Oncology Unscripted With John Marshall

Oncology Unscripted at ASCO GI: People, Pipelines, and Precision

John Marshall, MD:
Hello, everybody, from San Francisco, California. My name is Dr. John Marshall, and you are on—maybe unwisely—Oncology Unscripted. But thanks for joining me. I love this meeting, but let's first talk about the news of 2026.

Top of the line is: we're out to get new countries. Now, I'm sort of running for mayor of Havana. I don't know if it's important that I, in fact, speak Spanish—because I don't. I speak a little bit of French. My Spanish is terrible. But maybe it won't matter, because I am who I am, and they're looking for just my kind of person to go be mayor of Havana. So, if you see that and you get a chance to vote, vote me in. I love the whole country of Cuba—it's beautiful.

Second, in today's newspaper—I couldn't believe it—this guy named Dr. Oz, you know him, he's an actual cardiologist, believe it or not. Then he became the talk show host. And then, for some reason, he's the head of CMS at this point—one of the head overseers of healthcare here in the country. And he said his position was that alcohol is good. This couldn’t have made me happier. This couldn’t have been a better holiday present, because I'm a big alcohol fan myself, and now I can feel less guilty about it. His rationale is that if you drink more, you'll be with people more, you'll be more relaxed, and the camaraderie will pay off in terms of lessening your anxiety and stress—and the world will be a happier place.

So, don’t be smart. We don't want people in our country to be intelligent or educated. Drink more. Be less educated. You'll be happier in the long run. That's the official position of our government today.

Probably the most important new news from a healthcare perspective is that the House approved an extension on the Affordable Care Act. This has been an incredible threat and uncertainty for so many of our patients. The people who depend on that health insurance could never afford cancer care without it. Having the extension of the Affordable Care Act—for them—talk about lowering your stress. Maybe better than alcohol is actually being insured.

I don’t know if you go to many meetings out there, but this one is called GI ASCO. It's always in San Francisco. It's always in this building that I'm standing in now. I have perfect attendance. I’ve been to every one since they started. You should get a special ribbon for that. I think there’s probably one down there for that.

They are a little bit more environmentally conscious—no plastic covering to this. Just a piece of paper. Totally recyclable old name badge. Way to go, ASCO, on that.

Do you go to meetings or don’t you? I come to this one for a very, very important reason. I come to this one for the people. It’s a small meeting. It’s just the GI gang, both from the industry side and the academic side. It’s a very heavy global presence that comes. I know almost everybody here, and there are only like 3,000 people here. There’s time to stop and say hello to almost everybody you know—give them a hug, share a little COVID, maybe flu, with each other—but then know that you are connected again. And this is something Zoom doesn’t do. This is something you can’t check on—somebody’s kids—over a meeting. But that’s one of the main reasons I come.

I love these people. These are people that share in our values and our motivation to try and cure cancer. We all take care of the group of cancers—GI cancers—which are the most common, most fatal cancers on our planet. We are inspired to do this. We know it’s a steep climb, and we do it together. I’m so very pleased to be a part of this community, and it’s the main reason I come.

Main reason—people. Second reason—pipelines. There’s a lot of data out there, and there are a lot of companies here that finally have new products for GI cancers. We’ll talk a little bit about that in more specific detail, but if you just look at the number of groups that are here—the number of people who’ve got innovative, new approaches—whether it’s novel immunotherapy, targeted agents, combinations of those, targeted antibodies that are delivering toxic payloads—we’re seeing waterfall plots that we haven’t seen in decades.

So, response rates, survivals, progression-free survivals that really compare favorably to our traditional chemotherapy approaches. We are on the cusp of a true revolution in the world of GI cancer.

And, surprisingly, one more—led by the world of pancreatic cancer. So, let’s talk a little bit about precision in GI oncology. The biggest breakthroughs that we are seeing at this meeting have to do with RAS targeting.

There are a bunch of RAS drugs out there now. There are some that are more out in front than others. There are some that are degraders that break down the RAS. There are some that block pan-RAS, so they hit a bunch of RAS targets. There are some that are very specific for one particular kind of RAS mutation—and they’re working.

Now, they’re not curing everybody. But we’re seeing great waterfall plots, even with single agents, in a disease that we haven’t cracked in a long, long time—and that is pancreatic cancer.

So, we are all incredibly optimistic about what we are seeing. We are anticipating approvals this year for some—maybe one or more—of these agents. We’re excited about the possibility of combining these RAS-targeted agents with things like immunotherapy or others. We are already starting to try and think about: is the pan-RAS better than an isolated targeted RAS? What are the toxicities? How are we going to manage it? Because we’re fully expecting these drugs to get approval and to get rapidly incorporated into our day-to-day management.

First, pancreas cancer. We’re seeing it in biliary cancers. We’re seeing it in stomach cancers. Where we’re not seeing it just yet is in colorectal cancer. And I would’ve predicted a long time ago that colon was going to be the easiest nut to crack. And yet, we’ve made progress. But in fact, what we’re going to see now—biliary, hepatocellular, pancreas cancer, stomach cancers—we’re going to see a lot of evolution over the next several years.

A good friend, and really a fabulous speaker, Dr. Andrew Ko from here in San Francisco—UCSF—was the discussant just an hour ago in this building, where he did a great job of setting the stage of both the excitement for the future, but also a healthy respect for what we are going to need to understand to march forward quickly but effectively for all of those patients we’re sitting across the exam room from—that need our help.

So, precision medicine is finally making its way to GI cancers—led by the RAS wave that we are seeing. So, stay tuned. You’re going to have new drugs out there. There’s going to be competition. A lot of people talking about it.

As we talked a lot about pipelines and the new drugs that were coming out, one of the common questions we get is: what's missing? What have we not been studying well enough? And I have a pretty consistent answer—and that is the microbiome.

We don’t understand the impact of those bacteria on us, on our health, on the effectiveness of drugs, etc. And until we really start digging into that science, I don’t think we’ll see that next wave of innovation. So, the answer is microbiome.

So, why do I come to GI ASCO every year? Well, you already know the number one reason—that’s people. I love them. They’re my family, and I love to catch up with them just like you do with your family around the holidays. This is my family visit for the holidays.

Second—pipelines. Understanding what’s out there today, what’s coming, and how we are going to cure patients with GI cancer. It’s going to be through these pipelines.

And then last—the latest data. And that’s around precision medicine. We are about to embark on a wave of therapies that target RAS, and you’re going to start to see cancer shrink as these new drugs come into play.

Our job, then, over the next couple of years, is to take this new understanding, this new ability to control precision medicine, and apply it to our patients—to cure more patients with GI cancers.

Thanks for joining me from San Francisco. Totally unscripted. John Marshall, Oncology Unscripted.

Microbes, Mutagens, and Mortality: CRC in a Younger Generation

John Marshall, MD: John Marshall Oncology Unscripted. A lot of good data coming out on all sorts of things. You know, I'm a colon cancer guy, so I really want to talk about two clinical trials in the colon cancer space.

One was a paper in Nature—it's actually a few months old—but, you know, I keep seeing all these young people with colon cancer, and I keep thinking: it's the microbiome. It's gotta be. And this paper actually found a version of E. coli that produces a toxin that, if you're exposed to it at a young age—say 10, 11, 12 years old—it dramatically increases your risk of getting colon cancer later.

Now, I sort of didn’t think of it as one bacterium causing one toxin causing a toxicity. I always thought it was more of a gamish—what swamp do you have? What's the nature of your rainforest, your bacteria in the colon, that's causing it? But what I'm excited about is that we're continuing to see, week after week, month after month, new data that supports a better understanding of the microbiome—one that we hope will translate into not just identifying people who are at risk for early-onset colon cancer, but, as you know, other diseases as well.

And as a related story—this comes out of Cancer Investigation—patients who are taking GLP-1 drugs had lower colon cancer death rates. So basically, they looked at colon cancer patients, and the strongest signal was in those who were obese. But if you were on a GLP-1 versus not on a GLP-1, your survival was much better on one.

So, again, how do GLP-1 drugs work? Uh, we don’t really know. But I think probably our interface with our microbiome is one of the ways they have an effect. And so it kind of feeds back to this: the healthier we can get our innards, our inner colony of bacteria—I really think it's where our soul resides—the healthier we can get that, the better our outcomes will be. Again, not just for colon cancer, but for other diseases as well.

Just some high-level stuff that you probably didn’t see in your scanning of the week’s journals. 

John Marshall, Oncology Unscripted.

Rewriting the Gut Story: Diet, Microbes, and Modern Disease—Interview with Dr Robynne Chutkan

John Marshall, MD: Hey, everybody out there? John Marshall for Oncology Unscripted. I promised you my new office. It's not that great, is it? When you get old, they take you from the big office down to the small one, but I do have a view. You see, I've got the view out there—a rooftop. I can see all the air conditioners and whether they're working or not. The helipad’s just right over there. So that's gonna get exciting sometimes. I got a halo. You see my little halo in the window there? But I am sort of angelic, as you know. 

But really the reason we are gathered here today is to talk about maybe my favorite topic—so much my favorite topic that my family is tired of hearing about it—and that is our microbiome. And I honestly feel like it is where our heart and our soul reside. And I, as a good Presbyterian, I actually think this is where the soul must live.

And so I am lucky enough to have, as a friend and a colleague, Dr. Robynne Chutkan, who is joining us today. She is really an expert in the microbiome, as much as any of us is an expert right now. She's leading the way in understanding this companion that we have through life, of these bacteria and other organisms that we grow and live with all our lives. And so she's nice enough to join us today to help us oncology people get a better understanding of the microbiome and its impact on our health.

So, Robynne, we have spent decades as partners in crime, and I'm so grateful to get reconnected to you. So, give the crowd a little bit of your background, and how the heck did you get interested in the microbiome?

Robynne Chutkan, MD: Well, first of all, I couldn't ask for a more wonderful kindred spirit in my obsession with the microbiome and stool and all of it. So, I knew that we were connected through more than just Georgetown and Lombardi, so thank you for that.

I am a butt doctor amongst all these very distinguished oncologists. And thank you so much for the invitation to speak at the Ruesch Symposium a few weeks ago. One of the things I really saw there was how siloed we are. I was sitting there through the talks thinking, "I went to medical school, I was chief resident—I had no idea what you guys were talking about with the pharmaceuticals." And I think some of the oncologists felt similarly when I was talking about fecal Faecalibacterium prausnitzii and short-chain fatty acids and butyric acid.

So, we're very siloed. But one thing for sure—and I appreciate your comments about the soul and so on—because when you look down at where your GI tract is located, it is smack dab in the center of your body. So there's really no question: it’s sort of the engine for everything, and all the organs—your brain, your heart, your lungs, your immune system—rely on the nutrients extracted there and the processes to function properly.

John Marshall, MD: Yeah. But you're like this highly trained gastroenterologist, and you decided—I can't remember how long ago—to sort of say, you know, this isn't really the way I think people get better. So maybe talk a little bit about that.

Robynne Chutkan, MD: Sure. Yeah. Because it was very personal. I came to Georgetown in 1997, joined the faculty as an IBD gastroenterologist, primarily focusing on IBD, which had been the focus of my fellowship at Mount Sinai. And very quickly, I realized that nobody was talking about food—including me.

Patients would come in and tell me about their diet, and I was like, “Okay, that all sounds great. What are you taking?” And this was pre-biologics—this was the late ’90s. I remember actually going to that meeting in Amsterdam for the International Organization for IBD when they were presenting the data on cA2, which became infliximab. It didn’t even have a name at the time. And so I was as skeptical as the next about the role of diet. But something happened that really stopped me in my tracks. 

This was a patient—she actually worked at the hospital, a young woman—and she had relocated to New Jersey and came back after a couple of years. She worked in the radiology department, and I saw her, and I said to her, “So, what are you on? You look great.” And she said, “I’m on nothing.” And I gave my usual spiel of, “Oh, that’s like driving a car with no insurance. That’s dangerous, you know, if you have a flare-up.” And so I thought, okay, she’s feeling right, sure. Well, let me take a look at her colon.

I did her colonoscopy, and all—she had Crohn’s colitis—all the previous cobblestoning and ulceration—gone. And I was like, “You—I cannot believe this. You must be taking something. What are you doing?” And she told me about a diet she was on called the Specific Carbohydrate Diet.

John Marshall, MD: I thought it was like... because it was the Newark Costco—was just a better Costco. No, it’s a diet, actually. She was following...

Robynne Chutkan, MD: Yeah. But I'll tell you, I was really skeptical. And I wasn’t just skeptical—I was afraid for her. Because the idea that you could treat inflammatory bowel disease without medication just was so counter to what I’d been taught. I’d been taught by Dr. Janowitz, who was taught by Dr. Crohn, and came from this sort of IBD world. But I started really looking at this, and what I found—John, I'm sure it’s the same in the oncology world—is that patients were sort of in this “don’t ask, don’t tell.”

So we did a survey in my IBD clinic, and we found that 70% of the patients were using some sort of complementary or alternative technique. Now, this is 2025—it’s very different—but in 1997–1998, this was unusual. And a lot of those modalities were just things like massage, or some of them were doing herbal things. But patients were definitely looking for things. And so I started putting patients on these different diets and so on.

We ended up coming up with a modified version of the Specific Carbohydrate Diet, which is sort of a low-carb first cousin of Paleo, but adding more fiber because it seemed pretty clear that fiber was important for gut health. And we presented that data in 2014 at Digestive Disease Week, and we showed that we actually had a 79% remission rate using this diet. Now, this is 2014, so biologics had been around.

John Marshall, MD: Did anybody believe you?

Robynne Chutkan, MD: The craziest thing is that all my GI colleagues were in the exhibit hall looking at the scopes. A few foreigners—some Europeans, some folks from Asia—were interested. But there was zero interest. Crickets. It's so funny that you asked that. So it was a small study—it was 12 patients: 9 with ulcerative colitis and 3 with Crohn’s. But what we showed—not just that they felt better—we actually had endoscopic images of mucosal healing, which, as you know, is a gold standard for remission—not just “patients feel better.” And the vast majority of patients were able to get off medication completely or reduce it.

One of the things we found when we dug a little deeper with that data is that there was a clear correlation with the amount of fiber. So, the patients who just said, “Okay, I’m gonna stop eating the processed breads and pastries and cheese, and I’m gonna have bacon and eggs for breakfast, chicken for lunch, steak for dinner with two broccoli florets”—those patients really didn’t have the same result. So, there was a clear correlation with the amount of fiber people were consuming.

John Marshall, MD: Connect the dots for me. So, it is a diet modification that's changing health, and we're talking microbiome. So, I keep thinking about, you know, what is it that's actually—take us to pathways of what's that doing to our microbiome in order to sort of rebalance? I think of it as soil. I often use a rainforest, not just a pine forest.

Robynne Chutkan, MD: Absolutely—terrain. Love the—yes, the terrain. That’s exactly right. And so fiber really seems to be key. I always like to remind people it’s less about eliminating and it’s more about adding. You can overcome a hot dog or a piece of cake if you are eating enough fiber. And by fiber, I don’t mean—I always have this as a prop—this granola bar that’s been in my drawer for 10 years. Like, I don’t mean this. I should have my apple prop. But unprocessed plant fiber. Because what that does—it’s poorly digestible, indigestible fiber—the kind that gives you gas—because it’s supposed to, because it’s not there to feed you, it’s there to feed your gut microbes.

That fiber is fermented by gut bacteria in our colon by organisms like Faecalibacterium prausnitzii—ferment it, turn it into short-chain fatty acids. And short-chain fatty acids don’t just keep the lining of the gut healthy. They help to modulate the immune system to sort of keep it at that Goldilocks—not too high, not too low—level. And so, really critically important.

You can’t just take a short-chain fatty acid supplement. It doesn’t really work that way. These compounds are very labile. And so there is this direct line between fiber consumption, levels of short-chain fatty acids, and outcome.

And we saw the same thing during COVID. We saw this UMass study that looked at microbial analysis, and they found that the composition of the gut microbiome—specifically the levels of Faecalibacterium prausnitzii—were very positively associated with better outcomes with COVID, and very predictive—92% accuracy.

And what’s so interesting, John, is some of the same organisms that they found were inversely correlated with outcomes—so, Enterococcus faecalis. They saw high levels of Enterococcus faecalis were associated with poor outcomes. We see high levels of Enterococcus faecalis in the colon cancer microbiome. So, we're seeing that signature.

John Marshall, MD: So, okay. So, you've got diet affecting the rainforest or the terrain, as you say. You've got now a—I don’t know what the right words are—but a healthier balance or the right partners to go through life with. That then leads to health. So, in your case, IBD. In most of our audience's cases, you know, it’s immune responsiveness to immune therapies, to young people getting colon cancers, to, you know, primaries responding differently than metastases, for example.

So, can you sort of hypothesize connecting those dots?

Robynne Chutkan, MD: Absolutely. And I think one of the most profound ones is when we think about weight. So, we know that we can give two people the identical meal and they will extract a different amount of energy and calories from that, based on microbial composition.

Microbes can change a palate, they can change the metabolism of the foods, they can change the transit of the food through the gut. That can determine what’s absorbed. So, it is less about the meal in some ways—I mean, the meal is still important, don’t get me wrong—but your composition of microbes...

And again, you can’t just go borrow some Faecalibacterium prausnitzii from your plant-eating friend because they only stick around about half an hour or so.

So, one of the things that is very frustrating—and I’m sure you find the same thing, ’cause you talk about the CVS aisle that’s gonna fix all of this—is trying to explain to people: it’s not just some microbes; it’s the environment in which those microbes grow. And we all have plenty of healthy microbes in our gut—if we feed them correctly—that are gonna proliferate and really sort of take root, reproduce, and create shifts.

That’s much more effective than taking a store-bought probiotic. The analogy is: you take a cheetah from the plains—the Serengeti, wherever cheetahs live—and I put it in my backyard here near Rock Creek, and I feed the cheetah Cheetos... the cheetah is not gonna do very well. So, it’s not just the microbes—it’s really the environment. And you have to create that environment. And that environment seems to be a high-fiber environment.

We have data from the American Gut Project published in 2019—10,000 people from over 40 countries asking that question: what is the most important factor for a healthy microbiome? And the answer seemed to be the amount of plant diversity in the diet, with this magic number of 30. So again, it wasn’t being vegan or even vegetarian—it’s about eating more plant fiber.

John Marshall, MD: Since I first heard that magic number—30—from you just a couple of weeks ago, I’ve been counting through the week, and I’m actually pretty good. I was already pretty good, but I’m pretty close to that on most weeks.

Robynne Chutkan, MD: Fantastic.

John Marshall, MD: So, you gave me a target, and I’ve even started to share that...

Robynne Chutkan, MD: Oh, I love that.

John Marshall, MD: ...with other people out there. So I’m grateful.

John Marshall, MD: I scour the literature for papers on this subject, and mostly it's the cancer literature I'm looking for. And what I am seeing is increasingly the impact you and others like you are having on science. What was kind of fringy when you first started—to be fair—you've matured this into now being able to start to measure it and to start to be able to influence it for cancer prevention. I've seen literature around CNS disease and dementia, of course the connection to heart disease, in your world of IBD, etc. If you could wave a wand, what would you want to be able to do? What would you want to be able to measure or assess to say: you've got a good microbiome, and here's how you'll fix yours?

Robynne Chutkan, MD: Yeah, I mean, it sounds a little bit counterintuitive, but it's almost like we have to get away from the science a little bit. Because what I find is—the science—we're in this sort of retailization of medicine. It's about selling a product, whether that is a pharmaceutical product or a probiotic at CVS. And people have this idea that if I just buy the right product, I’m gonna be fine. So it really is this idea of: what sort of platform of health and wellness are we encouraging people to build?

John Marshall, MD: Well, I guess what I'm after is: is there a Chem 20 for the microbiome?

Robynne Chutkan, MD: Okay.

John Marshall, MD: Right? Uh, so how do I measure it?

Robynne Chutkan, MD: Right now—no. And let’s remember too, that after the billions of dollars and the decades spent on the Human Genome Project—how many genetic diseases did we cure? Right? So, just like the genes are just a suggestion, the microbiome isn’t magic—it’s important. We have large data sets now that show that early antibiotic use is a major risk factor for Crohn’s disease. So, I think it’s—yes—looking at a 30-year-old and what are they doing. But I think it’s really important to say: Was this person vaginally born or C-section? Were they breastfed? How many antibiotics did they get in early life? Because I think this stuff is developing decades back.

John Marshall, MD: I’ve observed that I think there are a lot of only children with early-onset colon cancer. I wonder if there is some sort of helicopter parent phenomenon.

Robynne Chutkan, MD: Oh no—that’s mine.

John Marshall, MD: We don’t have enough time to cover all of this, but I want you to talk a little bit about ultra-processed foods and what that means. But I also want you to prompt me, because in an hour I have a meeting with the dean of the medical school on another topic. But, you know, when we went to medical school, there was maybe two hours spent on microbiome. We learned it, we got the test right, and then we forgot it. Right? So, what should our curriculum be? 

Talk a little bit about ultra-processed food, and then sort of give us a quick version of—if you were in charge of the curriculum right over there—what you’d do with that curriculum?

Robynne Chutkan, MD: Wonderful. So, ultra-processed foods—the NOVA classification—it’s not an acronym, it’s actually Nova, developed by Dr. Monteiro and colleagues in Brazil. Four groups. One is essentially unprocessed or minimally processed foods—so fruits, vegetables, meat, eggs, etc. Two is processed ingredients—so that’s things like oils, butter, things like that. So, group three of processed foods is sort of taking processed ingredients and adding them to an unprocessed food. Okay. But ultra-processed foods are bioengineered ingredients. So, when you start to see—I mean, the good rule of thumb is: if you start to see maltodextrin...

John Marshall, MD: Don’t we need these to feed the planet? We have people dying of starvation, and I don’t think—I personally don’t think—there’s enough money or access to, you know, the Saturday farmers’ market down in Arlington. Right? So how do we balance the need to feed the planet versus this problem?

Robynne Chutkan, MD: I mean, that’s such an important point, John. But I think there’s a lot between farmers’ market food and ultra-processed food. Because, let’s be clear—these ingredients are not added just to create the food. They’re added to increase the shelf life and the palatability—to keep us eating more and to make it so this food never goes bad. That’s not necessary—that’s commerce.

And what’s really concerning is that a lot of the people eating these foods—these are health-adjacent foods. So they’re plant milks, and gluten-free, and dairy-free, and bars. And so a lot of the people eating them think they’re really healthy. They think, “Oh, this is great—I’m eating this gluten-free thing, and I’m eating this bar, and it only has these ingredients.” But these are foods that never...

John Marshall, MD: We had a guest a couple of episodes ago, and he was the one who uncovered the fact that ultramarathon runners get more colon cancer. And one of my hypotheses is that it’s because they live on those...

Robynne Chutkan, MD: ...on the go. Absolutely. The bars and the go. Absolutely.

John Marshall, MD: So what should I tell the people down the hall?

Robynne Chutkan, MD: Well, the first thing is—it’s not either/or. We cannot be in a situation where the patients know more about this stuff than the physicians. And I think part of the problem is it’s been this like, “Oh, it’s fringe,” and “That’s functional medicine.” I’m a conventionally trained doctor. I wear a white coat. I have a prescription pad. So, we have to—right—we have to bring this into how we’re approaching patients, how we’re educating patients. Because otherwise, people are getting this from a health coach who’s selling them $3,000 worth of useless supplements and telling them not to do chemo. So, it is really an imperative that we include this, and we have to teach our residents and fellows and patients about it.

John Marshall, MD: I’m gonna let that be the last word. Dr. Robynne Chutkan—just an amazing discussion. And we could go on for maybe several episodes—maybe we should. But we have to close it there.

We know this is important. We’ve got to figure this out. And I think the better we understand the topic that you are reviewing—the microbiome—the better we will be at preventing disease and treating it once it happens. So, Dr. Robynne Chutkan, thank you very much for joining us on Oncology Unscripted.

Robynne Chutkan, MD:

 Thanks for having me. Such a pleasure.

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MedBuzz
Tariffs, Taxes, and Trade-Offs: Can Raising Taxes in the UK Get You Cheaper Drugs in the US?

John Marshall, MD: John Marshall for Oncology Unscripted. There's been all sorts of stuff going on out there in healthcare—in the business of healthcare—and a recent article that was just published in The New York Times told us something about the relationship between the National Health Service, how patients get access to drugs there in Great Britain, and our relationship with them and the tariffs. You're like, how could the tariffs have anything to do with the National Health Service?

Well, let me give you a very short little background, if you don't know already, on the National Health Service—Britain’s public health system. The Brits love it. It's tax-based. It's not fancy, it's not frilly. But if we're going to bring in some new medicine or some new expensive therapy—whatever it is—the budget has to be balanced.So, either they have to remove something from what the patients have access to, or they have to raise taxes. And there is a committee known as the NICE committee, the National Institute of Clinical Excellence—staffed by physicians that, in fact, governs that. 

You're thinking, where is Marshall going with this?Well, where he is going—and The New York Times presented this—is that because of the tariffs, right? Britain makes some drugs, and we import them here and use them. Well, if the tariffs are in place, those drugs will be more expensive to import. And the whole idea behind the tariffs is to make it so that more Americans are doing the manufacturing.

Well, the Trump administration and the National Health Service just made a new deal where the Brits will get access to more drugs—so they'll raise their expenses, if you will. And it's going to hit the bottom line over there...because they're going to have access to medicines that they don’t currently have access to. In exchange, the U.S. is going to say, “Well, we'll waive those tariffs on drugs you import.” So, it is access over here for an economic change—an international economic change—around the tariffs.

I have no idea how this is going to work out. I didn’t really understand all the math—were taxes going to go up in Great Britain? Were they going to call it a wash because the tariffs were not going to be in place? I don’t know.

The good thing for patients in the UK is that they're going to have more access to more medicines. What I worry about is that it'll come on the backs of either going into debt—if the National Health Service goes into more debt, sort of like our healthcare system—or, in fact, they raise taxes, or somehow they magically make the budgets balance.

So, we need to look ahead to 2026 and see just what happens with this UK National Health Service–Trump tariff deal that was just reported in The New York Times.

Stay tuned here for more updates on Oncology Unscripted.

