Episode #1: Multi-Cancer Early Detection with Dr. Betsy O'Donnell

Foresight Medicine Episode #1 TranscriptThe present and future of multi-cancer early detection with Dr. Betsy O’DonnellRobert Rogers: I’m Robert Rogers, host of the Foresight Medicine Podcast at the Foresight Medicine Substack, where we are envisioning the future of preventive healthcare as a systematic, comprehensive, and whole body framework for leveraging new and emerging technologies to maintain health for as long as possible.In this podcast series I interview leading experts at the forefront of prevention and early intervention across medical specialties. I am very honored to have as our guest today Dr. Betsy O’Donnell. Dr. O’Donnell is Associate Professor of Medicine at Harvard Medical School. She’s an oncologist and a clinician and researcher who’s making big contributions across multiple fields, including multiple myeloma, nutrition, and exercise for cancer survivors. And in recent years, in the burgeoning field of multi cancer early detection. And it is in that capacity that I am most excited to speak with her today. She’s the director of the Multi Cancer Early Detection Clinic at Dana-Farber Cancer Institute, and an innovative thought leader in this field. Betsy.Welcome. Listeners should note that we are recording this on Monday, January 26th, 2026. This is a field with new data being published all the time, and this episode will not air for a few weeks. So if we say something that becomes slightly outdated, we’ll note that in the show notes, but the audio will stand and this conversation is for general information purposes only, and does not constitute individual. Medical advice. Throughout this conversation, you’ll hear us use the word MED, spelled MCED, which is an abbreviation for multi cancer early detection.Robert Rogers: So Betsy, thank you. I’m really excited to have this conversation. Thanks so much for coming on today.Betsy O’Donnell: Thank you so much for having me. It’s truly fun to get to talk about this and, and really go back and forth about such an exciting topic.Robert Rogers: For our listeners, I’ll just give them a little bit of a guide to this conversation where I’d like to take it. In the next 45 minutes or so, we’re gonna do a little bit of a, the sandwich technique. So we’re gonna end with our destination being some of the really new and exciting stuff that’s at the forefront of this exciting field of multi cancer early detection, the data that’s driving the field, what you see coming down the pipeline. But before we get there, I want us to build a little bit of a foundation in understanding the principles of cancer screening and early detection, early intervention. But I would like us to start out with understanding what it is that, that, that we’re gonna really be talking about today. So tell us what is multi cancer early detection, and how did you get interested in, drawn to this field.Betsy O’Donnell: Absolutely. So multi cancer early detection is really an evolving field, trying to think of means by which we can screen for multiple cancers at once. So if we start with what is the state of cancer screening currently? So right now the United States Preventive Task Force Service recommends screening for breast cancer, colorectal cancer, cervical cancer and lung cancer in smokers. So that’s four cancers. But we know that about 70% of the cancers that are diagnosed don’t have screening tests. And so multi cancer early detection is really aimed at trying to find cancer screening tests that can screen for many of the cancers that don’t currently have existing screening tests with a goal of finding more cancers earlier.And one of the challenges - there are many challenges to cancer screening, but one of the important ones is. As we think about screening and the number needed to screen to find a cancer, the more rare it is, the harder it is to justify screening thousand, a thousand patients to find one cancer if you’re that primary care doctor.And not only that, we don’t have good modalities to find those cancers, but if we aggregate cancers into one test. We need to screen fewer people to find a cancer. And the major goal of multi cancer early detection testing again, is to think about novel ways to find more cancers, but also to find them earlier.And so there are a lot of different ways in which people are exploring early cancer detection. I focus primarily on blood-based screening, and the reason I do this is for multiple reasons actually. One, I think most patients are accepting of blood tests as something they’re willing to do. And also they really offer the ability to be done anywhere, any point of care, location.And one of the major goals that I have when I think about the work that I do in multi cancer early detection, is not only. Bettering cancer screening, but making it more accessible. So when I think about multi cancer early detection tests, I’m thinking about it not only for finding more cancers early, but thinking about how that can affect the population and how we can better medical care nationally, potentially globally, um, through enhancing access.You asked me how I became interested in this. So,Robert Rogers: and lemme lemme just say for, for our listeners, you, said that your focus within multi cancer early detection is on blood-based tests. And, implicit in that is in contrast to these whole body imaging approaches, which are another modality. Let’s put a pin in that because that is a, an interesting kind of side story to the, to the MCED [Multi Cancer Early Detection] world, which maybe we’ll get into maybe how that could be combined with blood tests at the end. But I’d love to hear a little bit about your personal history and interest getting into the field.Betsy O’Donnell: Thank you so definitely put a pin. So as a person in general, I’m a very proactive person. I think most of us in our, in our lives are always thinking ahead, um, trying to figure out what we can do to achieve our goals or to prevent things from happening that we don’t wanna have happen.Oncology in general has been primarily been a reactive field. So a lot of that is history. There’s history and so much of what we do in medicine. But you know, I think about when I started my career in 2001, I was a clinical research coordinator at Dana-Farber, and that was really at the start of targeted therapy.All of the cancer therapies that we had historically really targeted the cell cycle, mitosis, cell division, and we had a limited number of chemotherapies that we combined to try to increase the efficacy, but using all of those same drugs in different cancers. And what’s happened over the past two decades is this dramatic revolution of cancer therapies, targeted therapies, small molecule inhibitors, CAR T cells, bispecific, T-cell engagers.I could go on and on. And what we’ve done is we’ve become much better at treating cancers and keeping people alive with cancer, but we really haven’t got it at the front end of the problem, which is finding cancer when it’s earliest, when it can be cut out, when it can be treated, look as a localized process, and that’s when it’s most