resection would come back and what the survival would look like. So, we think the number of circulating tumour cells early is a predictor of relapse. So that's the work we did in Tracer X and we're going to do more of it in Tracer X Evo. Which is the next big study between, between inside the Lung Cancer Centre of Excellence between Manchester and London. And again, we want to now test the test. So is that number of circulating tumour cells early at resection really predicting it’s really solid evidence in much more many more patients does subject relapse.  But we did a bit more than that. So, each single cell that we found in that pulmonary draining vein sequenced and what was really interesting is some of them didn't look like cancer at all. So, we've looked at those molecular profiles, they just look normal. So, they’re definitely epithelial cells not blood cells, but they're in the blood, which is odd. But they don't look like tumour. So, we don't know what they are yet and that's something else we want to find out. But the number of those and the ones that do look like tumour cells, that combined number predicts relapse. And then the other thing we did in a couple of patients is we, we, we did all that, we looked at all the mutations in each individual circulating tumour cell at that point that the tumour was resected. And we looked at mutation profile and what Charlie's team did was a resected tumour was cut into, into many pieces and they looked at the mutations in the tumour, the original tumour. And then when a patient got a metastasis, in this case ten months later, we compared the mutations we found in the circulating tumour cells. Mutations that Charlie found, and his team found in the, in the resected tumour. We said well what does the metastasis look like from that mutation file? And what we found is there were lots of mutations in the circulating tumour cells that we hadn't found in the original tumour because they were so rare. that they appear in the metastasis. So, putting all that together, it sort of says that these early circulating tumour cells are the architects, of the metastasis that comes later. So that springs another question. What are they doing in all that time. Presumably just sitting, not proliferating at some point. So, so there's lots of work that we need to do now in the next round of Tracer X, there’s huge study going on between London and Manchester which is going to be amazingly exciting. More brilliant science coming out. So, I think, you know, when Charlie and I started the Lung Cancer Centre of Excellence, well more than ten years ago now, there just weren't very many people studying lung cancer. It's difficult to study. Compared with breast cancer for. I'm not saying one is more important than the other. I'm just saying one is slightly easier to study. And you know, we felt because it was such a major killer cancer and so prevalent particularly here in the northwest. In areas of social deprivation, so on, you know, there just wasn't enough lung cancer research happening in the UK. And one of the things we wanted to achieve with the Lung Cancer centre was just to train more young, bright people to do lung cancer research and we've just a few weeks ago come back from York. So, every other year except in COVID, we take all the young researchers to York. And we have a couple of days where we all talk about science together and it's absolutely brilliant. You know, it's just wonderful for me to reflect on that over the over the past decade of how many young scientists we've trained in lung cancer research who are all doing amazing things now. So, and the number of students doing lung cancer research has really grown over the period of the Lung Cancer Centre of Excellence. And of all the things I do, I like training young bright things best. So that's particularly pleasing for me.

 

Sally Best

Yeah, like sponges. And I guess you've mentioned as well, because I had conversations with Phil Crosby in season one and he was talking as well about the lack of research behind lung cancer. And there's also that stigmatisation factor that breast was always funded really well and you've got a lot of breast cancer research funding. So obviously kind of.

 

Caroline Dive

Yeah. And I think you know what Tracer X and the lung centre have done this is balanced that out. All cancer research is important. Think of young women who get breast cancer. We certainly don't want to downplay that in any way. But an enormous amount of people have lung cancer. And we just didn't really have enough effort in that area. You know, with Tracer X and Tracer X EVO now beginning to rectify, have rectified I think in this country. So now the next challenge is the never smoker. Yeah, many people have heard Charlie Swanson talk about that. Yeah, that is another puzzle to solve. Yes.

 

Sally Best

We actually had Fabio Gomes on the episode before. So, you're talking about ALK positive never smoking. And yeah, like you say, it's that education piece, isn't it. And I think like you say, the more research that you do, the more research questions you develop. So, it's like catch 22.

 

Caroline Dive

The more of biology you understand, the more rational use of therapy you can, you can think about so yeah, it's been an extraordinary time here in Manchester. I don't regret any of it. I mean, you know, as I say, I'm a Sussex girl, but yeah, to do the work we do, this is the place.

 

Sally Best

Yeah. How many years do you think you got left? 40?

 

Caroline Dive

Oh, that's a horrible question! No, no. I think for me, you know what I'd like to think towards the end of my career, down the line is, you know, what do you leave behind? Did you do something meaningful? You know, and what I'd like to see is that cancer biomarkers tend to go from strength to strength. Yeah, there's every reason why it should. Yeah, that would be. I could look back on that and be pretty proud.

 

Sally Best

Your Cancer Biomarker Centre. Now I'm looking forward to seeing that to fruition and seeing what becomes of it because yeah, there are so many exciting things that I think are going to come from that. And you've, you know, you've laid the groundwork so well and like you say, it is in such great position. We've got the Christie for all this patient samples and things and the team are just phenomenal. Like even from walking around, I was absolutely blown away.

 

Caroline Dive

Well, I mean, I also like bringing the clinical side. So, we train we train folks who've come through a sort of a basic science route undergraduate. But I also really enjoy training the clinical fellows that come through. And often they come into the lab. They've never held a pipette before. You know, so for their very smart people. It doesn't take long to catch on and it's, it's really nice that what we can learn from them, what they can learn from us.

different languages, different training but one common goal. That's what really works, I think.

 

Sally Best

And yeah, and like you said, understanding the clinical needs. So, all your research questions are informed by that clinical need and the questions that clinicians are asking. Yeah, it's amazing stuff. And honestly, I think, you know, I've got a bit of a background in science and reading about all this and doing my research kind of pre-emptively before this I was just blown away by all the stuff that you guys do. And I think it's also understanding that even though things haven't seen fruition in terms of being applied in that clinical setting and you know, you've not got the biomarkers in a GP routine setting where somebody has a blood sample. You know, you look at the hope of things and you understand there is a lot behind it. There's that clinical trial need and the validation of, you know, the test site. You've said again and again and again. But it's the hope of understanding that things are looking really good.

 

Caroline Dive

Yes. And even in the phase one setting, which, you know, where patients have sort of failed all available therapies to and they go into this experiment that's yeah, phase one trial where a new therapy that's never been in a human before. They gradually increase the dose through folks coming through the phase where you need to find the right dose to make sure it's safe. You know, we're learning more even in that setting. So, I don't know whether you've spoken to Matthew Krebs who led the target trials in the Phase one unit. Now, that's nice because Matt was one of those clinical fellows that did their PHD with us, is now running what's called Target National. But what we collectively did there was we actually started to look at that circulating tumour DNA profiling in the folks that are being selected for a Phase one clinical trial. And whereas that was a little bit more empiric in the past, we can now say, well, this is the right clinical trial, this is the clinical trial for you that has the best chance of giving a benefit because we understand your molecular profile. So, we found a tumour sequence, but we've also sequenced for circulating tumour DNA and you put those datasets together. And that's help helping the clinicians in this case. Matt Krebs, who's running that trial helped pick the best trial for you. And it's not every patient that will benefit from that approach, but certainly some will. You know, and that whole process as well as the virtual molecular tumour board. Which is the sort of the dry science that we do in the biomarker centre by our digital team. We made, you know, we couldn't all get together in COVID to discuss all the data. But we had already developed a molecular tumour board that you could all have on your computer screen. Didn't matter where you were sitting. And you could all look at that data in real time together and discuss it. Yeah, that's called E- targets. Well, that's now been adopted across the country and Target National. So, you know some of the work that started off will you come on a Friday and do pharmacokinetics on Friday afternoon. You know this point culminated in a national Phase one clinical trial called Target National. Yeah, so you know it's been a journey, but you know things are happening

 

Sally Best

And there's a lot of things to be proud of there. I mean you must love looking back in the same sense that you love looking forward, but there's so many remarkable.

 

Caroline Dive

It just makes feel a bit old.

 

Sally Best

No, no, no. You've just crammed a lot into a few years.

 

Caroline Dive

But you know lots of new folks have come and joined us in Manchester and this whole team science. Which I know you spoke to Rob Bristow about. You know, it's something Manchester's really good at. And that's why I'm here. Yeah, I enjoy that collaborative spirit that we have here in Manchester.