[03:04]

Editorial/Main Topic
What I Tell Every New Patient With Cancer

John Marshall, MD: John Marshall for Oncology Unscripted.I start almost every new patient appointment by talking with the patient and saying that I—I don't really know why people get cancer. We memorize lists of what we're supposed to do and what we're not supposed to do, but, bluntly, almost everybody sitting across the room from me didn't do anything on the bad list, and yet here they are, sitting there with cancer.

It seems to me—and I think this is popular science thinking as well—that we probably all get cancer all the time. But our bodies actually have outstanding spell checkers and an outstanding functional immune system that can see early cancers and fix them before they cause any trouble. So, what that actually means, then, is that those cancers that make it—those cancers that survive through the spell checker or through the immune system—must have figured out a way to get around the spell checker, or have broken the spell checker, or maybe are hiding from the immune system.

And so, almost all of our new research going on right now in cancer medicine is either trying to fix the spell checker—and by this, I mean targeted therapies, signaling pathways, et cetera—or it's trying to turn back on, wake back up, or uncover the tumor from the immune system so the immune system can go in and do its job.

And so, I think what you see at almost any conference nowadays focuses on those two approaches. It's not some new chemotherapy, although chemo continues to be very important and has cured a whole lot of people, so don't get me wrong about that. But what we're seeing in terms of innovation has a lot to do with improving the immune system, measuring the immune system, having better immunotherapy or immunotherapy combinations, and, at the same time, uncovering the molecular abnormalities of our cancers and having targets to those—and, in some cases, combining those with novel therapies as well.

So, be on the lookout for the next innovation: either fixing your spell checker or fixing your immune system. But, in support of that, let's look at some of the coolest, latest data that's practice changing in our world today.  John Marshall for Oncology Unscripted.

[05:42]

Interview
New Hope in GI Cancer Care: A Candid Conversation with Dr Yelena Janjigian

John Marshall, MD: Hey, everybody out there in videoland or maybe you’re in podcast land walking your neighborhood. Maybe you have a pit mix dog you're walking because she hasn’t been out in a while, but wherever you are, this is for Oncology Unscripted, and I am a lucky guy because I am joined today by not only a great friend, but also someone who is really setting the standard of care for us in so many ways in GI cancers, and that's Dr. Yelena Janjigian. Yelena, how is New York City today? How is it up there?

Yelena Jangigian, MD: Thanks for having me, Donna. It's great. New York is the best place to be. It's beautiful and sunny, getting ready for holiday season. It's always good to catch up with you and talk research and talk gastric cancer and esophagus cancer outcomes.

John Marshall, MD: Do the stores already have, like, decorations ready to go up there?

Yelena Jangigian, MD: I have not been out, but I've noticed some things here and there in offices.

John Marshall, MD: What do you mean you haven't been out? You live in the hospital, in the clinic, don't you go out?

Yelena Jangigian, MD: Not out in shops, but I've noticed a few, like, you know, holidays, actually. Some of them are actually skipping Thanksgiving and going into holiday season decorations in random offices. So, but, you know, the spirit is, you know, cheerful in New York.

John Marshall, MD: It is a good time of year. I know you very well, and I know lots of our listeners know you very well. Give us a quick little bio on what you're doing right now.

Yelena Jangigian, MD: I'm a physician-scientist working at Memorial Sloan Kettering Cancer Center, focused on advancing care and helping patients with esophagus and stomach cancer live longer using both targeted and immunotherapies. Our lab is focused on trying to understand how we can overcome resistance to some of these medications using both tissue culture and other models. And, of course, I also lead a big group at Memorial Sloan Kettering Cancer Center. We have 45 oncologists all focused on one mission: to improve cancer care for worldwide options for gastric cancer, but also anywhere from esophagus down to the anal canal. So, it's a big group of very dedicated individuals. 

John Marshall, MD: So now I know why you haven't been outside. Because you haven't slept, you haven't left.

Yelena Jangigian, MD: Annual review time. A lot of paperwork. 

John Marshall, MD: Well, let's get into the weeds a little bit on how you are, in fact, helping to lead the improvement in outcomes for patients. But before we jump in, as an old guy in this space, I do have frustration that we in the GI cancer world haven't made more progress compared to our friends in some other cancers. And I know in upper GI and stomach and adenos, etc., precision medicine hasn't been consistent. Things that work in the metastatic setting haven't necessarily worked in the adjuvant setting. It's taken us a long time to get precision medicine targets that are viable for therapies, etc. What are your thoughts about that and why that might be so?

Yelena Jangigian, MD: So, yeah, I think it's important to start from basic knowledge that these diseases can be quite heterogeneous. And even in biomarkers such as HER2, cut-and-paste approaches from, for example, breast cancer into gastroesophageal cancer have not been the best way to do it. In fact, understanding the co-occurring alterations in our disease—the RAS pathway activation, the PD-L1 co-occurring with HER2—is what made the major milestone in the breakthrough in first-line setting beyond trastuzumab. So, I think understanding that this disease, in its nature, because of the nature of the GI epithelium, is more complex but also more heterogeneous than some of our other solid tumors is really critical. And also, because it's a rare disease in some countries, uniform and reflexive testing of biomarkers, where you get enough of a critical mass of data into the clinic so that you understand how each individual subset of a subset—for example, within HER2 tumors, p53-mutant tumors may do differently than p53 wild-type, RAS amplified vs RAS neutral—things like that. Until we do things in larger scale really going forward for all patients, we won't understand this nuance because in colon, breast, lung—the big three—there's more data, breadth and depth, these discoveries can be made.

John Marshall, MD: I was thinking about the idea of mostly colon cancer, and we've been seeing with IO therapy, where we're going to go in a minute, that even in MSS colon cancers, if it's primary disease, we are seeing responses when we would never see them in metastatic disease. So we're looking at microbiome interface or different biology of primaries versus mets. That's sort of what you're doing here with the Matterhorn study, is you're taking some leads from metastatic and applying them into the neoadjuvant-adjuvant setting. Does that feel right to you?

Yelena Jangigian, MD: Yeah, that's right. I think that whole paradigm of go to the late, late-stage setting, demonstrate benefit in heavily pretreated population, and only then move it to metastatic early line, and then only then move it to adjuvant or neoadjuvant space—that’s where the oncology field, I think, lacked an understanding of bigger leaps moved to perioperative settings or a minimal residual disease setting. Because you may not demonstrate a signal that you want in a fourth-line ECOG 2 patient with peritoneal carcinomatosis and ascites. By then, it may be too late. And that's what I think helped me bring, for example, agents like pembrolizumab-trastuzumab combination, Keynote 811. Because doing studies in later line, you understand that HER2 target becomes even more complicated. And again, targeting HER2 with just better HER2 inhibitors, as was working in breast, is not working in gastric. And so moving it to first line with dual immune checkpoint and anti-HER2 combination was the paradigm shift. And I think that's what we're trying to replicate in some other biologically important subset.

John Marshall, MD: I'll spare you having to do the weeds of the study. So, the Matterhorn study: neoadjuvant FLOT plus/minus durvalumab, regardless of PD-1 status, or as you measured tumor area positivity, or both, really, with pre-op/post-op kind of approach, placebo control, maintenance afterwards. Big study. Global. Josep Tabernero is always good to have as a first author. You're the senior author. How much of a pain in the neck is it to run a big clinical trial like that?

Yelena Jangigian, MD: It was fun to do, because we had to convince industry partners to do the study, because Merck had the Phase III registration perioperative pembrolizumab study. Going through to convince AstraZeneca leadership that their design was not as optimal as the modern FLOT approach—so high risk, high reward in some theory, right? But you're asking them to roll a bunch of dice—948 patients—and to be able to present that data. So, it was presented at ASCO in the plenary and then published in New England Journal of Medicine. It was definitely a high reward, and for the patient, and for the community. To be able to unify East versus West, put it all in the same trial—the trial actually recruited ahead of schedule at the time of the global pandemic—and it was always really rewarding to be able to tell patients that you had a great response, complete response, and to see the R0 resections. The dogma was that you need radiation for these patients, and we've moved away—even increasingly in the community setting. I hear from clinicians who came to me saying, “This is a perfect time for you to update us about this.” I'm taking this to the clinic, and it's part of the NCCN guidelines now. 

John Marshall, MD: So, give us the high level. I mean, you got survival benefit, you got PFS, you got response rate delta, toxicity as expected—not zero, but as expected. High level, for our clinicians out there—what are the numbers they walk into?

Yelena Jangigian, MD: The timeline of this was at ASCO we presented the pathCR and EFS data, which was also published in Nature Medicine. And in Berlin, this past ESMO, we also presented—and this was a big splash—because it's been shown with immunotherapy before that pathCR may be improved, but will it translate to eventual survival. Check. And then, for the first time ever, we were able to demonstrate that you will also see OS benefit. And that was the splash at ESMO. We will be publishing that data in a manuscript format. To show that a pathCR can be an early surrogate of survival, and I think it's all important for us as researchers because, in my program, I have three separate first-in-kind ISDs in perioperative setting building on MATTERHORN. So, to know early which of the strategies will be successful to take forward in Phase III—waiting for pathCR would be much more practical.

One common public service announcement I want to make—people are still a little confused about the number of cycles in the Matterhorn. In fact, that’s probably one of the most common emails or direct messages I get on social media: Why did you only give two cycles of FLOT? We did not. A cycle was defined as two doses of FLOT. So, it's two cycles, but four doses of FLOT, and two cycles of durvalumab. Durvalumab is given once a month; FLOT is given every two weeks. So, this was, as you said, standard approach, and we did see improvement in event-free survival.

What’s important to look at is not only the hazard ratio, but the two-year survival benefit which was meaningfully improved. And the grade 3/4 toxicities—we need to be careful about. Most of the side effects are related to chemotherapy. So, as clinicians are getting more and more comfortable using FLOT in the clinic, the dose reductions, the hydration, the prophylaxis, potentially the Neupogen if needed—all of those will be implemented. So, NCCN already adopted these regimens, and we're planning, hopefully, for the FDA approval in the near future.

John Marshall, MD: Yeah. I think about the number I go in with—oxaliplatin in the adjuvant setting in colon, which is, you know, overall maybe 3%, 5%, depending on how optimistic I am on that day. Here, what's the number I walk into the room with a patient? Is it another 5% or so cured by the addition of the IO therapy to FLOT? Is that a fair number to walk in the room with?

Yelena Jangigian, MD: I would say, well, it depends. So, if we're looking at a final OS, the difference was closer to 7%.

John Marshall, MD: So, a little higher. More than 5%, I can say, right? And that tail does exist, and you've got a follow-up.

Yelena Jangigian, MD: Right, and that's every year. And then, I think if you think about it, this is looking at a large Phase III study. These are all patients who did not have all laparoscopy. They didn't necessarily have the staging that you and I could do in our practice with specialty care. So, I suspect that number—or at least in our cancer center—is better.

John Marshall, MD: Got to hold up, okay. Tell me about PD-1 testing. I mean, I realize everybody could be in on this study.

Yelena Jangigian, MD: It was an all-comer accural. We used tumor area positivity (TAP) as opposed to combined positivity score (CPS). It's reproducible, and there's data to show the TAP and CPS are equivalent. The benefit appeared to be irrespective of PD-L1.

John Marshall, MD: So, they could come in cold for PD-L1 and they're still eligible for the therapy based on the study?

Yelena Jangigian, MD: NCCN restricted it by TAP-1. Unclear for regulatory reasons—that may be amended, because this was a restriction before the OS data came in. So, we'll have to see. The EMA appears to be interested in approving it, again just from the discussion with colleagues in Europe, irrespective of PD-L1 because that's a huge patient population. Irrespective of that, most tumors are PD-L1–positive. So, if you're seeing a negative case, I would call your pathologist and make sure the cellularity of the case is sufficient.

John Marshall, MD: Take a look again. You know, I think immunotherapy is certainly one of those classes of drugs that we have the highest patient awareness for. I mean, they're always coming in and saying, “Shouldn't I have some of that immunotherapy stuff?” And in some cancers, it can be quite dramatic, the impact. What's your thought, and what are we doing about trying to further optimize the impact of the immune system on treating our cancers? Where are we at?

Yelena Jangigian, MD: Yeah, so our large biomarker analysis of CHECKMATE 649, which was the FOLFOX–nivolumab vs FOLFOX study in stage IV patients, showed that chromosomal instability tumors—so CIN tumors the hazard ratio in metastatic setting for addition of immunotherapy—is not as good. Hazard ratio 0.9 for survival. So, we know those tumors don't do as well.

How do we improve? Because they're relatively cold or immune-excluded tumors, but we're trying to boost that. We know that combining the checkpoint blockade with CTLA-4 inhibitors may offer some benefit, especially from the data we see, as you said, in early-stage colon cancer. But it's very tricky to combine it with FLOT chemotherapy. So, combination with TIGIT may be helpful because, again, it's an immune-boosting, dual immune checkpoint blockade. That's to be determined.

There’s also now Fc silent bispecifics with PD-1, CTLA-4—drugs like cadonilimab, which are approved in China and actually are coming to the United States as well in metastatic settings. So that's what I'm interested in. I think for a subset of patients, it'll be a combination of PD-1 plus tumor targeting, for example, for HER2-positive tumors. For another subset, we’ll be doing dual immune checkpoint blockade—either PD-1–TIGIT, if that data pans out, or PD-1–CTLA-4—with the backbone of chemotherapy, of course, for all. Because it's been difficult to move away from chemotherapy unless it's an MSI tumor.

John Marshall, MD: Tell us how we move forward. What's next out there for the treatment of upper GI cancers?

Yelena Jangigian, MD: Well, you know, today we had a press release. The zanidatamab data—it appears to be a positive HERIZON-GEA-01 study, whatever that will be. So, it's a positive space that will be interesting to see at ASCO GI. And then, of course, the biggest disappointment of the year is the FGFR2b data with bemarituzumab—with FORTITUDE-101 having a huge splash with a large positive interim analysis that subsequently dissipated, and the curves came together. You probably saw ESMO. I think it shows that we're not quite done with biomarker development in gastroesophageal cancer, and the best is yet to come.

John Marshall, MD: Just to let you know, for Washington, D.C., that wasn't the biggest disappointment of the year. There’s been other stuff that beat that, but we don't have to go into that. Dr Yelena Janjigian—the world’s expert and really thought leader in the space of upper GI cancers—raising the bar, curing patients right and left, not just in New York City. Go shopping. Get out of there and enjoy a little time. You've deserved it. John Marshall, on behalf of Oncology Unscripted, thank you, Yelena, very much.

Yelena Jangigian, MD: Thank you so much, John. Be well. Take care. [22:20]

This transcript has been lightly edited for clarity.

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MedBuzz: From Hormones to Heroines: Couric, Cancer, and the Case for Change

John Marshall, MD
Hello, everybody. John Marshall for Oncology Unscripted, coming to you from my now almost empty office. I've been in this office for, gosh, 20-plus years. It's the big office. You may or may not know I stepped down as the division chief here at Georgetown. We planned it—I wanted to do it a while ago. They said no. So, I finally got to step down because I wanted to do some other things. I get a lot of time back from meetings I really didn’t want to go to in the first place, so I’m happy about that. And it’s enabled me to get back to the world of clinical cancer research and to try and innovate in our space and do a lot less administrative things. So, I am glad for the clean-out, moving down to a smaller office in a fresh region. Probably one of the last times—maybe the last time—I film from this spot. 

But I wanted to take some time to review some high-level things that have changed in a big way just in the last week or two. The one that struck me the most is that there's been a change in black box warnings around hormones for postmenopausal women. I lived this too, where we went from hormones being a good thing—and all postmenopausal women were more or less taking them—to then it was unopposed estrogens were evil. And then the cancer lobby—and the breast cancer lobby—really was responsible for making it so women stopped taking hormones. We made it so terrifying that hormones were going to cause breast cancer that, you know, certainly oncologists weren’t prescribing it. GYNs stopped doing it. Primary care docs stopped doing it because no one was really willing to take the risk. And I think about the suffering, quite honestly, that postmenopausal women have endured since this time. It is really, really remarkable. And only now—only now—that people have gone back to actually look at the clinical trials and look at the studies, they actually pretty clearly show that hormone replacement is not bad for these people. In fact, if you look at the colon cancer literature, surprisingly, there was evidence that it decreased the risk of getting colon cancer. And even despite that, they didn’t want to change it around. So, I am excited about that black box warning change. If you’re a postmenopausal woman or you know some that are around you, make sure that if they’re interested, there are new options for those patients.

But there’s a second warning that has been installed, and this is around 5-FU and DPD testing—dihydropyrimidine dehydrogenase testing—for 5-FU clearance. Why I think it's a big deal is not only is it an updated Black Box, but NCCN has embraced it. I think it’s a big enough deal that I hope you will click in and watch my interview with Howard McLeod, who is really the world’s expert in this space, about what we should be doing, how to do it, and some of the practical aspects of that.

So, make sure and click on that interview and watch it. It’ll be worth your time. All you clinicians out there should do it. Now, whether or not it will become routine, whether or not it will become standard of care, whether or not you’ll get sued if you don’t do it—those things will evolve. But I do think it will be part of your everyday life. So, good to keep up to speed on that.

And then lastly, sort of an emotional note to make—and that is, this is the actual 25th anniversary of something I bet you remember. That’s when Katie Couric had a colonoscopy on television, and it was on a morning TV program, The Today Show. She did that because, of course, her husband had had colon cancer, and she became quite a strong advocate.

Her sister Emily later developed pancreas cancer and died of that, and she’s been very involved in Stand Up to Cancer and so many things. But I think back about that moment when Katie Couric said, “You’ve got to be getting your colonoscopy.”

And the reason it comes up is that, one, we’re giving her a 25th anniversary award here at Georgetown—one of our Luminary Awards. So, we’re very excited about that. I’m going to get to see her later this week and thank her in person. But I was also thinking about the impact that I believe she has had on the number of people who get colon cancer.

If you really do the math, the interventions that have changed with colonoscopy, etc., in the United States have probably reduced the number of people who get colon cancer every year by about 20,000. Now, 150,000 people get colon cancer every year. It would be much higher than that if we didn’t have effective screening. So, screening works—fewer people in our clinics—and we need to applaud her for all that she has done.

So, that’s all the gossip that’s fit to print for this session of Oncology Unscripted. I hope it gives you a little something to think about, look up, or consider as you move forward in your day tomorrow.

John Marshall. See you later.

Editorial: How Do We Translate MRD Innovation Into Everyday Oncology Practice?

John Marshall, MD
John Marshall, Oncology Unscripted. I've talked about this a bunch on our program, and this is the impact of blood-based genetic testing on cancer care—maybe other health care problems as well. And the couple of ways we do blood-based testing: one is to look for mutations from a patient with a known cancer. But we're also using blood testing to see whether or not there is still cancer around—so-called minimal residual disease. And they're similar in technology but different in terms of how we're using them.

A lot of us out there are not using the MRD testing, whether it's tissue-based or not, because the truth is we don't really know what to do with that result. If it's negative, do I not give adjuvant chemotherapy? If it's positive, do I give more adjuvant chemotherapy? What if it flips? What if it doesn't? Et cetera. So there's a lot of unknowns, but there is this wave of data that continues to come out. San Antonio Breast coming up has new data around this. We've seen it at ASCO. We've seen newer publications more recently that suggest dramatic differences if your test is positive after surgery versus if it is negative, with hazard ratios that exceed 20. This is prediction of cancer still being around. And yes, the negatives are not perfect, but they, too, are pretty good.

So, we talk about finding the right patient to give treatment to in the adjuvant setting.I am certain that some sort of MRD testing is going to be part of this. And I was lucky enough to hear a fabulous lecture by a very, very good friend of mine, Dr Scott Kopetz from MD Anderson, who summarized the current data set around this and says that this is not going to go away. This is the inevitable. The question is: how are we, as health care providers, going to use this data to guide our patients, to guide our therapies, to improve efficiency around all kinds of therapy—most importantly, right now, adjuvant therapy?

So, review these data. Look at those hazard ratios. Decide whether or not you want to begin incorporating MRD testing into your general day-to-day care. And let's see what 2020 says with regards to treatment opportunities, clinical trials, et cetera, moving forward.
John Marshall for Oncology Unscripted.

Interview: Can Pharmacogenomic Testing Make Oncology Safer? A Candid Conversation with Dr Howard McLeod

John Marshall, MD:
Hey, everybody out there, John Marshall for Oncology Unscripted. You might notice that my studio is a little bit more bare today. One of the reasons is that I’m moving. They’re kicking me out of this office for a smaller office. That’s what you get when you get old. It’s discrimination—age discrimination. It’s actually job-appropriate job discrimination.

But we’ve got some blank walls in here, and we’ve got a lot of bright content, and I am so excited to introduce to you all—if you don’t already know him, pretty famous guy in his own right—Dr. Howard McLeod.

Howard and I have known each other for decades. We can say that, I think, with some certainty. And I want him to introduce himself, because what we’ve got to talk about is critical to almost everybody’s practice who’s listening in.

Howard, welcome. Give us a little background on who you are and what your area is.

Howard McLeod, PharmD:
Thank you, John. It’s great to be on your program. I’m an avid listener, first-time appearer, as they say.

I got dragged into this area of pharmacogenomics the hard way. A little girl nearly died of her therapy instead of her leukemia when I was a fellow at St Jude’s. We ended up finding the gene responsible for that.

Then a similar situation when I was over in Glasgow—a man got one dose of 5-fluorouracil and nearly died. So genetics as a way of predicting toxicity has been the theme of my life going forward—lots of implementation work, lots of large clinical trials and such.

Fast forward to our work at Utah Tech University: a lot of what we’re doing now is asking, “What do we do with this? How do we make it work in the real world?” Making it work at Georgetown is one thing. Making it work at a small practice “in the wild” is a totally different thing.

So, how do we implement this in all places, as opposed to just a few big centers? And the dihydropyrimidine dehydrogenase story that we’re going to talk about today is just one example. There’s a lot of activity around supportive care—Which pain med? Which antiemetic? Which antidepressant?—but this specific example is very much a toxicity example, and I’m looking forward to discussing it with you.

John Marshall, MD:
Let’s drill into this. One of our themes for this season right now is the increased utilization of molecular profiling—identifying positive signals for therapies.

I’ve always thought that pharmacogenomics—because I work with a guy named John Deeken here, who is a you, John—yeah, and he’s been preaching your same gospel for a long time: that we need to be doing more pharmacogenomic testing on our patients to optimize dosing.

There’s another discussion going on within the cancer community that we’re probably overdosing people, even up to the target, much less to toxicity.

Having lived this and preached this a long time, give me your take: why don’t you think pharmacogenomics has had stronger uptake in the community compared to, say, tumor molecular profiling?

Howard McLeod, PharmD:
Yeah, the oncology community is influenced by a couple of key things. One is strong, large, randomized clinical trials. It’s a little more difficult to do those kinds of trials for individualizing therapy—though they have now been done—for individualizing classes of therapy, not just individual drugs, particularly in the supportive care space.

So that’s part of it. Reimbursement needs to be there. There has to be a way of getting the test with a rapid turnaround. But part of it is also just: what are you used to?

I remember when PET scans first came out, no one would order one. Finally, radiology got more comfortable calling them—it wasn’t just nuclear medicine physicians, but radiologists would now call the PET component. Suddenly, you visit a cancer patient and you get a CT/PET. Maybe not quite that much, but conceptually it’s become so normal.

I think what we’re seeing now is a bit of a tipping point where some of the experience we’ve gained with tumor genomics and with inherited cancer genomics is causing us to say, “Wait a minute. I don’t need to waste my time—or the patient’s, more importantly—giving them the wrong drug when I can weed some things out and choose a better one.”

So, I think now it’s become more of a clinical efficiency tool, and that’s where we’re seeing the uptake start to happen.

John Marshall, MD:
There have been early adopters on DPD testing and then later adopters—I think our group here has been later adopters, to be quite blunt.

I’ll share with you that in the last, I would say, almost 10 years, when I write that first script for 5-FU or capecitabine for somebody, my sphincters are a little tight for the first couple of weeks. I personally have never written a script for somebody who turned out to be completely deficient at a life-threatening level, but I’ve taken care of several patients who’ve had that diagnosed and then come to us as a tertiary care referral.

Start us off, because a lot of our audience probably is not 100% sure where we are. I’m not asking for your hour-long, grand rounds, high-level talk, but: what are we talking about here? What are we testing for in these patients?

Howard McLeod, PharmD:
Yeah. So 5-fluorouracil has been around for longer than us—it’s been around a long time. Most of it is degraded to a less active or inactive metabolite that is then eliminated from the body.

Dihydropyrimidine dehydrogenase—or DPD, or DPYD as the gene name—is responsible for that first degradation step. If that enzyme is impaired—or completely deficient—then a lot more drug gets shunted down the active pathway: incorporating into DNA, into RNA, inhibiting thymidylate synthase, all the mechanisms we talk about in terms of how this drug really works.

So you end up with this preferential shunting into the active pathways. If you can’t get rid of it, then you’re forced to “use it,” and it all goes down that path.

Initially, the cases that were found by Bob Diasio and by other groups in the Netherlands and elsewhere were really those patients who had the extreme toxicity. Death, obviously, is as extreme as it gets. Then there’s prolonged, hospitalization.

The case that I first got involved with, where we ultimately discovered the DPYD*2A variant, involved a patient who had 21 days of ICU stay before he survived. His oncologist then asked for our help to figure out what in the world went wrong.

John Marshall, MD:
How many variants are there then? Are there… innumerable?

Howard McLeod, PharmD:
There probably are a lot more variants that haven’t yet been found, but currently the Association for Molecular Pathology—AMP, as it’s called—has two tiers of variants that they consider essential.

The first tier is especially essential, and there are 7 of those. In the second tier, there’s a lot of data but not as robust, and there are 7 of those as well. So, 14 total variants.

There have been a number of case reports that have come out even in the last couple of months, finding new variants. Those need to be vetted and proven to be truly pathogenic.

But the idea is: a handful or two—well, two handfuls or maybe three handfuls—of variants seem to be the ones that cause most of the difficulty in many populations.

So, for example, Jay Patel at Atrium Health in Charlotte has found some variants—and they were an early adopter, they’ve been routinely applying this—and he found variants that were more commonly seen in African American cancer patients. There have been others found more commonly in Southwest Asian patients—Indian, Pakistani, and so on.

But in general, those 14 seem to capture the bulk of it.

John Marshall, MD:
I was thinking about the situation in Europe, where there was a case—I think in France—where a patient died from toxicity. Correct me if I’m wrong, but it’s now a law in France, not all of the EU, that you have to measure this before you give 5-FU.