curable.And so I worked as the director of inpatient operations at MGHI was very involved in just thinking about how we can operate most efficiently. And as you recall, in 2020, you know, the world was shut down by COVID. And what that did to the hospital that you and I were both at, is we had to allocate most of our resources to treating patients with COVID, which meant we stopped doing elective procedures, things like colonoscopies.We put them on hold so we could manage the pandemic. The original publication, the Pathfinder publication of Grail’s Galleri test was presented ASCO in 2021. And this was at a time where our hospital was really trying to get back in action, trying to get back on its feet. But things like, because we had stopped doing elective colonoscopies, there was a backlog.And it was just tremendously challenging in the healthcare system to just get fundamental things done, like colonoscopies for patients who needed them. And so when I first heard about the data. From the Galleri study, which is a multi cancer early detection test. What really excited me as someone who is doing operations, who’s someone who’s forward looking, who someone believes in preventive medicine, is this is something that could be, you know, a win across multiple fronts.We can find cancer early, we can find multiple types of cancer, but maybe also we can mitigate the burden on the healthcare system. And what do I mean by that? I mean that we can keep patients out of chairs. It’s great. That we can treat cancers for longer, but that’s not what people want, and that’s not what the healthcare system needs.We need cure. And so that keeps people out of chairs, that minimizes the burden of resources needed, like blood products, like experts to give these novel therapies. And then also just the economic cost of ongoing cancer care for these very expensive but miraculous drugs. So not only did I think it was a twofer, I thought it was a lot more than that.This idea. That cancer screening could address a very specific problem, but have a lot of downstream impact on the entire operation of medicine. Particularly excited me.Robert Rogers: Wow. That’s, that’s great. Well, we definitely can hear the passion in how you describe it, and I think that’s sets up, the rest of our conversation really well.So I think when you mentioned how there are guideline recommended single organ cancer screening tests, and I think most people are basically familiar with the concept of how those work, what you’re looking for in a mammogram, what they’re looking for in a colonoscopy. Let’s talk a little bit about what the actual tests are when we talk about multi cancer early detection.Generally speaking, the idea here is that cancer cells are different than normal cells and they leak into the bloodstream things that are different than what normal cells would leak into the bloodstream and that those can be detected. And maybe walk us through a little bit what the different categories are of things that one could conceivably make the basis of a multi cancer early detection test. But then what’s actually being used and kind of showing most promise.Betsy O’Donnell: Yeah. so what’s really remarkable is just the different types of technologies that are being explored in trying to find cancers early. And so you talked about fragments of DNA that break off. So if we think about cancers that are growing, these are not normal healthy cells, often, they’re growing more rapidly, they’re unstable, they’re chaotic, and so.I once heard the analogy of, of a, a flaky loaf of bread, you know, where little crumbles are, are breaking off in the blood. And these are the DNA fragments that we can potentially detect and some cancers break off more flakes than others. And that can be one of the limitations. But what can we look at in that will help us distinguish those DNA patterns from healthy ones.We couldn’t do this 20 years ago, not at scale, not fast, and not at a cost that would allow people to actually purchase it. But some of the different technologies that are being explored and, and probably at the forefront right now is methylation. And so methylation is when we think about having genes have on and off switches.And so there are patterns by which every type of cancer has its own barcode, so to speak. And then when genes are turned on or turned off, there’s kind of an on and off switch. So when we look at methylation, which is really a tag. It’s put on that on off or dimmer switch. It’s turning it off and regulating gene expression.And what’s neat about this type of technology is that it’s uniform. You don’t need a lot of DNA to see the pattern. It’s pattern recognition. And so what’s amazing about. You know, just from thinking about, we first just sequenced the human genome just over 20 years ago, and now not only are we able to sequence the human genome, but we can also create libraries of what normal DNA looks like versus abnormal DNA.And that enables us to distinguish when we look at the blood or potentially other types of body fluids, normal DNA from abnormal DDNA, and that becomes the basis of screening for cancer. Going beyond methylation, though there are other ways in which we’re looking at sometimes those abnormal cancer, DNA have specific mutations, mutations that distinguish those again from healthy cells so we can look at mutational status.DNA is like a blueprint. It’s finely spliced following directions that are set out. And so sometimes there are fragments that can be identified of DNA and those fragments in and of themselves are abnormal, and we can recognize those fragments as abnormal DNA versus normal DNA fragments.And so these are some of the different technologies that are being explored. One of the other more, novel strategies now is looking at immune signatures. How is the body reacting to the presence of something abnormal? Are there specific proteins or meta metabolites, or even just t-cell repertoire that are altered in a predictable pattern in individuals who have cancer.So there’s actually a really broad array of ways in which people are exploring, trying to find cancer.Robert Rogers: Yeah. It’s so interesting that, what seems to be the single most advanced modality in terms of what’s being used is based on the DNA methylation signature. I think if you said to someone, you know, 10, 12 years ago before this field really took off, um, what do you think is gonna be the best modality you might say. Well, cancer is a disease of mutations we will directly detect the DNA mutations, you produce therefore mutated RNA, mutated proteins, different metabolites and all of those things. And you wouldn’t necessarily I think from first principles seized on, on the methylation signature as the thing.Could you just say a little bit more about why you think it is that that has for right now shown the single most promise? And then the follow up to that is, you mentioned how when you think about cancer therapy, now we’re combining all these different modalities. Where are we in terms of being able to combine these different aspects of what cancer cells secrete that’s abnormal into a single