Parker Moss - INTRO: Hello and welcome to Cancer Connections, a new podcast from Cancer Research Horizons, where we're gonna get to know, to question, but also to celebrate the experts that are helping us to beat cancer. Cancer Research UK is the world's largest charitable funder of cancer research. As the charity's commercial arm, it's Cancer Research Horizons' job to maximize the impact of that research by turning discoveries into treatments that reach patients with cancer. A huge part of that work happens through the Cancer Research Horizons Expert Network, a world-class community of scientific, technical, clinical, commercial and investment leaders. I'm Parker Moss and I'm proud to be your host for this series.
Parker: My guest today is Professor Sanjay Poppat. Sanjay is consultant thoracic oncologist at the Royal Marsden, where he heads the lung clinical unit and also the research program. Sanjay, you're the professor of thoracic oncology at the Institute of Cancer Research. You co-led the program that made the NHS the first national health service in the world to diagnose lung cancer from liquid biopsy. I know that you were a previous chair of the British Thoracic Oncology Group, and that you advised both the EMA and NICE. in the area of lung cancer. Sanjay, it's an incredible biography. You are very welcome to Cancer Connections. Thank you for being here.
Sanajy Popat: Yeah, a pleasure, Parker. Great to chat to you.
Parker: I thought I would first start by asking you a bit about your origin story. Because as I've read through your past papers, what really struck me is how you have consistently been ahead of the curve. So you started looking at liquid biopsy roughly 10 years before it reached the clinic. I know that you're very early now looking at novel Her 2 inhibitors in the lung cancer space. But what really struck me is going all the way back to the beginning of your career, it seemed not to have started in lung. The first paper I could find from you was actually on microsatellite instability in colorectal cancer, where you seem to be very early in pointing out its prognostic impact. And that was more than 12 years before it became the biomarker that Catruder, the famous checkpoint inhibitor from Mutt, was launched upon. So Just tell us a little bit about your story and how you have had this consistent ability to have great insight about the future of cancer.
Sanajy Popat: well I I think you know part of it goes to my interest in molecular biology and genetics and molecular genetics. and that that's always been a a real interest to me. I I qualified in medicine in in ninety-four and then did junior medical jobs and ended up at the Marsden. And thought actually, oncology is really where I want to be because I can really see how we are implementing what I've learnt in molecular biology and science into the clinic. I was very lucky as an undergraduate, which I did my medical degree at Guys and St. Thomas's to have done an undergraduate integrated BSc. And that was with a really inspiring chap called Frank Walsh, who is doing a lot of work on NCAM and its role in neuron biology. And during that course, you know, I picked up the basics of cell biology, molecular oncology, and started to dabble a little bit with immunology. technology and I thought, you know, in oncology you can really transform cancer care because you're taking the findings of basic science at a very, very early level and impacting them onto the patients and in some cases making huge benefits, stepwise changes. At that point it wasn't straightforward to be trained in medical oncology, so I took three years out to work with another inspiring character at the Institute of Cancer Research in the Sutton branch. a chap called Richard Holston and he's a genetic epidemiologist. who has an incredible breadth of knowledge around our our genes, the impact of our germline variation, its relationship with normal tissues and how that might change in cancer. And at that stage, it was really exciting. You know, we'd gone from traditional Sangha sequencing to ABI sequencing. sequencing was everywhere, that was the buzzword. And you know, Mike Stratton and Richard Wister were in the lab down the corridor. There was a lot going on And you know, Rich and I w were having chats about Microsoft by instability and we were he was doing a project, in the somatic evolution at the genomic level of colorectal cancer and I was interested in microsatellites which we were using at that at that stage for gene mapping, right? Because sequencing was not affordable. We didn't have the high throughput sequencing. So all we were able to do is to look at microsatellites and try and see how these segregate with families and diseases to try and map genes. And we ended up publishing you know paper which I think is still one of my most cited papers actually in the relationship of the presence or absence of microsatellite stability and outcome in colon cancer. I then went on to do a clinician scientist fellowship at the Marsden for three years, where I was looking at various somatic outcomes of colon cancer, looking at colon cancer, microsatellite instability, a a few other biomarkers, completed my training and at that point actually the Marsden needed a lung encore. Oncologist, We didn't have much for lung oncology at that point, to be honest. It was all a bit of chemotherapy, which didn't do much. A lot of nib had been in the clinic for a few years. We didn't really know about EGFR mutations at that point. and it was all a bit depressing. But you know, I thought, yeah, let's do it, let's take it on. There's a there's a lot we can achieve. So I think I I'm fortunate to have lived through a lot of changes in in. science and I'm even more fortunate to have been surrounded by can-do people. and people really make a difference to how we can move forward with the agenda to impact on patients.
Parker: I would love to hear a little bit from you about really how the experience of a lung cancer patient today is different to when you first joined that clinic back in the early two thousands.
Sanajy Popat: Yeah, you know, lung cancer's totally transformed. if I see a patient today, I need to give them a specific pathological diagnosis, what it looks like under the microscope. and what it looks like under the microscope and its precise name is very different to how it was back in the mid-two thousands. Mid two thousands, we were just happy to call it non-small cell lung cancer. You know, as long as it wasn't small cell, that was fine, right? Because small cells treated in a very different way to non-smell lung cancer. Non-smell lung cancer, by and large, button doublet chemotherapy. We knew that there's adenose and we knew that there's squames. We knew that maybe some chemos worked a little bit better than others in some scenarios, but really the genomics didn't really matter. we'd been faffing around a little bit with VEGF inhibitors, had modest impact. And actually the the the basis of how we treated our patient was chemotherapy for everyone and if you weren't fit for chemotherapy there wasn't really anything else and you know brain metastases were a big challenge a lot of these patients had brain metastases and as soon as you had brain metastases you're in trouble we didn't have what we now regard as standard stereotactic radiotherapy, we didn't have brain penetrant drugs. It was a terrible time. You know, our patients had terrible average survival. It you know, it'd be fairly routine for patients to be passing away within a year of diagnosis. and that's a bad place to come from. And that's not just in the UK. That's that's a global issue. And that's a global issue for what's a common cancer, right? so The the advances that we've seen in in science have really allowed and underpinned advances in trials and actually at the same time we've had also in parallel had a revolution in medicinal chemistry. I mean, for example, the small molecule revolution of quinaslone drugs never existed, right? Our ability to target kinases did not exist in the late nineties and early two thousands. That's only really come on at the same time as we've understood that there are a a group of somatic problems With cancer, with key drivers that if we have the right drugs, we can target. So now in the clinic, if I'm seeing a a patient, I'm saying, well, look, we need a precise diagnosis. I need to know whether it's an adenocarcinoma or a squamous carcinoma, I need to know whether it's a TTF-1 positive or TTF-1 negative adenocarcinoma. I need to understand the molecular biology of that cancer. And mostly we're dealing with adenocarcinomas these days, and there are at least 50. Different drug targets that we need the lab to have looked at to tell me what's going on at that genetic locus for that particular patient. And I would actually argue that's whether you can drug that target or not. For me, I need to understand the biology of that cancer. So I'm looking at the whole genomic architecture. I want to understand what sort of tumour microenvironment we're dealing with. You know, is it like an immunoin inflammatory microenvironment? Is it an in a suppressive microenvironment, you know, have we got copy number loss, have we got copy number change? So it's not just the single nucleotide variants we're interested in, you know, we're looking at the large scale architecture of the tumor to help me understand that. And then when we have
Parker: I think.