Early adopters have said, “Any information is better than none.” The later adopters, to your point about us continuing to find new variants, say, “I’m not really sure what to do with the result when I get it back. Does it mean I can’t give the drug, or I need to modify it? And if so, how?”

That lack of tightness, if you will, has been one of my personal struggles. But do you think now we’ve got enough data that we should be doing this in everybody?

Howard McLeod, PharmD:
I do. I’m obviously biased toward the early-adoption end of things, but I think we now have the ability to get fairly quick turnaround testing—not same day, by any means, but within 3 to 5 days. It’s being paid for by more and more insurance companies, so that issue is improving.

What we’re seeing is that if you have two bad copies—if you’re homozygous for variants—that’s really an extreme event.

Alan Venook at a presentation to the FDA back in January, during a public forum, data from a large Mayo study were shown in which the homozygous patients were the ones who did extremely poorly. That led to the first black-box warning in January from the FDA.

The heterozygotes had a lot of toxicity—hospitalizations, etc.—but they lived.

Those of us in oncology who are my age were literally taught, “You need to nearly kill the patient in order to kill the cancer.” So it’s difficult for folks like myself to look at this and say, “How can I under-dose this? Underdosing is worse than overdosing.”

But now I think we can refine it. We see that we can dose-reduce. If it’s an adjuvant patient, the recommended range is a 25% to 50% dose reduction. If it’s adjuvant therapy, I think a 50% reduction with subsequent dose escalation as tolerated is reasonable—and that’s a key point: don’t neglect the part about escalating as tolerated. If it’s a patient receiving active therapy for metastatic disease, then maybe you do a smaller reduction. Some patients will still get toxicity, but it’s unlikely to be fatal toxicity in that setting. So I think we’re at a point now where we’re as good as we are for renal dysfunction or liver dysfunction. It’s far from a perfect world, but we know this patient needs to be handled slightly differently.

John Marshall, MD:
That’s a really good point. I’m sitting here thinking about my electronic medical record, which I love and hate. The nurse brightly calls me to say, “Do you know the creatinine is 1.6?” And I say, “So what?”

What do I do? I probably do nothing most of the time, but every now and then I do something. There is a pop-up in my EMR that flags this, though.

But there is no pop-up in my EMR asking, “Did you do this [DPYD] testing?” Even though I’ve got all these criteria built in for other drugs.

I’m assuming that’s the next evolution—we’ll begin to increasingly see that kind of analysis.

Howard McLeod, PharmD:
Yeah. Dr Max Smith and Dr Jay Patel, whom I’ve already mentioned, and a few others have been working hard on that at their own institutions.

Right now, it’s mainly places with champions who are doing the hard work of integrating this into the EMR. But now that there have been two FDA label changes in the last seven months, and now that there’s an NCCN guideline change—at least for colorectal cancer, not yet for breast—places that make more wholesale updates are going to start doing that.

So Epic and Cerner and the others will start making big changes. The lookup tables that we all use electronically have now been updated.

It’s making it so that someone who doesn’t really know how to pronounce dihydropyrimidine dehydrogenase can still benefit from this. Frankly, you don’t want to know a lot about the enzyme, you just want to know, “I ordered the test.”

There was a day before your and my time when measuring bilirubin was a big deal. It certainly hasn’t been for the last 30–40 years. I think there will be a time when measuring this stuff is just what we do.

But right now we’re in this transition phase. We don’t want to underdose patients any more than we want to harm them with toxicity. Figuring out which side we err on as we move forward is the challenge each oncologist is facing.

John Marshall, MD:
Remind me—what percent of our patients would have some abnormality in one or more of these genes?

Howard McLeod, PharmD:
It’s right around 5% that would have some abnormality. The extreme toxicity is very rare—it’s less than 1 in 1,000. You may encounter it in your lifetime. In a busy practice like yours, it might have come through, but most practices will never see that extreme, fatal toxicity.

The fatal part will be caught by the testing we’re doing now, but really most of the testing is identifying those people who are going to have grade 4 toxicity with hospitalization, and asking whether we can at least manage them.

There is an approach whereby, if you know a patient is heterozygous—they have one good copy and one bad copy—you monitor them more closely and act quickly on any toxicity. The onus is on acting on it.

There is an antidote available. It has to be administered in a narrow window, and that’s the tricky part—can we orchestrate that? Often it’s just easier, in practical application, to start with a dose reduction and then move up.

John Marshall, MD:
I’m just setting out to lead a national platform clinical trial in colorectal cancer where we have not included testing as an inclusion criterion. Should we add it?

Howard McLeod, PharmD:
I would, only because it’s now in the label.

Many studies will have done DNA collection and can test retrospectively. That’s certainly another viable option—prospectively accrue, retrospectively test. But if the trial hasn’t launched already, it would be a straightforward thing to add. There is cost and logistics, but there’s a lot of pretesting going on in a clinical trial anyway. You can send all the samples to the same place—Labcorp, Quest, the big labs all do this testing now. It’s not as hard as it was even five years ago.

John Marshall, MD:
Even the molecular profiling companies for their liquid biopsies have started to bundle this in, along with germline testing and so forth. It’s going to be in our faces whether we want it or not, if we order these other tests.

Howard McLeod, PharmD:
This is just the kind of thing we can do to learn more about the patient. We’re now at a point where therapy is so successful that we can care about toxicity, pain control, and all these other issues in a more nuanced way. We’ve always cared, but there’s always been this existential piece of “saving the patient.” Now that therapies are active enough, we can start putting more attention on this next layer.

We saw what happened in pediatric oncology a couple decades ago, where survival rates got to the point where they could worry more about cardiac toxicity and such. Breast cancer has had that privilege; colorectal cancer is now starting to have that privilege, where the therapies are active enough that we can start worrying about this next layer of issues.

So it’s an exciting time. It’s inconvenient that we now need to add more testing, but I think it’s an exciting time—and a very straightforward way to apply it.

John Marshall, MD:
And hopefully it makes us more successful. “Who needs it, what are the right doses, and how do we move forward to optimize outcomes for our patients?”—that’s what we’re all about.

Dr. Howard McLeod, thank you for jumping on and letting me borrow some of your time. I know everyone who’s listening in has learned a lot and probably tomorrow will start changing their practice.

Dr. Howard McLeod, thanks a lot.

Howard McLeod, PharmD:
Wonderful to be here.

This transcript has been edited for clarity. 

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MEDBUZZ [0:00:05]

When the Sources of Trusted Information Change—Who Do We Believe?

John Marshall, MD:
Happy whatever day it is today when you're watching this. John Marshall for Oncology Unscripted. A little bit of a rainy day here in Washington, DC. It's been a little bit of a weird time here in Washington, DC—even weirder than it normally has been.

Let's start with a little of the business of our world today—the business of oncology. You may have seen that we have a new National Cancer Institute director: Dr Anthony. Professor of medicine, he's kind of a basic science guy, but he's also a medical oncologist from Dana-Farber. Would you take that job if it was offered to you? I knew some of the candidates who were in line for it—or the finalists—and you'd really have to want that job to take it right now, because of all the unsettledness at the NIH in general, et cetera. So, I'm grateful that this very smart person has said yes to the job. Now, what he does—one of his areas of expertise—is programmed cell death, which is sort of a subtle way of getting a cancer cell to kill itself, right? So maybe, just maybe, he'll use some of that expertise to help in the shifting of government. A little programmed cell death around here might go a long way. So, fingers crossed that he succeeds in maintaining and growing the research that we are doing in cancer, much of which is sponsored through the National Cancer Institute. So, fingers crossed.

But as soon as he gets the job, what happens? Well, we shut down the government.

We've done this before. It is weird in Washington when the government shuts down. Whether it's patients who now don't have a job for the moment and who risk not having health insurance to receive their ongoing cancer care—in my case—or care in general out there.We're clearly seeing an impact on patients. We're clearly seeing an impact on government operations. I'm supposed to fly to Florida to get measles, maybe, this coming weekend, and I'm not sure we will do it because—who knows if there'll be air traffic controllers available? Would you go to work if you weren't getting paid?

I had a recent call with an NCI colleague who is going to work, who is seeing patients, and is trying to manage things—but is uncertain about whether they will be paid.

I also happened to come across recently somebody in the medical center who works up in McLean. If you know what offices are in McLean, I'll let you figure that out—sort of secret spy stuff. Normally, they're incredibly busy, but because there aren't any other government activities going on, they're kind of sitting there saying, "Well, we can't do what we normally do because we're dependent on the rest of the government to do what we do." So even those who are going to work are kind of stalled.

So, there's a whole lot going on. The one positive—and it's not really a positive to make up for the negatives—is that the traffic's a lot lighter here in Washington. But still, not enough to make up for it.

Now, I do want to talk a bit about another big topic that’s come forward. You know that RFK Jr. fired 17 members of the Advisory Committee on Immunization Practices. This is the group that gathers to make recommendations around vaccines and immunizations in general. He fired a lot of them. He put some replacements in—many of whom have been featured in other articles—I won’t drill down into the weeds on some of this, but many of them are more than just anti-vaxxers. They’re suggesting that we’ve mismanaged this as a medical community, and that we’ve not been telling the true scientific story.

The new people who’ve been put in place haven’t made any formal recommendations yet. But the most recent one that came out is that there’s even some debate about whether newborns should be given hepatitis vaccines. And that data is very, very tight about how many lives are saved because of vaccines—as they all have been shown. But we’ve forgotten data, and we’re going to have to relearn the lesson going forward.

Do you read the front page of the paper or don’t you? In my family, it’s split. My wife only reads the sports section. I read the front section—or at least read the headlines.

In the Washington Post editorial page was an article written by the last six Surgeon Generals—right and left—appointed by different presidents over time. And this was a very thoughtful piece that basically summarized that RFK Jr.—he’s perfectly entitled to have his own opinions about things—but he’s not entitled (this was their conclusion) to put other people’s health at risk.

And they collaboratively, collectively, emphatically said that that is what is going on with this new ACIP committee—with RFK Jr. at the helm. That we are putting a lot of people at risk, and it’s what’s making us all very, very anxious in the medical community today.

Now, I want to talk in closing on this about a book that I am reading. Don’t worry, it’s not too boring.

And the stuff I’ve been seeing during Jeopardy—I always measure the pulse of America by what ads run during Jeopardy every night.

Now, the book I’m reading is brilliant.

It’s called Empire of Pain. It’s written by a guy named Patrick Radden Keefe, and it’s the story of the Sacklers, Purdue Pharma, and OxyContin. I’m sure you may have seen the movie about this. It’s brilliantly written, and it starts with the first advertising that was ever done for drugs.

This was Librium and Valium—done by Pfizer at the time. And the Sacklers kind of invented this strategy where they were figuring out how to tell a story of a new medicine—in this case, anti-anxiety, kind of anti-depression medicines, Librium and Valium.

These were for patients who weren’t psychotic—so they didn’t need to be admitted for their psychiatric anxiety and problems—but there were a lot of people out there who could use a little something to help take the edge off. So, they created a market. They had drugs that would solve this problem for people. And Librium and Valium became the biggest-selling drugs at their time. This was through peer-to-peer teaching. So, start thinking about your own role in this as you listen. Physicians who were trained to teach other physicians about the new medicine. Direct-to-consumer, certainly. The Sacklers owned a medical journal where they advertised in it and could write editorials about their medicine. They also had consultants that worked for it. 

Now, as I’ve been reading this, I’ve been thinking: I play all of these roles. I’m a consultant of pharmaceutical companies. I do peer-to-peer education. I do clinical trials. I write papers for journals. I do video podcasts, for God’s sake.

And so, I’m out communicating my bias, my opinions to others—to influence their practice on some level. Not my goal, but it’s certainly a downstream product of influencing their practice.

So, this family had figured out a way to take advantage—and coach and train us all—how to use medicines. And this was in the very, very early part of my career. But then what they figured out was how to take pain medicine, believe that the pain medicine would help, make it longer-acting, get a good price for it, sell it, convince us all that we needed to be on it, and increase the utilization of long-acting pain medicines. So, when I was just a fellow and a new faculty member, we were all coached that there is no high enough dose. That all patients need to be on it. That it’s normal to be on these drugs. And in point of fact, it is the right thing for people to be doing. Only now do we recognize that this was really an over-push for these people.

I’m just reading the section of the book now where people were abusing it. That they became addicted to it. And it was not really for cancer pain or other things—they were just hooked to the drug. And it took a long time for that to get broken.

So early in my career, I was pushing huge doses of this medicine. You were, too.

And now there’s nobody I’m giving much more than about 10, 20, 30 BID of long-acting pain medicine. So, we learned our lesson about how we were kind of lied to in this setting.

More recently, we have a new point-counterpoint with the government. I’m seeing it from Pfizer. I’m seeing ads today during Jeopardy and other shows like that, where Pfizer is basically reminding us all—as an audience—that vaccines can help.

The government is telling us, RFK Jr. is telling us, that vaccines are bad. That we shouldn’t be taking them. That they cause all sorts of trouble in patients, and we shouldn’t be messing with it.

But then I’ve got Pfizer doing a very clean ad over here that says, “Don’t forget vaccines.”

Let’s look a little bit at the science that’s being referred to. The science back when we were giving long-acting pain medicines, and now when we are making new recommendations by our government.

So, back then, they actually didn’t even get formal FDA approval for MS Contin, because morphine was already approved. They just got it. They just started shipping it out. They just started making it and shipping it out.

They then got approval for OxyContin—but the guy who approved it at the FDA, believe it or not, a couple of years later, starts to go and work for them outside the FDA. So, there’s a lot of question about whether that was legitimately covered.

But the idea was that OxyContin would be less addictive—but they never really showed that, even though they marketed that. 

So, the cleaner processes that we’re used to for drug approval were not put in place. And then the claims that could be made about how well these pain medicines worked—anybody could say anything. There wasn’t a lot of supervision around that until it kind of came back to bite them and haunt them.

We are, in today’s world, hearing the government, RFK Jr.’s gang, and other people talking about immunotherapy, vaccines, et cetera—saying things that have no real foundation in science. They are based on just speculation, or something somebody put on Twitter one day. And it becomes our job, in the medical community, to judge what is the correct thing to be doing.

And I think right now, you’re seeing insurance companies and pharmaceutical companies and the medical teams really sticking with the more clean science, and applying therapies based on what they know—and sort of ignoring what they’re hearing in the public media, et cetera, based on what the government is saying.

So, this has put us in a new and awkward position, where we are on the side of business in this case, and not on the side of government.

If you haven’t read this book, Empire of Pain, I would recommend that you do—particularly if you are an older person who’s lived through some of this. But I also want you to recognize that there’s a lot of pressure—mixed pressure—out there on just providing today’s standard of care.

And so, the next time you see that Pfizer ad, remember that you’re probably now on that side of the coin—advocating for ongoing immunotherapy for our patients in the form of vaccines to prevent, but also in managing and preventing other cancers from occurring through the use of immunotherapy.

Complex times. Lots going on in the news today. Lots that’s affecting our world and the treatments that we are offering. Lots to incorporate in your recommendations.

I hope this has been helpful in summarizing that, and it’s useful for you tomorrow in your practice.

John Marshall for Oncology Unscripted.

Main Topic [0:13:12] The Molecular Space Race: Will It Bring Earlier Detection and Better Treatment?

John Marshall for Oncology Unscripted. An amazing amount of science is going on right now in the cancer world—on the molecular side of things—and I like to think of it kind of like a molecular space race. Because the technology that’s out there—of being able to measure what’s going on in a tumor, what’s going on in the blood, finding different genetic characteristics, and being able to act on those—has never grown quite as fast as what we are seeing now. Just like we were racing to get to the moon or racing to orbit around the Earth, we are now seeing companies and different groups from all over the world developing and improving technologies to try and read the tea leaves of whatever’s going on in the blood, whatever’s going on in a tumor—in what I think of as a molecular space race. And I wanted to feature a paper about this that I thought was quite interesting and will set us up for the beginnings of what will be, really, a few-month-long discussion around precision medicine—to try and understand better how it’s going to help us evolve and become more efficient in the practice of not just cancer care, but healthcare in general.

Now, the paper I want to talk about is in this journal called The Journal of Clinical Oncology. Yeah, I still do get a paper version. And this one is from China. Now, I want to start by saying that I’m a little surprised this paper made it into JCO, because it is a molecular analysis done totally in China. 

But where I wanted to start from was that the funding for this work came from a bunch of philanthropic and government-supported stuff in China. A big, long list of different resources—including the healthcare system where it was started out of.

And I keep thinking about here in the United States—where we’ve been leading in investment, where we’ve been leading in discovery—we are now finding it more and more difficult to access the kind of support that came to make this science possible. So, when we think about our individual U.S.-based impact on outcomes and research and progress—without that funding—we’re going to clearly keep falling behind.

And the two papers I want to talk about—this one in China and the other one out of the European Union group—show that all of this novel, positive work is coming from other sources, other investment. Just food for thought.

But anyway, this group took patients with the attempt to try and find a blood-based test to detect early, early-stage pancreas cancer. Because, as you know, it is very, very difficult to cure pancreas cancer if it shows up clinically. I won’t go into the weeds on this paper—it’s in JCO—but they basically took some learning sets and some training sets, et cetera, and developed a panel—a blood-based panel. And they were able to show, with very high precision, that they could distinguish who had small-volume pancreatic cancer and who didn’t. They even had a cyst sub-study subgroup in there to look at—and things like that. And I think it’s worthy of being presented in JCO, because if you think about what we’ve been doing with our blood-based testing, is people who already have cancer—who then get blood-based or tissue-based genetic testing to decide what we’re going to do to treat them or how to follow them: looking for minimal residual disease or what targeted agent might be available for that individual patient. But this is the other end of where I think this kind of technology is going to go—and that is screening. Healthy population. Blood-based testing. See if you’ve got cancer or not—and intervene. And I’m very, very interested in seeing over the next 5, 10-plus years how this kind of technology shifts from just coaching us to be more efficient in the treatment of existing disease—existing cancer—and more shifting towards early detection and prevention strategies.

So, I think there’s nothing hotter than this blood-based testing that’s going on now, which is why we’ve decided to spend a few months on it. And this paper sets the stage.

The other paper I want to contrast that with also just came out in the Annals of Oncology. So yeah, good group, good journal—but not quite JCO, right? So, a little bit off the beaten path. But to me, maybe the most important paper of the week.

And this was the group from the PRODIGE 13 adjuvant colon cancer study, where after the intervention was done, patients were randomized into four groups of follow-up. Now, I don’t know what you do. NCCN says I’m supposed to do it maybe once a year. I do it a little more often than that, if I can get away with it—although that sometimes means I’ve got to do a peer-to-peer to get a scan or other things. I’ve incorporated, more recently, doing MRD testing. But the standard right now is a CEA every now and then, and a scan every now and then, and a colonoscopy every now and then.

Well, the study actually randomized patients into more intensive follow-up versus less. Now, remember why we do this in colon cancer. The primary reason is that we feel like if we can find a met before the patient feels it, that we could remove it—and maybe cure the patient, right? And so, unexpectedly, this study basically said the opposite. It didn’t matter how intensive your follow-up was. You had the same overall survival. Well-done study. Prospectively looked at.

So, then I’m thinking, oh my gosh—if it doesn’t really matter, like should we do what the breast cancer doctors do? They don’t even do follow-up scans at all, right? They do an occasional LFT and a physical exam, and that’s it. Should we begin shifting to something like that?

Know that we are dialing up in the other direction—because we’re increasingly doing MRD testing, where we’ll have an even more sensitive measure than CEA or scan to determine if somebody’s got residual or persistent cancer.

And I am hopeful that what we will show is that by identifying patients at the molecularly positive level—like an MRD test—we can intervene.

And in fact, I’m helping to lead a study across our country to test new agents in that space. That if we intervene with those new therapies, we will, in fact, cure more people through that earlier intervention than by waiting to see what grows out there in the patient’s liver or lungs, et cetera.

Recently, I have a patient—a colon cancer patient, a young man—who had an MRD-positive blood test. And his scan—regular conventional CT scan—was negative.So, I ordered a PET. Now, you could argue maybe I shouldn’t have. But he had two in a row—blood tests, positive; CT, negative. I ordered a PET. Guess what? The insurance company said, “No, you can’t order that.” So, I ended up doing a peer-to-peer review.

Don’t you love peer-to-peer reviews? How many of you initially say, “Are you actually an oncologist?” when you talk? I wasn’t—I was polite to the doc on the other end. I told her the story. She plugged in the data that now the patient was MRD positive, and she read out the approval code to let me go ahead and get the PET scan. So, clearly, MRD testing is having an influence on decision-making and insurance coverage. But it’ll become our challenge to demonstrate that knowing MRD testing is important enough that it will influence survival—unlike that Annals of Oncology paper that showed that CTs and CEAs maybe not so much.

I think this paper puts us at a higher bar for challenge—to make sure that following patients closely makes sense, and that this MRD testing better work for us. Or else, we’ll just be pulling back in general after patients are initially treated.

So, I hope you find this next series of discussions about MRD testing, et cetera, interesting and useful to you. And I hope you find these two papers a bit challenging—one that takes us to a screening test for pancreatic cancer, the other that takes us to: should we be doing anything after we follow patients, outside of these newer tests that are coming?

So, more to come. I hope it’ll be useful to you, and I hope you’ll tune in next time for Oncology Unscripted.

Crisis, Misinformation, and the Future of Cancer Care: A Candid Conversation with Dr Eric Winer 

John Marshall, MD:
Hey, everybody out there—John Marshall for Oncology Unscripted.

And I am a lucky guy to be able to talk with such an amazing contributor to our world of cancer: Dr Eric Winer. And I’m going to embarrass him for a minute. Not only are we Dukies—by the way, go Devils—but we all know he has, as everyone on this call knows, really led so much of the innovation and progress in solid tumors—specifically breast cancer. Transformed things up at Harvard first, now back to his home base of Yale, where he oversees an incredible group of people and a program. And I am just—first—honored that he said yes when I asked him for a quick interview on the world today. So, Dr Winer—Eric—thank you for joining us.

Eric Winer, MD:
Oh, pleasure to be here—and I was honored to be asked.

John Marshall, MD:
You are so cool. Thanks a lot.

I mean, what I wanted to talk with you about is the impact—the acute impact—that we are having in general around cancer research and around cancer care, since this academic versus executive branch battle that’s been going on around grant funding, around cancer care, but now more acutely with the government shutdown, we have NCI trials. You know, patients are losing insurance and this sort of thing. And I know what it feels like here in Washington, but I thought—you, having a pretty broad vision around things in the country and maybe on a global scale—might have some reflections on this.

So, maybe just wax poetic a second about what the last several months have been like, and how the last month has made that even more.

Eric Winer, MD:
Sure. So, the last several months have not been easy, for sure. In truth, there are not that many grants that have not been refunded at our center at Yale. There are some—and there are people who lost some funding—and we’ve done our best to backfill whenever possible.

I think there’s a lot of anxiety. There’s a lot of anxiety, particularly among young people—young people trying to make careers in the lab, trying to make careers in clinical research—and that’s been pretty tough on everyone. And at Yale, we are one of those institutions—which I guess I should say we’re lucky to have such a large endowment—but we are one of the 8% endowment earnings tax institutions. So that is hundreds of millions of dollars a year to the university that we will be losing. And so, there have been many conversations about how it is that we’re going to manage to keep doing everything that we want to do. This is not just at the School of Medicine or in the cancer center—this is the university at large.

With, you know, with that kind of hit, I think the last few weeks have even been harder. Today there was, of course, supposed to be a Cancer Director’s meeting at the NCI. And the reason we are in our offices all day is because that was cancelled because of the shutdown.

John Marshall, MD:
Tell me the impact of that.

I mean, you guys get a lot done. I know when Lou Weiner goes up to those meetings, he comes back with a lot of fresh ideas, new collaborations, progress.

Tell me what a missed meeting—I mean, somebody said, “Well, we meet too often anyway.” What’s your take on that?

Eric Winer, MD:
Well, I think missing a meeting—you know, one meeting—isn’t such a big deal. I mean, in truth, was I perfectly happy to stay at home in Connecticut rather than go to Washington today? Sure. On the other hand, I think these meetings serve a real purpose.

It allows us to talk to one another. It allows us to hear what’s going on at the NCI, and how the Cancer Center Support Grants potentially are going to change. It’s a way of collaborating. So, I think it’s serious, and it’s concerning.

I guess my biggest worry with the government shutdown is all the people who aren’t getting paychecks. All the people diagnosed with cancer, who are living with cancer, who are struggling to find food to put on the table. You know, there were multiple stories this week—just watching the various news outlets—about government employees going to food banks. And some of those people have cancer. And it’s very hard.

I think that all the anxiety that we feel in academia at the moment—particularly related to medical research—I think now, suddenly, the whole country is feeling, with the government shutdown. And it’s hard to be under multiple stressors at the same time.

John Marshall, MD:
With cancer being one of them—particularly, think about our patients.

So, my wife accuses me of a lot of hyperbole—and she’s probably right—but I think we’re about one in three, one in five of my patients here in Washington, where one of the couple has either lost their job, is on furlough, or it’s questionable. And they’re often the one the insurance is with, right? And so, we’re trying to make plans for next scans or next cycles. And hospitals are on their heels a bit too about: will these be maintained? Will people keep up their premiums?

And so, I’m assuming you all are feeling it there in Connecticut as well, right?

Eric Winer, MD:
I mean, we don’t have as many government employees—federal government employees—as you do in DC. But, you know, I think it’s this pervasive sense of angst that so many people have that just makes it so much harder.

You know, my patients come in—and I see patients one day a week and totally enjoy it—but I have to say that the anxiety level is up for everybody. And I think that’s hard.

And it’s very hard when you’re going through difficult treatment and a difficult diagnosis, and you may be facing a diagnosis that is going to shorten your life expectancy—and to deal with everything else is pretty tough.

John Marshall, MD:
You’ve had a career in drug development, and I know you have a very good sense of global cancer research and global cancer care. There was just another colon cancer study that popped positive—using an IO plus an oral VEGF—that beat regorafenib by a nose. And I think about very expensive therapies—trial done all around the world—for a U.S. market, primarily.

And I sometimes wonder if our patients understand—or our federal government understands—just what a privilege it is to practice medicine here. Because we do have access to all the innovations. We’re the first to have access to them. We can provide them for our patients. Yes, it costs a lot of money—but it is a privilege. And we’re sort of the leading point on breakthroughs and applying those breakthroughs to our patients.