test?Betsy O’Donnell: Yeah. So two great questions. I think methylation, so when we think about. Finding cancers. Remember we have tons of cells in our blood. And so, first of all, you have to find these abnormal DNA. And so there are challenges in, in and of that just the types of cancers, the amount of shed they have. So these are things that are not part of the question you just asked me, but very important in terms of multi cancer early detection.And so when you are looking for a specific mutation, it’s like looking for a needle in the haystack. Whereas when you find an abnormal cell that methylation pattern can be recognized in that small amount of DNA that you have. And the methylation patterns are unique to the different types of cancers.Like I mentioned, it’s almost like a barcode. Some mutations are shared mutations too. You can see, you know, KRAS in a number of different types of cancer cells. And so I think where methylation has been, particularly useful is that potentially don’t need as much DNA to find it.And also the signatures allow for the next step, which is identifying where that cancer is coming from. And so, I think that’s probably one of the specific benefits of methylation that makes it attractive. And we can talk about later why signal of origin or tissue of origin can be very important when we think about the broader application of cancer screening.You also asked me about combining modalities. And so I do think it’s very analogous to the way in which we’ve combined chemotherapies to improve the sensitivity of MCED tests. And there are currently a lot of different companies using these different techniques, but there are really a couple that have gone a little bit further.And what we see is the emergence of different strategies. Some focused on methylation, some focused on multianalyte modalities combining methylation with proteomics, with these other patterns, with the goal of increasing our ability to detect cancers. I do think that that makes a lot of sense.Intuitively, you’re trying to broaden the net, so it’s almost like, using a hook and line versus a net approach for phishing for these cancers from the bloodstream. So, I think that’s the very common sense application that’s being applied to the evolution of these tests.Robert Rogers: That’s great.So I think that’s a really nice place to take a step back now before we then turbocharge ahead into what the leading tests are in MCED and how they’re being used and what that data is, and really start to lay a little bit of foundation, about the problem that this tool is trying to solve.And that problem is of course, cancer, which is a big problem. And so I’m curious, when a healthy patient asks you, what is my risk of getting cancer? How, how should they think about that? How can they quantify that?Betsy O’Donnell: Yeah, so I think this is really the companion science to multi cancer early detection is evolving from a one size fits all screening model. So when we think about how we screen for cancer now, it’s really based on age for the most part. And there’s some nuance to it, which we can dive into. But the single greatest risk factor for cancer is age alone. And starting at age 50, our risk of cancer goes up 13 fold.And so really that’s just again, a common sense if we’re going to employ screening on a large population scale, trying to find the people who are most likely to have those cancers. And that’s an age related phenomena, but we know anybody who practices cancer, that there’s a lot of variability and we’re seeing a shift, on a population level to earlier cancers.So how do we evolve from a one size fits all model based on age to being a little bit more nuanced? There are a lot of other companies, and this is not something that I’m an expert on in terms of polygenic risk. So incorporating someone’s personal genetics with other risk factors. So when I talk about high risk, when our clinic sees patients who are quote, high risk, what does that mean?And what are for patients who are really trying to understand their risk, do they have strong family history? Do they have a familial cancer predisposition center? Things like BRCA, Lynch, Li-Fraumeni syndromes, which are small numbers within our population, maybe 2% of individuals. But knowing your family history is critical.Not only knowing if people had cancer, what type of cancer they had, at what age they were diagnosed with that cancer. But then there are other high risk features that patients can have. Smoking historically was and is the number one leading cause of cancer. People are smoking less than they used to.Obesity is the second leading cause of cancer. And as we know, it is a huge problem in the United States. Something that we aren’t necessarily addressing within oncology, but that we’re also seeing and a change in that. So there are a lot of smaller factors as well that can influence one’s personal risk. Having had certain chemical exposures like our veterans in Vietnam, and pesticides in in large quantities, and then chemotherapy cancer survivors who’ve had, are at risk for second cancer. So, these are some examples of people who might get a higher risk. But I think what would be really exciting just to close out, is if we were to be able to evolve more refined cancer risk strategies in parallel with better tests.Robert Rogers: I wanna double click on both aspects of your answer there, both, how we actually quantify risk for those who are considered average risk, as well as the people who are currently identified as being higher risk because of hereditary cancer syndrome. So, just stick with the average risk for a second. There are branches of medicine where clinicians actually use formal risk calculators that say something like a 10 or 30 year risk, for example, for cardiovascular disease, for example, for fractures with osteoporosis. But to my knowledge, there’s no sort of analogous, 10 year or 30 year risk calculator, across the serious cancers. And it’s kind of interesting that there isn’t, because we actually have remarkably good epidemiology on cancer relative to other diseases. Right. We have the SEER database covers a large portion of the country, and so, you could actually probably aggregate, you could say, given a person’s age, sex, race and region, kinda what their risk is across all these cancers. And then perhaps, bring in some of these other factors that might make them higher risk for particular cancers and give a little more quantitative detail. But that’s not something we actually do. Is that, is that, is that feasible or am I being seduced by the delusion of false precision.Betsy O’Donnell: No, we don’t do it.Yeah. I think it’s a low hanging fruit, just like I think multi cancer early detection is a low hanging fruit. I wonder now with the use of so many people on an electronic medical record, everybody using Epic, these are other opportunities to do large scale data analyses. So is there a future state where you log in and and a risk score is calculated through your EMR. These are things that should happen that could happen, but have not yet happened.Robert Rogers: Right. And then you