Sanajy Popat: an understanding of that, can we get the patient on the right drug And that is totally transformed the way we are managing our patients. And it's made a huge impact in Lung cancer, where we've got effectively two different biological subsets, those that are immune sensitive and those that are not. And those that are not tend to be oncogene addicted and need kinase inhibitors. But those that are immune sensitive, you we definitely have a small proportion, 20% of patients who are alive long term year five plus with no evidence of cancer, having presented to me with widespread metastatic malignancy. It's inspiring, it's wonderful, it's so lovely to be able to make these differences to our patients. And the issues that we deal with in the clinic now are sometimes issues about survivorship, right? thinking about long-term rather than everything being doom and gloom about, you know, what am I going to do next month? Which is, you know, what the angle was at the beginning. But don't get me wrong, Parker, we've got a lot of work still to do, I'm talking about the extremes of benefits that we see here. We still see the extremes of sadness as well in the clinic. Patients that come to us with super aggressive tumors that you know you throw the kitchen sink at it and it still grows. And you've got patients that have acquired resistance where some modest benefit initially and then relapse. So there's still a lot of work that we need to do in science. in drug development to continue to shift the the bar, the mission is not yet complete.
Parker: Yeah, the battle is still raging, I think one of the papers that I read a couple of years ago that that really struck me as fascinating in the lung case was that Charlie Swanson paper about particulate matter. two point five. I think back in twenty twenty three during COVID he published that. And he proposed a a really interesting new mechanism which was nothing to do with carcinogens at all, where small particulate matter of a around the the two point five micrometer size could come into the lungs, cause epithelial damage, attract macrophages, those macrophages excreted interleukin one beta, and that cause inflammation, which for a subtype of genetic groups, I think EGFR and KRAS, could drive cancer through a completely non-carcinogen mechanism. That struck me as a really important insight. And I'm wondering whether that's affected the way you think about patients, both in the smoking and also the non smoking subset of the people that you see in your clinic.
Sanajy Popat: Yeah, and I and I think this is a really important new field of biology that we need to explore. because you know, his phenomenal work has impacted on the question that patients ask me in the clinic every day, which is why did this happen to me? that's the key issue that folk want to know about. Now, if you've never smoked or you've had a few crafty cigarettes, you know, in university and you end up with lung cancer, it's clearly not tobacco related, which is by far the greatest cause of lung cancer. And in those patients in whom tobacco probably hasn't played a role, Charlie's data is very clear that this inflammatory change that we see with two point five particulate matter drives this inflammatory change through chip, through macrophages, through IL1 beta signaling. And what's really interesting is that it biologically gives us an understanding for why some patients may develop somatic mutation as a driver where others may not. working on The other foundational data that we have from Mike Stratton and others, which is that many of our cells develop somatic mutation in key drivers, but never become malignant in those cells. So the key issue is why biologically do some cells develop a driver, but then that never becomes transformative to an established tumor, and in some people it does. And I think this whole IL1 beta inflammome. hypothesis that charlie's really I think quite eloquently demonstrated does support and drive that so I think this has huge implications right because you know we can effectively inhibit IL1 beta right we have drugs which do that there's a there's a fantastic paper many years ago demonstrating that The NALP 1 inflammazone, which is also driven in that sort of scenario by L1 beta, you know, may contribute to the formation of asbestos inflammosomes, which then can drive asbestos-related malignancy and asbestos-related other conditions. So the whole concept of IL1 beta is in carcinogenesis, I think is really, really mission critical. and there's an opportunity I see here to, you know, try and test that and drug that with IL1 beta inhibitors. Now they've not really proven effective in widespread metastatic disease, but you know, we need to think about how we then select the right patients for the right trials in that right scenario. And maybe, prevention type of study is what we need to start thinking about doing. But these are very complex studies to set up and deliver on.
Parker: All right, let's switch subject away from Therapeutics into diagnostics, where I think you've had a huge impact, and I was lucky enough to witness some of that impact on the NHS. and what I think is a a breakthrough and a very rapid decision by them, to embrace the use of liquid biopsy for lung cancer in general. Talk us through what a liquid biopsy is, the different settings that it can work in and the importance for lung cancer, because this is a piece of news that I think is not widely appreciated and is going to really impact people across the country and not just in lung cancer, but in in many of the cancers.
Sanajy Popat: Yeah, so I mean liquid biopsy means different things to different people, but I broadly at this stage would summarize a liquid biopsy to be the same thing as testing for circulating tumor DNA. we all have really small fragments of circulating free DNA in the plasma of our blood. Remember, blood is composed of red cells, white cells, platelets, and the soup that they live in, called plasma. And in that plasma, the soup that all these things live in, you know, we do see these tiny fragments of DNA. Now, most of those fragments of DNA are from our host tissues. But in patients with cancer, some of those fragments of DNA can arise from the nucleus. Material of the patient's cancer. So, therefore, if you can sequence that tumour-derived free DNA, you then have a very accurate picture of the actual tumor genomics itself. And our sequencing technologies are now good enough that we can detect these very, very, very low levels of circulating free DNA, what we call circulating tumor DNA or CT DNA. And there are many companies that have validated technology to detect this and sequence it and tell you what the genomic aberrations are. And we've been using this for quite some time, looking at a single gene in the clinic. so the example here is the single gene called EGFR. And when we have patients with widespread metastatic disease, if we drug them with a first or second generation EGFR inhibitor, say cafetonib, a lotonib, epitonib, after a period of time, the cancer cells become resistant to those drugs, and they become resistant to those drugs by outgrowth of a clone of cells which have got an acquired change called a T790M mutation in the EGFR gene. And this results in a structural conformation in the EGFR protein in the cell, which prevents. Kinase inhibitor from binding effectively to the kinase domain site and therefore inhibiting EGFR. And we also have very good drugs which switch off T790M mutant EGFR very well, osimelotinin for example. so therefore the paradigm has been if you have a patient on first and second generation drugs, if you biopsy their tumour, identify T790m, they would then be suitable for Ossimotinib and we would have a very nice benefit from ossiometonib thereafter. Now of course biopsying patients you know is never straightforward. I mean none of us wants to have a big needle in our chest, right? None of us wants to have a big camera going down our throat. So wouldn't it be great if you could identify T seven ninety from fragments of C T DNA shed into the plasma by a simple blood draw? And that in fact is the technology that existed at that time. And that's exactly what we're doing, a blood draw to look at plasma to detect EGFR T790M. But the technology has moved on, and we actually have technology which looks at a variety of different loci at different levels, and that brings into the whole question of clinical utility. Where do you use it and what can you gain from it? And you can use it in many different ways. So we've talked about the example when you're using in a late metastatic setting where you're looking for acquired resistance. Now you could replace that single EGFR gene test with a multiple gene test C T DNA NGS where we're looking for a variety of targets so when the same patient then relapses on a fetonib Gafitonib, erlotonib or osimelotonib. The question is, are they resistant because of EGFR change or is there something else going on like metapregulation, another driver that's causing that? So that's one scenario you could use that. Now I said to you at the beginning of the conversation, these days, before I start treating a patient with advanced non-small cell lung cancer, I want to know what their genetic profile is. That's contingent on the biopsy that we take to make the diagnosis of their cancer undergoing somatic testing in the lab. Now you could also do that by simple blood draw. And if you time your blood draw really well in the patient diagnostic journeys, perhaps when the patient presents to the hospital, you might be able to do it very, very quickly before you know that the patient has cancer from a biopsy or before you know the tissue NGS. We'll come back to that in a little bit. And the other area that you might want to be using these blood tests are in the patient that has undergone cancer resection, where you're looking to see is there any evidence of the tumor CT DNA present after the patient has undergone resection? Because that may well change what you do after surgery. You may or may not want to give treatment in colon cancer, you may. Say, well, look, actually, this patient has a very low probability of relapse after resection. The patient does not need chemotherapy. You may want to intensify your treatment and say, actually, this patient has evidence of circulating tumor DNA despite surgery. This patient needs treatment intensification. We need to give more than just the basic chemotherapy, they need X, Y, and Z. And you can even monitor that on an ongoing basis. And you can see whether MI. MRD, we call it molecular residual disease, MRD positivity changes into negativity or even then becomes positive again. you know a lot of these questions about the dynamics of ct DNA or MRD testing in the post-surgical setting. how we should intensify or deintensify our treatment on the basis of this is still the subject I think of many clinical trials, but is something that I think is going to change where what we do in the next five years.