Do you think... you know, the administration before the Biden administration wanted this to happen. Certainly, RFK Jr. wants this to happen—some sort of leveling out of the playing field, of both the investment and the cost of cancer care.

Are you starting to see some of that?

Eric Winer, MD:
I don’t know that I’ve seen a lot of it.

I will—just to sort of shift a little bit—what I worry about is that the access that many people have to new treatments and drugs is not remotely distributed fairly or evenly in our country. And not all insurance is the same. Lots of people don’t have insurance. As there are threats to Obamacare and cutbacks in Medicaid and reductions in subsidies. You know, what the average family is going to pay in some states—where they've received subsidies—for their healthcare is huge. I mean, I think I read that a family of four living in Maine, when they lose their subsidy—a family of four making $130,000—is going to have to pay another $28,000 a year. They can’t do that.

That’s going to mean that people go without healthcare. And that’s going to lead to even greater inequities in the delivery of cancer care than we already know exist. You live in Washington, where the mortality for Black women with breast cancer is dramatically higher than for White women. And we know—if you look across the whole country—that if you’re a 20-year-old Black woman, a Black American woman, that you face twice the chance of dying from breast cancer as a 20-year-old White American woman before the age of 50. So, this is huge.

I will be the first to say: I believe in universal coverage. I think healthcare is a right, not a privilege. And it kills me that we’re getting further and further from that.

John Marshall, MD:
Further away. I couldn’t agree more about that.

And we spend—think how much we invest in our institutions, ourselves, and just the infrastructure and staff—to manage the complexity that you just described. And if we had a simpler system, we would reduce the cost of delivery just by that.

Eric Winer, MD:
Well, and it’s not even just about the dollars.

As treatments get more complicated, and they require more in the way of family involvement—if we have people who are struggling to get by, how are they going to have family members who can help them get through their cancer treatment?

You know, it’s interesting. We have a very large organization in New Haven called Sisters’ Journey, which is essentially a group of largely Black or African American women with breast cancer. And they are very effective advocates. They raise money. They try to help one another. And in talking to them, they realize that the care that many of their members have received over the years is just not the same—for a whole range of reasons—as the care that more affluent, and typically White, people receive.

John Marshall, MD:
Let me take you back and sort of—as we wrap up—to something you brought up at the beginning, and that’s younger people. You know, we are in the gray-hair part of our careers, but we’re still, you know, we’re out there doing our thing. But we’re OK. We’ll be OK individually.

But when you start thinking about somebody who’s 30, 40—early career—whether it’s medical or research or both. I think about my kids, who are in their early thirties. You know, what they’re going to have to deal with going forward about building careers—and the importance of that foundational science that really they provide us as we move the bar in research.

Maybe just share any further reflections you have. How vulnerable are these folks? Is it really angst that they should be worried about, or is it just angst because it’s unstable?

Eric Winer, MD:
Well, look. In the U.S. alone, we still have almost 2 million people diagnosed with cancer every year, and over 600,000 people who die from cancer. We need a lot of research still. We need research, and we need people who deliver the care. It’s just absolutely critical.

And you and I aren’t going to be those people with the breakthrough ideas. You need young people. And when a person who is 30 or 35 or 40—who’s finishing a PhD or an MD or an MD/PhD—looks at the likelihood that they’re going to get funded on their next R01, you know, with a chance of 4%. And maybe, if they’re a new investigator, it’ll be 7%. It’s hard to maintain enthusiasm. And yet, we desperately need those people to keep going into cancer research, or else we’re truly going to have a brain drain. Maybe not tomorrow. Maybe not next year. But in five years—we will.

And so, the damage that’s potentially done through these cuts in funding—and it’s not as if funding was so very generous ever—but at least there was a hope that people would get funded. But with the kinds of pay lines that exist at the moment, if I were a young person, it would be hard to maintain enthusiasm. And I’d be thinking about doing other things. I hope they don’t, but I fear they will.

John Marshall, MD:
Let me go one last place—and this is really what sometimes hurts me the most or makes me the most upset—and that’s the misinformation that’s being put out.

You know, as a GI oncologist, to see the word leucovorin on the front page of The Washington Post was shocking to me. Because, you know, we were going to cure a different problem with folic acid—fancy folic acid. And you see so much of it.

And so many of our patients are clearly reading this, because they’re coming into clinic and asking about it. So, I feel that I’m spending a much greater amount of my time just resetting reality—of what we know as science today and medicine today.

What’s your thoughts on that? Do you have any reaction to that?

Eric Winer, MD:
Well, I think, of course, misinformation is incredibly dangerous. And it’s hard for people who aren’t medical professionals to keep track of all the medical facts. I mean, medicine is complicated. But if at times people are hearing things that are just blatantly incorrect—and particularly when those comments come from people who they may respect—then it’s really challenging. I think we have to do our best to educate society about what we know and what we don’t know, and what steps people can take to improve their health and their family’s health. And when there are false statements made—it’s hugely damaging.

John Marshall, MD:
Thank you. Thank you for that feedback and thank you for your time.

I know it is Breast Cancer Awareness Month. You may or may not know that I’m sort of grumpy about that as a GI oncologist. So, if you want one of our stickers, here’s a “Love Your Butt” sticker—for, you know, the colon cancer people that are out there.

But let me again thank you so much, Dr Winer, for giving us your time and your knowledge and your experiences as we all navigate these challenging times.

We really, really appreciate your time.

Eric Winer, MD:
You bet. Take care.

John Marshall, MD:
John Marshall for Oncology Unscripted.

Thank you all very much.

[38:13]

This transcript has been lightly edited for clarity.

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[00:00:05] Main Topic 

ESMO, Efficiency, and Evidence: New Data, China’s Science Leap, and Leucovorin and Autism 

John Marshall, MD: Hey everybody, John Marshall from Oncology Unscripted. There is so much going on right now that we're gonna need a full hour-long show, but we're not gonna do that to you. We still promise short bites here and there of the stuff that's going on, just to make sure you're in the loop. I'm sure you are.

But let's start with a little science. And the science we wanna focus on is the upcoming ESMO meeting. We've looked at the leading abstracts that are gonna be presented there, and there's not gonna be a lot of surprises about the content. There's a lot of innovation in precision medicine and immunotherapy and different diseases, and positive randomized trials, and some exciting early-phase clinical trials. 

But what I think is worth noting is that a pretty high percentage of the science that's being presented at ESMO actually comes from China—Chinese pharmaceutical companies sponsoring it, China's institutions running the clinical trials. And there's been a lot of discussion about the quality of Chinese data.

Just recently, on September 23rd, Scott Gottlieb—who used to be, of course, the head of the FDA—did a very nice opinion piece in The Washington Post about the impact of Chinese drug development. The quality wasn't actually that bad—it was just less expensive. They were able to do clinical research much less expensively than we can here in Western society, if you will.

So, it's not so much intellectual innovation—it's efficiency in getting answers out. His whole editorial is about: how do we reshape and reprioritize our own clinical research infrastructure? How does the opportunity of a, I don't know, a world turned upside down in terms of regulatory oversight, et cetera, give us a chance to maybe improve the process, to lower the cost of drug development, so that our innovation—which we really still remain the hub for—can actually be brought forward and not create some sort of global intellectual property war, which he refers to, but more: how do we keep up with the pricing structure and the innovations that are out there?

So, I encourage you to not only look through the abstracts from ESMO—because there are some very important positive results from that—but also think a little bit about how we, in different parts of the world, even the playing field around the cost of new drug development. I encourage you to read that Scott Gottlieb Washington Post editorial.

One of the big abstracts that will be presented is around MRD ctDNA testing and using that technology as a way to define who should receive adjuvant therapy and who should not. Of course, we are interviewing the lead author on that paper, so stick around for that interview. But we clearly can see that genetic testing may, in fact, have a major impact on making us more efficient on who should get adjuvant therapy and who should not.

So, I do clearly think that's the evolution that's going forward. You wanna make sure to keep your finger on the pulse of MRD ctDNA testing in the decision-making process for adjuvant therapy and subsequent treatment.

I'm lucky enough to be running a protocol here in the United States looking at MRD positivity in patients with colorectal cancer, and others are doing it in other diseases.

One of the ways that could, in fact, make that much less expensive is digital pathology. Because it turns out that a digital image of an H&E slide—and there's some fascinating data around this—can actually predict risk almost as well as genetic testing. So, that's very inexpensive. It takes 20 minutes to scan it in, send it off to the computer, AI reads it back, and gives you a risk factor.

So, I do want you to also keep a nose out for digital pathology as an impact.

But maybe the most unsettled science that I saw in the last week actually was also in The Washington Post. Now, The Washington Post, in one issue, reported on vaccines killing children, our administration down the street is going to be talking about how evil vaccines are—continuing that discussion that their rising costs are gonna break us in the U.S. Our economy is so built around healthcare that the rising costs are eventually gonna break it. And the risk is that what I'm saying right now might land me in the same boat as Jimmy Kimmel—of getting fired. But you know, last night he was back on again. So maybe that will only be temporary. But the science I wanna talk about is this whole connection between, say, Tylenol—acetaminophen—and autism. And the only reason it says “Tylenol” is that Donald Trump can't say the word “acetaminophen.” And so many people out there are affected with autism over many, many decades—even well before Tylenol/acetaminophen was invented. But what really caught my eye is these smaller studies that have suggested that leucovorin—which is folinic acid, okay? It’s reduced folic acid—was helping in some clinical trials.

Now, I wanna remind us all that in the United States, in 1998, our diets began to be enriched with folic acid. They did that because there was very good evidence that if you had enough folic acid in your diet and you were pregnant, that you reduced the risk that the baby would have any neural tube defects.

So, our entire country is on folic acid supplementation so that we would have a reduced rate of neural tube defects. And for us—or the administration—to now be saying that we should be giving people leucovorin, which is simply a reduced form of folic acid, to try and treat autism is really wild. To the point where the recommendation came out—even this morning—pushing from the White House up to the FDA to relabel leucovorin.

Now, I give a lot of leucovorin. I'm a GI oncologist. So, let me just remind you that when we don’t have leucovorin—remember the plant broke, and so we, for a while, didn’t have leucovorin—if you just took folic acid, if you went down to Costco and bought yourself some folic acid and you took it, your body converts it to folinic acid using dihydrofolate reductase—an enzyme we all know and love, 'cause that’s where methotrexate works.

So, we’re on it anyway, right? We’re all supplemented through our diet, but also many people take multivitamins and others. But we’re all on folic acid—so much so to the point that side effects from 5-FU in the United States are different than 5-FU side effects in other parts of the world because we're all on low-dose leucovorin, if you will.

And so, before we all go crazy—and I know, if you are the parent of somebody with autism or you know somebody, you're tempted to say, “Well, let’s go out. Let’s take some folic acid”—I don't think there's any harm in that. But I think for our administration to change a label based on this amount of data is unprecedented. And I'm anxious about that because it meets a cause that they care about, but you know, it may be influencing how we develop drugs in the future.

So, it's science. Yes. Is it early? Yes. Would I like it to be true? Yes. I think we ought to study it further. Should we change a label? I think that’s taking the step too far.

So, a lot of science—whether it’s ESMO or in The Washington Post—a lot to learn as we go forward. Pay attention. Value the data that you see in front of you. Qualify it in a way that makes sense to you. And then make your recommendations to your patients and your friends based on that. I think we’ll be better off if we stick to traditional scientific method. Yes, accelerate it. Yes, make it more efficient. But we need traditional scientific method in order to improve outcomes for our patients around the world.

John Marshall, Oncology Unscripted.

[00:09:11] MedBuzz

How Are You Holding Up?

John Marshall, MD: Last Monday, I was walking around the hospital and I noticed a different mood. The hospital, in today’s world, has been kind of a safe haven. Whether you're reading the world that’s changing every day and all the rules are thrown out—in the hospital, we all had a common enemy. We had a common purpose.

And so, it’s not a political place at all. We were holding doors for each other, we were smiling and encouraging each other—whether you were a patient, whether you were administrative staff or medical staff, whatever—you were part of a team that was working together.

But this last Monday, I was walking around, and it really felt different. It felt like people were flat. It felt like people were withdrawn. It was no longer that safe space that we wanted it to be, and I was very anxious about the mood creeping in. The mood that's out there in the world today, about all the changes, was creeping into the hospital itself. It got a little lighter through the week, but I still think it’s a different place. I think it's because of the stuff that’s out there. 

Now recently—just last weekend—I was down giving a lecture to the International Society of GI Oncology, a group I helped found many years ago, and I was honored to be given the chance to give a talk at this group. It was an overview of where we are in GI cancers in general. I was thinking about and talking about our jobs, and the work we do, and the pressures that outside is applying, and the emotional connection we have with our patients and with each other, quite honestly, as a team. And I don't often do this, but all of a sudden, my throat got a little caught. I was… I was sad. A loss for words. Anxious for those around us. I'm an old guy—I can survive. But I was worried about the 30- and 40-year-olds that were in the room, that needed to carry the torch forward. I was worried about just all of those pressures that were around. And for the first time, maybe ever, I was struck by the emotion of the time. And it sort of went along with the mood of the hospital.

I'm hoping that we can kind of come out of it. I don’t know about you, and I’d love for you all to provide feedback. Is this something that you're feeling in your practices? In your workplace? Is it creeping into the medical community in a way that's disrupting what we do and how we feel?

Because I do think it’s really important right now. Part of my message back at us all is that we need to make sure and take care of each other. Support each other—whether you're supporting a patient, whether you're supporting your team or your colleague—we need to make sure that we're reading each other and are there for each other through these hard times.

So, what's the mood in your hospital right now? Is your throat getting caught a little bit when you read something or have to share thoughts with others? Or are you hanging in there and doing all right?

I hope it’s the latter, 'cause somebody needs to keep holding the torch for us and keeping things moving forward.

John Marshall, Oncology Unscripted.

[00:12:47] Candid Conversations with Experts

How Do We Treat Smarter? An Interview with Dr Thomas Powles

John Marshall, MD: Hey everybody, this is John Marshall here in Washington, DC, where nothing is normal lately. A little bit rainy today, but we need it, so maybe it’ll wash away some of our sins.

But Oncology Unscripted is fortunate enough today to have an amazing guest, Dr. Thomas Powles from London. So, it’s a little later in the day where he is than where I am. Tom has really led the charge in innovation in treatment with GU cancers. And I was first attracted and wanted to interview him not only because he’s a famous social media guy—he's really had a major impact on information sharing in our cancer community—but really because of the clinical trial that he oversees. But first off, Tom, welcome. I’m hoping you’re having a lovely day in London. We love it there—our kids live there. Do a quick introduction of yourself for our audience.

Professor Thomas Powles, MBBS, MRCP, MD: Well, John, firstly, I’ve followed your work for many years, and I’m incredibly honored to be here with you and the amazing things that you’ve done, and I’m very happy to join you.

I’m Tom Powles. I’m an oncologist in London. I’ve led a number of different trials—some have been successful, many have not been successful—and I also have collaborated with a huge number of people. And those trials which I have led have clearly been a huge team effort.

And we are making a, as you said, in GU cancer, a big charge towards curing patients with bladder cancer. We’ve done very well in kidney cancer, but we haven’t quite got there yet. And, of course, prostate cancer is a complex beast, but there are huge numbers of new therapies. So, really exciting times in GU cancer.

John Marshall, MD: Totally. So, in MRD testing—let’s jump right into that—I think of adjuvant therapy as one of the most inefficient things we do. On one level, some people were already cured by our surgical team members, if it truly is postoperative adjuvant. On another case, some patients are not cured despite receiving therapy; they have microscopic metastatic disease and relapse anyway. Then there’s that wedge of people who we do fix—we treat 100 people to help, I don’t know, a quarter of them, right?

And so, how do we find the right patient to be treated? This is where, at least in GI cancers, we’re increasingly looking at MRD, and it’s really quite controversial as to whether this has value or not. The study that you have presented and continue to update around this in GU cancers, to me, is a demonstration of just the value of it. So, maybe drill down a little bit on that study.

Professor Thomas Powles, MBBS, MRCP, MD: So, John, first, before I do, I’d like to agree with you. I think the next generation of oncologists will look at the way we select patients based off lumps on x-rays to define the presence or absence of disease as a long way from reality. Probably in the same way as we currently look at doing surgery without anesthetic—as a similar. You know, how could you treat 70% of patients who have no chance of relapse, giving them a 20% chance of life-changing toxicity, to try and help the 30% with disease. And of course, if you focus on those 30 with disease—if you have a 10% absolute survival benefit, but you're dragging along 70% at no risk—you can actually double or triple that benefit, from a 10% to a 30% survival benefit. So, it’s not just about sparing those patients who don’t need treatment—it’s about improving your hazard ratios, and that’s absolutely crucial. But then, of course, there’s the sensitivity and specificity of the tests you use. Radiology, obviously, are very, very good tests—because if you’ve got big lumps on an x-ray, you know you’ve got cancer there. But of course, postoperatively, treating unselected patients—we are scrambling around in the dark.

We currently hope that a pathology sample defines high- and low-risk disease—not biology. You know, “How big was it?” Which, of course, is completely, in my opinion, hopeless. So, we’re treating those patients who have bigger cancers because we feel they’re at higher risk.

What about if we can develop an MRD test—circulating tumor DNA—using an informed approach where we do whole exome sequencing on the primary tumor, identify up to 16 mutations, and then track those mutations over time? Can we identify those mutations in the blood?

And the answer is: yes, we can.

And what is the positive predictive value and the negative predictive value? It turns out they’re both pretty high in the adjuvant setting in bladder cancer.

Essentially, what I can tell you is that if you do an operation in bladder cancer, about 50% of the patients will relapse after that operation. And about the same proportion of patients are ctDNA positive after surgery. There’s a very strong correlation: if you’re ctDNA positive six weeks post-surgery, you’ve got a 95% chance of relapsing. If you’re ctDNA negative post-surgery, you’ve still got about a 25% chance of relapsing. But you can change that—because if you're negative and you track those patients and they become positive, they do poorly. But if they remain negative, they do really, really well.

So, the chances of dying of urothelial cancer—and this is data from the TOMBOLA trial, and also from other prospective series—if you track those patients who are negative and remain negative, the chance of dying at two years or three years of bladder cancer is minuscule. You know, it’s 3% or 4%. The chance of relapse is still about 5% or 6%, so it’s still there—it’s not perfect in those negative patients—but it’s very good in the positive patients.

What we showed in a study called IMvigor010 is that those patients who had had surgery—successful surgery for urothelial cancer—and there was no evidence of disease on radiology, that 50% who were ctDNA positive, if they received atezolizumab, you could reduce the risk of relapse and the risk of death by about 40%. Hazard ratios between 0.44 and 0.5. But atezolizumab in unselected patients had hazard ratios between 0.8 and 0.9.

So, it's that dilution of those negative patients. Focusing on the positive patients.

In those negative patients, atezolizumab had no benefit. Although many of those patients—30% of those patients who were negative—relapsed, atezolizumab made no difference, because the risk was low.

Now, if you track those patients—and in the upcoming study at ESMO in the near future, we are doing a repeat of the experiment prospectively—if you are negative, we’re continuing to track your negativity. And if you are negative and become positive, you can then enter into the study. We hadn’t done that before, and that’s novel. That will give us the reassurance that we’ve got those negative patients who remain negative—we do well—but those negative patients who become positive—can we salvage those patients?

Also, immune therapy in bladder cancer: there are two important components. One, we know that by the time you’ve got measurable disease, the cancer’s growing too fast. We lose many of those patients. So, we have to go earlier. That’s why we’re doing it in the adjuvant space. Two, it does appear the biology of the disease is potentially more sensitive to immune therapy the earlier you treat these cancers. Put that together, and we’re hoping for great results.

We’ve looked at other settings. We’ve looked at ctDNA in the neoadjuvant space. But that’s more complicated because you can be ctDNA positive because of your primary tumor or your metastatic disease. So, to define that better, we are now looking at urinary tumor DNA.

We’re beginning to get great results for utDNA. So, if you are utDNA positive and ctDNA negative, you might have bladder-only disease. If you're utDNA negative but remain ctDNA positive, you may have had a pathological complete response in your bladder. We know many of those patients relapse—and that means you haven’t gotten rid of that nodal disease, which is still micrometastatic.

So, it’s the first chapter of a series of chapters that I think is going to transform urothelial cancer.

The last part to it, which I think is important, is monitoring those patients. And ctDNA clearance is an early indicator of good drug activity. In the future, we’re going to be using ctDNA and not radiology to assess that clearance. There’s a study called the MODERN trial—Matt Galsky is leading that study. He’s comparing nivolumab to nivolumab plus a LAG-3 inhibitor, to see if ctDNA clearance is higher with the combination.

And I feel this is a revolution that’s going to stand the test of time.

John Marshall, MD: I want to dig down a little bit on the whole biology question, because in GI cancers, we don’t enjoy that sort of transitive result—where something that works in the refractory setting, metastatic disease, will work in the adjuvant setting. And I actually think MRD-positive is its own biology.

From a drug development perspective, one of the things that I’m leading here in the United States is a platform of MRD-positive colon cancers where we can then test for novel therapies. Because I don’t think the old FOLFOX and FOLFIRI are the right answer in that setting.

And I think you feel like—what I’m hearing you say is—that you’re sort of aligned with that. It’s its own unique biology, different from… it’s the difference between seeds and small plants, if you will. There’s a different biology there.

Professor Thomas Powles, MBBS, MRCP, MD: I feel strongly that that’s the case. When you drill down into some of the biology of the 010 paper—and we put that in Nature, not in a clinical journal—and the reason we went there is: we did whole exome sequencing, obviously, because that’s how we track the ctDNA using the informed approach. We also did RNA sequencing—looking at immune signatures—and we did immunohistochemistry. When you pull that together, there was some indication that there were distinct biological features of the ctDNA-positive patients compared to the negative patients. And as you track— which you can do with time—you can obviously see dynamic changes associated with ctDNA and the different mutations.

So, I do think there are different biological components to this disease. I think those patients who are ctDNA positive may not just represent lower or high risk, or disease that’s inevitably going to relapse and just isn’t yet radiologically visible. It may represent its own distinct biology, which I think is worthwhile exploring.

And in terms of coming to your trial—I don’t know enough about GI cancer—but I do feel that exploring beyond these chemotherapy regimens is really attractive. If you want to accurately identify early active signatures, MRD must be the best way of doing that.

I think it’s a really good way—across different tumor groups—of delivering positive trials for interventions which perhaps, by the time you’ve got advanced disease, it’s too late for some patients.

John Marshall, MD: And we are actually thinking even deeper than that—that maybe you begin to have disease-agnostic interventions at MRD. You might see some cross-reactivity there. So, fingers crossed that the setting you have shown, positively—the interventions around this—will trickle out to other diseases.

But I want to go one other place before we let you go. And that is—we come from different cultures. We work in different cultures.

In the United States, people feel like they have the right to whatever it is. So, if there’s an adjuvant therapy, we treat everybody. And we’re incentivized, right, as physicians to treat people—that’s how we make a living around here. Whereas in the rest of the world, this is very expensive therapy, and so we have to demonstrate positive impact.

So on our side, we’re having to show that it’s okay not to give it—that it won’t work. And usually that requires very large studies to show that you’re not even missing one person, right? The breast doctors do thousand-patient studies to show a 1% improvement in whatever intervention they’re doing.

Whereas in our kinds of cancers, we’re looking for anything that’ll help. And our cultures are different. So, talk a little bit—I know you know both cultures, you interact, and this trial is open across the various cultures—where do you see oncology going? The rising costs of drugs, the limited access to these drugs around the world, the role that MRD might play to improve access globally?

Professor Thomas Powles, MBBS, MRCP, MD: What a complicated question—and I’m going to do my best to answer it.

The first thing to say is: I’m a huge fan of the United States of America. I think it’s an aspirational culture. And when one looks around the world—and I travel the world all the time—you look at the ambition and the aspiration, the dynamism in the United States of America, it’s second to none. I’m a great fan, and I spend a lot of time there.

I’m also a fan of the FDA. Given a choice between the FDA and the EMA, I see advantages and differences between both. But I feel the FDA is a more pragmatic organization, and I have to say—I’m a great fan.

In terms of drug development, I think the last 10 or 15 years have been transformative in the cancers that I’ve treated. That wouldn’t have happened with the universities alone. We weren’t making amazing progress, and the incentive to develop multiple targets at the same time and do parallel trials has been successful.

Indeed, many of those trials that weren’t successful—we’ve learned from and moved forward. We wouldn’t have been able to do those thousand-patient trials with just the university structures that are in place. At the moment, you can’t do a study in Europe and the United States—it’s almost impossible together in a university structure. I’m sure you wouldn’t be able to do that in Asia Pacific, Europe…

And the final bit I want to say before I get to the second part is: in the cancers I treat, median survival in urothelial cancer—10 years ago—was one year. It’s now tripled to three years, with a 30% CR rate. That’s going to get even better next year, in my opinion. Kidney cancer—again, 15 years ago: one year. Now: five years.

And that’s not because of radiology. It’s not because of better diagnostics. It’s not because of better surgery. That’s all because of drug development. So, we have to look at that success and celebrate it and say, “Yes, it may have been expensive, and it may be difficult—but what else are we investing in?” We’re investing in—dare I say it—arms, we’re investing in banks, in all sorts. Isn’t it terrific? This is a good investment.

And going back to your former presidents—and of course I’ve studied Jimmy Carter and all the way through—that race against cancer that each of the presidents has tried to achieve: I think we are winning that race. I think that’s very positive.

On the other hand, there is a twofold concern:
The “no stone unturned” approach where I have to have received every drug, that approach is not helping many patients. Indeed, it’s probably harming quite a few. There are two reasons for that: One, there is this difficulty around families and aspirational societies saying, “If it’s there, I have to have it.” And two, my experience of third- or fourth-line bladder cancer—dare I say it, second-line bladder cancer—is that it’s a law of diminishing returns. In the end, it goes wrong for almost everyone. It’s probably doing as much harm as benefit for many of those patients.

You and I have both seen many patients suffering from toxicity toward the end of life, trying to get more and more cycles in. I do think Europe is more pragmatic about that. I do think if your median overall survival is seven months, your response rate is 10%, and it wasn’t significantly better from an OS perspective than placebo, I think Europeans—and the EMA—are much more pragmatic, saying, “We want to see more.” And I think that’s very reasonable.