 

Sally Best

Oh, it's great. Honestly, I think that's why I'm here too. I just. You love speaking to somebody, asking if they know somebody and they're like, Yeah, yeah, I did this paper with them. And you think, what the heck? But it's just amazing, you know,

 

Caroline Dive

Shout out to the Christie, you know. You begin to realise very quickly what an incredible place the Christie is. You know I've had so many people tell me how they had relatives who've been treated. Wonderful care they got. So, we are really privileged to have science and that Christie hospital right here.

Sally Best

I love that as well. It's quite a hard thing when you hear that somebody has had a cancer diagnosis, but I feel I breathe a sigh of relief when somebody tells me they're being treated in the Christie. And I was sent an email really recently and I just said, look, you're in the best hands possible. But anyway, just a question. What's your favourite biomarker, Caroline?

 

Caroline Dive

Oh goodness, I don't know. I think my favourite biomarker ultimately will be the one that actually makes a difference. So, I think this this blood test we're developing a cancer of unknown primary. I think we've got a lot of work to do, but I think that has a real opportunity because, you know, patients who come in with a cup, you know, what my clinical colleagues tell me is it can take almost a year sometimes to get a diagnosis. Whereas I think in two or three weeks with a blood test, if it works as well as I think it's going to. That needs evidence. But if that comes to pass, you know, you could be giving them a diagnosis or at least informing your clinical colleague who's looking after that patient. This looks like it's come from whichever organ and give them information that really helps them make a treatment decision for that patient in a much quicker way than the current practice. So, we will do an enormous amount of work to get that through. Yeah, I think, you know, I can see the potential for that blood test, if we get to a point where we can subtype small cell lung cancer with a liquid biopsy, put folks on to, targeted therapies that have the best chance of giving them a good effect. Yeah, that will also be something I think will be incredible

 

Sally Best

So just to summarise our discussion, I guess these biomarkers are detection agents, subtype agents and looking at the prognosis and relapse potential of a cancer response.

 

Caroline Dive

You know how a patient responding when to switch therapy because the tumour is evolving and becoming resistant? When is the tumour coming back after surgery? Yeah, there are lots and lots of ways that the biomarkers can, can help support patients. You know, in our biomedical research centre in Manchester, which was a huge effort by so many people to have that increased in scope and amount of funding in Manchester just recently we’re in year one now of BRCA two, you know, there are four cancer themes, there's cancer precision medicine that I lead on this early detection. Emma Crosbie, advanced radiotherapy and living with and Beyond cancer, which was the new one. And you know, actually the, the journey for someone who's had cancer now it is a long one you know. You might get a secondary cancer; you might have cancers come back. Years and years after your, your treatment. So, so having biomarkers that you can use in the longer term. To live with and beyond cancer. That's a really important area and I think John and Kim really, really are developing that well and obviously playing some role in that one as well. So, so biomarkers really can be used right across the entire spectrum of cancer patients from early detection all the way to living with and beyond. Yeah, we've got plenty to keep us occupied, that's for sure. And let's not forget that it completely changes, the invasiveness of the investigation as well, because, I mean, some people might not like blood tests, but they are certainly a lot less invasive than a resection or surgery. You know, we will still need tissue biopsy. We will still need to know that what we're measuring in the blood is relevant to what's in the patient's tumour in an area where it's particularly difficult is immunotherapy. So, one of the things that's a big goal going forward is how do we develop predictive biomarkers to tell who's going to benefit from immunotherapy, the re-awakening of a patient's immune system to tackle their cancer. You know, and there's been some incredible developments, as you know, in oncology with immunotherapy. And some patients get remarkable responses that are durable, and others don't. and we don't really know yet how to pick the winners. You know, so and who is not going to respond, and we don't want to give expensive and sometimes toxic therapy to patients who are not going to respond. So it's that predictive biomarker for immunotherapy which is a huge ambition and goal that we must tackle. So, whether we'll need a tissue biopsy or whether we can do that in a blood test remains to be seen. But the tissue biopsy obviously gives you the whole microenvironment, including all the immune landscape. inside a patient's tumour. And that's when we're going to need to really understand if we're going to develop biomarkers.

 

Sally Best

Great. We'll be talking again Caroline. So, my two final questions are quite personal, but I guess it's just, you know, you talked about your granddad and that inspiration behind becoming involved in cancer research. How does it feel to know that, you know, you're benefiting such a vast patient population?

 

Caroline Dive

Well, yeah. I mean, you know, cancer research, very few of us that end up with, you know, few folks who end up with a Nobel Prize. Understanding immunology enough to think about these therapy agents just being one clear example. A guy that figured out how cells defined being other folks who did the structure of DNA. You know, we don't end up with Nobel Prizes, that's for sure. So, everyone makes their contribution in small, iterative steps. You know, I actually think training. Training the next generation. One of the ways I've perhaps made the best contribution. You know, and I'd like to continue to do that. But I think, you know, looking back on a career, you just want to make sure you gave it all you had. You know, I think that that's, I think the thing that drives me nuts is laziness and boredom. My two most hated things. If I ever feel that in myself, I get very upset. So, I think, you know, it's just giving it everything. Giving it your very best shot. Yeah, for sure. That’s what a career in cancer research should be about. So, you know, we're not all going to when will win Nobel Prizes, but we all make a contribution in our own ways. And for me, training the next generation is actually really important.

 

Sally Best

Yeah, for sure. Yeah. Teachers are the most valuable people because otherwise, how are you going to have a succession to anything?

 

Caroline Dive

And that life is ironic, isn't it? Because my own father died last December of cancer, of unknown in his liver. And so, I was a bit fed up with that for all sorts of reasons, obviously. But I wish I'd just got my blood test done a bit quicker. he drove discipline into me.

 

Sally Best

Caroline you couldn't have done it any greater. I'm sure you're very, very steadfast in the way that you move, but I'm sure he'd be absolutely blown away by what you're doing now. And I guess my final question is, how did you do it all? I mean, you've already said you don't like boredom or laziness, so I'm kind of anticipating that you have a very fast-paced life.

 

Caroline Dive

Everyone asks that question. It's quite a difficult one. I just do. I don't know. I don't know how to answer it. I, you know, I did have a very disciplined childhood. My dad was in the Army for a long time. So, it was never there never any unstructured time. Then I guess I've learned important lessons of how to be self-disciplined and organised. If you ask my husband, he will just laugh because I'm very disorganised at home. But no, I love being busy. Yeah, I don't like time wasting. Yeah, you know, I'm either busy on the tennis court or I'm busy at work or and you know, I like to travel. I don't often sit down and do nothing. Because I just don't enjoy sitting down and doing nothing. So, I don't know, I guess the default position is busy.

 

Sally Best

Yeah. No, I'm the same I have, I have to occupy my brain at all times. It has to be occupied. I have to be doing something. And you know, some people aren't like that, but if you are, it becomes the par for the course. You have to you have to do things.

 

Caroline Dive

I think I quite like problem solving. Yeah. You know, so my daughter tells me you don't have to solve every problem, you know? Yes, I do. It's kind of who I am. So yeah, I do like to solve problems. And I mean, it's an exciting legacy that you have at the minute, and it will be very exciting in the next five, ten years as well

 

Sally Best

Watch this space.

 

Caroline Dive

Watch this space. Well, honestly, thank you so much. I know it's difficult getting time in your diary and I really appreciate the time that we've had with you today. And I hope people have really enjoyed. For anything that we've mentioned I will link it in the show notes, the papers, Tracer X, and also just get on, have a bit of a read about the biomarker centre because there's some exciting things that are going on there for sure.

 

Sally Best

But honestly, thank you for your time, your input, your wise words and a bit of a background about you. It's been really great to delve into the world of, Dive into the World of Caroline. Dive. Okay, Thank you so much. And we'll see you next time. Bye bye now.

 

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 heard today.

 

Please see the show notes 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 and Advanced Materials, biotechnology, cancer, energy and global inequalities go to Manchester dot ac dot UK forward slash beacons.

 

Professor Caronline Dive complted her PhD studies in Cambridge before moving to Aston University’s School of Pharmaceutical Sciences in Birmingham, where she established her own group studying the mechanisms of drug-induced tumour cell death. She then moved to The University of Manchester to continue this research. Caroline was awarded a Lister Institute of Preventative Medicine Research Fellowship before joining the Cancer Research UK Manchester Institute (CRUK MI) in 2003.