Parker: Okay, so i if I could extract from that, I think there are the four settings. So there's early detection of lung cancer, which you you might do on patients that have not yet presented symptoms. Then there's the diagnosis of lung cancer, where you can use a liquid biopsy to look for this circulating tumor DNA in the blood. then there's a search for minimal residual disease or molecular residual disease after surgery and then presumably also a fourth setting of surveillance after treatment to make sure the patient's not relapsing. So please just tell us a little bit about what has the UK now approved in the NHS? what's available to patients today and what role did you play in in making that happen?
Sanajy Popat: the UK actually I think is spearheading a lot of liquid biopsy implementation. The the biggest impact I think that we've been able to to make, I think globally, to be honest with you, but certainly in the UK, is the implementation of CT DNA for patients with metastatic non-swan cell lung cancer, or suspected lung cancer. So, you know, the problem that we had was we have patients walking into the clinic or in the hospital with what looks like on a CT scan widespread lung cancer. We're meant to get these patients on treatment within 62 days. That's the government target. And in that time, we need to do multiple scans, we need to do biopsy, the biopsy needs to undergo pathological analysis, it needs to undergo DNA NGS, it needs to go RNA NGS. We then need to get the patient on treatment. And actually, what we're finding is that around 50% of patients are undergoing treatment within 62 days, not 85% or above.
Parker: Mm.
Sanajy Popat: So this is a big problem because we know for every week that the patient doesn't have treatment, there is a graduate. Gradual deterioration because cancers grow. So, how do we get patients treated within the quickest time possible? Because you know, if it's you or I, that went to the clinic, we want to be on treatment as soon as possible, right? We don't want to be fluffing around for three months, waiting for people to decide. It's a completely unacceptable state of affairs. Now we have in our centre been doing quite a lot of work with CT DNA. we did a large pilot of 300 patients where we looked at these patients. They'd gone through the traditional diagnostic workup and we said, let's do a CT DNA test alongside the tumour DNA test, And what we found is actually that rapidly speeds up the time-to-molecular information. And actually there's pretty good concordance between tissue NGS and liquid NGS. There is discordance, that's well described, but there's discordance both in CT DNA not picking up things that are present in the tissue, but also tissue not picking up things that are present in CTDNA. So, you know, tissue is not necessarily the gold standard when it comes to NGS because of issues with tumor cellularity and purity and other technical matters. We then worked with the N NHS, to show them some of our other pilot data because when COVID hit, we couldn't do biopsies, right? So we had an internal program which one of my colleagues, Mary O'Brien, led, where we tested about 30 patients with CT DNA. We found a small but important number of patients that had drivers that we could just get them straight onto a tablet without even a diagnosis officially needing to be made. So that made us think actually, if we have a patient that's in the clinic, they've got a CT scan that looks like lung cancer, why don't we do a CT DNA test at that time point? Because I'm going to get the molecular information back on the basis of the previous data that we published 50% quicker time than I would if We are then going to have a biopsy and then undergo tissue NGS. So we had quite a lot of discussions with NHS England, and that led to a national pilot where we were testing this in a phased implemented manner. And as of April 2025, we now have national rollout of CTDNA NGS at the time of presentation to the lung clinic if you've got suspected lung cancer. That's a fantastic state to be in.
Parker: That's really great news. And so it sounds like you were really able to get that over the line by proving a kind of operational benefit to the NHS. They they didn't force you to go through some kind of five year long overall survival trial. Is is that right?
Sanajy Popat: that's correct. I mean there's two things that we had to prove. Number one, it was economically viable. So we had to embed health economics within the pilot program. because actually the economics are clearly important. But actually operational benefit is key, right? Because we know from other data sets that CT DNA recapitulates very nicely what's going on in the tumour. And there are very good biological reasons for why you may not be shedding adequate CT DNA to inform your decision. So the key issue with CT DNA is is the report that you're getting demonstrative of an informative sample? is the there adequate information in the ct DNA for you to make a key judgment decision on? And if there is, all of our data have shown that this rapidly truncates the diagnostic journey, gets your patient on treatment quicker, and importantly what a health economic case demonstrated is it gets you on the right treatment. because your risk of false positives and false negatives is also abrogated as well. So it's an operational solution rather than needing a traditional does it make people live longer? Because the other thing Park you to remember is if you're shedding CT DNA, you've got by definition a poor prognosis tumor anyway, right? It's twenty to thirty percent poorer prognosis. So there are all these biases which impact on why a survival study wouldn't be the right way forward.
Parker: So health economics, operational improvements and also concordance sounded like the the three things you needed to get that over the line. But I also think you worked very differently with the technology companies. I know you've had a long association with Gardens and that rather than just bringing a US test over to the UK, you set up a kind of joint development lab with the Marsden. That that strikes me as a really important and creative way of of bringing UK science and also the UK health system al along the journey. could you just tell us a little bit about what what you did there and and if you think that made an impact. I'm thinking about just being instructive to other people working with technologies from around the world in the UK.
Sanajy Popat: Yeah, definitely. I mean I think this was the key driver of the success of the program is the fact that we had a tech transfer agreement with Garden Health and we now have their technology in our Garden Lab which we formalised prior to this this program. and that was on the background of all the pilot data that we did for several years previously working with the company to implement their technology. But I think, you know, what is very clear is the NHS does not want Tests going overseas, right? All it wants is overseas companies investing in the UK, And that has, I think, given us great operational benefits as well. But it's given our lab fantastic insights into CTDNA pipeline, allele calling, the technical aspects of it. it's really helped both parties, I think. and it's Given us a a a breadth of understanding and technological innovation that has really helped the group move forward and it's also opened up other avenues as well. And from the NHS viewpoint, it's fantastic, right? Because it's not a garden test, it's a Marsden 360 which is the same technology but done by our group. And they want to have this done in another lab in the north as well, and the similar models being done by Manchester for the Foundation One liquid test. But I think this is the track for other companies moving forward is to have a collaborative agreement to be able to deliver their test in the UK rather than outsourcing it outside.
Parker: Now, so far we've talked about liquid biopsy mostly in the diagnostic and the surveillance setting, but I I would be remiss not to mention the importance of it in early detection and particularly in lung. And there was a great chart that Cancer Research UK put out a few years ago, which really makes so clear why lung cancer is the place that we have to get early detection right. And if I describe this to you just a little bit. I mean, the big four cancers in the UK and and around the world really are breast, prostate, lung, and colorectal in that order. But there's a stark difference when you look at two other things. When you look at the survival curve for patients diagnosed at the different stages of that disease, and then also the incidence of diagnosis at the different stages. And if you compare breast to lung, for example, roughly the same number of patients in the UK get diagnosed with breast and lung, a little bit more with breast. But in breast, about 85% of those patients get diagnosed at stage one or two. And their survival is in the high 80s or 90 percentile. Whereas in lung, only about 25-30% of patients are diagnosed at stage one or two, and and the vast majority of patients are sadly diagnosed at stage four. And stage four lung cancer patients, despite all this innovation, still have really, really terrible. Outcomes. So I think this this chart shows the importance of generating a stage shift and and detecting lung cancer early, even compared to all of the other terrible cancers out there. So this is clearly a very promising setting for liquid biopsy, both CT DNA but other liquid biopsy technologies. I'd love to hear what your thoughts are for the future about how we could catch a few more of those patients earlier in their in their cancer journey.