also mentioned how there are these well-defined syndromes that we learn about in medical school and in our medical training, even if we don’t specialize in oncology as you have, where, generally these are genetic mutations where the gene is responsible for repairing or responding to DNA damage. And there’s, there’s like 80 or more of them. And collectively, maybe 1- 2% of the population has them and it puts them at high risk of multiple cancers. And before we jump too far ahead, are we using MCED specifically in those populations who are at risk of multiple types of cancers?Betsy O’Donnell: So I think it’s really important to understand that the data and the research that have been done thus far, it’s very limited. And I think it would be important in our conversations to talk about the difference between a lab developed test and FDA approved drug. So there have not been to date studies in high risk populations.People are using it. And we, specifically at Dana-Farber have a study looking at the use of MCED tests in high risk individuals because we don’t yet know what the best application of the current test is. And so intuitively it makes sense. If you are at high risk, how can we augment your screening? So we’re doing a thousand patient study right now looking at GRAIL’s Galleri test in 500 individuals with a germline predisposition and 500 individuals who have strong family histories sufficient to warrant germline testing because that’s another population too. These people who have clearly some strong familial predisposition but don’t have one of the known mutations that we associate with cancer risk.Robert Rogers: Great., I think at a high level you described the fundamental promise of cancer screening and of multi-cancer early detection. But maybe just one more time so that our listeners really understand. When we talk about cancer screening, early detection, early intervention, there are benefits and risks. I wanna kind of elaborate on the risks in a little bit, but I want us to kind of clearly state what the potential benefits are. So the benefit of catching cancer early is...Betsy O’Donnell: The benefit of catching cancer early is that we can cure it. And so we know, and I’ll use the example of colorectal cancer, that when we find cancers at stages one and two, the survival rates are upwards of 90% versus when we find it late, when it’s spread to distant organ stage four disease where the survival the is much lower on the order of below 15%. And so, you know, the goal is to find cancers when they are most curable and eradicate them and cure patients.Robert Rogers: Great. And some cancers inherently by their biology seem more amenable to screening than others. And colon cancer is perhaps one of the best examples because it’s slow growing. When you have a colonoscopy, you can actually remove the pre-cancerous lesion. And then there are other cancers that seem by their biology just to be fundamentally more challenging and what makes them more challenging? And what’s maybe an example of that end of the spectrum?Betsy O’Donnell: Yeah, you use the perfect example of colorectal cancer where you have a pre-cancerous lesion, like a polyp that can be removed. The cancer in and of itself sheds a good amount of DNA, so that’s the other thing. It’s leaving lots of crumbs. We can pick it up. And there are other tests besides colonoscopy that are FDA approved for colorectal cancer screening. Um, and you know, there’s usually kind of this latency period where you can find it and treat it. The more challenging cancers are the ones that don’t leave these little breadcrumbs. They’re not high shedding tumors, and also they grow rapidly. Things like pancreatic cancer, ovarian cancer, some of our most lethal cancers. You know the other thing about colorectal cancers that may have symptoms early, you may have blood in your stool, for example, that can be either visualized or detected versus something that’s growing in an open space such as our pancreas or our ovaries where they don’t create focal symptoms. But I think in terms of screening, ideally a great screenable cancer is one that if you find it early, you’re going to impact survival. And that it has enough in the case of multi cancer early detection tests shed so that it can be DNA shed, that it can be detected.Robert Rogers: Got it. Alright. Now, I don’t want anyone to think that the relative amount of time we spend on benefits versus risks says anything about the relative level of benefits versus risks.But it’s kind of, I think, more intuitive to understand the potential benefits of multi cancer early detection are, and cancer screening is that, like you said, if you catch it early, you can cure it. The risks are not necessarily intuitive to people if they haven’t spent a little time thinking about this field. But there are, there are some. I tend to think of them in a few different buckets. False positives, false negatives, and potential for overtreatment. And I would love for you to maybe walk through how you think about each one of those in the context of MCED. Why don’t we start with false positives first.Betsy O’Donnell: Yeah, so false positives are probably the greatest fear of the healthcare system, I would say. Right? And why is that? So let’s think about where cancer screening lives now and where MCED would live in the future. It’s in primary care, and if you don’t know, primary care doctors are about the most busy doctors that there are out there.And so if you’re asking people to administer a test and it has a lot of false positive meaning the test says abnormal signal detected, but someone doesn’t actually have cancer, then that requires a series of tests to adjudicate that result. And those can be quite complicated. The person though, at the center of false positives is the patient.So what does it do to a patient to have a false positive? So you take a blood test. It’s not a diagnostic test, it’s a screening test. And it comes back positive meaning an abnormality is detected that can cause anxiety. The patient then has to go on this diagnostic odyssey to determine whether or not they truly have cancer.All of that can be stressful. If you don’t have a cancer, then you’re paying for copays and other expenses associated, whether it be time off work to have tests to determine whether or not you actually have a cancer on a systems level, that can be quite burdensome. When we look at the specificity, which is really how we look at false positive rates, most of the companies are erring on the side of having high specificities.To address this, it comes at the cost of sensitivity, which we can talk about also. But even if it’s 99.5% specific, if you’re doing this in thousands and thousands of patients, the concern is that they start to rack up the number of false positive workups you have to do. But to be fair and to balance that, we have lots of screening tests now, mammography, for example, where we get abnormal responses that have to be adjudicated. So it’s a balance of understanding the limitations of these tests, recognizing that there will be some false positive, but a very small amount and, and