One caveat: occasionally, those drugs that weren’t great in a second- or third-line setting have turned out to be quite active in combination in the frontline setting. The FDA is good at that. I have examples where we’ve had underwhelming results second or third line, and we moved it to the frontline setting in combination—and we’ve achieved those survival advantages.

So, I think that pragmatic approach is important. But I do not feel that every patient needs every therapy. I don’t think every patient benefits from every therapy.

One of the key questions—when one looks from a European, U.S., and global perspective—is how we assess PFS and OS endpoints. It’s clear to me that in the perioperative setting, we need to achieve OS. That’s my feeling on this. I don’t think disease-free survival as an endpoint is enough.

Two reasons—one, you can give salvage therapy subsequently to those patients that need it. And number two, you are overtreating all those patients who are not going to relapse. So, for me—we need that. I know many of my American colleagues feel DFS is important because that has a higher rate of not achieving advanced disease and avoiding advanced disease as a goal.

I have mixed feelings about that. I think patients want to live longer and feel better. In the perioperative setting, if you don’t have OS, you’re not achieving either of those goals.That’s relevant.

The last bit I’d like to say around that issue—which I think is important—is that MRD has a really important way of achieving OS. You enrich those patients that need therapy. You put some patients in harm’s way, but you do achieve OS. And MRD studies—of course—OS should be the endpoint.

The second part is: you’re sparing big groups of patients therapy who almost certainly don’t need it. Treatment would be overtreatment. Achieving overall survival advantages in that negative subgroup will be almost impossible. And indeed, the risk is low.

So, MRD achieves those goals that I think we are looking for. And I suspect, John, in the future, we won’t be talking about adjuvant therapy in the way we are now. I think we’re going to be talking about patients with MRD or without MRD. And I think, as you’ve said in your study, those patients with MRD—novel trial design to improve survival—in the end, is going to be a really important chapter in where we go next.

John Marshall, MD: I would bet—if I had enough money to throw on the table—that in fact MRD testing will become screening. And maybe in 10, 20 years, you don’t even get your bladder taken out or your colon taken out, but you just get systemic treatment and make the cancer go away before it’s a problem. But you and I can work toward that end and put ourselves out of a job.

Professor Dr. Thomas Powles, thank you so much for spending your valuable time with us. You’re clearly transforming cancer care through incorporation of MRD and innovative clinical trial design and teaching us all about how we’re going to go forward—including about how we’re going to do that as a unified global medical community.

Professor Thomas Powles, MBBS, MRCP, MD: Good pleasure. I really enjoyed it. Thank you very much indeed.

Hosted by Simplecast, an AdsWizz company. See pcm.adswizz.com for information about our collection and use of personal data for advertising.

[00:00:05] MedBuzz: Back to Being ‘Just a Doctor’

John Marshall, MD: John Marshall for Oncology Unscripted, coming to you live from this big office. This is the biggest office because, you know, I've been the Chief of the Division here at Georgetown for 20 years. I didn't want the job when I was first offered it a long time ago. I ended up saying yes. Of course, that's a dramatic change in one's academic career—taking on administrative roles like this. You do get the big office, which is nice, but you also get a lot of other stuff. You know too much. You know who's mad at whom, you know who you need to recruit, and who you need to un-recruit—all of those things. You have the business side of a cancer business going on, and you're a doctor, and you're doing clinical research, and you're trying to educate everybody around you.

About a year or so ago, I decided in my own head that 20 years is enough. And so, as of this summer, I have officially stepped down as the Chief of the Division here at Georgetown. My colleague and much smarter friend, Dr. Steven Liu—lung cancer expert, world expert—is stepping in to be the Chief of our Division, and he's already hit the ground running. The fresh voice is honestly already a positive. You can just hear the freshness of his voice and his attitude and his energy. 

You know, the Mayo Clinic actually has a structure where you can only be in a leadership position for so many years, and it has to turn over. And I really like that. It's sort of like what we hope our presidential terms will be. But who knows—that may change. But there's a limit: you do the job for a certain period of time, and then someone else steps in and gives you that fresh voice and fresh perspective. But that's not the traditional way of doing it. Most of the time, people hold on to their position as long as they can hold on to it, until they can't do it anymore or they decide to go to some other institution.

But the reason I'm sharing this is that I'm now in this sort of weird new place. I'm an ordinary staff physician. All of a sudden—yep. I have my patients, I'm doing my thing, I'm putting people on clinical trials, I'm educating the brand-new fellows who just showed up here about a month ago. Great fun having brand-new fellows 'cause they don't even know how to spell 5-FU, much less how well it works, how it works, and the side effects, etc. So, I love the first few months 'cause you're teaching people a lot of new things that they need to know. But anyway, that part's very exciting. So, I'm still doing all of that.

But what I'm gonna have to get used to is not knowing everything—also not feeling responsible for everything. And that's gonna be a change for me. So, any of you out there who've either been through that transition or who maybe wanna offer me some therapy—I'm in line for some therapy as I transition, as I begin to slow down my academic career, withdrawing as the Chief of the Division, but still doing my day-to-day job and still trying to cure cancer.

Take care of each other out there. Take care of your bosses and those leaders. It's not a great, fun job. But also, remember: those of us who are now back in the trenches—we need to take care of each other as well. John Marshall for Oncology Unscripted.

[00:03:35] Editorial: Watching Vaccine Access Collapse In Real Time

John Marshall, MD: John Marshall Oncology Unscripted. First piece of advice: don’t read the newspaper. Second piece of advice: don’t watch C-SPAN, for sure. Just yesterday on C-SPAN was the big congressional hearings. I did read the summary of it in The Washington Post, where RFK Jr. was interviewed—cross-examined for three hours by both sides of the aisle—about what he has been doing with the CDC. And I think we all, as medical professionals, need to take a big step back and a pause and sort of ask: what the hell is going on?

You know, the specifics first. He fired everybody at the CDC. He has hired new people at the CDC. They have not come forward with any formal vaccine recommendations. This is all about vaccines and the like.

Yesterday in clinic, a patient of mine—who would be a candidate for both flu and COVID vaccines, who could have, a month ago, walked into CVS and gotten both of those injections—now, in the state of Virginia (and I think there are about 14 other states where this is true), has to have a prescription. This came out from CVS and Walgreens—that you have to write a prescription. Physicians have to write a prescription so that patients can take it to the CVS and Walgreens to get their vaccines. Some states are not providing them at all. Some states have gone the other way, where they’ve formed collaborations—and this is those cool West Coast states: Washington, Oregon, Hawaii, California. They’ve formed a consortium to say, “We are gonna set our own policy,” because the government’s policy right now is up in the air about whether you can get access to them, whether we should be providing them. How do you get access to them? And so we’re all up in the air about what's going to happen.

And then, of course, our brilliant RFK Jr.—who, by the way, doesn’t live very far from where I’m sitting right now. There was one day I was walking through Georgetown and crossed paths with him. I was like, “Ugh.” But anyway, he doesn’t live very far from here. But he’s saying that we should kind of get rid of vaccines in general—not just COVID vaccines, but vaccines in general.

And so there is, coming out from the ACIP, a set of recommendations. And a lot of states—and I live in one, Virginia, which is over that direction—had agreed from the beginning (and I think there are seven—I don’t know, a bunch of states) that they will follow whatever the law is, they will follow whatever the ACIP says. But that was before we got this new group of people who’ve stepped in to oversee this. And so it may be that it undoes things, and we’re gonna need to put new laws in place.

We just can’t have this discussion about CDC and vaccines without saying the word “Florida.” So, Florida has a Surgeon General named Joseph Ladapo. And Joseph Ladapo is a physician—MD, PhD, incredibly well-trained. He is a professor at the University of Florida. He trained at Harvard and other really good places, and he is all about public health. That’s his thing—more on the cardiovascular side of things. But during the pandemic, he was an anti-vaxxer then. And now, of course, you all know that Florida is trying to put forward where children no longer have a vaccine requirement to go to school, etc.—that they can undo that. And these are recommendations and laws that have been in place for over 100 years. And he says, “Nope, we’re not gonna do it anymore.”

You know, my mother had polio, for goodness’ sakes. Do we want to go back to that sort of world where children are going to be getting these infections that we had solved—pretty much solved—in the past? And so, you know, we’re joking about, you know, who’s gonna want to go to Disney World. Take your children to Disney World if everybody there is unvaccinated. Maybe it’s the alternative. Maybe that’s the place to go get exposed—like you remember when we were kids? We used to be told to go over and play with the kid who has chickenpox so that we would all get chickenpox. Well, maybe we’ll all just go to Florida so we all get measles, mumps, rubella, and polio—and other things like that.

So, who knows how this well-trained person has got it in his mind that this RFK Jr. sort of “vaccines are evil” is part of his mantra, and he’s applying this across the state of Florida.

So, I am so anxious about this because I think the next step is access to medical care in general. Right? We know that there are major cuts to Medicaid about to happen—influencing the shutting down of hospitals. Even in the state of Virginia, if we apply the current Medicaid cut recommendations that the new big bill signed, seven rural hospitals will have to close. Those people will not have access to hospitals in their area. Right? Also talking about reducing Medicare support. So, okay, fine—we're gonna reduce the amount of healthcare that’s available to people out there.

But what about medicines? What’s lifesaving, and what is a hoax that causes autism? Right now, the CDC and RFK think that vaccines are a hoax that cause autism. Okay, what about immunotherapy for MSI-high patients, right? Is that a hoax, or is that amazing, life-saving therapy? And so we’re splicing and dicing all of these things to the point where we’re not gonna have access to things that we know help broad populations avoid bad infections and death.

When is that gonna start to trickle down to other healthcare access, and who’s going to be making those decisions?

I think about the HPV vaccine. Right? This is available to both boys and girls. We think—we’re pretty sure—that if everybody were to get this, cervical cancer, head and neck cancers, and others would diminish dramatically because so many of them are caused by HPV infections. Are we gonna do away with those? That’s, in essence, a cancer vaccine—a prevention-of-cancer vaccine. Is that next on the chopping block? So that now our incredible discoveries of the linkage between HPV and cancer are undone—because we can’t prevent it anymore?

So, I am very unsettled. The people around us in healthcare are very unsettled. Pharmaceutical industry is very unsettled. Healthcare providers—small hospitals, rural hospitals—are very unsettled. Yet we are being led by people who do not represent the population, who do not represent the 80–90% majority of parents that want their children to have vaccines. What these people are representing are the 5–10% of people who are convinced that vaccines don’t do anything and are crazy to give.

And so we need to figure out how to push back, how to represent the majority against these people—to stand up against these people. Both sides of the aisle are uncomfortable about this. And my fingers are crossed that if enough of us get out and scream, if enough of us go up and hold a sign over a bridge or out on a walk somewhere, that enough people will hear—and we will rise up and take back our healthcare, take back our successes so that we can at least not step backwards. More people dying. More people suffering—when we’d already figured out how to prevent it.

I am hopeful, hopeful, hopeful that the months ahead will be better than the last eight months.

John Marshall for Oncology Unscripted.

[00:13:02] Main Topic: Running Into Risk: Colon Cancer and Marathon Runners

[00:00:05] MedBuzz: Back to Being ‘Just a Doctor’

John Marshall, MD: John Marshall for Oncology Unscripted, coming to you live from this big office. This is the biggest office because, you know, I've been the Chief of the Division here at Georgetown for 20 years. I didn't want the job when I was first offered it a long time ago. I ended up saying yes. Of course, that's a dramatic change in one's academic career—taking on administrative roles like this. You do get the big office, which is nice, but you also get a lot of other stuff. You know too much. You know who's mad at whom, you know who you need to recruit, and who you need to un-recruit—all of those things. You have the business side of a cancer business going on, and you're a doctor, and you're doing clinical research, and you're trying to educate everybody around you. 

About a year or so ago, I decided in my own head that 20 years is enough. And so, as of this summer, I have officially stepped down as the Chief of the Division here at Georgetown. My colleague and much smarter friend, Dr. Steven Liu—lung cancer expert, world expert—is stepping in to be the Chief of our Division, and he's already hit the ground running. The fresh voice is honestly already a positive. You can just hear the freshness of his voice and his attitude and his energy. 

You know, the Mayo Clinic actually has a structure where you can only be in a leadership position for so many years, and it has to turn over. And I really like that. It's sort of like what we hope our presidential terms will be. But who knows—that may change. But there's a limit: you do the job for a certain period of time, and then someone else steps in and gives you that fresh voice and fresh perspective. But that's not the traditional way of doing it. Most of the time, people hold on to their position as long as they can hold on to it, until they can't do it anymore or they decide to go to some other institution.

But the reason I'm sharing this is that I'm now in this sort of weird new place. I'm an ordinary staff physician. All of a sudden—yep. I have my patients, I'm doing my thing, I'm putting people on clinical trials, I'm educating the brand-new fellows who just showed up here about a month ago. Great fun having brand-new fellows 'cause they don't even know how to spell 5-FU, much less how well it works, how it works, and the side effects, etc. So, I love the first few months 'cause you're teaching people a lot of new things that they need to know. But anyway, that part's very exciting. So, I'm still doing all of that.

But what I'm gonna have to get used to is not knowing everything—also not feeling responsible for everything. And that's gonna be a change for me. So, any of you out there who've either been through that transition or who maybe wanna offer me some therapy—I'm in line for some therapy as I transition, as I begin to slow down my academic career, withdrawing as the Chief of the Division, but still doing my day-to-day job and still trying to cure cancer.

Take care of each other out there. Take care of your bosses and those leaders. It's not a great, fun job. But also, remember: those of us who are now back in the trenches—we need to take care of each other as well. John Marshall for Oncology Unscripted.

[00:03:35] Editorial: Watching Vaccine Access Collapse In Real Time

John Marshall, MD: John Marshall Oncology Unscripted. First piece of advice: don’t read the newspaper. Second piece of advice: don’t watch C-SPAN, for sure. Just yesterday on C-SPAN was the big congressional hearings. I did read the summary of it in The Washington Post, where RFK Jr. was interviewed—cross-examined for three hours by both sides of the aisle—about what he has been doing with the CDC. And I think we all, as medical professionals, need to take a big step back and a pause and sort of ask: what the hell is going on?

You know, the specifics first. He fired everybody at the CDC. He has hired new people at the CDC. They have not come forward with any formal vaccine recommendations. This is all about vaccines and the like. 

Yesterday in clinic, a patient of mine—who would be a candidate for both flu and COVID vaccines, who could have, a month ago, walked into CVS and gotten both of those injections—now, in the state of Virginia (and I think there are about 14 other states where this is true), has to have a prescription. This came out from CVS and Walgreens—that you have to write a prescription. Physicians have to write a prescription so that patients can take it to the CVS and Walgreens to get their vaccines. Some states are not providing them at all. Some states have gone the other way, where they’ve formed collaborations—and this is those cool West Coast states: Washington, Oregon, Hawaii, California. They’ve formed a consortium to say, “We are gonna set our own policy,” because the government’s policy right now is up in the air about whether you can get access to them, whether we should be providing them. How do you get access to them? And so we’re all up in the air about what's going to happen.

And then, of course, our brilliant RFK Jr.—who, by the way, doesn’t live very far from where I’m sitting right now. There was one day I was walking through Georgetown and crossed paths with him. I was like, “Ugh.” But anyway, he doesn’t live very far from here. But he’s saying that we should kind of get rid of vaccines in general—not just COVID vaccines, but vaccines in general.

And so there is, coming out from the ACIP, a set of recommendations. And a lot of states—and I live in one, Virginia, which is over that direction—had agreed from the beginning (and I think there are seven—I don’t know, a bunch of states) that they will follow whatever the law is, they will follow whatever the ACIP says. But that was before we got this new group of people who’ve stepped in to oversee this. And so it may be that it undoes things, and we’re gonna need to put new laws in place.

We just can’t have this discussion about CDC and vaccines without saying the word “Florida.” So, Florida has a Surgeon General named Joseph Ladapo. And Joseph Ladapo is a physician—MD, PhD, incredibly well-trained. He is a professor at the University of Florida. He trained at Harvard and other really good places, and he is all about public health. That’s his thing—more on the cardiovascular side of things. But during the pandemic, he was an anti-vaxxer then. And now, of course, you all know that Florida is trying to put forward where children no longer have a vaccine requirement to go to school, etc.—that they can undo that. And these are recommendations and laws that have been in place for over 100 years. And he says, “Nope, we’re not gonna do it anymore.”

You know, my mother had polio, for goodness’ sakes. Do we want to go back to that sort of world where children are going to be getting these infections that we had solved—pretty much solved—in the past? And so, you know, we’re joking about, you know, who’s gonna want to go to Disney World. Take your children to Disney World if everybody there is unvaccinated. Maybe it’s the alternative. Maybe that’s the place to go get exposed—like you remember when we were kids? We used to be told to go over and play with the kid who has chickenpox so that we would all get chickenpox. Well, maybe we’ll all just go to Florida so we all get measles, mumps, rubella, and polio—and other things like that.

So, who knows how this well-trained person has got it in his mind that this RFK Jr. sort of “vaccines are evil” is part of his mantra, and he’s applying this across the state of Florida.

So, I am so anxious about this because I think the next step is access to medical care in general. Right? We know that there are major cuts to Medicaid about to happen—influencing the shutting down of hospitals. Even in the state of Virginia, if we apply the current Medicaid cut recommendations that the new big bill signed, seven rural hospitals will have to close. Those people will not have access to hospitals in their area. Right? Also talking about reducing Medicare support. So, okay, fine—we're gonna reduce the amount of healthcare that’s available to people out there.

But what about medicines? What’s lifesaving, and what is a hoax that causes autism? Right now, the CDC and RFK think that vaccines are a hoax that cause autism. Okay, what about immunotherapy for MSI-high patients, right? Is that a hoax, or is that amazing, life-saving therapy? And so we’re splicing and dicing all of these things to the point where we’re not gonna have access to things that we know help broad populations avoid bad infections and death.

When is that gonna start to trickle down to other healthcare access, and who’s going to be making those decisions?

I think about the HPV vaccine. Right? This is available to both boys and girls. We think—we’re pretty sure—that if everybody were to get this, cervical cancer, head and neck cancers, and others would diminish dramatically because so many of them are caused by HPV infections. Are we gonna do away with those? That’s, in essence, a cancer vaccine—a prevention-of-cancer vaccine. Is that next on the chopping block? So that now our incredible discoveries of the linkage between HPV and cancer are undone—because we can’t prevent it anymore?

So, I am very unsettled. The people around us in healthcare are very unsettled. Pharmaceutical industry is very unsettled. Healthcare providers—small hospitals, rural hospitals—are very unsettled. Yet we are being led by people who do not represent the population, who do not represent the 80–90% majority of parents that want their children to have vaccines. What these people are representing are the 5–10% of people who are convinced that vaccines don’t do anything and are crazy to give.

And so we need to figure out how to push back, how to represent the majority against these people—to stand up against these people. Both sides of the aisle are uncomfortable about this. And my fingers are crossed that if enough of us get out and scream, if enough of us go up and hold a sign over a bridge or out on a walk somewhere, that enough people will hear—and we will rise up and take back our healthcare, take back our successes so that we can at least not step backwards. More people dying. More people suffering—when we’d already figured out how to prevent it.

I am hopeful, hopeful, hopeful that the months ahead will be better than the last eight months.

John Marshall for Oncology Unscripted.

[00:13:02] Main Topic: Running Into Risk: Colon Cancer and Marathon Runners

John Marshall, MD: We have been preaching on Oncology Unscripted about the very cool new data showing that if you had a personal trainer, you had an improvement in survival in colon cancer compared to if you were just told to go exercise. Right? What an amazing abstract that was presented at ASCO this year. And so we're all wondering whether Blue Cross Blue Shield should go out there and start covering personal trainers. And maybe the answer is yes.

But follow-up data on that says—and these are things we all knew before—is that too much of a good thing can be bad. A very good friend of mine and colleague of ours, Tim Cannon, here in the Northern Virginia area, actually has been doing a study that made the big time—New York Times published work that they had been doing—showing that marathoners and ultramarathoners actually had an increased risk of colon cancer. So yeah—personal trainer a few times a week, improving your cure rate. Whereas if you go too much, you strain the body. Maybe it’s an alteration in diet, maybe it’s microbiome—we’ll talk about it. You actually can make things worse.

So, I want you to listen in to our interview together. Dr. Tim Cannon and I discuss this way cool science, with an idea of trying to figure out what the heck’s going on.

Join us for Oncology Unscripted.

[00:14:38] Interview: Running Into Risk—My Interview with Dr Timothy Cannon

John Marshall, MD: Hey, everybody out there—John Marshall for Oncology Unscripted. You're frittering away more of your time, but we've got something that is clearly worth your effort. You know what? I have run, myself, three half marathons. I hated every one of them. I did it 'cause I thought I was supposed to. I trained up for it—it took a whole season to train up for it. I didn’t hurt anything too bad, which is good. I wasn’t fast—let’s be clear. I was always glad to not be doing the other half of the marathon.

So why do you care about this? Well, there's been new evidence—it’s been building over time—and it's been really led by and championed by a very good friend and colleague of mine, Dr. Tim Cannon, where too much exercise—or too much strain on the body, maybe we should rephrase that—might, in fact, be bad for us, specifically around colorectal cancer. We already know the data—'cause we've talked about it—around a personal trainer improving your survival if you had colon cancer. But what about joining an ultramarathon team?

Dr. Tim Cannon has something to say about that. Tim, introduce yourself and tell the gang your science.

Timothy Cannon, MD: Sure. So, I'm Tim Cannon. Thank you so much for having me, John. This is a study that you cite, that we've just done in the DC area, on ultramarathoners. And I had seen, in the course of about a year, three different ultramarathoners—actually, two were ultramarathoners, one was a triathlete. They had both done dozens of those types of races. And they had stage IV cancer in their 30s.

And I thought, you know, there may be a connection here. They were all describing bleeding after they run. I had heard a lot about runner's trots, or bleeding when you run long distances. And I can see how there could be a mechanism—that this could cause cancer if you run so much that you're having repeated insults to your colon, and bleeding.

And so, we decided to start a study. We opened our Cancer Prevention Center here, and that's what we're here to talk about today. I'm really glad that you had an interest in this.

The study was of 100 long-distance runners. I would call them all extreme. They had all run at least five 26.2-mile marathons. Most of them had run ultramarathons. Many of them had run 100-mile ultramarathons. They had to be between the ages of 35 and 50, not have a known familial syndrome, and not have inflammatory bowel disease. And we screened them to see if they had precancerous polyps.

John Marshall, MD: And, as you found—they did. And some of them had an increased risk for cancer. So, fascinating work. When people were doing what they thought was gonna keep them outta trouble, they might've been getting themselves into trouble.

And I know you, you and I and others have had discussions about the “why” of this. And you just described sort of a trauma. I was always thinking like watershed—not enough blood flow, maybe hypoxia. There's also the other side that I’m, you know, obsessed with—and that's microbiome. These ultramarathoners eat all sorts of funky stuff. They do these protein gels, and they do all sorts of things that are not your classic Mediterranean diet.

If you had to put your quarter down, what do you think's the reason for it?

Timothy Cannon, MD: Yeah, and we haven’t proven anything quite yet. But I'm believing more and more that there is a connection here. And like you, I thought the watershed idea made the most sense to me initially.

Since this came out, everyone is emailing me with their own ideas about it. And some of them are pretty compelling. Microbiome, I think, may be among the most compelling. You know, I've been reading about differences in abundance in people who do endurance sports. There’s a bacteria called prevotella, for instance, that's more abundant in runners—and it may be related.

Sure, there's so much we don't know about this, but that's what we're hoping to explore in part two—analyzing the microbiome. And then, of course, there’s the lifestyle. Things that characterize long-distance runners—the goos, the... you know, I’ve worried about everything. They drink a lot of electrolyte drinks out of bottles, and maybe they have high exposure to BPA. Or maybe it’s the high-protein diet that was highlighted this week in The New York Times. Who knows? It could be any of these exposures that could cause it. It’s hard to know, hard to study. To isolate any one of these variables is tricky. But I think it’s important to try to get to the bottom of it.

John Marshall, MD: We're into prevention, right? We tell people not to smoke. We tell people to eat right. Should there be some sort of sign at the beginning of a marathon that says, “You're running at your own risk”?

Timothy Cannon, MD: Yeah, like the Surgeon General’s warning. I'm not sure we know enough quite to recommend that yet. And of course, I want to emphasize what you did first at the beginning here: that exercise is—by and large—going to be a good thing. We’ll have much bigger problems from there not being enough exercise. And I think we know fairly definitively that exercise reduces the risk of cancer recurrence. So, I want to emphasize that from the beginning.

But the question is whether there’s a dose of exercise that is too much. I believe there is. I’d like to get more evidence before we start putting signs on marathons or discouraging people too much. But I could see a future where there is something like that out there.

John Marshall, MD: Breakthrough work, in my opinion. Dr. Tim Cannon, thank you so much for, I’m sure, taking time out—when you're in The New York Times, you're much needed on the interview circuit. So, it's a real honor that you’ve taken some time to talk with us and our audience. Dr. Tim Cannon—

Timothy Cannon, MD: No way. This one means the most to me, John. Thank you.

John Marshall, MD: I love being lied to on a Wednesday. Hang in there everybody, and we'll see you next time on Oncology Unscripted.

This transcript has been edited for clarity. We have been preaching on Oncology Unscripted about the very cool new data showing that if you had a personal trainer, you had an improvement in survival in colon cancer compared to if you were just told to go exercise. Right? What an amazing abstract that was presented at ASCO this year. And so we're all wondering whether Blue Cross Blue Shield should go out there and start covering personal trainers. And maybe the answer is yes.

But follow-up data on that says—and these are things we all knew before—is that too much of a good thing can be bad. A very good friend of mine and colleague of ours, Tim Cannon, here in the Northern Virginia area, actually has been doing a study that made the big time—New York Times published work that they had been doing—showing that marathoners and ultramarathoners actually had an increased risk of colon cancer. So yeah—personal trainer a few times a week, improving your cure rate. Whereas if you go too much, you strain the body. Maybe it’s an alteration in diet, maybe it’s microbiome—we’ll talk about it. You actually can make things worse.

So, I want you to listen in to our interview together. Dr. Tim Cannon and I discuss this way cool science, with an idea of trying to figure out what the heck’s going on.