Currently, she is Interim Director of the Institute and Director of its Cancer Biomarker Centre, with research spanning tumour biology, biomarker discovery and preclinical pharmacology, alongside regulated laboratories for biomarker assay validation and qualification within clinical trials to Good Clinical Practice standards supporting clinical decision-making.

Caroline was awarded the Pasteur-Weizmann/Servier International Prize in 2012 for her Biomarker Research, the AstraZeneca Prize for Women in Pharmacology in 2016 and was presented with the 2019 Heine H. Hansen Lectureship Award by the International Association for the Study of Lung Cancer (IASLC).

In 2018, Caroline was awarded Commander of the Order of the British Empire (CBE) for her services to cancer research. Most recently, she became an elected member of EMBO (2020), received the inaugural Johann Anton Merck Award in recognition for exceptional contributions to the field of preclinical oncology (2020) and was the recipient of the Mary J. Matthews Pathology/Translational Distinguished Service Award by IASLC (2021). Caroline was President of the European Association for Cancer Research from 2020 – 2022.

The CRUK MI Cancer Biomarker Centre

Professor Caroline Dive's research profile

cfDNA methylome profiling for detection and subtyping of small cell lung cancers

The evolution of lung cancer and impact of subclonal selection in TRACERx

Pulmonary venous circulating tumour cell dissemination before tumour resection and disease relapse

Sally Best

Hello, everybody. Thanks for joining us for our first episode of season two, which is focusing on lung cancer. Very exciting. I'm really excited to be hosting the series and talking to an amazing and erudite selection of people, including the one and only Colin Lindsay. God we’re already at Season two. How are you feeling?

 

Colin Lindsay

All right. It's a pleasure to be here. What can I say? Thank you. It's a privilege.

 

Sally Best

God, I'm loving that. Yeah. I mean, thank you so much for coming and sitting with us and having a chat. Um, it's kind of. It's great to get people like you on this, and we'll kind of go more into who you are and what you do. But, I mean, we're here today to talk about basic biology of lung cancer and then about oncogenic drivers. We will explain that to everybody. And yeah, I'm just wondering if you could start by introducing yourself and a little bit about what you do and what your day to day is and the life of Colin Lindsay.

 

Colin Lindsay

Yeah, of course. I mean you know, there's so many ways, different ways you can think of this, but I guess technically my term as a clinical senior lecturer for my job title. My split between the research and the clinic is 5050, and in the clinic, I mainly focus on lung cancer. And as a guess, we'll discuss later on. And in terms of the research focus, it's very much on this gene called KRAS. And there's three different types of it I can see early and so KRAS is one of the RAS genes and it's most commonly mutated oncogene in lung cancer and cancer overall. So that's where my research strategy is, is really focused

 

Sally Best

And just in terms of the clinic, where’s your clinic.

 

Colin Lindsay

Yeah, my clinic is at the Christie, the NHS Foundation trust the Christie hospital. Yeah. So we I personally lead two clinics a week on a Tuesday and a Friday mainly with the lung cancer team, also research team as well as far as clinical trials and sample collections of cancer are concerned.

 

Sally Best

And yeah, the Christie is obviously what is it, the biggest cancer hospital in Europe. So it's an amazing place to work. I'm sure.

 

Colin Lindsay

it really is. And you can tell I'm not from here and it was such a pull to come here. Yeah. One of the big reasons I came here was, is, you know, an internationally dynamic lung cancer centre. But also and I think maybe, maybe being elsewhere kind of helps me appreciate having the labs and it all being in the same site as the hospital makes such a fundamental difference to what you can do for translation.

 

Sally Best

It's like that cancer campus idea, isn't it? Yeah. Yeah. Oh, fabulous. And I mean within your role. So you've explained that you're kind of in the clinic in your research. What, what are your main responsibilities? Like what, what are you accountable for?

 

Colin Lindsay

Well, I guess if I start with the clinic, I guess first and foremost the patients and the patients lives. So I'm responsible for making sure they're on the right treatment and that it happens on time that we're making the right decisions about when to pause things, when to just reduce doses and when not to treat. And everything, I guess, really comes down to some level of risk  balance. And I think I'm responsible for being honest, to the patients. And not glossing over what are often very difficult situations. Yeah. And that would be the first bracket of things and the clinic and crossing over into the research. The second part of things is making sure clinical trials run properly so I'm, I'm the chief investigator and which means that you know I’m the main lead in the UK for a number of different clinical trials. Many are related to this gene called KRAS and we need to make sure that the governance and all the paperwork and all the ethics of that, that these are carried out responsibly again, and, you know, crossing over to patients and making sure we’re as transparent as possible in terms of what we can achieve and what we can achieve. And then at the last main back of what I'm responsible is the research that we do beyond the patients. And that's pre-clinical research. So I supervise, I think, three PHD students and one or two postdocs as well who all lead projects that are linked with some of the samples we try and take from the clinic so that we're really trying to use the samples from the clinic as a basis for our research and driving the questions rather than probably the traditional model was to do it the other way round.

 

Sally Best

Yeah, So it's really like bench to bedside bedside to bench in that translational mono, which has a certain parts of that same tone.

 

Colin Lindsay

And it's really, really difficult to articulate how difficult that is. Yeah. And it's quite boring to in terms of making sure all the applications are right and it is a difficult thing to achieve. And the infrastructure in Manchester is really second to none and help you with that.

 

Sally Best

So yeah, if you guys have listened to season one, you'll have heard the research journeys of some of our other researchers. I don't know if you've had a chance to Colin but all you guys are in the right place because you got to listen to Colin now. And I mean, if you haven't listened to season one, go and listen. It's I personally think it's great, but I also host it. So, you know, it might be about bias, but I mean, my next question would be kind of personal, like, how did you become involved in cancer research? You can take it as far back as you want. You know, maybe if you have a story from when you were a kid?

 

Colin Lindsay

Probably no, I'm not one of those kids that knew, for instance, that I wanted to do medicine from an early age. It was a sort of late realization to some extent. And what that brings me back to is my general medical training. And when I was very much in your junior doctor, still in my mid-twenties and I worked in Glasgow, at the time in the hospital called the Glasgow Royal Infirmary, which covers the east end of Glasgow probably, you know, like many areas of Manchester and there are many similarities between the two cities it covered a lot of deprived areas in particular. And, and there are constituencies in the east end of school where an average life expectancy falls short of retirement age, quite a few of them. And so for me, being on the shop floor and receiving what I would see very, very commonly was a patient who would come in breathless or with a cough for the first time, and they should have probably been to doctors months ago since they hadn't done that. And so this was their first presentation. We would do a chest X-ray and we'd see that they likely have metastatic lung cancer, even with a biopsy. And and so I think a lot of it comes back to those sorts of patients and being able to offer them something because by virtue of the fact that they came to casualty, we knew that they were probably too frail to actually receive chemotherapy, which was our mainstay of treatment at the time. And so what we needed and we still need for those patients is a treatment like chemo. Yes, it works quickly, but it needed to be a tolerable treatment. Yeah, and that's what we couldn’t offer at the time. And we're only just beginning to realize, if I'm being honest.

 

Sally Best

And I mean, it's crazy thinking about that. I mean, people are coming into A&E and then being diagnosed with lung cancer. And I think it kind of it shows the, you know, it's late presenting in terms of a symptom. So you're presenting kind of with that cough and that shortness of breath and maybe coughing blood and maybe fatigue. And that's, you know, on stage four of the journey of cancer where your metastatic rate

And it's crazy about that presentation. And we've kind of talked about like early detection previously, but it links in with that. And I mean, you flag something as well about the east end of Glasgow and the deprivation. And I'm just wondering correct me if I'm wrong, I think Manchester has some of the highest rates of lung cancer in the country. And I'm wondering if you could tell us a bit about the factors that drive that and the inequalities in in lung cancer here.