entrusting the companies to focus on that as one of their primary endpoints.Robert Rogers: And one of the things that I think is so interesting is which of these risks you most prioritize depends somewhat on your perspective. I think as you said, from the healthcare systems perspective, we are really, worried about false positives. But you wrote pretty eloquently about the development of these tests. And you cited some studies where you asked the people that have actually been the early pioneers, healthy people signing up for these MCED tests, and they’re remarkably tolerant of false positives. You ask them something about how many scares that didn’t turn out to be cancer would you be willing to accept to catch one cancer that was real? And the ratio is like remarkably high, right? And so that tells me something about the difference between thinking at a broad one size fits all systems level to how do we individualize this for an individual patient’s risk tolerance?Is that right?Betsy O’Donnell: So yeah. Two things on that. You know, when we think about anxiety and distress, which is something I’ve written about, I specialize in multiple myeloma, which is an incurable blood cancer. You know, anxiety and distress of a potential screening test versus anxiety and distress of having an incurable cancer.[00:29:00] Those are very different things. And so I have spent a decade trying to mitigate the distress associated with caring for patients and their family members who really are along for the hard ride of a cancer diagnosis. I think it is individualized. People have a choice in terms of the cancer screening. We make recommendations all the time. But there are people who really want cancer screening who have distress because they’re worried about having cancer. They go to their mammogram religiously, they get their colonoscopy ‘cause they wanna do everything they possibly can to mitigate their own anxiety around a potential cancer diagnosis. So. I don’t think we should make generalizations about what people want and what the population wants. I think we should allow people to have the opportunity to decide and to learn from those people. We have to study this on every level, on a systems level, what it costs, and on a patient level, you know, how do] they feel about these tests? Let’s not make assumptions.Robert Rogers: Right. Right. Okay. Let’s move to false negatives.Betsy O’Donnell: Yeah, so that’s the greatest challenge because when we look at what’s been done in terms of the study so far, we’re not randomized. We don’t have a gold standard test for cancer detection. And you mentioned whole body MRIs. You know, there are tests that we use to stage patients who have cancer, things like PET-CT, but those aren’t part of our cancer screening processes currently. So when you look at the studies that have been done, there is no gold standard control arm. Something that will absolutely find cancers. So the false negative rate, meaning you have a screening test, you get a result that says no abnormal signal detected, but actually do have an occult cancer is underestimated or it’s not well characterized by the prospective studies that have been done thus far.Robert Rogers: Do we know anything about the level of distress in addition to the underlying cancer diagnosis for patients who have undergone something, kind of gotten the reassurance, like everything, I’m in the clear, I had this, and then subsequently find out they have a cancer diagnosis. Does that impose a significant additional level of emotional stress on them?Betsy O’Donnell: It’s a great question and I don’t think anything’s been done study-wise to address that question. We don’t know. And I think where you might be able to do something is in longitudinal studies where you’re screening annually and incident cancers are then found in those intervals, but that work, there is a longitudinal study going on right now, the NHS Galleri study in the UK that is doing testing once a year for three years and, and they are baking in some of these quality of life assessments to their analysis.Robert Rogers: Great. And now let’s talk about something that, that doctors also worry about, which is overtreatment, right? The detection of cancers that may have been indolent or lied rather dormant in a patient, or maybe they would’ve ultimately succumbed to something else and this cancer never would’ve caused a problem for them in their, in their lifetime, but now we’ve discovered and we have to do something about that.How do you think about and advise about that risk in the context of MCED?Betsy O’Donnell: There are a couple different cancers that I would say fall into that category. Prostate cancer being one of them, right? There’s some thyroid cancers, some indolent lymphomas, multiple myeloma. The cancer I treat has a precursor condition. Not everybody’s gonna evolve for that. The other half of my research focuses on this. So, you know, this is something I’m very attuned to in my own oncology practice. It used to be that we screened for prostate cancer. There were several large studies on a population level, and what we found was that we were overtreating, this is not using MCED, this was through PSA. That we were overtreating, meaning there were some people who had prostate cancer that would potentially never have caused them symptoms or never have been life limiting in terms of their overall survival. And that’s a morbid surgery. To remove someone’s prostate causes a lot of symptoms and side effects. So does radiation. And so what you don’t wanna do is overtreat and create worse symptoms treating something that would never have been a problem. But I think we really have to look at the broad range of cancers that this includes.Look at the different types of cancers being targeted by these tests. So multi cancer early detection testing is not a one size fits all. A lot of this is company-driven focus on different cancers. Some are really focusing on the low hanging fruits like pancreatic cancer, ovarian cancer, esophageal cancer. But you know, you can pick up some indolent diseases that then need to be monitored, and you do have to think about what the anxiety is for those individuals. What’s interesting in the example of multiple myeloma, there’s a screening study going on in Iceland right now. Population-based 80,000 people have been screened for multiple myeloma and finding the precursor condition MGUS [Monoclonal Gammopathy of Unknown Significance] is actually not associated with long-term increased anxiety. So I think that’s something I do wanna underscore, just the importance of research. Let’s not jump to conclusions that are not based in actual research.Robert Rogers: Yeah. And it sounds like it’s a topic that needs a lot more research and also, again, a case for individualization. What is an individual patient’s tolerance for, say, monitoring? And now I want us to jump back now to the exciting stuff going on with, with MCED, the current studies and what you’re looking forward to. But I just wanna make one more point there ‘cause I, I think it was an important one. Cancer screening is within medicine, a