Sanajy Popat: Yeah, I I have no doubt that some form of blood based cancer screening is going to be routine over the course of the next few years. the question is which technology and how will we operationalize it and how will we use it. So you know the other thing to bear in mind, Parker, is that lung cancer screening is mission critical. And we are by far ahead of most European countries. I'm I would actually say we are a global leader. in lung cancer screening because of the way we've been able to systematically implement at a population our screening program. It's made a huge difference because now we're seeing so many more stage ones in our clinic, in our MDT, compared to the stage four cancers, and I'm sure that's driving up the mortality that we see. But screening for lung cancer is only in the high risk population, and you've had to have a reasonable amount of tobacco exposure to be eligible for screening. So, what about those patients that I see in my clinic that have not had that level of tobacco exposure? Exposure that would not be eligible for lung cancer screening, that still get lung cancer. We're not picking them up, right? So we need to have another better ways of picking them up. And I think some sort of blood-based testing is going to be the way forward. And you you know, I think the the NHS has moved really very quickly on implementing and trialling blood-based diagnostics for early detection precisely for this reason, right? and I think the most famous of these is the NHS Galeri trial at which the NHS has partnered with Galeri to evaluate the role of a multi-cancer evaluation detection test MCED test versus not doing anything in in normal patients and these data were presented at ASCO this year by Charlie Charlie Swanton and you know the the end point of the study was unusual insofar as normally for a screening study you want to be looking for an intervention to reduce mortality. And here what we were looking for is to reduce the number of stage three and four cancers. And unfortunately that primary endpoint was not met. But within that there is a semblance of something there. Which does give us hope that actually you know blood-based diagnostics to detect cancer are possible and may well be implementable in the near future. So, for example, there was a reduction in in stage four cancers. And over a period of time, over a number of screening rounds, that reduction in in numbers of stage three and fours did become statistically significant. Now there are arguments on both sides of the equation. Right, there are the the naysayers who say, Well look, you know, you're just detecting cancers which are never going to kill a patient. This is lead time bias. And you know, you're really not doing anything other than causing harm by detecting cancers in people who are destined to die of natural causes. You're also causing problems by giving false reassurance and false negatives by patients that are told the test is negative and actually they have a cancer. Because one of the problems that we've got with all of these MSAN tests is their limited sensitivity to pick up early cancers. They're very good at picking up advanced cancers, but where we need the difference is a test that can pick up a stage one cancer. Stage one cancers may not be shedding much in the CT DNA, and that's why. why we need to think about other technologies to see how we try and implement these MSAT technologies moving forward.
Parker: Yeah, absolutely. there certainly was signal within that Galera I trial, even though, as you say, it sadly didn't quite meet its endpoints. I know you're close to the technology. There's a lot of exciting tech coming this way, including fragmentomics, there's work with exosomal DNA. So maybe just my my last question on lung cancer for you, Sanjay, which is you you mentioned right at the start that the lung cancer was a pretty bleak place 25 years ago when you got started, and it's much more promising now. In five to ten years from now, and I'm sure you will still be working in the Marsden. how do you see the journey of healthy patients who are trying to assess their lung cancer risk all the way through to late stage not diagnoses. What what do you see the future for the lung clinic in a few years from now?
Sanajy Popat: Right, it's gonna get busier and that's not a bad thing, right? because I think we are going to have some form of early detection test within the next five to ten years, that we will have a whole bunch of people being picked up with lung cancer, who will be completely asymptomatic, won't know about it, they'll have been picked up on a blood test. We will be either operating or ablating these early early lung cancers, but we are moving all our interesting genomically based, immunologically based stage four treatments up into these operable patients who will otherwise have still a very high risk of death. you know, we've got the kinase inhibitors, but we've got all the checkpoint inhibitors, but more importantly than that, we've got really novel. things coming through like personalized mRNA based cancer vaccine technology which are looking very exciting in melanoma, which I think could really make a big difference in stage one lung cancer as well. We've got a trial of that ongoing at the moment in the UK, which you know may well change practice in five years time. and you know, we've got all sorts of new newer drugs coming through. The the the two drug classes that I'm very excited about are the bi-specifics, you know. PD one, PDL one checkpoint inhibitors have totally revolutionized cancer care. Who'd have thought that we could improve on where we are with Pembroke, but it seems to be that PD one, VEGF bi-specifics do seem to be moving the goalposts and are giving us additional benefit over PD1, PDL one alone. And Many companies have got PD1, PDL1, VEGF bi-specifics in development. I think these will really take off. And we also have the newer drugs coming through, like T cell engagers. Now, in the world of myeloma, CAR T and T cell engagers have totally transformed the face of myeloma. CART are difficult to give currently for various technical reasons. We've got the newer CAR T's coming through, the Invivo CAR T's, which I'm very excited about. But in solid tumours, certainly lung cancer, small cell lung cancer, CART has been bypassed by T cell engagers. And a drug called Tylatomab is making massive inroads in small cell lung cancer by bringing the T cells to the tumour. And we're now seeing HLA-specific other T cell engagers coming through in in other solid indications. So, for example, we already have one approved called Tibendophyll. Us in UVL melanoma. There are companies who've launched trials in lung cancer of similar allele-specific T cell engagers. So I think in a few years' time we are going to still be extremely busy with lots of innovative new immunological and genomic-based technologies. The future is definitely very bright for our lung cancer patients and for cancer innovation
Parker: Yeah, I can hear the excitement in your voice So there is so much going on and it's great to hear someone like you who's come from a very bleak cancer and seen the whole journey of it turning much more positive for patients. Maybe a word for kind of early career doctors and early career scientists who are working in the cancers that are still bleak today. So many of the pediatric cancers, brain tumours, pancreatic cancer, for example. it struck me how the connections you've made throughout the UK ecosystem and also your relationship with with new technologies has been a big part of your success. and also a big part of the kind of energy that you've derived from the field. maybe a word to these early researchers. What what would you advise them when they're working in these dark parts of the of the cancer field.
Sanajy Popat: Well first thing first thing is don't give up, right? Because the only way is up. That's the bottom line, right? And if you look at what's happened to most cancers, it's taken a biological breakthrough in the science lab, funded by our amazing science partners, C I U K, MLC, etc. Together with innovation through understanding how that science then links into therapy innovation. So there then needs to be networking with those scientists, with the clinicians who understand the therapy field, with the medicinal chemists, with the companies to bring new innovative treatments to the clinic. We're already seeing this. I mean, pancreatic cancer, we have RAS inhibitor making massive impact, and this is the beginning of the RAS journey in pancreas cancer. And I think we're going to be, in a very, very interesting place Very similarly with sarcomas, pediatric cancers, and many others. I think this is really carry on persevering, understand the science. When we understand the science, then we can really action the vulnerability. But you've got to have the knowledge of who you interact with within the network, both nationally and internationally, to be able to exploit those findings. So make sure you know who the key people are in your field and carry on interacting with them because you know tomorrow they may be the most important person that you need to know.
Parker: I completely agree. And that's the whole purpose of this Cancer Connection podcast. And so maybe I'll end with my final question, which is the same question I ask all of our guests. Who would you like to hear me interview next on Cancer Connections?
Sanajy Popat: Great question, great question. I think probably I'd love to hear from Mike Stratton or Professor Sir Michael Stratton. So Mike is a pathologist who's working with his group with with Richard Worcester when I was doing my PhD as a year one PhD scientist. and he was very busily mapping BLCA2. And since then the work that he's done in tumor sequencing in setting up the cosmic database and understanding the biology of genomics for tumors I think has underpinned many of the advances that we are now reaping the benefits from in the clinic. So I would love to hear from him. You know, where does what does he think? is going to be the impact of our scientific advances over the next few years and how do we optimize those for those hard-to-treat cancers. I I'm very excited for the future and I'd love to hear from him.
Parker: That's a great suggestion. Mike, one of the UK icons who led the Sangra Institute for many years, I will be giving him a call. Thank you very much for that suggestion, Sanjay. And thank you again for spending an hour of your Saturday morning with us. And lastly, I'd love to thank our listeners.