 

Colin Lindsay

And I mean, like most people, I think I do refer to CRUK statistics intermittently for this sort of information. And I think probably Manchester's slightly better than what it was, but ultimately it's still top five in terms of lung cancer incidence across all the different regions across the country. And you know, the Northeast is terrible as well. But given the sheer population in the Northwest, I think it's reasonable to estimate that. And you know, the highest numbers of patients with lung cancer exist in this part of the country. And so this kind of comes brings me back to the other reason I wanted to get into it, which was it was a simple case of what can I do? that will offer the biggest impact. two thirds of lung cancer patients, unfortunately, present with advanced disease and a lot of the patients who present with early stage disease still unfortunately recur and become incurable. And lung cancer is easily still the biggest cause of cancer mortality of all the cancers, about 20% of cases. And so in terms of wanting to offer an impact for patient wellbeing, this was clearly the place that I wanted to work in. I wouldn't deny there are parts of it that really just bring in things that I enjoy we’ll talk on later in terms of the research. But it was certainly important to me to be to be cantered around this. Cancer affects people's lives in so many different ways.

 

Sally Best

Yeah. And I mean, I think one of the rhetorics that we want to carry through the series is really important to me, and I think it should be propagated as that kind of the idea that you only need a pair of lungs to get lung cancer, do you? We understand that parts of it are a smoking driven disease and those are the kind of cofactors such as, you know, tracer X has been looking at pollution and what was it like a radium or something? And I mean, do you see kind of smoking driven lung cancers, especially in the clinics here in Manchester? Because I know smoking's kind of a a, one of the counterparts of social deprivation and they kind of come hand-in-hand. And there are a lot of deprived communities here as we know. So my question would be, do you see that translating into the clinic?

 

Colin Lindsay

I think we definitely do. And equally because the christie is, you know, a tertiary cancer centres to and we do see frequently see alterations, genetic changes that are more associated with the never smoking type of lung cancer as well. And so we do get and I think, you know, a very and from our point of view in terms of knowledge, a very helpful mix that keeps, you know, keeps up her knowledge and expertise in all the different facets of lung cancer. But if you speak to my colleagues in the periphery of hospitals here referring patients, they will tell you that it's more of that consequence of deprived areas continuing in Manchester in the Northwest is inherently linked with that. And, you know, most of us get into lung cancer because we believe smoking is an addiction. It's not the patients fault at all and they pay a heavy price in terms of their taxes. Yeah, I think, you know, I think we try and offer the same level of care to absolutely everyone. Who walks in the door. And lung cancer is particularly fantastic because sometimes we've got we've got patients that ask for nothing and thank us for everything. Yeah. And they don't, they don't really question that too much. And so I find that really important to be their advocate as they don't have as big of a voice as it should do

 

Sally Best

Yeah, and I think that's one of the things, isn't it? Removing that stigma and removing the blame because it's one of those cancers, I think kind of melanoma ties in with it where there's that like causal blame associated with it and it should just be completely ignored. There's no blame to it, its an addiction. And like you say, I mean, I know there's been kind of in the past there were stigmas behind it and funding issues.

You know, you get cancers like breast cancer that are massively funded because there's not that kind of causal link between something that you do and then you present with breast cancer. Whereas with lung cancer and some of the cases are smoking driven. But number one, that shouldn't be a stigma. And number two, in a lot of cases is it's something like 14% as people that have never smoked.

 

Colin Lindsay

Yeah. And so that's right. And so very understandably, people who have lung cancer or have never smoked are increasingly concerned that they're going to be stigmatized, stigmatized as well. And it is about I would normally just bracket this 10 to 20%. I think it depends on the region You may be working in, yeah, to some extent. So and it gets a little bit more complicated as well. And so we need to be very careful in how we approach, it as I'm sure we'll talk about it but there are genetic changes more associated with smoking related cancers. The genetic changes are very, very associated with smoking related cancers. But there's also a gray area on the side where a never smoking patients can actually still not infrequently have mutations associated with smoking related cancers. And patients who have smoked in the past not infrequently have genetic changes associated with never smoking cancers. Yeah, and so if we're too strict with our terminology, then those patients that fall into that gray zone can potentially be disadvantaged.

 

Sally Best

Yeah, but it's a minefield, isn't it? So just taking a step back and looking at the basic biology. So I, the way that I understand lung cancer is divided into those kind of two subtypes, one of which being small cell lung cancer, the other non-small cell lung cancer, and then with a non-small cell am I right and saying the squamous adeno and large cell?  So please could you tell us a bit more about those kind of like derivatives of the cancer and how that defined.

 

Colin Lindsay

Yes, sure. So they're different, the different divisions in terms of this of this classification. And so the first thing, as you mentioned, the small cell and non-small cell, and that's the most fundamental part of what we look for, whether it’s early stage or late stage disease and the small cell is is as simple as it sounds in many ways. I mean, the pathologists are looking for little blue cells when they're looking at biopsy sample or a liquid sample we called cytology sometimes I mean, that's about 10 to 20% of cases. So a minority, but a very important minority because it's usually  the more aggressive subtype of the two lung cancers which we generally are able to offer less in terms of treatment and treatment modalities and survival benefit and non-small cell is clearly the biggest subtype. And it can be broken down further. It's about 80 to 90% of cases we will see. And because it tends to be slightly less aggressive in small cell and probably more early stage cases with non-small cell that can be cured. And beyond that, the things you mentioned, Sally, is that non-small cell can mainly be broken down into adenocarcinoma and squamous subtypes as well, with adenocarcinoma being about 40 to 50% of cases, we see Adenocarcinomas and other types of I would call epithelial cancers like colorectal cancer, pancreatic cancer but these Adenocarcinomas we can tell, through pathology or specific to the lung with squamous cancers, about 10 to 20% of cases, they're actually

more difficult to differentiate from squamous cancers in other parts of the body, which can cause diagnostic problems sometimes.

 

Sally Best

Yeah, well, I'm glad that I've been doing my homework at least. And in terms of who's most at risk of developing cancers is that people with these things called oncogenic drivers or is that a variable?

 

Colin Lindsay

Yeah, I, I think it's a big, big debate just now about what point in the cancer revolution, those oncogenic drivers come on. And there is an increasing body of research suggesting that there to some extent in healthy cells and so it is difficult to say that they are the cause of cancers. I don't think they are, to be honest. It's much more complicated than that. And that's where one big aspect of cancer research is to just know what is that tipping point that leads a healthy cell to become a cancer cell. So I don't think it is just one of these oncogenic drivers to clearly help with increasingly. And lung cancer is really the pioneer, the leader for this in terms of setting the example and for precision medicine as they allow us to prognosticate and offer treatments for the specific changes that can often be beneficial. For example, if you have an EGFR mutation in your lung cancer, we can give you an EGFR inhibitor and that will extend it. That will be very likely to extend your life. And it's a tablet as well. So it really offers quality of life and we have an increasing number of these genetic targets that we're uncovering in non-small cell lung cancer in particular and adenocarcinoma in particular.

 

Sally Best

Okay. So just back to the definition. We just okay to tell our listeners like what exactly is an oncogenic driver?

 

Colin Lindsay

An oncogenic driver gene that either through population studies or preclinical work has really been thought to make the cancer cells signal in the way that it likes to do driving proliferation of the cancer cells and the cells dividing and allowing it to evade a cell death signals. So this survives back to the healthy cells as well.

 

Sally Best

So you've mentioned KRAS or EGFR. What were the kind of common oncogenic drivers in lung cancer?

 

Colin Lindsay

Yeah, I guess many people might remember from some sort of previous schooling or training that they can be broadly split into oncogenes and tumour suppressor genes. Yeah. So, so first thing to say is we were mainly talking about oncogenes and because of that, because clearly tumour suppressor genes are things that you wouldn't want to target. Yeah. And so I would move them to one site and then the oncogenes and the two main ones you've mentioned. So KRAS which probably is more associated with smoking. But as I say, we can still see it in never smoking and patients and EGFR, which again is always the opposite, is more associated with never smoking that we can still see in smoking patients going beyond that. And one very successful story is actually a gene called ALK, which is which is rearranged in lung cancer. then we have almost a never ending list of genes that affect very small percentages of patients such as RET one and ROS one. There's one called N Trac, which is NTRK, B-RAF is another one with the targets.