somewhat controversial area in the sense that people have strong opinions about it. There’s people who think it should be much more widely deployed, and there’s people who are skeptics of even what’s what’s currently done. And I think that centers a lot on the story around prostate cancer. Many studies, but I think there was one that was particularly, well known and cited that came out about 10 years ago from the Harvard School of Public Health that showed when they looked at autopsies of thousands of men, many, most, the vast majority of whom died of something completely different from prostate cancer and some large percentage of them, they found histologically confirmed prostate cancer. And that’s sort of cited as a blow against widespread cancer screening because those cancers were obviously indolent, but prostate cancer is perhaps the exception more than the rule, right? I mean, we don’t have massive autopsy databases, and I don’t think anytime soon the NIH is gonna do the, the random million autopsy study. So I don’t think we have perfect data on this question, I think what we do know is that for, for most of the deadly cancers that we’re most concerned about, it doesn’t seem like there’s large numbers of indolent ones lying around. Right? So prostate cancer is an interesting exception, but it’s not the norm. Okay, great.Betsy O’Donnell: It’s not call prostate cancer either, Correct. It’s, it’s a very small subset. Yeah.Robert Rogers: Right. Okay. Alright, so you’ve mentioned a few times the studies, the big clinical trials that have been done and that are ongoing, that are shaping our evidence base for this evolving field of MCED and I’d like to get into that a little bit now. First, maybe just talk us through this general framework of how companies tend to develop new tests in this space where I think generally what they do is they look at first some patients who they already know have cancer and then patients that don’t have cancer, and sort of define the test characteristics of how their test does, and then they move into prospectively looking at patients and seeing how many cancers they pick up.Maybe just describe that framework and then take us through a couple of the major studies that you referenced when thinking about the evidence base for this.Betsy O’Donnell: So I think that this is critical talking about evidence. As alluded to on numerous occasions, this is an exciting area of technology. Lots of companies wanna go into this space. These are lab developed tests or LDTs, and they have a separate pathway for being able to reach patients or people versus a drug that has to be studied, that has a very set pathway from phase one to phase two to phase three to demonstrate evidence that it, it does what it says it’s going to do and to get FDA approval.And so what we see is that companies are developing tests and going direct to consumers. And that is not something that happens when we have new drugs. And so there are companies though that are doing evidence and even the companies that have already gone straight to individuals without doing validation studies that you just talked about are doing what are called case control studies, just as you said, where you have cases of people who have lung cancer, for example, and those who do not, and you test your tests to see how good it is at correctly identifying those who have lung cancer versus those who do not.If you think you have a good signal, then you might move into a prospective study. So you administer this test into individuals who you don’t know what their cancer state is as a screening study to see what you pick up. And so there are very few companies who have actually moved this far into the process of validating their tests.So the two best examples thus far that have published data are GRAIL’s Galleri test that was published in Pathfinder 1 and now Pathfinder 2. And then what is now called Cancer Guard, which is Exact Sciences multi cancer early detection test that was evaluated in the Detect A study. There are a number of ongoing studies, but I think it’s really important to understand that these have to be tested prospectively in asymptomatic individuals.Right now there is bipartisan legislation suggesting that if an MCED test gets FDA approved, that they’re trying to create a Medicare pathway for reimbursement. So right now, a pathway for Medicare reimbursement for MCED tests does not exist. But as we think about the importance and the promise of MCED, this is necessary because these tests are quite costly right now.And so in order for patients to have broad access, which is critical to me, you need to do the work. To do the studies that demonstrate the efficacy lead to an FDA approval, and you have to have, even if you do have an FDA approval, a pathway for reimbursement so that people can actually get these tests and not have to pay out of pocket for them. But when we think about the difference between phase one, two, and three studies, what we often see with drugs is that what looks really good in phase one and two doesn’t pan out in a randomized trial. So I really believe it’s important that we do the work, we do the clinical trials, and we evaluate these tests the same way we would cancer therapies.Robert Rogers: Pathfinder is a major touchstone in the field. What did we learn from it? And what questions has it left not yet answered.Betsy O’Donnell: So the Pathfinder study was originally presented ASCO, as I noted in 2021, it just gives you a sense of, of just chronology of how these things are moving along. This test can screen for up to 50 different types of cancer. It gives a result that says positive or negative. So a screening test saying yes, abnormal signal detected, no abnormal signal not detected, and then it gives a CSO, a cancer signal origin.So it uses DNA methylation, which you talked about earlier, as the main modality for finding abnormal signatures of cancer in the blood, and then using that barcode that we talked about, tries to pinpoint where that abnormal signal is coming from. And so when you look at the data from the Pathfinder study, it had a very high specificity over 99%, and then the sensitivity varies by the cancer. It’s better at some cancers than others, but perhaps the most important kind of focal point for many people is the positive predictive value. And what does that mean? That means if you get a positive result, how probable is it that you actually have a cancer?So in that study, the positive predictive value was about 40%. Meaning if 10 people had a positive signal, four of them actually had cancer. In October of this past year, Pathfinder 2 study was presented, and here we saw that with changes and improvements to the assay. positive predictive value was closer to 62%, meaning that six out of 10 individuals who had a positive test had a cancer result. So those are the kind of most important data to date. The other piece is looking at were these early versus late cancer, so let’s call early stage one and stage two and late stage three and stage four. In both Pathfinder 1 and Pathfinder 2, over half of the cancers found were early