Parker Moss - OUTRO: Thank you for listening to Cancer Connections. Please subscribe wherever you get your content. And if you've got any questions or feedback, I'd love to hear from you. I'm Parker Moss and until the next one, goodbye.
Parker: My guest today is Professor Sanjay Poppat. Sanjay is consultant thoracic oncologist at the Royal Marsden, where he heads the lung clinical unit and also the research program. Sanjay, you're the professor of thoracic oncology at the Institute of Cancer Research. You co-led the program that made the NHS the first national health service in the world to diagnose lung cancer from liquid biopsy. I know that you were a previous chair of the British Thoracic Oncology Group, and that you advised both the EMA and NICE. in the area of lung cancer. Sanjay, it's an incredible biography. You are very welcome to Cancer Connections. Thank you for being here.
Sanajy Popat: Yeah, a pleasure, Parker. Great to chat to you.
Parker: I thought I would first start by asking you a bit about your origin story. Because as I've read through your past papers, what really struck me is how you have consistently been ahead of the curve. So you started looking at liquid biopsy roughly 10 years before it reached the clinic. I know that you're very early now looking at novel Her 2 inhibitors in the lung cancer space. But what really struck me is going all the way back to the beginning of your career, it seemed not to have started in lung. The first paper I could find from you was actually on microsatellite instability in colorectal cancer, where you seem to be very early in pointing out its prognostic impact. And that was more than 12 years before it became the biomarker that Catruder, the famous checkpoint inhibitor from Mutt, was launched upon. So Just tell us a little bit about your story and how you have had this consistent ability to have great insight about the future of cancer.
Sanajy Popat: well I I think you know part of it goes to my interest in molecular biology and genetics and molecular genetics. and that that's always been a a real interest to me. I I qualified in medicine in in ninety-four and then did junior medical jobs and ended up at the Marsden. And thought actually, oncology is really where I want to be because I can really see how we are implementing what I've learnt in molecular biology and science into the clinic. I was very lucky as an undergraduate, which I did my medical degree at Guys and St. Thomas's to have done an undergraduate integrated BSc. And that was with a really inspiring chap called Frank Walsh, who is doing a lot of work on NCAM and its role in neuron biology. And during that course, you know, I picked up the basics of cell biology, molecular oncology, and started to dabble a little bit with immunology. technology and I thought, you know, in oncology you can really transform cancer care because you're taking the findings of basic science at a very, very early level and impacting them onto the patients and in some cases making huge benefits, stepwise changes. At that point it wasn't straightforward to be trained in medical oncology, so I took three years out to work with another inspiring character at the Institute of Cancer Research in the Sutton branch. a chap called Richard Holston and he's a genetic epidemiologist. who has an incredible breadth of knowledge around our our genes, the impact of our germline variation, its relationship with normal tissues and how that might change in cancer. And at that stage, it was really exciting. You know, we'd gone from traditional Sangha sequencing to ABI sequencing. sequencing was everywhere, that was the buzzword. And you know, Mike Stratton and Richard Wister were in the lab down the corridor. There was a lot going on And you know, Rich and I w were having chats about Microsoft by instability and we were he was doing a project, in the somatic evolution at the genomic level of colorectal cancer and I was interested in microsatellites which we were using at that at that stage for gene mapping, right? Because sequencing was not affordable. We didn't have the high throughput sequencing. So all we were able to do is to look at microsatellites and try and see how these segregate with families and diseases to try and map genes. And we ended up publishing you know paper which I think is still one of my most cited papers actually in the relationship of the presence or absence of microsatellite stability and outcome in colon cancer. I then went on to do a clinician scientist fellowship at the Marsden for three years, where I was looking at various somatic outcomes of colon cancer, looking at colon cancer, microsatellite instability, a a few other biomarkers, completed my training and at that point actually the Marsden needed a lung encore. Oncologist, We didn't have much for lung oncology at that point, to be honest. It was all a bit of chemotherapy, which didn't do much. A lot of nib had been in the clinic for a few years. We didn't really know about EGFR mutations at that point. and it was all a bit depressing. But you know, I thought, yeah, let's do it, let's take it on. There's a there's a lot we can achieve. So I think I I'm fortunate to have lived through a lot of changes in in. science and I'm even more fortunate to have been surrounded by can-do people. and people really make a difference to how we can move forward with the agenda to impact on patients.
Parker: I would love to hear a little bit from you about really how the experience of a lung cancer patient today is different to when you first joined that clinic back in the early two thousands.
Sanajy Popat: Yeah, you know, lung cancer's totally transformed. if I see a patient today, I need to give them a specific pathological diagnosis, what it looks like under the microscope. and what it looks like under the microscope and its precise name is very different to how it was back in the mid-two thousands. Mid two thousands, we were just happy to call it non-small cell lung cancer. You know, as long as it wasn't small cell, that was fine, right? Because small cells treated in a very different way to non-smell lung cancer. Non-smell lung cancer, by and large, button doublet chemotherapy. We knew that there's adenose and we knew that there's squames. We knew that maybe some chemos worked a little bit better than others in some scenarios, but really the genomics didn't really matter. we'd been faffing around a little bit with VEGF inhibitors, had modest impact. And actually the the the basis of how we treated our patient was chemotherapy for everyone and if you weren't fit for chemotherapy there wasn't really anything else and you know brain metastases were a big challenge a lot of these patients had brain metastases and as soon as you had brain metastases you're in trouble we didn't have what we now regard as standard stereotactic radiotherapy, we didn't have brain penetrant drugs. It was a terrible time. You know, our patients had terrible average survival. It you know, it'd be fairly routine for patients to be passing away within a year of diagnosis. and that's a bad place to come from. And that's not just in the UK. That's that's a global issue. And that's a global issue for what's a common cancer, right? so The the advances that we've seen in in science have really allowed and underpinned advances in trials and actually at the same time we've had also in parallel had a revolution in medicinal chemistry. I mean, for example, the small molecule revolution of quinaslone drugs never existed, right? Our ability to target kinases did not exist in the late nineties and early two thousands. That's only really come on at the same time as we've understood that there are a a group of somatic problems With cancer, with key drivers that if we have the right drugs, we can target. So now in the clinic, if I'm seeing a a patient, I'm saying, well, look, we need a precise diagnosis. I need to know whether it's an adenocarcinoma or a squamous carcinoma, I need to know whether it's a TTF-1 positive or TTF-1 negative adenocarcinoma. I need to understand the molecular biology of that cancer. And mostly we're dealing with adenocarcinomas these days, and there are at least 50. Different drug targets that we need the lab to have looked at to tell me what's going on at that genetic locus for that particular patient. And I would actually argue that's whether you can drug that target or not. For me, I need to understand the biology of that cancer. So I'm looking at the whole genomic architecture. I want to understand what sort of tumour microenvironment we're dealing with. You know, is it like an immunoin inflammatory microenvironment? Is it an in a suppressive microenvironment, you know, have we got copy number loss, have we got copy number change? So it's not just the single nucleotide variants we're interested in, you know, we're looking at the large scale architecture of the tumor to help me understand that. And then when we have
Parker: I think.
Sanajy Popat: an understanding of that, can we get the patient on the right drug And that is totally transformed the way we are managing our patients. And it's made a huge impact in Lung cancer, where we've got effectively two different biological subsets, those that are immune sensitive and those that are not. And those that are not tend to be oncogene addicted and need kinase inhibitors. But those that are immune sensitive, you we definitely have a small proportion, 20% of patients who are alive long term year five plus with no evidence of cancer, having presented to me with widespread metastatic malignancy. It's inspiring, it's wonderful, it's so lovely to be able to make these differences to our patients. And the issues that we deal with in the clinic now are sometimes issues about survivorship, right? thinking about long-term rather than everything being doom and gloom about, you know, what am I going to do next month? Which is, you know, what the angle was at the beginning. But don't get me wrong, Parker, we've got a lot of work still to do, I'm talking about the extremes of benefits that we see here. We still see the extremes of sadness as well in the clinic. Patients that come to us with super aggressive tumors that you know you throw the kitchen sink at it and it still grows. And you've got patients that have acquired resistance where some modest benefit initially and then relapse. So there's still a lot of work that we need to do in science. in drug development to continue to shift the the bar, the mission is not yet complete.