 

Sally Best

There you go, everybody some genes that for you. Yeah just on ALK we're actually going to be speaking to Fabia Gomez who is doing positive research now, looking at the ALK gene and never smokers, so very exciting times ahead. So you guys are in the right place now. But stay tuned, please, because I've so much more coming on. So you've said that you target treatments towards a cancer like a precision medicine so you target them in accordance with if they present with a certain mutation. So we'll get onto KRAS because it's, you know, a big bulk of this podcast don't want to give you spoilers is too early.

But in terms of KRAS, you'd kind of target that with a specific kind of drug to target that mutation. Just taking a step back, how do you test a lung cancer for mutation? Like how would you pick up if it has EGFR or ALK or KRAS?

 

Colin Lindsay

I mean the first thing to say is that we need to get a good biopsy specimen and that that is very challenging and there is, there was a study in our main international cancer meeting at school one or two years ago that in terms of achieving a good enough biopsy sample and to see a full biomarker every day is still not being done well enough even in the States. And so it was less I think it was less than 50% of patients that were getting at that were managing five biomarkers. And so and I've already rattled off I mean, I haven't even mentioned PD-L1 for immunotherapy, but I've already reeled off a list of, I think, about 67 genes. Yeah, that are important for people. And so the challenge with that is that we have an increasingly great level of technology that can diagnose patients with cancers at this two points of the bronchial tree. And of course, to do all these extra tests we need as much material as possible. But once we get into these distant points, it's very hard to achieve that. And so I would say probably we're looking at a little bit of a future. A second biopsy is something we need to consider more and more, given the range of possibilities that can be offered in terms of treatment. I need to go back to your question.

 

Sally Best

Don't worry. It's just how do you test for the lung cancer mutations?

 

Colin Lindsay

So once you've got a good biopsy, I'm going to be pretty brief here. Basically, just across the road. St Mary's Manchester genomic centre. What we can do is various tests and next generation sequencing many, many people will have heard of and that can test for many of the genes I've mentioned. We do have single gene tests still such as PCR when we need to focus our testing and then we still do. I mean that is the chemistry and fish testing.

 

Sally Best

And has that routine for before lung cancer treatment begun?  Or is that something that you're trying to introduce

 

Colin Lindsay

There are a lot of ongoing conversations about this and most of the targeted treatments and biologicals are in treatment of advanced disease, which we said is the majority of patients. But increasingly we're bringing systemic treatment and immunotherapy into early-stage disease. And it's important to do this testing in the early-stage disease, we've realized. And so I think it's something we're going to be offering to all patients. Yeah, it's actually easier to offer it to early-stage patients because they're likely to have surgery. Yeah, we're going to have a good specimen.

 

Sally Best

Yeah. Yeah. Interesting. So time to shine, Colin. We've mentioned KRAS. It has to do with oncogenic drivers. It's like going back to A-level for you. So, I mean, in terms of KRAS, could you tell me a bit more about this specific mutation? And then we'll kind of like feed onto the work that you've been doing and what have you?

 

Colin Lindsay

Yeah. So RAS was first discovered as an Oncogene over 40 years ago, and so really during my PhD where I worked on the gene next to it called BRAF. I knew that the BRAF mutation had been discovered and the drug had been generated for a very, very quickly within the space of about 5 to 10 years. And that BRAF inhibitor was showing success in the Melanoma Clinic very nicely, you know, offering quality of life to patients. Arguably the survival benefits could have been better, but unquestionably it was helping patients. And so knowing about RAS being there for 40 years and also knowing that it was the most commonly mutated oncogene in cancer and lung cancer as well, I became really fascinated about the possibility of drugging it and why that hadn’t happened yet, to understand that. And it does come back to this thing where I want to also tell you the biggest impact and like I say, it was so common in patients, and I just wondered how transferable that BRAF example was. And the answer is it's extremely difficult to drug RAS, and that's why it's taking so long. Perhaps no surprise. Yeah, the big difference between RAS and all the other targets we tend to talk about, it's as they are, they are enzymes fundamentally if you go back to school chemistry and RAS is a different type of enzyme called the GtPase, where as RAF and many of our other targets have kinase activity and RAS binds much, much more tightly to substrate GTP and kinase is bind to their substrate ATP. So it's very difficult to find drugs that will interfere with that interaction.

There is a second thing, Sally, which I can just be brief on which is that it's actually a very small, smooth protein. Yeah. So it's as simple as just thinking about is there a pocket or, you know, a little hole in the protein for a drug to cling onto. And that was something that was very difficult to find.

 

Sally Best

Really sending us back to GCSE chemistry and biology. Got it. Sending me because I know there's chemistry in there as well. We see this and never smokers as well. Just, just looking back. So this is a non-small cell lung cancer that, you know, that KRAS is found in.

 

Colin Lindsay

Actually mainly in adenocarcinomas. It accounts for over 90% in the pancreatic cancer. You know, if anything has an even worse outlook than lung cancer that counts for about 40 to 50% of colorectal cancer. So making, you know, making impact. Yeah. In this space it's a huge thing for patients

 

Sally Best

And then is there MRAS melanoma?

 

Colin Lindsay

So I don't know if a percentage available for you, but it is a very you know it's it's less than 50% and it's maybe yeah, 20% I think of melanoma cases. And then in never smokers is I think I read is it like two thirds of the never smokers that present with KRAS are female? 

 

Sally Best

So there's also that difference between the male and female presentation. I guess you don't know why that is.

 

Colin Lindsay

Yeah. Yeah. So there's more females with a KRAS mutation and so I don't think we fully understand why that is the case is, I mean we should say it's also a mutation that seems to be fundamental more to Caucasian population. whereas and mutations like EGFR, you know, are far more prevalent in the Asian population.

 

Sally Best

Yeah, it's interesting like the population level of it. Looking at KRAS and the mutation in terms of survival of a patient, does it, is there any kind of like empirical evidence that shows that it affects, you know, somebody with a KRAS mutation has a lesser survival rate than somebody without it? Is there any kind of research on that at the minute?

 

Colin Lindsay

Yeah, that that's a really good question, because I always said this junction of scientists and clinicians and five years ago when I started here, we haven't seen any drugs come through for KRAS and I was telling people that they were coming and a lot of people, I think in the clinic didn't believe me. So and the mismatch was such that scientists I think are a bit reluctant to get involved with RAS because it's such a competitive area. They see such fundamental differences in models that the research output is very high in the preclinical space. But for clinicians I always struggle to get them interested because I can I could see why, ultimately there weren't many studies that really showed clearly that offer to prognostic patients compared to cancers that didn't have the RAS mutation. And also clearly at the tine, I mean, this has changed in that we didn't have any drugs available for RAS. And so and so that is a better matter for oncologists. Yeah. And so there wasn't much more to say as far as that was concerned. The one place that has had a clinical impact for a number of years was actually as a negative biomarker. SO if you had colorectal cancer and it had the KRAS mutation some of my colleagues in that space, that EGFR inhibitor wasn't going to work. And the reason for that was the EGFR inhibitor was blocking upstream to the KRAS mutation that was turning it back on again.

 

Sally Best

Okay. So interesting. And do you know about any factors the well, does the cross mutation affect metastatic rate at all?

 

Colin Lindsay

I wish I wish it was clear cut, but this probably comes back to that point I made earlier about it's not you know, I have to admit that it's not just about KRAS in tumour initiation. Yeah and then in later stages of cancer. I also think it's not just about KRAS but I do think, you know ultimately we need to choose out target. You know, where we focus our research wisely. I do think for so many reasons, RAS is such an important space to focus on. But the studies that look into prognostic prognostication. And for instance, with KRAS mutation versus no cure as mutation, different subtypes of KRAS as well, which maybe talk about in terms of the drugs, they offer conflicting stories. Yeah, I don't think there's a clear line of evidence that if you have a cross mutation, your prognosis is worse. And that's because other factors come into play I'm sure You have experts who are talking about all the different kinds of biology that is around the KRAS mutation.

 

Sally Best

And the message today people is things are never as simple as you want them to be. So, I mean, just in terms, I'm going to really summarize this in a lay way, but you've previously said people thought KRAS was undruggable just because it had a massive affinity to GTPase and it was hard to kind of get a molecule in there that would it would have a greater affinity to. And it's also a really smooth protein. So it's hard to find a binder for that, Right? Okay, cool. So leading on from this, I mean, you have looked into treatments for KRAS, You know this undruggable mutation.