stage, stage one, stage two, and very importantly, over 90% of the cancers found did not have recommended screening tests. So these are all real, these are not meant to replace the screening modalities we talked about. This is to complement. And so I think that’s one of the most important things is what cancers did they pick up over and above what screening tests did. And so they demonstrate efficacy in finding early cancers and a broader range of cancers.Robert Rogers: And that’s a really nice recap of the data. I’m curious what sort of upcoming studies or data readouts you’re watching most closely that you think will give us the next batch of evidence to see how these tests really perform.Betsy O’Donnell: The study that I’m watching most closely is the NHS Galleri study.Robert Rogers: Yeah. Tell us about, tell us about that and take a little time to describe it in detail, ‘cause I think this is gonna be a very important evidence base for the field.Betsy O’Donnell: Yeah. So this is a large population-based study that’s going on in the UK right now using GRAIL’s Galleri tests and it’s a randomized trial. Looking at the use of the Galleri test at annual intervals for three different testing time points. So once annually for three years versus just standard of care screening. And I think this should read out this spring. I think that this is really going to be, um, what a lot of. GRAIL’s, FDA approval prospects hinge on which will be very meaningful not only for that company, but also for the entire field, just in terms of creating a pathway and for others who want to seek FDA approval and for understanding at a larger scale, the benefit or lack thereof. It’s hard because tests will continue to evolve. They’re using a specific test and, and if this is positive, fantastic. If it’s not, what lessons can you learn from these in terms of is it the test not being sensitive enough? So I think this is a really important readout.Robert Rogers: Just tell us a little bit more about the specifics of the endpoint that they’re looking at in that NHS study, ‘cause I, I think it was actually very thoughtfully designed.Betsy O’Donnell: Yeah, so again, this is a randomized controlled trial. It’s about 140,000 individuals, ages 50 to 77, and the primary objective is to assess whether adding the Galleri test to standard screening reduces late stage, stage three and stage four, cancer diagnoses compared to usual care.Robert Rogers: Got it. And so that sounds like a very reasonable way to do the study because of course, if you were gonna have to run the study all the way until it could detect a mortality difference, that could be a very, very long and expensive study. But I think it’s basically making the assumption that if you prevent cancers from being diagnosed at stage four or late stage, then that’s probably gonna be correlated with actually improving morbidity and mortality. Is that the underlying assumption?Betsy O’Donnell: That’s the underlying assumption, and that’s one of the biggest challenges of cancer screening and evolving technology, is that the gold standard is mortality and mortality takes years, decades even to read out. And the rate at which our science is evolving is so fast. So how do we find an endpoint that keeps pace with the changes in technology, but still honors the importance of understanding that screening tests are of greatest benefit if they actually change your ultimate outcome, as has been defined historically by cancer screening tests.Robert Rogers: Right. And you’ve made the point that baked into the design of these tests is a preference for high specificity, perhaps at the expense of early stage sensitivity. And for example, in some of the precursor work before the Pathfinder study, where they looked at several thousand patients who had a known diagnosis of cancer and several thousand healthy people, and they said, how well is this test doing? A positive test really correlated very much with stage, right? So it was very good at finding patients who had known stage three and stage four cancer, 70%, 90%. Stage two was about 40%. Stage one, it was about 15%. And I guess I would just be curious, this is really an opinion question:how do you think that performance is? I think you could look at the only 15% pickup of stage one cancers in one of two ways. One is that, that’s really lacking. That’s not quite where we need to be. I suppose the other way to look at it is that maybe that’s a feature, not a bug, right? We’re gonna kind of wait until the cancers cross, at least that stage two threshold and then catching 40% is actually, pretty good. That’s maybe how I look at it, but I’d be curious how you look at it.Betsy O’Donnell: Yeah, I think it’s a little bit like looking at the iPhone 1. It’s a starting point, We are at what the iPhone 18 at this point, you know? And so I think you have to have a certain benchmark to start from and build from. I like the perspective that you have. I haven’t heard it ever stated like that. Where we’re our starting point is we accept that stage two, but I don’t think that’s the ultimate goal.Tying back to what we talked about earlier with, with evolving technologies beyond just looking for DNA shed. Can we increase our ability to find things earlier? Can we, and, and also something that’s talked about, which we haven’t brought up, is longitudinally following individuals. So do we see changes in the patterns of people’s protein expression and their immunophenotyping over time? So that it’s not just about finding something that is already specifically there, but can we identify signatures of things that are evolving? I mean, there’s a lot of exciting science that’s going on in this area, but I think.We need a starting place. You always need a starting place. I have a story I always tell about STI571, which was Gleevec, which is one of our first targeted therapies that we were studying and everything, just like we had any alkylating agent and studying in prostate cancer was the study I was assigned and obviously it’s not a drug we now understand that worked for prostate cancer, right? But it was a starting place. So I really look at where we are in MCED similar to what I looked at in STI571, when it was assigned to me back in the early 2000s. It’s somewhere to start, and I believe that these will get better, they will get more sensitive as we learn, as the technologies evolve, as more interest grows in this area. But hopefully we will do better than just finding stage two disease.Robert Rogers: Great. Couple of rapid fire questions, and then I just wanna end with talking about the experience you’ve had directing this extraordinarily innovative clinic at Dana-Farber. So, you’ve touched on this, but how will the optimal frequency of testing be established here?Betsy O’Donnell: You have to have longitudinal studies where you demonstrate it. And so, companies are going to want you to do it more frequently, of course. Right. But you have to demonstrate that there’s benefit. We don’t do colonoscopies annually. We do do mammography annually. You have to have evidence. These studies have to have multiple time points. And