Parker: Yeah, the battle is still raging, I think one of the papers that I read a couple of years ago that that really struck me as fascinating in the lung case was that Charlie Swanson paper about particulate matter. two point five. I think back in twenty twenty three during COVID he published that. And he proposed a a really interesting new mechanism which was nothing to do with carcinogens at all, where small particulate matter of a around the the two point five micrometer size could come into the lungs, cause epithelial damage, attract macrophages, those macrophages excreted interleukin one beta, and that cause inflammation, which for a subtype of genetic groups, I think EGFR and KRAS, could drive cancer through a completely non-carcinogen mechanism. That struck me as a really important insight. And I'm wondering whether that's affected the way you think about patients, both in the smoking and also the non smoking subset of the people that you see in your clinic.
Sanajy Popat: Yeah, and I and I think this is a really important new field of biology that we need to explore. because you know, his phenomenal work has impacted on the question that patients ask me in the clinic every day, which is why did this happen to me? that's the key issue that folk want to know about. Now, if you've never smoked or you've had a few crafty cigarettes, you know, in university and you end up with lung cancer, it's clearly not tobacco related, which is by far the greatest cause of lung cancer. And in those patients in whom tobacco probably hasn't played a role, Charlie's data is very clear that this inflammatory change that we see with two point five particulate matter drives this inflammatory change through chip, through macrophages, through IL1 beta signaling. And what's really interesting is that it biologically gives us an understanding for why some patients may develop somatic mutation as a driver where others may not. working on The other foundational data that we have from Mike Stratton and others, which is that many of our cells develop somatic mutation in key drivers, but never become malignant in those cells. So the key issue is why biologically do some cells develop a driver, but then that never becomes transformative to an established tumor, and in some people it does. And I think this whole IL1 beta inflammome. hypothesis that charlie's really I think quite eloquently demonstrated does support and drive that so I think this has huge implications right because you know we can effectively inhibit IL1 beta right we have drugs which do that there's a there's a fantastic paper many years ago demonstrating that The NALP 1 inflammazone, which is also driven in that sort of scenario by L1 beta, you know, may contribute to the formation of asbestos inflammosomes, which then can drive asbestos-related malignancy and asbestos-related other conditions. So the whole concept of IL1 beta is in carcinogenesis, I think is really, really mission critical. and there's an opportunity I see here to, you know, try and test that and drug that with IL1 beta inhibitors. Now they've not really proven effective in widespread metastatic disease, but you know, we need to think about how we then select the right patients for the right trials in that right scenario. And maybe, prevention type of study is what we need to start thinking about doing. But these are very complex studies to set up and deliver on.
Parker: All right, let's switch subject away from Therapeutics into diagnostics, where I think you've had a huge impact, and I was lucky enough to witness some of that impact on the NHS. and what I think is a a breakthrough and a very rapid decision by them, to embrace the use of liquid biopsy for lung cancer in general. Talk us through what a liquid biopsy is, the different settings that it can work in and the importance for lung cancer, because this is a piece of news that I think is not widely appreciated and is going to really impact people across the country and not just in lung cancer, but in in many of the cancers.
Sanajy Popat: Yeah, so I mean liquid biopsy means different things to different people, but I broadly at this stage would summarize a liquid biopsy to be the same thing as testing for circulating tumor DNA. we all have really small fragments of circulating free DNA in the plasma of our blood. Remember, blood is composed of red cells, white cells, platelets, and the soup that they live in, called plasma. And in that plasma, the soup that all these things live in, you know, we do see these tiny fragments of DNA. Now, most of those fragments of DNA are from our host tissues. But in patients with cancer, some of those fragments of DNA can arise from the nucleus. Material of the patient's cancer. So, therefore, if you can sequence that tumour-derived free DNA, you then have a very accurate picture of the actual tumor genomics itself. And our sequencing technologies are now good enough that we can detect these very, very, very low levels of circulating free DNA, what we call circulating tumor DNA or CT DNA. And there are many companies that have validated technology to detect this and sequence it and tell you what the genomic aberrations are. And we've been using this for quite some time, looking at a single gene in the clinic. so the example here is the single gene called EGFR. And when we have patients with widespread metastatic disease, if we drug them with a first or second generation EGFR inhibitor, say cafetonib, a lotonib, epitonib, after a period of time, the cancer cells become resistant to those drugs, and they become resistant to those drugs by outgrowth of a clone of cells which have got an acquired change called a T790M mutation in the EGFR gene. And this results in a structural conformation in the EGFR protein in the cell, which prevents. Kinase inhibitor from binding effectively to the kinase domain site and therefore inhibiting EGFR. And we also have very good drugs which switch off T790M mutant EGFR very well, osimelotinin for example. so therefore the paradigm has been if you have a patient on first and second generation drugs, if you biopsy their tumour, identify T790m, they would then be suitable for Ossimotinib and we would have a very nice benefit from ossiometonib thereafter. Now of course biopsying patients you know is never straightforward. I mean none of us wants to have a big needle in our chest, right? None of us wants to have a big camera going down our throat. So wouldn't it be great if you could identify T seven ninety from fragments of C T DNA shed into the plasma by a simple blood draw? And that in fact is the technology that existed at that time. And that's exactly what we're doing, a blood draw to look at plasma to detect EGFR T790M. But the technology has moved on, and we actually have technology which looks at a variety of different loci at different levels, and that brings into the whole question of clinical utility. Where do you use it and what can you gain from it? And you can use it in many different ways. So we've talked about the example when you're using in a late metastatic setting where you're looking for acquired resistance. Now you could replace that single EGFR gene test with a multiple gene test C T DNA NGS where we're looking for a variety of targets so when the same patient then relapses on a fetonib Gafitonib, erlotonib or osimelotonib. The question is, are they resistant because of EGFR change or is there something else going on like metapregulation, another driver that's causing that? So that's one scenario you could use that. Now I said to you at the beginning of the conversation, these days, before I start treating a patient with advanced non-small cell lung cancer, I want to know what their genetic profile is. That's contingent on the biopsy that we take to make the diagnosis of their cancer undergoing somatic testing in the lab. Now you could also do that by simple blood draw. And if you time your blood draw really well in the patient diagnostic journeys, perhaps when the patient presents to the hospital, you might be able to do it very, very quickly before you know that the patient has cancer from a biopsy or before you know the tissue NGS. We'll come back to that in a little bit. And the other area that you might want to be using these blood tests are in the patient that has undergone cancer resection, where you're looking to see is there any evidence of the tumor CT DNA present after the patient has undergone resection? Because that may well change what you do after surgery. You may or may not want to give treatment in colon cancer, you may. Say, well, look, actually, this patient has a very low probability of relapse after resection. The patient does not need chemotherapy. You may want to intensify your treatment and say, actually, this patient has evidence of circulating tumor DNA despite surgery. This patient needs treatment intensification. We need to give more than just the basic chemotherapy, they need X, Y, and Z. And you can even monitor that on an ongoing basis. And you can see whether MI. MRD, we call it molecular residual disease, MRD positivity changes into negativity or even then becomes positive again. you know a lot of these questions about the dynamics of ct DNA or MRD testing in the post-surgical setting. how we should intensify or deintensify our treatment on the basis of this is still the subject I think of many clinical trials, but is something that I think is going to change where what we do in the next five years.