 

Colin Lindsay

Yeah, its undruggable. Yes. And it's lovely to be able to say that. I used to talk entirely on the disappointments of KRAS targeting in the past. And now, that's just one side of my talk, my sort of standard talk back to audiences. We we have many drugs. They are for a specific and this is how precise we've had to be precision medicine. Arguably, these are the most precise drugs we have available and we have offered to us and like I say, they're not kinase inhibitors and technically they're GTPASE inhibitors, but I guess we loosely refer to all these drugs as small molecules. And the point mutation of KRAS is just by luck for me, it's the most common one in lung cancer, which is G12C . And so you take codon- 12 from the gene and you swap a glycine amino acid for cysteine, right? And so we have other amino acid changes such as glycine for aspartic acid called T12D. These drugs available just now will not work even with that one amino acid change, so that’s what I mean by the level of precision they offer. And so they have shown the G12C inhibitors, just in case we start talking about other mutations and they've offered clear activity in lung cancer, colorectal cancer and pancreatic cancer. unfortunately is not as common in pancreatic and colorectal cancer, it’s broadly associated with smoking, the G12C mutation, which is why many people assume it's common in lung cancers. Yeah, 10 to 15% of cases.

 

Sally Best

Okay. And guys, no worries if you don't know about those amino acids  all those. No, no, don't apologize. And it's fine. It's just very complex landscape that we're working in. But I will do my best to translat it. Please, could you tell me about sotorasib. Is that. Is that right?

 

Colin Lindsay

Sotorasib was the first detailed G12C inhibitor on the clinical scene. I should say that, I mean the development of these drugs was first and foremost an academic drive. And so it was work for the chemist in the University of California, San Francisco called Kevin Choquette. And he had a lot of discussions with a guy called Gary Carmack. He's actually an Englishman, and he unfortunately departed England and I think many decades ago. And Frank basically encouraged Kevin to focus in on RAS with his chemistry experience. And that's why we have these drugs. What happens is they publish the chemical structure. Then pharma absorbs all of that and creates their own slightly different and drugs that fundamentally I think mostly do the same thing. And so sotorasib is the first example of a pharma iteration of these drugs and it's produced by a company called Amjey and for balance they are also a front runner which became came slightly behind sotorasib showing good clinical trial success as well and they’re made by a company called Moraty. And so sotorasib that we've looked at in lung cancer mainly in trials called the code brake studies. And what we published recently in The Lancet, with Manchester and leading this in the UK is the code break 200 study. What the code break 200 study has shown is that in patients who are due for a second treatment. There advanced lung cancer and metastatic non-small cell lung cancer with the G12C mutation. this drug is better than our previous standard of care of those attacks called docetaxel. you can interpret it in many different ways. But one big thing clearly is that it's a tablet offers convenience for patients and I would say far less in the way of side effects and risk. But there have been one or two eyebrows raised about the level of efficacy or activity it offers. And it isn’t synonymous with what we see with tyrosine kinase inhibitors. I probably say that that probably the best metric that I can see for the code 200 study is that one year about 25% of patients in sotorasib of the cancer have grown still, but with docetaxel it was 10% of patients, so 90% of the docetaxel and those attacks of the cancer were just active, growing again by that one year landmark.

 

Sally Best

Yeah. And just for you guys, we will put the links to these papers in the show notes, because it's very useful to look at them. I probably will read them a lot more than you guys do, but that's okay. And so when was that paper? What was it called? Code break 200- God it sounds like some kind of like double 0 seven mission, Colin you are going on the Code break 200.

 

Colin Lindsay

And I never thought about it that way. Yeah. That these acronyms are getting out of control. We've got a whole series of clinical trials that are dedicated to butterfly acronyms. So we have a chrysalis. Mariposa.

 

Sally Best

Yeah, yeah. There's a study going on at the minute called CUP and they're like putting kind of like teacup or like egg cup. And that's the kind of the way that they’re naming it is bizarre.

 

Colin Lindsay

I mean, we were at a lung cancer meeting on Friday. I think I've got a colleague that works heavily with mesothelioma and he has one of his studies at miso origins and that he realizes that everyone just thinks of it like another Marvel maybe. And then, and then with some of the bio bank stuff we’ve done with RAS I called our study and I think it's too difficult to change this now, RAS BIO.  But it just sounds like some kind of dangerous yoghurt brand.

 

Sally Best

Yeah, don't get people onto the wrong, RAS bio is not for your gut health. But anyway. Yeah. Back to it. When was when was that study the codebreaker when did that start?

 

Colin Lindsay

That probably started a couple of years ago and the interest in these drugs is such that these trials are recruiting like lightning. And so the recruitment period was short and we were lucky enough to have patients involved in Manchester, one of whom did particularly well with this study. But it was short and one big thing we're focusing on is creating more opportunities for patients to access these drugs in the future. I mean, maybe if I can say we have a number of trials and with the potential to access G12C inhibitors, you know, not just for lung cancer. And what colleagues emailed me about frequently is the other KRAS mutations and G12D is the most common RAS mutation in cancer in general. It’s still pretty common in the lung. But It's very common in pancreatic and colorectal. So G12C is is more dominant in lung based but Third, most common overall and clearly the the emails I get from colleagues is when are you going to have drugs for G12D. Yeah. And I'm, I mean, I really want to be able to offer it to patients. And fortunately I can see it's not just limited to the transferability of creating G 12 D inhibitors, G12 V inhibitors.

There has been this sort of follow up now where Pan-RAS inhibitors are being created so we don't necessarily need to be completely restricted to these point mutations, hopefully in the future. Yeah. The question of toxicity and side effects with pan- RAS inhibitors is going to be a big one.

 

Sally Best

I bet you're like blooming hell calm down a second. Let me get this out.

 

Colin Lindsay

Yeah, it's complicated. Yeah. It’s a test of the brain, even when I get to focus. So. Yeah, but it's, you know, it's. It's great to see.

 

Sally Best

Yeah, Yeah. So just, just taken it back a second. I'll try and kind of put this eloquently. Sotorasib was compared to standard of line treatment in patients with non-small cell lung cancer that already had like first line would have been chemotherapy or immunotherapy.

 

Colin Lindsay

Yeah. Either together or one after another.  

 

Sally Best

And then so that was compared to docetaxeal?  Yeah. And then it was found that sotorasib was better in terms of the patient survival, but also reducing kind of toxicities and side effects for that patient. Yeah, right.

 

Colin Lindsay

It gets more complicated. I'm not going to go into the specifics. You know, I don’t know if you’ll do it in another episode, but there’s better progression for survival in there. So yeah the benefit wasn't showing for overall survival. But there’s good reasons for that in terms of methodology that are difficult. That are difficult to normalize for. But the progression free survival benefit was there.

 

Sally Best

So progression free is just like no tumour shrinkage, but you're not metastasizing or growing.

 

Colin Lindsay

Yeah, so progression free survival is time until tumour growth or death, whichever comes first.

 

Sally Best

Yeah. Okay. Cool clear things up. I mean, where is sotorasib at now

 

Colin Lindsay

It’s probably long approved by the FDA. we are doing better than some some of our and brother and sister countries in Europe. I know that Spain doesn't have access to any KRAS inhibitors. It's a particular shame for them because they are really, really strong research base. But, setoraisb is accessible for a second line treatment of advanced non-small cell lung cancer if your cancer has a G12C mutation. Yeah. Which is fantastic and it is much quicker than it used to be in terms of the government changes increasing availability of the drugs. Yeah. The next step and this is again another key differentiator from tyrosene kinase inhibitors is how well it combines with immunotherapy. Okay. Because the cancer is driven by EGFR, ALK and some of the other ones I've mentioned unfortunately don't respond to immunotherapy Very well. One of the big reasons why KRAS inhibitors are still in the second line space is actually because most KRAS mutant non-small cell lung cancer can do very well with immunotherapy. So that’s set a very high bar for these drugs to enter this first line space and I think realistically they’re far more likely to do that if they combine with immunotherapy in some way rather than trying to knock them off the top tier, if you like.