I think again, that’s why the NHS Galleri study is important. You can’t make up a number that sounds good. It has to be evidence-based.Robert Rogers: Got it. Where do you see whole body imaging - Usually MRI based - fitting into this ecosystem. Could it be complementary or is it really it’s kind of own thing for now?Betsy O’Donnell: Yeah, I think it could be. We have different reasons we do things and as I noted, I’m really interested in helping healthcare systems operations and also broadening accessibility. And so whole body MRI are incredibly sensitive. They pick up, they have the potential to pick up cancers early. They can pick up a lot of other incidentalomas, incidental findings as well. So you really need to evaluate if you’re thinking about that as a screening modality in the general population. Do you have enough MRI machines to screen the population?A lot of people are claustrophobic. What percent of the population is going to want to have an MRI? Um, and then when you do have incidental findings, do you have the resources to properly evaluate them? And so they’re very sensitive.I’m not the only physician doing this type of work. In fact, just two weeks ago we had a meeting, a kind of a consortium of doctors who are interested in MCED, practicing and studying them. 25 doctors on a call. Some people are looking at randomized studies of blood tests versus whole body MRI, and I think it’ll be very interesting just what we can learn about the sensitivity of MCED tests from these tests. MRI is exciting.I think for my practice, so my number one priority, and I hope I’m betting on the right horse, but is really thinking about accessibility and, and really trying to get at how do we get more people screened.Robert Rogers: Got it. A quick prediction here. Forever is a very long time, but let’s say in the next 20 years, do you think it’s feasible that MCED could ever replace the existing single organ screening tests, or is its future gonna be an additional layer for selected patients?Betsy O’Donnell: I think it’s hard to imagine replacing those modalities not where it is currently. Maybe 20 years from now, potentially. 20 years is a long time. Long time. So that would be amazing. But I think it will take a lot to displace and should take a lot to displace our currently well adjudicated means of, of screening for cancer. But, for now, the current state, this is a complement not a replacement.Robert Rogers: Got it. A few closing questions about building this MCED care model that you are building. Tell us a little bit about the impetus for creating a dedicated clinical home for this kind of testing. And if you don’t mind, walk us through kind of the patient experience of coming to the MCED clinic.Betsy O’Donnell: Yeah, so this program really started to kind of emulate or model what we’ve done for drug development. So it’s a research platform where we really try to, anybody who’s coming in, these tests are very costly, several hundred dollars, close to a thousand dollars. So we try to offer these tests in clinical trials so that patients are not paying for the cost of the test.But patients are getting these tests, they’re buying them off the internet. They’re getting ‘em from doctors who are prescribing them, but then may not necessarily know how to work up the cancer that’s suggested. And so we created a clinical home for these patients, especially when we’re looking at a Pathfinder 1 data where the positive predictive value is 40%.What do you do with a patient who has a positive test and a negative workup? They need a home, they need to be followed because I think that’s the population for whom I think there is greatest anxiety. And so our clinic is both a research program, but also really focused on those patients who have positive tests, trying to do an expert evaluation.We get them through the diagnostic procedure as quickly as possible. And a lot of patients we found don’t necessarily easily identify providers when they’ve gotten, when they’ve purchased their tests or had them through means other than a providing physician. So it’s been interesting. We’ve seen just over 20 patients with positive tests since we’ve been open and we screen many, many more through clinical trials. 69% of those that we’ve seen have had cancers. Takes us about two weeks to do a diagnosis. We employ the retest in our patients and about a three month follow up, and that really helps us adjudicate the false positives.I love it. I see all the patients myself. I think it’s really important to practice this medicine to understand the limitations, to have to talk to the patients about the tests we’re gonna do. And, in the situations of false positives, how do you reassure those patients?Robert Rogers: I think that’s amazing and really speaks to extraordinary clinical innovation on your part that you can get them from test to diagnosis in a short period of time. Because when we talk about the anxiety around a positive test, part of that is the amount of time you’re lingering with the uncertainty, right? And if you can cut that down, that’s hugely valuable. So the amount of anxiety patients experience is not just some property of the universe. It’s determined by the care system that they have access to. So I think that’s really cool.Betsy O’Donnell: Thank you.Robert Rogers: So as we sit here in January of 2026, is there anyone for whom you would definitively recommend MCED, or anyone who you would definitively recommend against it?Betsy O’Donnell: That’s a great question. So I would recommend the study of MCED. I would recommend participation in a clinical trial.Robert Rogers: So if you’re gonna do it, do it through a clinical trial so that it’s done in a very rigorous way and it contributes to this knowledge base that’s evolving. So that’s an important caveat. If you’re gonna do it, if you’re curious to do it, do it through a clinical trial, that’s one message you wanna get across. Is that right?Betsy O’Donnell: That’s my number one message, I think because, for a variety of reasons. Let’s understand these tests so that we can be authorities and so that I can confidently say, you should or should not do these tests. We need that evidence. I think for individuals who are high risk, who have significant anxiety, these tests are there. You have to, if you understand the properties of the test, you understand exactly what you’re signing up for, then that’s an individualized decision. And we have the resources, not just at Dana-Farber and a number of institutions too, to support people who want to take on. You know, exploring other types of cancer screening.Robert Rogers: Excellent. Dr. Betsy O’Donnell, thank you for coming on today for sharing your immense expertise with us in this area. I think you are really practicing at the forefront of one of the most exciting areas of preventive medicine, and I’m excited to see where this goes and, and maybe redo this conversation in a couple of years and see what more we’ve learned. Thank you so much for joining us.Betsy O’Donnell: Thank you for having me. Get full access to Foresight Medicine at foresightmedicine.substack.com/subscribe