Join us for Oncology Unscripted.

[00:14:38] Interview: Running Into Risk—My Interview with Dr Timothy Cannon

John Marshall, MD: Hey, everybody out there—John Marshall for Oncology Unscripted. You're frittering away more of your time, but we've got something that is clearly worth your effort. You know what? I have run, myself, three half marathons. I hated every one of them. I did it 'cause I thought I was supposed to. I trained up for it—it took a whole season to train up for it. I didn’t hurt anything too bad, which is good. I wasn’t fast—let’s be clear. I was always glad to not be doing the other half of the marathon.

So why do you care about this? Well, there's been new evidence—it’s been building over time—and it's been really led by and championed by a very good friend and colleague of mine, Dr. Tim Cannon, where too much exercise—or too much strain on the body, maybe we should rephrase that—might, in fact, be bad for us, specifically around colorectal cancer. We already know the data—'cause we've talked about it—around a personal trainer improving your survival if you had colon cancer. But what about joining an ultramarathon team?

Dr. Tim Cannon has something to say about that. Tim, introduce yourself and tell the gang your science.

Timothy Cannon, MD: Sure. So, I'm Tim Cannon. Thank you so much for having me, John. This is a study that you cite, that we've just done in the DC area, on ultramarathoners. And I had seen, in the course of about a year, three different ultramarathoners—actually, two were ultramarathoners, one was a triathlete. They had both done dozens of those types of races. And they had stage IV cancer in their 30s.

And I thought, you know, there may be a connection here. They were all describing bleeding after they run. I had heard a lot about runner's trots, or bleeding when you run long distances. And I can see how there could be a mechanism—that this could cause cancer if you run so much that you're having repeated insults to your colon, and bleeding.

And so, we decided to start a study. We opened our Cancer Prevention Center here, and that's what we're here to talk about today. I'm really glad that you had an interest in this.

The study was of 100 long-distance runners. I would call them all extreme. They had all run at least five 26.2-mile marathons. Most of them had run ultramarathons. Many of them had run 100-mile ultramarathons. They had to be between the ages of 35 and 50, not have a known familial syndrome, and not have inflammatory bowel disease. And we screened them to see if they had precancerous polyps.

John Marshall, MD: And, as you found—they did. And some of them had an increased risk for cancer. So, fascinating work. When people were doing what they thought was gonna keep them outta trouble, they might've been getting themselves into trouble.

And I know you, you and I and others have had discussions about the “why” of this. And you just described sort of a trauma. I was always thinking like watershed—not enough blood flow, maybe hypoxia. There's also the other side that I’m, you know, obsessed with—and that's microbiome. These ultramarathoners eat all sorts of funky stuff. They do these protein gels, and they do all sorts of things that are not your classic Mediterranean diet.

If you had to put your quarter down, what do you think's the reason for it?

Timothy Cannon, MD: Yeah, and we haven’t proven anything quite yet. But I'm believing more and more that there is a connection here. And like you, I thought the watershed idea made the most sense to me initially.

Since this came out, everyone is emailing me with their own ideas about it. And some of them are pretty compelling. Microbiome, I think, may be among the most compelling. You know, I've been reading about differences in abundance in people who do endurance sports. There’s a bacteria called prevotella, for instance, that's more abundant in runners—and it may be related.

Sure, there's so much we don't know about this, but that's what we're hoping to explore in part two—analyzing the microbiome. And then, of course, there’s the lifestyle. Things that characterize long-distance runners—the goos, the... you know, I’ve worried about everything. They drink a lot of electrolyte drinks out of bottles, and maybe they have high exposure to BPA. Or maybe it’s the high-protein diet that was highlighted this week in The New York Times. Who knows? It could be any of these exposures that could cause it. It’s hard to know, hard to study. To isolate any one of these variables is tricky. But I think it’s important to try to get to the bottom of it.

John Marshall, MD: We're into prevention, right? We tell people not to smoke. We tell people to eat right. Should there be some sort of sign at the beginning of a marathon that says, “You're running at your own risk”?

Timothy Cannon, MD: Yeah, like the Surgeon General’s warning. I'm not sure we know enough quite to recommend that yet. And of course, I want to emphasize what you did first at the beginning here: that exercise is—by and large—going to be a good thing. We’ll have much bigger problems from there not being enough exercise. And I think we know fairly definitively that exercise reduces the risk of cancer recurrence. So, I want to emphasize that from the beginning.

But the question is whether there’s a dose of exercise that is too much. I believe there is. I’d like to get more evidence before we start putting signs on marathons or discouraging people too much. But I could see a future where there is something like that out there.

John Marshall, MD: Breakthrough work, in my opinion. Dr. Tim Cannon, thank you so much for, I’m sure, taking time out—when you're in The New York Times, you're much needed on the interview circuit. So, it's a real honor that you’ve taken some time to talk with us and our audience. Dr. Tim Cannon—

Timothy Cannon, MD: No way. This one means the most to me, John. Thank you.

John Marshall, MD: I love being lied to on a Wednesday. Hang in there everybody, and we'll see you next time on Oncology Unscripted.

This transcript has been edited for clarity.[00:00:05] MedBuzz: Back to Being ‘Just a Doctor’

John Marshall, MD: John Marshall for Oncology Unscripted, coming to you live from this big office. This is the biggest office because, you know, I've been the Chief of the Division here at Georgetown for 20 years. I didn't want the job when I was first offered it a long time ago. I ended up saying yes. Of course, that's a dramatic change in one's academic career—taking on administrative roles like this. You do get the big office, which is nice, but you also get a lot of other stuff. You know too much. You know who's mad at whom, you know who you need to recruit, and who you need to un-recruit—all of those things. You have the business side of a cancer business going on, and you're a doctor, and you're doing clinical research, and you're trying to educate everybody around you.

About a year or so ago, I decided in my own head that 20 years is enough. And so, as of this summer, I have officially stepped down as the Chief of the Division here at Georgetown. My colleague and much smarter friend, Dr. Steven Liu—lung cancer expert, world expert—is stepping in to be the Chief of our Division, and he's already hit the ground running. The fresh voice is honestly already a positive. You can just hear the freshness of his voice and his attitude and his energy.

You know, the Mayo Clinic actually has a structure where you can only be in a leadership position for so many years, and it has to turn over. And I really like that. It's sort of like what we hope our presidential terms will be. But who knows—that may change. But there's a limit: you do the job for a certain period of time, and then someone else steps in and gives you that fresh voice and fresh perspective. But that's not the traditional way of doing it. Most of the time, people hold on to their position as long as they can hold on to it, until they can't do it anymore or they decide to go to some other institution.

But the reason I'm sharing this is that I'm now in this sort of weird new place. I'm an ordinary staff physician. All of a sudden—yep. I have my patients, I'm doing my thing, I'm putting people on clinical trials, I'm educating the brand-new fellows who just showed up here about a month ago. Great fun having brand-new fellows 'cause they don't even know how to spell 5-FU, much less how well it works, how it works, and the side effects, etc. So, I love the first few months 'cause you're teaching people a lot of new things that they need to know. But anyway, that part's very exciting. So, I'm still doing all of that.

But what I'm gonna have to get used to is not knowing everything—also not feeling responsible for everything. And that's gonna be a change for me. So, any of you out there who've either been through that transition or who maybe wanna offer me some therapy—I'm in line for some therapy as I transition, as I begin to slow down my academic career, withdrawing as the Chief of the Division, but still doing my day-to-day job and still trying to cure cancer.

Take care of each other out there. Take care of your bosses and those leaders. It's not a great, fun job. But also, remember: those of us who are now back in the trenches—we need to take care of each other as well. John Marshall for Oncology Unscripted.

[00:03:35] Editorial: Watching Vaccine Access Collapse In Real Time

John Marshall, MD: John Marshall Oncology Unscripted. First piece of advice: don’t read the newspaper. Second piece of advice: don’t watch C-SPAN, for sure. Just yesterday on C-SPAN was the big congressional hearings. I did read the summary of it in The Washington Post, where RFK Jr. was interviewed—cross-examined for three hours by both sides of the aisle—about what he has been doing with the CDC. And I think we all, as medical professionals, need to take a big step back and a pause and sort of ask: what the hell is going on?

You know, the specifics first. He fired everybody at the CDC. He has hired new people at the CDC. They have not come forward with any formal vaccine recommendations. This is all about vaccines and the like.

Yesterday in clinic, a patient of mine—who would be a candidate for both flu and COVID vaccines, who could have, a month ago, walked into CVS and gotten both of those injections—now, in the state of Virginia (and I think there are about 14 other states where this is true), has to have a prescription. This came out from CVS and Walgreens—that you have to write a prescription. Physicians have to write a prescription so that patients can take it to the CVS and Walgreens to get their vaccines. Some states are not providing them at all. Some states have gone the other way, where they’ve formed collaborations—and this is those cool West Coast states: Washington, Oregon, Hawaii, California. They’ve formed a consortium to say, “We are gonna set our own policy,” because the government’s policy right now is up in the air about whether you can get access to them, whether we should be providing them. How do you get access to them? And so we’re all up in the air about what's going to happen.

And then, of course, our brilliant RFK Jr.—who, by the way, doesn’t live very far from where I’m sitting right now. There was one day I was walking through Georgetown and crossed paths with him. I was like, “Ugh.” But anyway, he doesn’t live very far from here. But he’s saying that we should kind of get rid of vaccines in general—not just COVID vaccines, but vaccines in general.

And so there is, coming out from the ACIP, a set of recommendations. And a lot of states—and I live in one, Virginia, which is over that direction—had agreed from the beginning (and I think there are seven—I don’t know, a bunch of states) that they will follow whatever the law is, they will follow whatever the ACIP says. But that was before we got this new group of people who’ve stepped in to oversee this. And so it may be that it undoes things, and we’re gonna need to put new laws in place.

We just can’t have this discussion about CDC and vaccines without saying the word “Florida.” So, Florida has a Surgeon General named Joseph Ladapo. And Joseph Ladapo is a physician—MD, PhD, incredibly well-trained. He is a professor at the University of Florida. He trained at Harvard and other really good places, and he is all about public health. That’s his thing—more on the cardiovascular side of things. But during the pandemic, he was an anti-vaxxer then. And now, of course, you all know that Florida is trying to put forward where children no longer have a vaccine requirement to go to school, etc.—that they can undo that. And these are recommendations and laws that have been in place for over 100 years. And he says, “Nope, we’re not gonna do it anymore.”

You know, my mother had polio, for goodness’ sakes. Do we want to go back to that sort of world where children are going to be getting these infections that we had solved—pretty much solved—in the past? And so, you know, we’re joking about, you know, who’s gonna want to go to Disney World. Take your children to Disney World if everybody there is unvaccinated. Maybe it’s the alternative. Maybe that’s the place to go get exposed—like you remember when we were kids? We used to be told to go over and play with the kid who has chickenpox so that we would all get chickenpox. Well, maybe we’ll all just go to Florida so we all get measles, mumps, rubella, and polio—and other things like that.

So, who knows how this well-trained person has got it in his mind that this RFK Jr. sort of “vaccines are evil” is part of his mantra, and he’s applying this across the state of Florida.

So, I am so anxious about this because I think the next step is access to medical care in general. Right? We know that there are major cuts to Medicaid about to happen—influencing the shutting down of hospitals. Even in the state of Virginia, if we apply the current Medicaid cut recommendations that the new big bill signed, seven rural hospitals will have to close. Those people will not have access to hospitals in their area. Right? Also talking about reducing Medicare support. So, okay, fine—we're gonna reduce the amount of healthcare that’s available to people out there.

But what about medicines? What’s lifesaving, and what is a hoax that causes autism? Right now, the CDC and RFK think that vaccines are a hoax that cause autism. Okay, what about immunotherapy for MSI-high patients, right? Is that a hoax, or is that amazing, life-saving therapy? And so we’re splicing and dicing all of these things to the point where we’re not gonna have access to things that we know help broad populations avoid bad infections and death.

When is that gonna start to trickle down to other healthcare access, and who’s going to be making those decisions?

I think about the HPV vaccine. Right? This is available to both boys and girls. We think—we’re pretty sure—that if everybody were to get this, cervical cancer, head and neck cancers, and others would diminish dramatically because so many of them are caused by HPV infections. Are we gonna do away with those? That’s, in essence, a cancer vaccine—a prevention-of-cancer vaccine. Is that next on the chopping block? So that now our incredible discoveries of the linkage between HPV and cancer are undone—because we can’t prevent it anymore?

So, I am very unsettled. The people around us in healthcare are very unsettled. Pharmaceutical industry is very unsettled. Healthcare providers—small hospitals, rural hospitals—are very unsettled. Yet we are being led by people who do not represent the population, who do not represent the 80–90% majority of parents that want their children to have vaccines. What these people are representing are the 5–10% of people who are convinced that vaccines don’t do anything and are crazy to give.

And so we need to figure out how to push back, how to represent the majority against these people—to stand up against these people. Both sides of the aisle are uncomfortable about this. And my fingers are crossed that if enough of us get out and scream, if enough of us go up and hold a sign over a bridge or out on a walk somewhere, that enough people will hear—and we will rise up and take back our healthcare, take back our successes so that we can at least not step backwards. More people dying. More people suffering—when we’d already figured out how to prevent it.

I am hopeful, hopeful, hopeful that the months ahead will be better than the last eight months.

John Marshall for Oncology Unscripted.

[00:13:02] Main Topic: Running Into Risk: Colon Cancer and Marathon Runners

John Marshall, MD: We have been preaching on Oncology Unscripted about the very cool new data showing that if you had a personal trainer, you had an improvement in survival in colon cancer compared to if you were just told to go exercise. Right? What an amazing abstract that was presented at ASCO this year. And so we're all wondering whether Blue Cross Blue Shield should go out there and start covering personal trainers. And maybe the answer is yes.

But follow-up data on that says—and these are things we all knew before—is that too much of a good thing can be bad. A very good friend of mine and colleague of ours, Tim Cannon, here in the Northern Virginia area, actually has been doing a study that made the big time—New York Times published work that they had been doing—showing that marathoners and ultramarathoners actually had an increased risk of colon cancer. So yeah—personal trainer a few times a week, improving your cure rate. Whereas if you go too much, you strain the body. Maybe it’s an alteration in diet, maybe it’s microbiome—we’ll talk about it. You actually can make things worse.

So, I want you to listen in to our interview together. Dr. Tim Cannon and I discuss this way cool science, with an idea of trying to figure out what the heck’s going on.

Join us for Oncology Unscripted.

[00:14:38] Interview: Running Into Risk—My Interview with Dr Timothy Cannon

John Marshall, MD: Hey, everybody out there—John Marshall for Oncology Unscripted. You're frittering away more of your time, but we've got something that is clearly worth your effort. You know what? I have run, myself, three half marathons. I hated every one of them. I did it 'cause I thought I was supposed to. I trained up for it—it took a whole season to train up for it. I didn’t hurt anything too bad, which is good. I wasn’t fast—let’s be clear. I was always glad to not be doing the other half of the marathon.

So why do you care about this? Well, there's been new evidence—it’s been building over time—and it's been really led by and championed by a very good friend and colleague of mine, Dr. Tim Cannon, where too much exercise—or too much strain on the body, maybe we should rephrase that—might, in fact, be bad for us, specifically around colorectal cancer. We already know the data—'cause we've talked about it—around a personal trainer improving your survival if you had colon cancer. But what about joining an ultramarathon team?

Dr. Tim Cannon has something to say about that. Tim, introduce yourself and tell the gang your science.

Timothy Cannon, MD: Sure. So, I'm Tim Cannon. Thank you so much for having me, John. This is a study that you cite, that we've just done in the DC area, on ultramarathoners. And I had seen, in the course of about a year, three different ultramarathoners—actually, two were ultramarathoners, one was a triathlete. They had both done dozens of those types of races. And they had stage IV cancer in their 30s.

And I thought, you know, there may be a connection here. They were all describing bleeding after they run. I had heard a lot about runner's trots, or bleeding when you run long distances. And I can see how there could be a mechanism—that this could cause cancer if you run so much that you're having repeated insults to your colon, and bleeding.

And so, we decided to start a study. We opened our Cancer Prevention Center here, and that's what we're here to talk about today. I'm really glad that you had an interest in this.

The study was of 100 long-distance runners. I would call them all extreme. They had all run at least five 26.2-mile marathons. Most of them had run ultramarathons. Many of them had run 100-mile ultramarathons. They had to be between the ages of 35 and 50, not have a known familial syndrome, and not have inflammatory bowel disease. And we screened them to see if they had precancerous polyps.

John Marshall, MD: And, as you found—they did. And some of them had an increased risk for cancer. So, fascinating work. When people were doing what they thought was gonna keep them outta trouble, they might've been getting themselves into trouble.

And I know you, you and I and others have had discussions about the “why” of this. And you just described sort of a trauma. I was always thinking like watershed—not enough blood flow, maybe hypoxia. There's also the other side that I’m, you know, obsessed with—and that's microbiome. These ultramarathoners eat all sorts of funky stuff. They do these protein gels, and they do all sorts of things that are not your classic Mediterranean diet.

If you had to put your quarter down, what do you think's the reason for it?

Timothy Cannon, MD: Yeah, and we haven’t proven anything quite yet. But I'm believing more and more that there is a connection here. And like you, I thought the watershed idea made the most sense to me initially.

Since this came out, everyone is emailing me with their own ideas about it. And some of them are pretty compelling. Microbiome, I think, may be among the most compelling. You know, I've been reading about differences in abundance in people who do endurance sports. There’s a bacteria called prevotella, for instance, that's more abundant in runners—and it may be related.

Sure, there's so much we don't know about this, but that's what we're hoping to explore in part two—analyzing the microbiome. And then, of course, there’s the lifestyle. Things that characterize long-distance runners—the goos, the... you know, I’ve worried about everything. They drink a lot of electrolyte drinks out of bottles, and maybe they have high exposure to BPA. Or maybe it’s the high-protein diet that was highlighted this week in The New York Times. Who knows? It could be any of these exposures that could cause it. It’s hard to know, hard to study. To isolate any one of these variables is tricky. But I think it’s important to try to get to the bottom of it.

John Marshall, MD: We're into prevention, right? We tell people not to smoke. We tell people to eat right. Should there be some sort of sign at the beginning of a marathon that says, “You're running at your own risk”?

Timothy Cannon, MD: Yeah, like the Surgeon General’s warning. I'm not sure we know enough quite to recommend that yet. And of course, I want to emphasize what you did first at the beginning here: that exercise is—by and large—going to be a good thing. We’ll have much bigger problems from there not being enough exercise. And I think we know fairly definitively that exercise reduces the risk of cancer recurrence. So, I want to emphasize that from the beginning.

But the question is whether there’s a dose of exercise that is too much. I believe there is. I’d like to get more evidence before we start putting signs on marathons or discouraging people too much. But I could see a future where there is something like that out there.

John Marshall, MD: Breakthrough work, in my opinion. Dr. Tim Cannon, thank you so much for, I’m sure, taking time out—when you're in The New York Times, you're much needed on the interview circuit. So, it's a real honor that you’ve taken some time to talk with us and our audience. Dr. Tim Cannon—

Timothy Cannon, MD: No way. This one means the most to me, John. Thank you.

John Marshall, MD: I love being lied to on a Wednesday. Hang in there everybody, and we'll see you next time on Oncology Unscripted.

This transcript has been edited for clarity.

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Why Are More Healthy Young Adults Getting GI Cancer?

[00:05]

John Marshall, MD:
John Marshall for Oncology Unscripted. Big paper coming out of _JAMA_—it's actually a review article. Really, really smart people and friends up in Boston looked at this. We all see it: this emerging trend of younger and younger people getting all kinds of cancer. This particular paper wasn’t about all kinds of cancer, but we’re clearly seeing it in GI cancers. We don’t really understand what’s going on, but we see it—it’s impacting our clinic. Maybe it was first recognized in the colon cancer clinic, but we’re seeing it in other clinics as well.

We have two kinds of schools of thought on why this is happening. On one side, we’ve got this sort of traditional “here’s who gets cancer” list. So, you have a gene, you’ve inherited it, or you have some behavior that increases your risk, or you’re overweight or something, right? You have some known risk factor that we all learned in medical school that’s causing this cancer.

Now, if that were true, then our normal 60/40 split of cancers—40% on the right side, 60% on the left side—would hold true in colon cancer. But in fact, most of these young people with colon cancer—up to like 90-something percent—all have rectosigmoid cancers. So, what the heck’s going on? And most of the patients that we see, at least that I see here in Washington, DC, don’t have any of those things on the list that we all memorized.

They’re all very fit. They have no real reason to have this—no strong family history and certainly no gene. So, we are looking for novel explanations. The leading one right now has mostly to do with microbiome and understanding what that’s all about. We’re not going to drill down on that today, but we are looking for the explanation as to why.

Now, the other piece that goes with this is: if you’re a young person, is your cancer better? Well, it actually doesn’t look that way. If anything, it looks like it might be worse. We know that we fail to diagnose it earlier because it’s not on our radar. If I’m in an urgent care clinic or in an ER or something—or even if I’m a patient with the symptoms—you don’t think to yourself, “Oh, I could have colon cancer,” because you’re 40 years old, and it’s too young to have colon cancer.

So, it isn’t a better cancer. But on the flip side, because you’re younger as a patient, doctors tend to be more aggressive. They tend to push treatments harder because young people can take it well. On the flip side of that, they also have much longer to live if we give them some sort of permanent toxicity—say, neuropathy from oxaliplatin.

So, it is clearly its own thing. It has its own impact on day-to-day living for these people, because they have to keep working, because they need health insurance here in the United States. They have to tell people about it. So, the impact on their lives is much bigger than, say, if you’re a retired 73-year-old with a good support system.

So, that impact is a bit worse. The disease probably is worse. The failure to diagnose is worse. We don’t really know what the biology and the cause is, and more isn’t necessarily better. So, there’s a lot to talk about and think about. Take a look at this paper, see the emerging trends, and share it with your colleagues in other areas of healthcare so that they’re aware of it, too.

John Marshall for Oncology Unscripted.

[03:51]

MedBuzz: Fellows, Funding, and Fewer Radiologists

[00:05]

John Marshall: John Marshall for Oncology Unscripted, with a little bit of buzz, a little bit of gossip, a little bit of stuff that's trending.

You know, this is the end of July when we're filming this, and the squeaky-clean new fellows are here. Don't you love July? New residents and new fellows—you get to teach 'em how 5-FU works and where the bathroom is, and all of those things. But it is—I love this time of year with the new fellows because they're very eager and very interested in learning everything they can. They're not too tired. Everything is good and positive as they learn and go forward. And so, it's just been a great month for us here at Georgetown, and I hope if you work with new trainees—residents, fellows—that you too are having a positive time with them.

I've also—the month of July—been struck by a certain late-night TV host who was fired, let go, because his message was to counter the sort of government message that is going on right now. So, I've been really anxious about having any sort of counter message that's out there, because you know what? You might get canceled if you are caught too often with this sort of counter message.

How that's affecting us here at an NCI-designated cancer center—or wherever you are—is that I'm not sure what the NCI is gonna look like too long from now. We know there are gonna be cuts. We know the payline—there have been predictions that it'll drop as low as 4% for grants. So, if cancer research was being—most, or a lot of it—was being funded by NCI, and that is being cut dramatically and refocused, how does anybody doing the kind of research that we're doing continue? And so, we spend a lot of time at our center—and I'm sure it's true at your center as well—trying to understand how we evolve from here. Is it gonna be philanthropy? Is it gonna be public-private partnerships? Are we gonna work in a different way to keep the progress going that we are seeing?

Now, the other component that's affecting all of us—or gonna affect all of us—is changes in public health. So, if Medicaid cuts are dramatic, then a lot of patients won't have access to cancer care in general. It'll be too expensive or unreachable for a lot of patients. There are certain regions of the country where there is a lot of Medicaid—not just necessarily cities, could be rural places as well. So, those of us who have oncology practices are also trying to understand what the future is gonna look like if we have fewer patients able to get cancer care. So, changes in academia, changes in practice that are coming ahead because of all the changes that are top-down happening in our nation today.

One that is affecting me—and I don't know if it's affecting you as well—is that there has actually become a fairly dramatic nationwide shortage of radiologists. Now, radiologists right now often work in their basements at home. They have shift work. There is support from AI, but it's also a threat from AI. Could it take their jobs eventually? Is the support that it's providing making their job easier or less easy? But regardless, we don't have the same number of radiologists. And so, instead of having a scan being read in a day or two—which is fairly standard for the industry—we see it now taking three, four, five days. And our patients are nervous because they don't know why their scan hasn't been reviewed and the like. So, I'd love for you all to share with me if you're having the same issue too. I meet with my radiologist. We love them. We consider them very tight partners with us, and we are supportive of trying to make their increasingly stressful job less stressful. But that's one of those things that we're gonna have to figure out before too long. Otherwise, we are gonna be stuck without radiologists to read our scans—or we're gonna let Elon Musk read all of our scans. One way or the other, we'll figure it out, I guess. But a lot of changes have occurred just in the last month of July. A lot of those are affecting our day-to-day practice and our ability to deliver the best cancer care and the best research opportunities for our patients in our communities.

I'm not sure what August holds, but I think I'll go to the beach and take a break from it all. John Marshall**,** Oncology Unscripted.

[04:40]

The New Face of Colon Cancer: A Patient’s Story

[00:00:05]

John Marshall, MD: Hey, everybody—John Marshall for Oncology Unscripted, and this session is all about a really big problem that I hate. It's changed my clinic. I really don't like anything about it. It is not what I signed up for. It is young people getting GI cancers. And, you know, the deal was that they were all supposed to be 60, 70, 80 years old with colon cancer, and now close to half of my clinic is under the age of 50. It's a totally different impact, a totally different disease.

There was a recent JAMA paper, which we are featuring, about the statistics around not just colorectal cancer but all GI cancers showing an increase.

And I am lucky enough to have, as one of those young patients, Chad Leo, who has taught me as much about this whole thing as I've taught him about the management of this. He was first diagnosed when he was age 42, and it was out of the blue. So, first, Chad, thank you for your willingness to jump onto this risky venture of Oncology Unscripted. Tell us a little bit about yourself and how they first found it—the sort of "out of the blue," something on your list that was never on your list before.