Parker: Okay, so i if I could extract from that, I think there are the four settings. So there's early detection of lung cancer, which you you might do on patients that have not yet presented symptoms. Then there's the diagnosis of lung cancer, where you can use a liquid biopsy to look for this circulating tumor DNA in the blood. then there's a search for minimal residual disease or molecular residual disease after surgery and then presumably also a fourth setting of surveillance after treatment to make sure the patient's not relapsing. So please just tell us a little bit about what has the UK now approved in the NHS? what's available to patients today and what role did you play in in making that happen?
Sanajy Popat: the UK actually I think is spearheading a lot of liquid biopsy implementation. The the biggest impact I think that we've been able to to make, I think globally, to be honest with you, but certainly in the UK, is the implementation of CT DNA for patients with metastatic non-swan cell lung cancer, or suspected lung cancer. So, you know, the problem that we had was we have patients walking into the clinic or in the hospital with what looks like on a CT scan widespread lung cancer. We're meant to get these patients on treatment within 62 days. That's the government target. And in that time, we need to do multiple scans, we need to do biopsy, the biopsy needs to undergo pathological analysis, it needs to undergo DNA NGS, it needs to go RNA NGS. We then need to get the patient on treatment. And actually, what we're finding is that around 50% of patients are undergoing treatment within 62 days, not 85% or above.
Parker: Mm.
Sanajy Popat: So this is a big problem because we know for every week that the patient doesn't have treatment, there is a graduate. Gradual deterioration because cancers grow. So, how do we get patients treated within the quickest time possible? Because you know, if it's you or I, that went to the clinic, we want to be on treatment as soon as possible, right? We don't want to be fluffing around for three months, waiting for people to decide. It's a completely unacceptable state of affairs. Now we have in our centre been doing quite a lot of work with CT DNA. we did a large pilot of 300 patients where we looked at these patients. They'd gone through the traditional diagnostic workup and we said, let's do a CT DNA test alongside the tumour DNA test, And what we found is actually that rapidly speeds up the time-to-molecular information. And actually there's pretty good concordance between tissue NGS and liquid NGS. There is discordance, that's well described, but there's discordance both in CT DNA not picking up things that are present in the tissue, but also tissue not picking up things that are present in CTDNA. So, you know, tissue is not necessarily the gold standard when it comes to NGS because of issues with tumor cellularity and purity and other technical matters. We then worked with the N NHS, to show them some of our other pilot data because when COVID hit, we couldn't do biopsies, right? So we had an internal program which one of my colleagues, Mary O'Brien, led, where we tested about 30 patients with CT DNA. We found a small but important number of patients that had drivers that we could just get them straight onto a tablet without even a diagnosis officially needing to be made. So that made us think actually, if we have a patient that's in the clinic, they've got a CT scan that looks like lung cancer, why don't we do a CT DNA test at that time point? Because I'm going to get the molecular information back on the basis of the previous data that we published 50% quicker time than I would if We are then going to have a biopsy and then undergo tissue NGS. So we had quite a lot of discussions with NHS England, and that led to a national pilot where we were testing this in a phased implemented manner. And as of April 2025, we now have national rollout of CTDNA NGS at the time of presentation to the lung clinic if you've got suspected lung cancer. That's a fantastic state to be in.
Parker: That's really great news. And so it sounds like you were really able to get that over the line by proving a kind of operational benefit to the NHS. They they didn't force you to go through some kind of five year long overall survival trial. Is is that right?
Sanajy Popat: that's correct. I mean there's two things that we had to prove. Number one, it was economically viable. So we had to embed health economics within the pilot program. because actually the economics are clearly important. But actually operational benefit is key, right? Because we know from other data sets that CT DNA recapitulates very nicely what's going on in the tumour. And there are very good biological reasons for why you may not be shedding adequate CT DNA to inform your decision. So the key issue with CT DNA is is the report that you're getting demonstrative of an informative sample? is the there adequate information in the ct DNA for you to make a key judgment decision on? And if there is, all of our data have shown that this rapidly truncates the diagnostic journey, gets your patient on treatment quicker, and importantly what a health economic case demonstrated is it gets you on the right treatment. because your risk of false positives and false negatives is also abrogated as well. So it's an operational solution rather than needing a traditional does it make people live longer? Because the other thing Park you to remember is if you're shedding CT DNA, you've got by definition a poor prognosis tumor anyway, right? It's twenty to thirty percent poorer prognosis. So there are all these biases which impact on why a survival study wouldn't be the right way forward.
Parker: So health economics, operational improvements and also concordance sounded like the the three things you needed to get that over the line. But I also think you worked very differently with the technology companies. I know you've had a long association with Gardens and that rather than just bringing a US test over to the UK, you set up a kind of joint development lab with the Marsden. That that strikes me as a really important and creative way of of bringing UK science and also the UK health system al along the journey. could you just tell us a little bit about what what you did there and and if you think that made an impact. I'm thinking about just being instructive to other people working with technologies from around the world in the UK.
Sanajy Popat: Yeah, definitely. I mean I think this was the key driver of the success of the program is the fact that we had a tech transfer agreement with Garden Health and we now have their technology in our Garden Lab which we formalised prior to this this program. and that was on the background of all the pilot data that we did for several years previously working with the company to implement their technology. But I think, you know, what is very clear is the NHS does not want Tests going overseas, right? All it wants is overseas companies investing in the UK, And that has, I think, given us great operational benefits as well. But it's given our lab fantastic insights into CTDNA pipeline, allele calling, the technical aspects of it. it's really helped both parties, I think. and it's Given us a a a breadth of understanding and technological innovation that has really helped the group move forward and it's also opened up other avenues as well. And from the NHS viewpoint, it's fantastic, right? Because it's not a garden test, it's a Marsden 360 which is the same technology but done by our group. And they want to have this done in another lab in the north as well, and the similar models being done by Manchester for the Foundation One liquid test. But I think this is the track for other companies moving forward is to have a collaborative agreement to be able to deliver their test in the UK rather than outsourcing it outside.
Parker: Now, so far we've talked about liquid biopsy mostly in the diagnostic and the surveillance setting, but I I would be remiss not to mention the importance of it in early detection and particularly in lung. And there was a great chart that Cancer Research UK put out a few years ago, which really makes so clear why lung cancer is the place that we have to get early detection right. And if I describe this to you just a little bit. I mean, the big four cancers in the UK and and around the world really are breast, prostate, lung, and colorectal in that order. But there's a stark difference when you look at two other things. When you look at the survival curve for patients diagnosed at the different stages of that disease, and then also the incidence of diagnosis at the different stages. And if you compare breast to lung, for example, roughly the same number of patients in the UK get diagnosed with breast and lung, a little bit more with breast. But in breast, about 85% of those patients get diagnosed at stage one or two. And their survival is in the high 80s or 90 percentile. Whereas in lung, only about 25-30% of patients are diagnosed at stage one or two, and and the vast majority of patients are sadly diagnosed at stage four. And stage four lung cancer patients, despite all this innovation, still have really, really terrible. Outcomes. So I think this this chart shows the importance of generating a stage shift and and detecting lung cancer early, even compared to all of the other terrible cancers out there. So this is clearly a very promising setting for liquid biopsy, both CT DNA but other liquid biopsy technologies. I'd love to hear what your thoughts are for the future about how we could catch a few more of those patients earlier in their in their cancer journey.