 

Sally Best

Okay. We’ll come on to that. Definitely, because that's interesting stuff. And I mean, for the listeners that are kind of, you know, long term have been here since season one, we spoke to Katherine Payne and also Emma Crosby about, we spoke to them about kind of NICE and getting into and I said also the National Institute of Health and Care Excellence, don't know where the H went but probably wouldn't have created such a nice acronym. And we talked to them about kind of Lynch syndrome and getting kind of standards of care and um, things changed. I mean, what was the process for you in terms of getting sotorasib into NICE in that approval process? How kind of were you involved in it? Were you on the sidelines?

 

Colin Lindsay

I have a brief answer to this and mercifully I wasn't involved in it at all. Yeah, but in terms of the scrutiny, I wasn't involved in it. Perhaps this is probably a good thing that I wasn't involved in that because I wouldn't have been able to be very impartial, I don't think. And I probably mentioned that. Sorry, just sidestepping your question. I probably mentioned I did mention there have been one or two raised eyebrows about how these drugs compare with tyrosine kinase inhibitors because they don't compare as favourably and it's clear to see in terms of their activity. But I would defend them clearly in the context of what I said, which is it's taken so long and so much effort to come so far that I, for one, am really glad that they have a footprint in the clinical space. But also this is a fundamentally different target and because most of the patients are treating smoking related lung cancer, it's a fundamentally different disease. Yeah, the potential for rewiring of the cancer cell, I think probably inevitably meant that they weren't going to be quite as good as tyrosine kinase inhibitors in this first iteration I would stress that sometimes I refer to it as knowing your enemy. Yeah, the absolute crucial part of this and this is just the first set of drugs we're seeing in this space. EGFR and ALK inhibitors is certainly to expect from third generation of the impact that this is changing lives and on a regular basis.

 

Sally Best

Even if you think about it like five years ago, something that was classified as undruggable like it’s a massive breakthrough, irrespective of how kind of the effects that you see from if there is an effect, however, kind of minuscule or whatever, it’s amazing that this has progressed so far. And yeah, congrats to everybody.

 

Colin Lindsay

It's really not been me. But it’s been nice to be part of. I think. I think that there are probably two or three different fits in principle, that we don’t reinforce and it was the first time, really it's a small molecule like this working with smoking related lung cancer, which as I say, I think is really a fundamentally different disease given the mutation burden that’s accumulated in that cancer. I mean, there was big worry as well that that there's always the worry that preclinical models just aren't representative of patient cancers.

That oncogene addiction that we see in models and cell models really going to be seen in patients when we treated with this drug? But we can say yes, maybe not as well as is the case with EGFR now. Clearly there is a dependence of the cancer on KRAS that will and that's why these drugs are showing benefit. Yeah. And there is a proof of principle and that’s in my head but it'll come back to me

 

Sally Best

We'll wait for it to come back to but I'll some other questions before it comes back to you. So in terms of the next steps and working with NICE, you said something about kind of looking at the drug in combination. So looking at the sotorasib in combination with other treatments, how would you see that kind of working? Like what? What examples would you have of that?

 

Colin Lindsay

Yeah, not easily is the answer. And it does have an added layer of complexity with toxicity comes into this. Yeah. We had previous trials with tyrosine kinase inhibitors where they were combined with immunotherapy and we saw quite severe toxicity and to some extent unexpected idiosyncratic toxicity, particularly affecting the liver. And so those trials were mostly sidelined because it wasn't so important. As I said earlier, immunotherapy isn't so important to EGFR mutant lung cancer. And so ultimately, it's not been prioritized for future progress. Now with KRAS, as I said, fundamentally, it's important to try and combine these drugs. More than any molecular targets in space of cancer. And this is the space we're going to be where we're going to be trying to convey the two most exciting modalities of treatment as a medical oncologist and immunotherapy. And the problem is that the initial indications are that we're still seeing that toxicity. With KRAS inhibitors. And so that's been described to me in particular and another could be studied with sotorasib. There is a suggestion with the other drug I mentioned that there might be less toxicity when combining with factors of immunotherapeutic ever, but we still need to see the data. What I do know is that there are clinical trials definitely trying to do, you know, trying to combine the drugs in the first line treatment for advanced non-small cell lung cancer and inevitably they're trying to take precautionary measures like changing the dose of the RAS inhibitor and looking at different dosing possibilities as well. So just a step back because I think this is kind of a question that's popped into my head now and it might be relevant for earlier on in the episode. So in terms of first line treatment, that's when a person first presents and you have that kind of standard of care. So if there, say, stage one, you might have a resection, which is like the cutting away of the tumour in the lung. And then kind of following on from that, you've got that metastases.

 

Sally Best

What kind of sort of treatment would you provide at the other end of things? What would be that first line treatment? Would it be like radiotherapy, chemotherapy?

 

Colin Lindsay

Yeah. No, I have to say, yeah, it's so complicated. All of this terminology that it's kind of second hand to us, but by first line I’m really talking about advanced disease.

 

Sally Best

Okay.

 

Colin Lindsay

And so and so I just mean the first treatment and once you've been diagnosed with a metastatic or advanced cancer? What you're referring to is probably called either adjuvant or neoadjuvant. Yeah. Neoadjuvant treatment, mostly some neoadjuvant is then you get systemic treatment before an operation and have the cancer that's curable and adjuvant the treatment that follows an operation and they'll look for it to still try and you know, to try and add to the potential for cure, already offered them surgery.

 

Sally Best

And then the first line is for that metastatic core and then for the metastatic, what treatments do they have specifically? So that would be what was given before the sotorasib?

 

Colin Lindsay

Yeah. I mean, I our standard bearer really and, and something that I've said, as I've said, it's going to be very difficult to supply is chemo immunotherapy or in patients whose tumours look particularly receptive to immunotherapy sometimes we can actually it by using PD-L1 immunohistochemistry just drop the chemo.

And give the therapy by itself yeah and so keynote 24 of pembrolizumab in keynote 189 and with chemo and pembrolizumab I believe that there are a number of trials now looking at different immunotherapies in this space. But really the two main trials that we follow with our treatment.

 

Sally Best

Okay, cool. Right? Yeah, it's difficult to understand kind of clinical terminology, but I do my best sometimes. Not very well, but yeah, it's good to have you here because you can you know, pick me up. So, I mean, in terms of next steps for this research, what have you got under your belt?  

 

Colin Lindsay

Oh good question, how to articulate I mean like consider driving forwards here are probably three main channels of work and first of all, when I joined, I really want to make sure that we had the clinical trials to for patients. But I've also mentioned that we need to work harder in trials for G12D, you know, like, for instance, uh, what I can say is that we are the UK lead for most of the very selective trials that we get involved with. And I think that I'd like to think Manchester's a Centre for RAS based clinical trials. And very link in very closely with international colleagues who I think recognize it in that respect. So that's a nice place to start from. The two main facets of what we pursue beyond that are, and this comes really to my background is that we do have wet lab PhD students looking at RAS research and so there are the students, mainly medical oncologists you know who are using their pipette every day, but perhaps doing some mouse work as well. And they're looking at different, um, different stories in terms of future vulnerabilities for RAS. One of them is looking at G12C, for instance, that tells you that it's a resistance and that's beyond the other RAS mutations. I would say that's a big, big thing that people are picking up, um, what they can do with I mean we haven't talked about resistance. You mind if I Segway a little bit?

 

Sally Best

No, go on Colin, you can Segway

 

Colin Lindsay

But the resistance that’s offered by the cancer cells to G12C inhibitors is really, really striking because of the sheer range of different resistance mechanisms. Okay, so we're getting resistance and the same codon, codon 12 of the RAS gene, different mutations there. we're getting mutations in different parts of the gene containing resistance. We're getting mutations in new parts of the gene where We didn't see mutations before because it's where the drug's binding. And we're also seeing mutations in downstream genes and parallel pathway genes. And so the analogy I give for is like it's like hitting the cancer cell in the stomach and it is fighting back with its head, its arms, legs, It's hands and its family is right there as well. And so that's a real, real challenge. And one of our PhD students is looking at that in great detail just now. We have another type of RAS mutation affecting codon 13, which is quite common in lung and varied mutation that more common in colorectal cancer. And one of our students is looking at differences with that mutation compared to and compared to the standard codon 12 mutations. And then on the other side of things we have bioinformatic projects. Yeah, and I work with a cancer evolutionary bioinformatician called David Wedge. We have a common PhD student just now, he's doing a fantastic job, really trying to unravel, you know, really the taxonomy and classification of some of this so that we can start with some more fundamentals in terms of what we're trying to achieve.