Chad Leo: Well, first let me say, Dr. Marshall, thank you very much for having me on here. You know, through this entire journey, I'm just overly grateful to be able to kind of give back and share my experience in the hopes that maybe it'll help other people my age—and, unfortunately, people even younger than me—that are being diagnosed with colon cancer.

So, when I was first diagnosed, I was going through some severe abdominal pains. I later found out that was sort of similar to the symptoms that other people diagnosed with colon cancer were going through as well. I was reluctant to really get it looked at, and as time went on, the symptoms progressed. Finally, I was convinced to go to the ER.

I think the way that doctors first saw me—they go, "He's 42, there's no way that this could be anything that severe"—and it was almost a detriment, to the point where I wasn’t fully examined to the extent of what should have been part of the full checkoffs that probably should have been done.

John Marshall, MD: So, what did they think it was? Just like constipation or something else?

Chad Leo: Yeah, their initial thought was that it's probably just Crohn's disease or some type of colitis. That was in my head—I was like, "Okay, that's probably what it is." And then a month later, I'm back in the ER again. The scans indicated that there was, in fact, a mass in my large intestine.

John Marshall, MD: Well, when I went to medical school a thousand years ago—you probably weren’t even born—we were taught that only older people got colon cancer, so it shouldn’t even be something we look at. There has been a growing message about young people getting the disease, but for a lot of folks, it's just not on their checkoff list. So, the patient doesn’t know to ask about it. The physicians are saying, “That can’t be that,” as you just said. To your knowledge, did you have any known risk factors? I mean, your family, your other medical issues—anything that would’ve teed you up for colon cancer?

Chad Leo: No, nothing would’ve indicated that—especially in my family history. I think I had a grandfather who had bladder cancer. My paternal grandmother had ovarian cancer, but nothing along the lines of colon cancer. It wasn’t on my radar. It wasn’t anything where I was directed to start getting screened early.

John Marshall, MD: One of the reasons I’m asking is that this paper we’re featuring lists the standard risk factors. We’ve got to look out for those people. Those people are kind of being followed—or they should be already—because they’re in that risk factor category. But most of my patients are more like you, where it’s just out of the blue. Very fit, obviously, otherwise very healthy, and then—out of the blue—with a diagnosis of colon cancer. So, message heard loud and clear that we’re sending out to the medical community with this discussion.

Tell me what it was like to—out of the blue at 42 years old—all of a sudden have colon cancer, surgery, chemo. How disruptive was all of that?

Chad Leo: It was a huge disruption. So, my job—I’m a detective with the DC Police Department—requires me to be very active. And so, going through the treatments meant that I had to take a break. I planned essentially to use my sick leave as much as possible just so I could focus on getting better.

All of these thoughts start going through your head at 42. I was single then. You start kind of thinking, “What have I done? What have I accomplished with my life?” That plays a heavy toll on your psyche.

Also, I think—being a little bit further removed from some of this—it pushed me to really take a look at my life and not take anything for granted.

John Marshall, MD: Yeah, I would rather you not have to have had that life stress to do that, but I hear you loud and clear.

Chad Leo: Neither would I. But I guess, you know, you’ve got to take everything with a grain of salt. There's always a silver lining to something, and I think that sort of mindset just kind of kept me going and just being hopeful. I think obviously having a terrific care team—such as yourself and the team you had with you—made a huge impact. I felt like my best interests were at heart.

John Marshall, MD: Yeah. And did you tell the gang at work? Did they make accommodations? Did people try and help you? Or did you feel like you wanted to keep it quiet?

Chad Leo: I basically told my close friends and obviously my supervisors what was going on. Pretty much everybody from work was super supportive, and would reach out or come visit, and every once in a while send encouraging messages. I couldn’t have asked for a better support system.

John Marshall, MD: Yeah. So, you went through surgery, did some chemotherapy. We were in follow-up. You've been getting the fancy ctDNA test as well as scans. Describe a little bit about that, because you’ve had a rollercoaster there too.

Chad Leo: It was. The initial surgery I had was to remove the mass, and then I was affixed with a colostomy bag. And, you know, no pun intended—I don't know if we're allowed to curse on the podcast—but I won’t. Oh, okay, I’m getting a thumbs up. So, pun intended, it was a very shitty situation. That was a huge adjustment, where not only did I have a colostomy bag, but I had to learn how to do daily activities with that.

And just the sheer embarrassment of looking at myself in the mirror with this stoma poking out of my stomach. You still want to go out, still want to try to be somewhat normal, but then you have this colostomy bag. I remember at times meeting up with people, and you start to smell something, and you’re like, “I gotta go—it’s a leak or something.” So, I would limit my exposure with my friends to a few hours just because I didn’t know what could happen.

Once we got to a point where I was essentially no evidence of disease, I think I was kind of encouraging—or pushing—you to, like, “Hey, maybe we can look into getting this resection surgery.” So that was good to get to that point.

Then the follow-up tests and the blood tests post-surgery just kind of set up a platform, if you will, of, “Okay, let’s just keep banging out whatever the next steps are.”

John Marshall, MD: Yeah. I know we talked about the role of exercise. One of the big studies we featured in a previous episode was the dramatic impact that having a personal trainer had.

I don't know if I’ve shared this with you yet, but half the patients got a pamphlet that said, "Go exercise," and the other half were assigned a personal trainer. There was actually a survival delta between those. You're already very active, but when you talk about the ostomy—if we’re recommending exercise—an ostomy is exactly counter to that. It makes it very, very difficult to do the kind of physical activity that I know you like to do.

Chad Leo: Yeah, that was—so, I had started an intense workout routine before I even got diagnosed. So, to have the ostomy, basically, my exercise routine just consisted of lots of walking. Maybe just some push-ups. I tried hard not to do anything that would disrupt where the ostomy or the bag was, just because I was so self-conscious. I didn’t even want to go to the gym. I didn’t want to deal with the embarrassment of people seeing the colostomy bag.

But overall, I felt it was just important to stay active and move no matter what.

John Marshall, MD: Yeah. You're a few years out now. With each new scan, with each negative blood test, we’re a little bit further off. You know where we’re gonna be. All right.

And fingers crossed—we’ve had some nervous times still. You’ve got an audience of docs right now, all around the country, all around the world, other people in the industry. What sort of message would you like to share, given your experience? Is there anything you’d like us to hear about?

Chad Leo: I think most importantly—and you do a great job of this—it’s giving your patients hope. Giving someone like myself hope, even through the early stages where you feel like everything is at a loss. The way that you would say, “Hey, look, these are the steps that we’re going to take to try to get you to a point where you can hopefully live as much of a normal life as possible”—I think that’s one of the key things. Because if you have hope in your mind, who knows the benefits that provides the rest of your body? Your body may just continue to keep on fighting.Despite the chemo treatments or even the subsequent blood tests and scans that we go through afterward, you’re still clinging to that hope. Even though you get that little bit of anxiety every time a blood test or scan comes up.

Like I mentioned before, I know that I’m in good hands, and if something does come up, we’ll be able to treat it as early as possible and just give myself a better chance. Again, from my own personal experience, it’s about trying to live your life as normally as possible after going through an experience like that. You and your team have afforded me that ability.

John Marshall, MD: We’re happy to do it, and there are a lot of people out there who can do it well too.

One of the things that was fairly new when you were getting your chemo a few years ago was three months versus six months of chemotherapy. At a young age, you have a physical job, you need to be able to use your hands. The reason for three months versus six months was the cumulative neuropathy of oxaliplatin. We had those discussions about that. There are a lot of docs out there who might be listening in, who, as a young guy, might think, “You can take it because you're young,” and push it to the six months. But right now, one thing I’m glad about is your scans—you’re good. You’re good. And no neuropathy, or limited neuropathy.

Chad Leo: None that I can detect.

John Marshall, MD: And you’re a detective!

Chad Leo: Yes! I mean, I gotta do a lot of typing too. So, it’s important that everything works—at least where I can type. But yeah, I remember there was a point where I started feeling some neuropathy in my hands.

Subsequently, whatever happened after that, it has now since subsided.

John Marshall, MD: Chad, thank you so much for taking some time to discuss this with us.

We all hate this trend. It’s why there’s a big, important paper on this. You are the real kind of person who’s being affected by this. And for you to share all of this with us means a lot to us—and teaches us, as I said at the opening, maybe more lessons than we’ve ever taught you.

So, Chad Leo, thank you very much for joining me on Oncology Unscripted.

Chad Leo: Thank you so much, Dr. Marshall. It’s my pleasure.

[00:14:00]

The Rise of Young-Onset GI Cancers: Interview with Dr Thejus Jayakrishnan

John Marshall, MD: Hey everybody, John Marshall for Oncology Unscripted, and I promise there is no script anywhere in front of us right now. As you know, what we are focusing on this edition is: why are young people getting cancer all of a sudden? I thought we were supposed to be getting healthier.

We just blew up the EPA earlier this week, so I guess we're all going to die of cancer sooner rather than later, if that all works out to be true. But even before we blew up the EPA, some very, very smart people have been watching and monitoring this increase in young people getting colorectal cancer and other GI cancers.

And I am honored to be joined by the lead author of a very, very important review paper that looks at this.

That's been going on all around the world and in the United States. Thejas Jayakrishnan has just joined me today from the mecca of all knowledge—that would be Boston—at Dana-Farber. So, Thejas, thank you very much for joining us, and maybe give us a little bit of an introduction and a little bit about what drove you to put together this paper.

Thejus Jayakrishnan, MD: Thank you very much for the kind introduction. I am a gastrointestinal medical oncologist at Dana-Farber Cancer Institute, an instructor in medicine at Harvard Medical School and Brigham and Women's Hospital, and I work closely with the Dana-Farber Young-Onset Colorectal Cancer Center. I predominantly do clinical research and also translational work, trying to identify what are the biomarkers or molecular characteristics associated with young-onset GI cancers.

I finished my fellowship at Cleveland Clinic, and I had wonderful mentorship there with Dr. Khorana. I spent a lot of time during my fellowship trying to understand the molecular characteristics of young-onset GI cancer. It's mainly during the fellowship that I noticed there's increasing incidence, and the mentorship was helpful in getting me more attuned to recognizing those aspects and realizing some of the unique characteristics of this population. That led me to get involved in research related to the microbiome and metabolomics—trying to integrate different aspects of early-onset GI cancers. I've continued that work since moving to Dana-Farber Cancer Institute.

John Marshall, MD: I'm an old oncologist, right? And so, I didn’t sign up for a lot of my clinic being 20-, 30-, and 40-year-olds. Back then, they were all what we later found out to be Lynch syndrome patients and had genetic inherited syndromes, etc.

Nowadays, that’s not who all of these people are. They are very fit, very healthy, with no real strong risk factors that are showing up. And I think early on, people like the American Cancer Society and others were saying, “Oh, that’s just because they have bad behaviors,” or, “They have the wrong parents,” or something was causing it.

And I noticed that in your all's review, those things were mentioned again, but also, to your acknowledgment just now, we still really haven’t uncovered what the heck’s going on. Let me ask specifically—'cause I did a lot of work with our molecular database—we could not really find any clear next-gen sequence differences based on age. Have you guys got any more insight into the genetic piece of this?

Thejus Jayakrishnan, MD: Yeah, I mean, you're very right, Dr. Marshall. Genomically, we do not see a huge difference in early versus average onset. Certainly, there's a higher prevalence of germline predisposing syndromes in younger people, but that doesn't explain the increasing incidence over time.

The vast majority of these cancers are sporadic, meaning they are not inherited-type syndromes. We do see certain subsets of early-onset GI cancers—for instance, early-onset cholangiocarcinoma—where there’s a higher prevalence of _FGFR_2 fusion. That has been described and is a targetable mutation in cholangiocarcinoma.

In pancreatic cancers, there’s a higher prevalence of not having th_e KRAS_ mutation in early cancers, but having other targetable mutations like IDH1. But again, that’s not a standard targeted therapy in pancreatic cancer. These are still very small percentages.

So, what we really see is also the fact that most patients with young-onset GI cancers present with more aggressive disease. There’s a higher prevalence of, say, signet ring cell cancers or poorly differentiated cancers across the different early-onset GI cancers. A lot of patients present with stage IV disease at diagnosis, which could be partly from delays in diagnosis. But then, we also see higher prevalences of these aggressive variants.

Even with aggressive treatments—younger people, you can imagine, don’t have a lot of comorbidities that may prevent them from getting intensive treatments—we do not see a proportionate improvement in the outcomes. So, there's definitely more molecular factors at play that we need to understand better.

John Marshall, MD: Yeah. So, bad cancers—not necessarily better cancers. Yes, they're younger, and you can beat ’em up more, but that doesn't necessarily mean it's translating into improved outcomes for those patients.

Let’s sort of talk a little bit about current theories as to why. One of the things that only recently—in the last three to five years—that I recognized is that for colon cancer, and it's not necessarily the other GI cancers, instead of the normal sort of 40% right, 60% left, we're seeing this very high percentage of rectosigmoid tumors.

And so, I've been sort of thinking, this must be some sort of microbiome issue. My God, I hope it’s not Starbucks. And I hope it's not bourbon, because then I'm just gonna get it too—those are like my two favorite things.

But, you know, some people are looking at exercise, antibiotic use, or other kinds of components. Microplastics—people are out there.

Thejus Jayakrishnan, MD: Absolutely.

John Marshall, MD: If you had to put a quarter down right now and bet, what do you think the common sort of theme or molecular pathway that’s causing this would be? What would you say?

Thejus Jayakrishnan, MD: I think it is an interaction between environmental factors and the microbiome. That’s what a lot of our studies are trying to do—like a deconvolution—to understand how much one component is contributing.

We definitely have seen an increase in obesity over the last 40 years. Childhood obesity is increasing, and it has been shown that early exposure to adult and maternal obesity can be a risk factor for early-onset GI cancers. But, you are right. I do see a lot of people who do not have these risk factors, so there have to be other factors as well. Physical activity correlates—lower levels of physical activity are associated with higher risk for these types of cancers. But again, we see people who are athletes who do develop early-onset GI cancers.

I do think that exposures play a role. Dietary patterns have changed over time. We see associations with Western-style dietary patterns, which include higher intake of processed meat and sugar-sweetened beverages. Even if someone may not have obesity or metabolic syndromes, they may still have higher exposure to unhealthy diets. Another common factor that connects all of this is microplastics. There are actually studies that have shown microplastic exposures in experimental models lead to higher rates of growth of colon cancers.

There's also synergism between high-fat diet and microplastics, which has been demonstrated in experimental models. We need more epidemiological data and tissue-based analyses to really understand how this may be contributing.

Studies—including ones I’ve been involved in—do show differences in microbiome characteristics, both tissue-based microbiome and stool microbiome, in early-onset versus average-onset GI cancers.

Now, some of it could be associated with the development of cancer, but there are unique differences. We have also identified that these microbiome differences correlate with the metabolites in the body. So, there are a lot of connections between exposures, microbiome alterations, and metabolic changes in the body.

What we are trying to do—through the young-onset colorectal cancer cohort—is prospectively collect tissue, blood, and stool from young-onset patients, along with exposomal data. That includes dietary exposure, physical activity, and other lifestyle factors. We’re really trying to integrate that to understand how different factors may be interacting with one another in the development of cancer.

John Marshall, MD: Part of the reason we're focusing on your great paper is that we don’t have widespread awareness in primary care and urgent care clinics that young people can get cancers. Our screening is not well established. We did drop it to 45 for colon, but we don’t screen for cholangio. We don’t screen for pancreatic.

So, we need to think about: is it enough of a problem that we need to begin shifting screening?

On one level, you’re trying to figure out who’s getting it and why, so we can intervene and reverse whatever it is that’s causing it.

Thejus Jayakrishnan, MD: Mm-hmm.

John Marshall, MD: On the other end, from a public health perspective, we’re trying to say: should we be looking more aggressively, as a healthcare system, at a time when our system is already stretched to the nines?

But let’s go one other place. You’re 42 years old, and now you’ve got stage III GI cancer. You have to work to pay for your insurance. It’s disruptive, because none of our treatments are easy.

Talk a little bit about the impact of cancer for a 40-year-old versus what we all signed up for, which was a bunch of 70-year-olds.

Thejus Jayakrishnan, MD: Yeah, you know, that’s what makes it even tougher to manage. A lot of the people that you diagnose with this cancer are at a stage where they have a growing family. They may have recently gotten married or had kids or just started a new job.

They’re gradually progressing in their careers when they’re faced with this diagnosis. Many of the young patients I see don’t have previous exposure to the healthcare system. So now they’re going back and forth to the hospital for biopsies, chemotherapy, managing complications—and it’s all new to them. That’s combined with other life stressors—managing a career, a family, everything. So, we do see higher psychosocial distress.

John Marshall, MD: I gotta throw this in. You know, 70-year-olds don’t complain about any side effects, but 40-year-olds complain about every single side effect that we cause. It’s always interesting to say, yeah, you're young, you're tough—but they list them all—whereas that 70-year-old is just used to feeling that way.

Thejus Jayakrishnan, MD: That’s also something that’s part of our research—trying to figure out if there’s a biological mechanism that may be responsible for a higher risk of toxicity. But it definitely impacts the ability to deliver the treatments we want to. We do want to give intense treatments, but then you see significant side effects, whether it's nausea, vomiting, or even neuropathy from oxaliplatin.

And then, we have to think about long-term side effects—even in curable colon cancer, where you have to receive adjuvant, postoperative chemotherapy to decrease the chance of recurrence. But then you’re faced with having to deal with some of these side effects.

Even post-surgical complications, like low anterior resection syndrome after rectal cancer surgery, can have a big impact on quality of life. So, there are a lot of considerations there.

John Marshall, MD: You know, part of it—being the end of July—is we’ve got our brand-new fellows coming in, and we’re teaching them as much as we can.

I think when it comes to young people, for example, young patients, we often say, “We want to be very aggressive.”

Thejus Jayakrishnan, MD: Mm-hmm.

John Marshall, MD: But I keep trying to swing us away from that word. Being more effective is really what we want. And this young group—I was thinking mostly around colorectal, but it’s true in other diseases too—there’s increasing interest in organ preservation, avoiding radiation. These are the kinds of strategies we’re using because if you’re going to have this problem and you’re going to survive it for the next 30 or 40 years, we want to optimize your quality of life.

I know your center does a lot of this. We do a lot of this. It’s less easy to do as a generalist or someone out there who doesn’t feel quite as comfortable, but I know we’re all out there to help them and offer advice to try and optimize that patient’s quality of life—to be the most effective, not necessarily the most aggressive.

Thejus Jayakrishnan, MD: Yes, totally agree. With the PROSPECT trial and the OPRA trial in rectal cancer, we have more evidence that we could potentially avoid radiation or help a portion of people avoid surgery altogether for rectal cancer.

Over time, I think we will see increased adoption of these approaches. There are also studies looking at early-stage rectal cancers—T1, T2—whether we can use chemotherapy or chemoradiation and avoid surgery in those subsets of patients.

There are newer immune checkpoint inhibitor combinations coming up. So whether those translate into opportunities for non-operative management in microsatellite-unstable tumors remains to be seen.

And can we develop effective immunotherapies for microsatellite-stable rectal cancer that can also help us avoid the risks of some of these other treatment modalities?

John Marshall, MD: I can’t thank you enough for taking the time. I know you’re busy—I know we’re all busy—but this is such an important topic. Your paper got the appropriate big national recognition—on news channels and the like.

I just wanted to make sure that our audience also had a little bit deeper dive on this issue, because we’re the ones that are going to be meeting these people across the exam room table from us.

And we want you to know out there as much as we know, so that we can make it a little easier on all those folks out there. Thejus, again, thank you very much.

And for Oncology Unscripted, this is John Marshall. Thanks for joining.

[15:26]

This transcript has been lightly edited for clarity.

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ACCESS THROUGH INNOVATION: THE POWER OF SMARTER CANCER CARE STRATEGIES

[00:00:05] John Marshall, MD: John Marshall for Oncology Unscripted. Really no script at all, but we are post-ASCO here in Washington, DC, trying to take all of those major innovations that we all get so excited about—curves with big deltas that we saw in all sorts of different cancers, including the humblest of them all: GI cancers.

So, now the question is: how do you take those innovations and those changes—some of them are added to NCCN, some of them may be FDA-approved, some of them in The New England Journal of Medicine, some not—and apply them to our patients? Many of them are novel tests, maybe not covered by insurance.

Many of them are new drugs that don't have a label and may not yet be approved by healthcare coverage. Many of them, as we will talk about, are not available to most of the world. In fact, they're only available to us here in the wealthy corners of our planet. And so, how do we go from that innovation to the patient to realize those benefits?

I want to highlight two papers because, thematically, they go along with what we are talking about this cycle. So, you've probably seen this journal before—it's called The New England Journal of Medicine—but I want you to make sure and look at this paper by Andrea Cercek. You know about it. This is using IO therapy in MSI-high positive primary cancers, and of course the rectal cancer data. This bar plot right here: 100% of patients with rectal cancer, MSI-high, had a positive clinical response and didn't need surgery. It's not quite 100% in some of these other cancers, but it's dramatically positive, and we here in the United States have access to those therapies for patients with these dramatically positive benefits. But, as you will hear, not everybody has that access and, therefore, they don't even really want to know what their MSI-high status is, because they can't do anything about it.

A second paper, also from a journal you've probably seen before—recent cover change; I kinda like the old cover better myself—Journal of Clinical Oncology. This is also a GI cancer paper. This is from a European consortium group, and there are also some US folks here. They took samples from adjuvant clinical trials in colon cancer and developed a sort of digital path–generated signal of risk, and were able to sort patients into their risk categories so that we could know who needs chemotherapy and who doesn't—who's going to benefit from chemotherapy and who doesn't. Similar to what we are seeing with the MRD ctDNA testing.

This is pretty damn cool because everyone's getting surgery, or most of the world who has healthcare is getting surgery. The analysis that this requires is actually relatively inexpensive compared to some of the fancier tests that are out there. It enables a sorting of patients into risk factors—so much, importantly, for whom needs treatment. Because, right now, we're treating everybody. But more importantly, who doesn't need treatment? How much value can we find with these tests that actually identify the patient who's already cured or who will be upfront resistant to the treatment, therefore not needing it?

This is really where AI is going. And both of these papers speak to this concept of access and value. When something's a 100% benefit rate, the whole world should have access to that—and that's where you can have MSI for rectal cancer with IO therapy. When, on the other hand, an inexpensive test—a series of tests—can show you who needs treatment and who doesn't, there's incredible value. The whole world saves money if we can apply that kind of metric to decision-making going forward.

So, I think these two papers are really good examples of how the progress we are making improves the value and our efficiency going forward, so that as we approach the next generation of cancer care and cancer interventions, we can do it better, more effectively, less expensively—so that one day we can say, yeah, that was worth it.

John Marshall for Oncology Unscripted.

MEDBUZZ: WHAT IF THE BEST CANCER DRUG IS THE ONE YOU CAN’T GET?

John Marshall, MD: We've been talking a lot and thinking a lot about access to cancer care. And let's start hometown—let's start here in the good old US of A—and talk about unequal access to cancer care. Here, we all know that what color you are, what your race is, what your gender is, who your parents were, what type of insurance you have, urban versus rural—we all know about those differences in access to cancer care. A new one that's emerging is specialization of the team that you're seeing. So, general oncology teams versus disease-specific oncology teams tend to produce different outcomes, simply because everything is moving so fast, the subtleties are something that the specialized team can keep up with, that a generalist would struggle with. And this is an important issue that we need to figure out, as a nation, how to distribute that specialized knowledge to everyone so that we level that playing field as well.

We all know about the threat that's out there right now with health insurance changing—where Medicaid is being threatened. Just yesterday, Planned Parenthood was talking about, well, the Supreme Court says, yep, you don't have to have Medicaid for Planned Parenthood. Like, that's the Supreme Court's decision on—I give up anymore. But so, where's that gonna trickle down to in the expensive world of cancer medicine?

And so, we'll talk about ex-US, but I want to start with us a little bit more, because I was on a call the other day with a congressman—U.S. Congressman from Georgia’s First. That’s the southeast coast of Georgia. It's also where I—so one of my favorite places to escape. But the congressman there is a guy named Buddy Carter, and he was a pharmacist before he became a politician. He was saying—Republican—and he was basically saying that we can't afford, in this country, healthcare. We can't afford cancer care, for sure. We're spending a lot more than we have, which means we're just continually going into debt every time we add a new medicine or do a new CT scan or whatever it is. Yep, insurance is covering it. Healthcare systems are being paid for it. But we're going into overall debt because of that. And his main shtick, which sort of upset me, was all about cleaning up the rolls—making sure that people who don't deserve U.S. healthcare aren't getting it. So, if you're a non-national or you're not working or whatever it is, that you don't get access to the support for your healthcare without demonstrating your worth, your value to the system. So, that sort of got me on my heels. 

What also putting me further back on my heels was that he was ranting about 340B pricing. We all know that that is an uneven system in our country, where certain health system sites get different prices than other sites, making a bigger markup to pay for the infrastructure of cancer care. That was the reason it was originally developed. But, of course, it creates an uneven reimbursement system right now here in the good old US of A—even within the Beltway, we have different rules, different healthcare sites.

He also went on about PBMs, the pharmacy benefit managers, the middle people who are taking their skim off the top for managing cancer care and the expense of therapeutics. So, they clearly, up on Capitol Hill, are upset about this and anxious about this. And they want to blow it all up like they do with everything, but they don't actually have a plan for what they would do in place of that.

As we thought about this, we thought about: okay, if we're gonna blow up the U.S. system that's covering so much of our world's healthcare economy and research, what are we gonna replace it with? So, we thought it would be interesting to talk to folks from around the world and get their opinions about this. So, certainly continue to listen in and listen to those interviews from people who are very well respected around the world.

But one other thing that we thought about is that if you are from a poorer country and you know about these novel therapies, and some manufacturer is willing to make your biosimilar or your generic for you outside of the patent laws that exist—at least in this country—do you know if you're getting a good product or not? And so, there is increasingly data to say that it's inconsistent—that if you're a physician in a less wealthy part of the world and you've ordered some fancy drug that's being provided by some manufacturer, not the original one—maybe it's not active, maybe it's too active, maybe it's toxic. So, it's unpredictable.

And so, in the desire to have access to these very positive therapies, these very positive interventions, it makes people make risky decisions about, well, better to try it than to not try it, because I got nothing better than that.

So, we think this is a major issue for us as a global market as well.