Sanajy Popat: Yeah, I I have no doubt that some form of blood based cancer screening is going to be routine over the course of the next few years. the question is which technology and how will we operationalize it and how will we use it. So you know the other thing to bear in mind, Parker, is that lung cancer screening is mission critical. And we are by far ahead of most European countries. I'm I would actually say we are a global leader. in lung cancer screening because of the way we've been able to systematically implement at a population our screening program. It's made a huge difference because now we're seeing so many more stage ones in our clinic, in our MDT, compared to the stage four cancers, and I'm sure that's driving up the mortality that we see. But screening for lung cancer is only in the high risk population, and you've had to have a reasonable amount of tobacco exposure to be eligible for screening. So, what about those patients that I see in my clinic that have not had that level of tobacco exposure? Exposure that would not be eligible for lung cancer screening, that still get lung cancer. We're not picking them up, right? So we need to have another better ways of picking them up. And I think some sort of blood-based testing is going to be the way forward. And you you know, I think the the NHS has moved really very quickly on implementing and trialling blood-based diagnostics for early detection precisely for this reason, right? and I think the most famous of these is the NHS Galeri trial at which the NHS has partnered with Galeri to evaluate the role of a multi-cancer evaluation detection test MCED test versus not doing anything in in normal patients and these data were presented at ASCO this year by Charlie Charlie Swanton and you know the the end point of the study was unusual insofar as normally for a screening study you want to be looking for an intervention to reduce mortality. And here what we were looking for is to reduce the number of stage three and four cancers. And unfortunately that primary endpoint was not met. But within that there is a semblance of something there. Which does give us hope that actually you know blood-based diagnostics to detect cancer are possible and may well be implementable in the near future. So, for example, there was a reduction in in stage four cancers. And over a period of time, over a number of screening rounds, that reduction in in numbers of stage three and fours did become statistically significant. Now there are arguments on both sides of the equation. Right, there are the the naysayers who say, Well look, you know, you're just detecting cancers which are never going to kill a patient. This is lead time bias. And you know, you're really not doing anything other than causing harm by detecting cancers in people who are destined to die of natural causes. You're also causing problems by giving false reassurance and false negatives by patients that are told the test is negative and actually they have a cancer. Because one of the problems that we've got with all of these MSAN tests is their limited sensitivity to pick up early cancers. They're very good at picking up advanced cancers, but where we need the difference is a test that can pick up a stage one cancer. Stage one cancers may not be shedding much in the CT DNA, and that's why. why we need to think about other technologies to see how we try and implement these MSAT technologies moving forward.
Parker: Yeah, absolutely. there certainly was signal within that Galera I trial, even though, as you say, it sadly didn't quite meet its endpoints. I know you're close to the technology. There's a lot of exciting tech coming this way, including fragmentomics, there's work with exosomal DNA. So maybe just my my last question on lung cancer for you, Sanjay, which is you you mentioned right at the start that the lung cancer was a pretty bleak place 25 years ago when you got started, and it's much more promising now. In five to ten years from now, and I'm sure you will still be working in the Marsden. how do you see the journey of healthy patients who are trying to assess their lung cancer risk all the way through to late stage not diagnoses. What what do you see the future for the lung clinic in a few years from now?
Sanajy Popat: Right, it's gonna get busier and that's not a bad thing, right? because I think we are going to have some form of early detection test within the next five to ten years, that we will have a whole bunch of people being picked up with lung cancer, who will be completely asymptomatic, won't know about it, they'll have been picked up on a blood test. We will be either operating or ablating these early early lung cancers, but we are moving all our interesting genomically based, immunologically based stage four treatments up into these operable patients who will otherwise have still a very high risk of death. you know, we've got the kinase inhibitors, but we've got all the checkpoint inhibitors, but more importantly than that, we've got really novel. things coming through like personalized mRNA based cancer vaccine technology which are looking very exciting in melanoma, which I think could really make a big difference in stage one lung cancer as well. We've got a trial of that ongoing at the moment in the UK, which you know may well change practice in five years time. and you know, we've got all sorts of new newer drugs coming through. The the the two drug classes that I'm very excited about are the bi-specifics, you know. PD one, PDL one checkpoint inhibitors have totally revolutionized cancer care. Who'd have thought that we could improve on where we are with Pembroke, but it seems to be that PD one, VEGF bi-specifics do seem to be moving the goalposts and are giving us additional benefit over PD1, PDL one alone. And Many companies have got PD1, PDL1, VEGF bi-specifics in development. I think these will really take off. And we also have the newer drugs coming through, like T cell engagers. Now, in the world of myeloma, CAR T and T cell engagers have totally transformed the face of myeloma. CART are difficult to give currently for various technical reasons. We've got the newer CAR T's coming through, the Invivo CAR T's, which I'm very excited about. But in solid tumours, certainly lung cancer, small cell lung cancer, CART has been bypassed by T cell engagers. And a drug called Tylatomab is making massive inroads in small cell lung cancer by bringing the T cells to the tumour. And we're now seeing HLA-specific other T cell engagers coming through in in other solid indications. So, for example, we already have one approved called Tibendophyll. Us in UVL melanoma. There are companies who've launched trials in lung cancer of similar allele-specific T cell engagers. So I think in a few years' time we are going to still be extremely busy with lots of innovative new immunological and genomic-based technologies. The future is definitely very bright for our lung cancer patients and for cancer innovation
Parker: Yeah, I can hear the excitement in your voice So there is so much going on and it's great to hear someone like you who's come from a very bleak cancer and seen the whole journey of it turning much more positive for patients. Maybe a word for kind of early career doctors and early career scientists who are working in the cancers that are still bleak today. So many of the pediatric cancers, brain tumours, pancreatic cancer, for example. it struck me how the connections you've made throughout the UK ecosystem and also your relationship with with new technologies has been a big part of your success. and also a big part of the kind of energy that you've derived from the field. maybe a word to these early researchers. What what would you advise them when they're working in these dark parts of the of the cancer field.
Sanajy Popat: Well first thing first thing is don't give up, right? Because the only way is up. That's the bottom line, right? And if you look at what's happened to most cancers, it's taken a biological breakthrough in the science lab, funded by our amazing science partners, C I U K, MLC, etc. Together with innovation through understanding how that science then links into therapy innovation. So there then needs to be networking with those scientists, with the clinicians who understand the therapy field, with the medicinal chemists, with the companies to bring new innovative treatments to the clinic. We're already seeing this. I mean, pancreatic cancer, we have RAS inhibitor making massive impact, and this is the beginning of the RAS journey in pancreas cancer. And I think we're going to be, in a very, very interesting place Very similarly with sarcomas, pediatric cancers, and many others. I think this is really carry on persevering, understand the science. When we understand the science, then we can really action the vulnerability. But you've got to have the knowledge of who you interact with within the network, both nationally and internationally, to be able to exploit those findings. So make sure you know who the key people are in your field and carry on interacting with them because you know tomorrow they may be the most important person that you need to know.
Parker: I completely agree. And that's the whole purpose of this Cancer Connection podcast. And so maybe I'll end with my final question, which is the same question I ask all of our guests. Who would you like to hear me interview next on Cancer Connections?
Sanajy Popat: Great question, great question. I think probably I'd love to hear from Mike Stratton or Professor Sir Michael Stratton. So Mike is a pathologist who's working with his group with with Richard Worcester when I was doing my PhD as a year one PhD scientist. and he was very busily mapping BLCA2. And since then the work that he's done in tumor sequencing in setting up the cosmic database and understanding the biology of genomics for tumors I think has underpinned many of the advances that we are now reaping the benefits from in the clinic. So I would love to hear from him. You know, where does what does he think? is going to be the impact of our scientific advances over the next few years and how do we optimize those for those hard-to-treat cancers. I I'm very excited for the future and I'd love to hear from him.
Parker: That's a great suggestion. Mike, one of the UK icons who led the Sangra Institute for many years, I will be giving him a call. Thank you very much for that suggestion, Sanjay. And thank you again for spending an hour of your Saturday morning with us. And lastly, I'd love to thank our listeners.
Parker Moss - OUTRO: Thank you for listening to Cancer Connections. Please subscribe wherever you get your content. And if you've got any questions or feedback, I'd love to hear from you. I'm Parker Moss and until the next one, goodbye.