 

Sally Best

Just just looking back at your, um Yeah, kind of. What was that? Your kind of  hitting in the stomach analogy. Analogy, that's the word.  In this instance, the hitting in the stomach is that sotorasib?

 

Colin Lindsay

Sorry, I should have clarified that

 

Sally Best

don't worry, don't worry.

 

Colin Lindsay

To be honest, it just feels a little bit unseemly? I mean, probably is better to say it in the heart because that is the heart of the cancer. Yeah, that's what I mean hitting it with G12C inhibitors. We have the American Association for Cancer Research meeting coming up in a couple of weeks.

 

Sally Best

Dot, dot, dot.

 

Colin Lindsay

And so a really the pioneers of RAS cancer research and based in the US they will be presenting I think our latest updates in the first plenary session at that meeting. That’s a main international cancer research meeting. So all I'll say is watch this space and I guess would be surprised if we didn't find out more about G12D inhibitors. We definitely will this year if it's not this meeting and yes we will certainly find a bit more, I think we will certainly find it a bit more refined iterations of it given the speakers that are going to be there.

 

Sally Best

God it’s going international.

 

Colin Lindsay

Oh it started international but yeah, I think I, I think it's, it's, it's just fantastic to see it doesn't really matter where it comes from. And one thing you know that's an unenviable position but people are really interested in here it’s just that we do have this patient base that can’t be underestimated. The translational research is very difficult and a lot of hospitals in the States because they are focused on a much smaller cohort of patients. There is a lot you know, a lot of patients affected by cancer which are getting channelled towards, you know, our team. That means that, you know, it means it can be more chaotic. If also means if we're more organized, our potential is stratospheric. What I said about taking these patients samples by biobanking and make sure we do, we do that reverse translate.

 

Sally Best

Yeah. So you couldn’t do it with all the patients. Now is the power of the Christie. And I mean, you know you've been great to talk to you so passionate and kind of yeah clued in on all of this stuff and especially with KRAS and things and I think my question to you would be the question that I ask everybody that comes on her is just like, how does it feel to work in cancer research and know that, you know, at the end of the day, you kind of you are balanced between the clinic and the and the research lab, but knowing that that is all being translated to patients and like clinical trials are patient facing. Right. And that's a lot of the work that you do. So how does it feel to know that, you know, you're having this kind of benefit and converting that previously kind of undruggable rhetoric into a no no recovery drug? Don't worry, guys.

 

Colin Lindsay

Yeah, I mean, a feels I mean, I think what you're suggesting is it feels great.

 

Sally Best

Yeah. Just tells us it feels great.

 

Colin Lindsay

I do get the other question course which is you know, you know you see incurable patients in your practice. And so doesn't that feel you know, doesn't that feel terrible. And truthfully, you know, you, you know, and it’s always the patients that teach you and they are so impressive. Absolutely all of them in different ways. And they never feel too I mean, I'm not a person that's easily surprised, but it's really the patient in the patient example that surprise me because they're just so gracious with their time and their energy at a time when they've got far, far more important things to focus on. And so it's, it really is a privilege and, and I, that's all I can really say, you know, we're at the forefront from some research but and that more importantly, you know we're seeing these patients whose lives are totally disrupted. And they're opening up to us and you know, we do our best to help

 

Sally Best

You all do a brilliant job, I know for a fact. So applause to everybody as a clinician like Colin. And how do you balance it all?

 

Colin Lindsay

Oh, I hope I'm not the best example in that respect. But I think the key thing is that, you know, if you choose to be, busy, you try not to impose your expectations on others, your own self-expectations on others. I mean, you know, you tend to bounce off, you know, working most hours. Yeah, I Mean I think it's fair to say if I at least give myself one day off a week from it all. Yeah. I've got two kids and a wife that is a consultant out in North Manchester.  We don’t have any other family here. So yeah, it is frantic at times. I mean it's, it's mostly great fun. I try to see the positive in all of it, but it doesn't mean to say that it's not. Yeah, there are very difficult weeks.

 

Sally Best

You'll never be bored though. How old are your kids?

 

Colin Lindsay

Ten and seven. Oh, it feels a bit easier than it did a few years ago as they can do some things for themselves.

 

Sally Best

Just wait. Three years right to that teenage phase. Yours might be better than me though. And just like, how is it working in Manchester? I mean, you said previously that you moved from Scotland to here.  Scotland's glorious Colin. I love Scotland. Why? Why leave?

 

Colin Lindsay

Yeah. Oh, I mean, this is this is a two hour conversation in itself, but I mean, I mean, I think I say I have to say first and foremost comes down to work, it does for my wife that’s from my wife.I don't think that my job would be able to be the same in Scotland as the way things are set up right now. But the people I've met here are just phenomenal people. And you know, there are so many similarities between like Glasgow and Manchester that really didn't take long to feel comfortable, and a grounding influence always are the nurses around you. The nurses we have at the Christie team, they’re easily the best nursing team that I have worked with in my time and that makes my life and the patient's life so much easier. And so, you know, we try and go for a drink a couple of times a month and have a laugh as well. And I think I think that's so, you know, a group of colleagues that you think of with questions. Yeah I'm hugely thankful to them and they're so impressive in everything they do. Yeah.

 

Sally Best

As are you but yeah it's yeah it's phenomenal to see the way that the cancer research landscape works here. And like you say, you can't forget the jobs that facilitate everything because those people, the kind of the back of everything that happens, yeah, it's the way of production, but, and production of great research.

 

Colin Lindsay

So yeah, if I could make a pitch for them. think, I think that there's still a big gap in terms of advocating for people without a voice. Yeah. And and so that could be yeah, that could be the people in the shop floor in the hospital, who just don't have time to go for a PE. but also it's the patients who are have morbidity and die so quickly they don't have time to be involved with patient forum. And you know and tell us their experience. Yeah. And so focusing you know it's clearly my research is focused on RAS but giving all of those people an opportunity to speak think is just got to be a huge part of the future for sure.

 

Sally Best

Great stuff. Well, thank you everybody, for listening. If this is your first time, I hope you enjoyed Colin and I having a lovely chat on the basis of biology of lung cancer and KRAS and all the hopes for the future. If you've listened before, you know you're in the right place and you're staying, I hope. But thank you to the James Bond of KRAS. I really hope that you've enjoyed your time and it's been great to have you on. It's really good to hear about everything. And yeah, from kind of such a personable person as well as usual guys, I'll link everything in the show notes if you want to have a bit a read around, I'm sure Colin will provide us with some kind of articles as well. But yeah, there's, there's a lot of background reading, if that's what you're interested in and a bit of a nerd like I am nerd, it's probably a derogatory statement, isn't it?

 

Colin Lindsay

Not at all

 

Sally Best

We love science nerds here, but yeah, thank you guys so much. And we will speak you next time.

 

Dr Colin Lindsay is a Clinical Senior Lecturer in Medical Oncology and also works at the Christie NHS Foundation Trust, dividing his time between research and clinic work. Colin trained at the CRUK Beatson Institute and Cancer Centre in Glasgow, where he completed a PhD under Owen Sansom, studying genetically modified mouse models of RAS and RAF-driven melanoma.

Following that he changed focus to lung cancer translation through involvement with the CRUK Stratified Medicine Programme, as well as a two-year ESMO translational fellowship with Benjamin Besse and Jean-Charles Soria at the Gustave Roussy Institute in Villejuif, France. His main research interests are the implementation of effective treatment strategies for cancers driven by RAS mutation and successful and efficient translation of genomic results for optimal clinical gain. 

EPAC-lung: European pooled analysis of the prognostic value of circulating tumour cells 

KRAS: Reasons for optimism in lung cancer 

On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma 

Sotorasib versus docetaxel for previously treated non-small-cell lung cancer with KRAS^G12C mutation: a randomised, open-label, phase 3 trial 

Molecular characterization of primary and secondary resistance to RET inhibitors in patients with advanced NSCLC and RET fusions (2022) 

1116P United Kingdom real-world experience of sotorasib in KRAS G12C mutant non-small cell lung cancer: A British thoracic oncology group review (2022)