So, lots going on out there as we try and bring innovation forward, try to keep our advantages that we have been able to achieve, and distribute them evenly and more effectively to more people—not only in the United States but around the world.

So, I hope you will continue to listen to Oncology Unscripted as we do a deeper dive into this issue of access and healthcare decision-making around the world.

GLOBAL REALITIES OF ASCO INNOVATION: PERSPECTIVES FROM THE UK, LATIN AMERICA, AND EASTERN EUROPE

John Marshall, MD: Hey everybody. John Marshall for Oncology Unscripted sort of still on ASCO, not letting go of that, and this little bitty series is about I Access to treatments around the world. We all go to Chicago or to ESMO this year in Berlin, and we see new big productions, new data, expensive medicines, but medicines that are having major impact.

And here in the United States we have this sort of perspective that we can have whatever we want. And for the most part, we are the primary market for a lot of these new cancer drugs. And we've talked about that before, but I thought. Post-ASCO. It's really, really important for all of us to pause and think a little bit about rest of world because we don't have the same access around the world.

INTERVIEW WITH DR DAVID KERR

And to help me discuss this is an incredible leader in the world of oncology today. And also, I am lucky enough to call him my friend and have spent some time with him and his family in that beautiful spot over his shoulder there in Oxford, and this is professor Dr. David Kerr, who is down from Scotland, in his current, place of, Oxford. and he's been willing to join us. So David, welcome to Oncology Unscripted. Give the fans here a little bit, background about you, and then maybe just jump right in in terms of access and how you folks there in the public health service figure that out.

David Kerr, CBE, FMedSci, FRCP: Great to see you, John, and of course, welcome to you and the rest of the gang from the dreaming spars of Oxford, which you can see over my shoulder. so I'm David Care Professor of Cancer Medicine at University of Oxford. I, sidekick friend of John for more years than either of us would care to account and probably have lost the sort of distant tracks of time for former president of esmo.

I chaired the ASCO International Committee for a while. Fantastic outfit, and I've just been elected to the board of the UICC, which gives quite an interesting overview globally. About inequity, the, the unfairness, the lack of reasonable distribution of access to. medicines in the uk. many years ago, I served as a health advisor to then Prime Minister Tony Blair, we set up something called nice. This was a National Institute for Clinical Excellence and effectively. a rational means of drug rationing. that's not oxymoron. We can put that into the same sentence. And what it does is it looks at the data.

What are the clinical benefits of it?  How much does that cost? And in the context of a socialized healthcare system, such as our NHS, how does it stack up against hip replacements against vaccinations for children, against smoking prevention programs and so on. The whole gamut of cancer control, but, but placed within the wider context of all of medicine and, and poses a question, can we afford it?

Are the benefits sufficient for us to recommend that all the patients in NHS can get access to it? at one level, I think it's fear and transparent. And it's not a deal done in smoke-filled rooms. The old days was a machinery, a, logic, a statistical approach. All of us could understand, of course it's frustrating because quite often the answer can be no.

We come back from, ASCO, full of the joys of spring, full of the joys of early summer. and of course, medical oncologists wanting to do their very best for the patients that we look after, but frustrated by nice often saying no. And by the time taken, to be honest, it can take months, if not years, for the process to to go through. So, while the gold standard has moved ahead in the United States. But we find ourselves in stages, waiting to see if it can be done or afforded. And there's a frustration in that, as you would imagine.

John Marshall, MD: Let me drill down on some of this because, I've been always impressed by your work and the creation of the NICE committee. First, the transparency. As you say, you publish the analysis in Lancet Oncology of, of a yes or a no. Is that right? And, and the committee is a formal charge on behalf of the nation, if you will, instead of me dealing with the Blue Cross physician. You all are taking the responsibility on the backs of, on, on behalf of your country. Is that, is that the way it works?

David Kerr, CBE, FMedSci, FRCP: It, it, it is, it's a national committee. So, when, when the, the reason that we kicked this off all those years ago with the Blair government, we had a thing called postcode prescribing. So even with NHS there was significant variation. Variation is a word that we might come back to 'cause that makes us nervous. 'cause variation is usually, it's usually leveling down rather than leveling up the NHS was set up, different regions, different districts. you're living in a, a village in England, if, if one side of the village road happened to be in District X rather than District Y, you know, your neighbors might get the drug, but you wouldn't. It was extraordinarily ridiculous. So, we created this national body exactly as you said. That we take a decision on behalf of all the citizens of the United Kingdom.

John Marshall, MD: The other piece that, or a second piece that I wanted to focus on is this, this concept of you take something away, if you're gonna bring a new thing in, if you're gonna bring a new product in, you're, you're trading off something, or on the other side, making some recommendation to raise taxes. Is that true or is that my version of it?

David Kerr, CBE, FMedSci, FRCP: No, so, so you, you've opened up to a philosophical canof worms. One is we're a taxation-based health service therefore, like Moby Dick, it's the ever-open mo that we are a sort of endless money pit. To, to use a sort of term from Hollywood and so on. So, we just go on and on consuming and using, and successive governments health secretaries talk about the form of NHS, improving efficiencies and so on. But this is an organization with 1.35 million employees. I think we're the fourth largest outfit in the world after the Chinese People's Liberation Army, the Indian Civil Service. Then probably is actually, so you can imagine managing that outfit is horrendously complex and we have disconnected hierarchies.

The boss, the health secretary says I've made the decision and he thinks that that will sprinkle down throughout the NHS far, far, far from it. But other thing that you, that, the other thing that fascinates me is the concept of value in the headroom. So, so you're exactly right. If, if I had the. If I hit the national cancer budget under my control, then I wanted to bring innovative. Worthwhile new drugs coming through you, you and I would recognize these, so we're not talking about an improvement in disease-free survival of six weeks, but we're talking about impactful real drugs that make a difference. Exactly. So, we, we make a secret sign But in order to bring that in, how do we create the headroom? Well, by not doing stuff that's useless, should we be giving 10th line breast cancer chemotherapy? I, I dunno why I particularly said that, but you get the point, way beyond the evidence base using I I don't mean this to sound horrible using chemotherapy as an emotional, psychological crutch for me as well as for my patients. It's, it's, it's a trap that we mustn't fall into and those of us older, wiser, I think, often manage to avoid it. But for young colleagues who want to do the best they can to leave no stone unturned, we give quite a lot of actually, ultimately treatment. I'm sorry to say.

John Marshall, MD: I think you're totally spot on.. One thing that sort of came to me, this ASCO. As we talk about the cost of precision medicine, doing the tests, let's just start there. Or could be MRD testing, ctDNA testing, identifying those people still at risk, et cetera, instead of just treating everybody and crossing your fingers you know, how do we identify value to your word? And I like this word. It's like when I see someone presenting a new study at the plenary session, the slide that's missing. Is the value slide. So, if I do a test and it identifies the 9% of BRAF patients in colon cancer and my survival delta is big, what we're not showing and the cost of that, let's be fair.

The added cost of both the test and the new drugs, your, to your point, what we are not showing is the useless medicines that we are not giving. And so, on some level, we've made ourselves. More efficient, it becomes worth it because then we don't give the therapies that don't have the value. So, I, it's always about adding on instead of what is it taking away when we make progress.

You think that's right?

David Kerr, CBE, FMedSci, FRCP: Isn't value an interesting word and it's a double-edged sword. So, all of us want to get value for money. We're buying a new car, we're doing this, we're doing that. You know, the value are usually where you get cheat cuts of meat. It's usually of inferior quality. And so somehow wrongly value can be associated with a poorer effort. A poorer outcome, and a a, so I'm going to plug like crazy, A wee book that's Grain I wrote called how to get better value healthcare, the focus on cancer, and this is trading in some fantastic work coming out of Harvard. And how do we define value? And we defined it in terms of what the inputs are exactly as you said, what all the various costs and elements are, and so what the outputs are, what, what we achieve in some way. And so, it's moving just beyond the health economics of it. I agree with you. That's one element of it, but not, not the most important of it, too sharply focused on, you know, the impact of the new drug and the new test without taking account of the wider picture. 

John Marshall, MD: Let's go to one other area, and this is just the, the cost and the negotiation process. So here in the United States under there’s a law that says we are unallowed to judge value. That whatever the industry asks for, the product we are on, government and Medicare, et cetera, is going to pay that and that markup. Again, our secret sign, that big markup is what is going back into drug development or global drug development. That's part of the budget that these multinational companies have, and since the last administration we have that's been challenged, and so everyone's very anxious that we won't have that money for reinvestment. I also see on your side. A different level of negotiation is that, you know, if, if, if, if you charged, you know, one of the big companies this amount, you could fit in under our budget. Right? So, you are getting a different price hopefully for takes too long. I granted, but you're getting a different price at the end of the day than we are. So on some level, when we talk about the imbalance or the inequity, I think the American public needs to recognize that we, and it's our taxes and other things coming out of our paychecks are paying more for a given thing than you guys are able to negotiate as a collective. And, you know, so I, the individual versus the collective.

What, what are your thoughts about that?

David Kerr, CBE, FMedSci, FRCP: I think if it wasn't for US drug market, with all the elements that you said, I'm sure that there wouldn't remotely be the same drug development expertise going on in the world. the idea about that imbalance being redressed in some way, be fascinating to see how, how your administration will deal with it. Our civil servants are negotiating behalf of the whole, of the, a whole country, you know, 65 million people, so they'd hope to be able to get a good deal. clearly your administration have spotted the huge differential in prices comparing many, if not all European nation states with the, the prices going on. United States, it doesn't seem fair, and I've said that I've benefited from your large s scientific and tax dollars for the past 40 years. I, I, I'd be very honest about it.

John Marshall, MD: I always wonder about the other side of this argument is that only, I think the figure is somewhere around one in seven people on our planet has access to cancer care at this level. And so, I, my sort of running joke about this is that we're selling Lexuses when in fact we could be selling Toyotas and selling it to more people.

And I've never really understood to this. What feels like false economy, and we are in the middle of it of course, because we are counseling and consulting with the industry people. We are providing care. You on a national level, coaching, you know, your country on how best to do this. It would seem like there should be some opportunity here to sell to more individuals and therefore make up the difference in that way and solve.

One of the problems that you and I recognize all along is that so many people just simply don't have access.

David Kerr, CBE, FMedSci, FRCP: If only we knew more about economics of, you know, sell low, something like that, which is.

John Marshall, MD: Behind you, they teach that, don't they? 

David Kerr, CBE, FMedSci, FRCP: No, you're right. There are a couple of Nobel Laureates their people, the Fields Medal. So, there are some bunch of smart people, but they, they, God, you know, they do their own thing. 

So, the UICC. great organization is a multi-member institution. It's a union, international control of cancer. We've got a brilliant program called Atom, working with pharma to make expensive drugs available in low-income countries. And I, I think both you and I would agree that the perfect as enemy of the good, rather than saying that every citizen on earth deserves a gold standard Cruiser, deluxe, NCCN ASCO and ESMO guideline driven cancer treatment. That's that, that cannot be the deal. It just cannot. And I was my president, I was very keen to see what we could do to establish. Functional, sensible guidelines that took account of individual countries could afford. And I would rather that we gave something that was decent but not perfect rather than nothing at all and had all sorts of interesting ideas.

But I ran into a few problems. It was fascinating and that some of my colleagues from low-income countries said that. I was trying to, how did they put it? Quite strong language. I was imposing an imperial, Imperial approach to saying, I'm denying people from income countries perfect treatment.

I said, I'm not, I'm being utilitarian. Let's treat more people pretty effectively rather than. people very effectively 'cause that that was a price differential, low dose metronomic, oral chemotherapy for breast. Why not? It's not, it's not like humdinger. This would do some good for the masses. Vast majority of people. I'm getting about it, but no, I mean, you've hit upon something that. that bugs me. and, and we need to find a better way of doing it. And I think we are the WHO Essential Medicines list, with work that's going on to reorient the guidelines and, and to make them more cost sensitive and to work with colleagues to say, let's reach out to wider segment of our population, moderately effectively, run a tiny sector with cruiser, deluxe drugs. it's a hobby horse, as you can tell.

John Marshall, MD: I could go on for a while, which is why I think they created pubs in your beautiful land. and maybe next time we are together, we should do that. But for now, let us, Call it an evening. thank you one more time for taking your valuable time away to share with our audience actually on a pretty global audience nowadays with electronics and all of that, our reflections and discussion around, the impact of innovation and how do we distribute that innovation to more people. Professor, Dr. David Ker. Thank you very much for joining us on Oncology Unscripted.

Good to see you, John, and delighted to take part. 

John Marshall For Oncology Unscripted

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“Badge-up” with Dr Marshall at ASCO 2025

John Marshall, MD: John Marshall coming to you live Oncology Unscripted, not from my office back in Georgetown, but from beautiful downtown Chicago, Illinois at ASCO 2025. Look at this amazing place. 40,000 of our closest friends.

To get in, you need to have one of these. So, I'm gonna go ahead and badge up. I got a fancy red collar thing here, boy, that makes me stand out even that much more.

But what we're gonna talk about today first is the social aspect. You remember in anticipation of coming, we were a little worried about would people from outside the US come to the meeting, and, yep, they've come, but not to the same extent that they have in years past. So very clearly international travel being affected by the world today, and, therefore, our community, which is so important to get together on a regular basis, probably being a little bit affected by this. But it is an incredible time to get together, to share thoughts, to give a hug or two, to shake a hand or two, and connect with those of us in our community who are dedicated to trying to cure cancer to find positive outcome for our patients for Monday morning, for Tuesday morning, in the week ahead.

So, let's start with some high-level reviews of the most important science. Later today, we will have the plenary session where five abstracts will be presented, each one of which has significant impact on our patients going forward. Let's start, in my world of GI cancer, where immuno-oncology, again, doubling down in the microsatellite unstable patient adjuvant IO in MSI patients with chemotherapy proving to be better than chemotherapy alone. Not tested against IO alone, which will clearly be the next question, but for now, starting next week, MSI-high, IO plus chemotherapy in the adjuvant setting in colon cancer.

What about gastric cancer? Same thing, IO, and this is not an MSI-high, added to chemotherapy showing survival benefit for our patients with gastric cancer. So, as of today, new standards where IO will be added to adjuvant perioperative therapy for patients with gastric cancer.

And the third area where IO has been shown to be a benefit in this plenary session is adding it to radiation and chemotherapy in head and neck cancer, something we've long been needing. Improved novel therapies for head and neck cancer. IO has just entered that field too in the curative intent combo chemo RT setting. So, three major places where IO is gonna have an impact starting today.

Now I'm not even gonna try to talk about polycythemia vera. I'm not even sure I can spell it, so I'm gonna make you look that one up yourself.

But I wanna finish from a plenary perspective on this breast cancer study. Of course, it's always breast cancer. They are the smartest, they have the most money, they have the highest survival of all of our solid tumors, and, yep, they did it again. They actually show that if you monitor patients who are getting therapy and you can use circulating tumor DNA, so a blood test that can demonstrate the emergence of resistance before there's a change in the clinical scenario. And if you add in, in this case, an androgen hormone degrader, that in fact you can intervene and actually extend survival and progression-free survival significantly. So, this is real time monitoring, using novel blood tests for resistance and changing your therapy in advance of any other clinical signal. Clearly, this is the way things are gonna be going more and more as we define therapies for our patients. Not so much using CT scans and waiting on progression, but blood tests that demonstrate resistance at a much earlier time point.

Two other important GI papers. Not part of the plenary. There wasn't room for everything in the plenary, and this is, guess what? It's now good to be BRAF colon cancer. Do you remember when it used to be bad to be HER2-positive breast cancer? Do you remember when it used to be bad to be MSI-high? Well, it's not bad anymore for those two because the therapies work. It used to be bad to be BRAF V600E-mutated colon cancer. Just a bad prognostic sign. Nothing you can do about it. Study just presented showed that the addition of BRAF-targeted therapies and frontline metastatic colon patients with a 30-month median survival. So, that took a bad marker, we can now deal with it. What does that mean for your clinic? I'm gonna be strong here. It now means that it is malpractice,  you are not practicing the standard of care,  if you're not doing frontline molecular testing in colorectal cancer. You are obligated to find Ras mutations, BRAF mutations, MSI, and HER2 before you initiate treatment. So, this positive BRAF study affects standard of care in your practice today, so you have to do that going forward.

There was a study looking at the novel, local therapy for pancreas cancer called tumor treating fields. That showed some positive data, finally, in pancreas cancer, so that's exciting. Tomorrow morning frontline trastuzumab deruxtecan data will be presented for patients with HER2-positive breast cancer, showing dramatic deltas and PFS and OS when you initiate treatment within trastuzumab deruxtecan instead of the traditional therapies there.

Practice changing common cancers. Precision medicine driven, IO-driven. It's a dramatic year for new data; new standards of care being presented here in Chicago. ASCO 2025.

John Marshall, Oncology Unscripted.

Live from ASCO: What the Slides Don’t Show

John Marshall, Oncology Unscripted ASCO 2025.

You know what this is? It's called the ASCO Daily News. They hand you one of those as you enter the building here every morning. And yeah, there's a lot of good science here, a lot of cool things, and pictures of prominent presenters. Even old oncologists get their picture here as well. But there's a whole bunch of stuff that's not in the oncology news that's really important to our future.

On Friday, Trump unfolded his budget. His budget includes a 40% reduction in the NIH budget. It is a huge delta in what will happen at the National Cancer Institute, if indeed this happens. 15% indirect rate officially now on the table. The Cancer Center Directors, NCI Cancer Center Directors, visited Capitol Hill last week hosted by Georgetown’s Lou Weiner, my boss, and they all went up to the hill to talk to various congressional folks about what the heck's going on. If you cut this budget, we will lose ground in terms of America's ability to contribute to cancer research at a time when we know more than we ever did.

Our European colleagues have put out advertisements to attract some of our major thought leaders to go to Europe, granting visas so that they can in fact do their own brain drain of us now that our budgets are being cut. So, we really have to figure it out. What we are doing and the impact this is gonna have day to day, not only on our research, but on our cancer care delivery, for our patients here in the United States. And I don't think folks have really thought that through very well.

Secondly, we of course have no NCI director right now. They're sort of an interim. And one of my friends, a guy named Wafik El-Deiry, who's at Brown, has put his hat in the ring. He had said some pro-Trump stuff coming into this year thinking that shaking up clinical research was gonna be a good idea, but he's sort of like, what are we talking about now? And he said, I'll do it. I'll do the job if you give me $50 billion for cancer research. Well, that's more than the current budget is. And of course, I just told you they're cutting the budget. So, I don't see any way that angle, that argument, is gonna take any traction with our current administration. So Wafik, I hope you get what's on your Christmas list, but my guess is you will not. And my guess is we will continue to go without an NCI Director, and an unclear future about the role the NCI is going to play, in global cancer drug discovery and drug development and looking for cures.

The other major theme that we're hearing here at this cancer meeting is that artificial intelligence is gonna be important. That if you're not doing it, if you're not embracing it on the education level, on the research level, any level you wanna look at, then you're gonna fall behind. And I think most of us probably agree that it's gonna be a very, very important tool.

But you that little thing called Make America Healthy again, that just came out from somebody named Kennedy. Well, that actually includes seven papers that were hallucinating. References in our national policy proposal that never were written that AI wrote instead. So, where's truth? How are we gonna know what's real? How are we gonna know what's a hallucination when we do our Google searches? How deeply does a journal need to review a paper to know whether AI wrote it or in fact, some fellow who wants to get a paper on their CV wrote it, right? How are we gonna prove truth going forward when a government policy paper has seven references that never existed, supporting what we're proposing. How are we as a major cancer community gonna keep track of what's real and what's not real? So, I'm very anxious about AI and how we're gonna manage that going forward. We know we need it. We don't know how to control it. Figure this out. Everybody.

John Marshall 

Oncology Unscripted.

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Badges, Booths, and Buses: Welcome to ASCO 2025

John Marshall, MD: John Marshall Oncology Unscripted. You know what this is? Yeah. You know what this is. This is my ASCO badge. It is that time of year again where I. I don't know, 40, 50, 60,000 of us and our closest friends all fly up to Chicago, stay in hotels that are overpriced, get bused around downtown Chicago, even on Saturday and Sunday. We get in nice clothes. We go to the convention center. We probably share a virus or two, but we mostly share important new information around the world of cancer. Maybe the most important cancer meeting there is on an annual basis, both from a social but also professional level do we gather to really exchange ideas and hear what's happening out there in the world Now. I also in my badge, got this, a 30-year member, God. know what that means? I got one also called ASCO Ambassador. I'm not even really sure what that means. Maybe I owe 'em money. I don't, I don't know what that's all about. I got my thing that I'm gonna submit to win whatever it is they're giving out, this year at ASCO. So, I've got all my equipment, I'm ready to go.

Titles of the abstracts have been released, and there's a lot of really cool information. I know we've been kind of having a sub-theme around pancreatic cancer, last few episodes and during the oral presentations, there are three very important, probably practice changing abstracts around pancreatic cancer, around perioperative treatment for resectable pancreas, cancers, novel therapies that are being brought to the table for pancreas cancer. So, whether you're going or not, you need to know what happened at ASCO. And so, stay tuned because we're also going to be broadcasting from the meeting, and we'll of course follow up with some of the key data post ASCO. 

Now, most of us, when we think about ASCO, we start with what are the plenary papers this year? And there are five. Two of the five happen to be GI. That's, that's a record. I think for us. Normally it's all breast and then maybe something else. But two of these five are in fact, GI cancers. One is around immunotherapy in the perioperative setting of gastric cancer. Gotta be positive. It's why it's in the plenary session. The other is not news in some way, but, God, if it had been negative, we would really need to rethink things. It's using IO therapy in the adjuvant setting for MSI, high mismatch repair deficient colon cancer. Important study around head and neck and immunotherapy. So, big, continued theme around immunotherapy, incorporation, some targeted therapy in breast cancer. Again, positive. Yet another positive breast cancer study, and the last is around polycythemia vera. Have to kind of throw something to the heme team there. So, it looks like a very interesting year for new data and new research.

But if you are thinking about ASCO, I mean. Will people be going? The United States is not the favorite place to be, particularly if you're from another country right now, a huge number of people usually come from around the world. I'll be interested to see do they decide to come, or do they decide to stay home because they're concerned about being in the US and feeling vulnerable at a time when nobody wants to feel vulnerable.

Have you ever been to ASCO? It's a zoo. It's a huge convention center, like I say, 40, 50,000 people that are there. But you keep crossing people that like, you know, we did fellowship together, or I know you, you're a friend of mine. Let's stop and talk for a second. Or let's just wave at each other and remember that each other still exists. It's a wonderful experience and if you've never been. You should absolutely go. If you've been every year for the last 30 years like me, then you're eager to go back and see all of your friends and show off your new comfortable shoes and your new tie.

ASCO has become more commercial. If you've ever been in the big area, the booth area where all the displays are, they're just remarkable and they have to be divided by US and EX-US because of the different rules. Although still, I've never seen one as quite as good as one I saw early on in my career where they actually had a flowing fountain of water through the entire exhibit. because it was a medicine to help dry mouth and so this water was going to improve your overall feeling, this water in the desert, if you will. I don't even think that drug actually ever really stuck around. But, anyway, they had the best booth, the most remarkable booth that I have ever seen, but it's still pretty commercial, pretty crowded. A lot of people crosstalk on the academic side as well as on the corporate side.

I was talking to a company the other day and they were saying that a very high percentage of their business actually gets transacted while in Chicago. Not just ideas exchanged in a follow up email or a call later, but they actually do the discussion and sign on the dotted line while they're in Chicago. So, a lot more closure at ASCO than I thought. I thought it was mostly openings, if you will.

In one word, what does ASCO mean to me, it's community. reminds us that we are part of a huge, invested, caring global community that's focused on curing cancer, and we get together to remind ourselves every year, recharge ourselves and take that energy back so that we can make it another year doing the hard job that we do. Community.

After ASCO, you definitely wanna tune back into Oncology Unscripted. We might have a couple of interviews that'll be interesting to you, but mostly we're gonna focus on the new data, the practice, transforming data that's out there that we're gonna want to, know about for everyday practice for you and your patients.

So, if you are a busy clinician. Maybe a generalist. Almost always the answer is 'no, I don't have time to go to ASCO.' It's not an efficient use of your time. Right. So, you would rather go on a Saturday to the best of ASCO and hear the best of, in one afternoon, one day. So, that, that's the practice changing stuff you need to take back with you. And I don't blame you one bit. I think it is the responsibility of us specialists to go to ASCO. like that and pull out all that we can pull out in our area. So, I'm not gonna go to the breast meeting and I'm not going to the lung meeting. I'm gonna focus on the GI meetings So, I can learn every little bit I can to help me be a smarter parson So, that I can help develop the next study and help those around me provide the best GI cancer care we can.

ASCO's a really, really special time for many of us. Usually, the weather in Chicago is pretty nice. We get a chance to meet new people that do what we do. We get a chance to check up with old people to know that, hey, you're still out there and you're doing okay, and you're making progress in the world of cancer care.

So, it's really an incredibly busy time. Sleep is out of the question. You just don't do it. You work all day long. You party until the wee hours, and then you get up and do it all over again, usually four days in a row. some of the busiest and hardest days of the year. But also, I would say some of the best days of the year. I can't wait to see many of you in Chicago at ASCO.

Crumbling Crown: The Collapse of America’s Research Backbone

John Marshall, MD: How's your week been this week? What's the federal government done to you in your world this week? I've been doing a little bit of math and I've been tracking my patients coming through clinic, and yes, I'm in Washington DC, So, my numbers are going to be higher than yours are in this regard. But right now, about one out of every five patients I'm seeing has been directly affected by changes in employment due to the changes that the government's putting into place. One in five. Either they've lost their job, they chose the fork in the road, or they're feeling eminently threatened by their current job status. Their current job status is vulnerable, if you will.

I sit in section 309 at the Nats Park. I have a half season. I'm there a lot. I drink an occasional beer while I am there. Baseball is my escape. The nice woman who sits right behind me, who's been sitting there for years as well. She, every time I go to a game, is there, and I said, did it happen? And so, last night I was at the game, and she said, no, not yet, but she thinks this week. So, it's everywhere around us, this dramatic downsizing that's just sort of sweeping the country, and we don't really know how it's going to have an impact on any of us going forward.

Now we, in the academic world, we in the cancer world are feeling this in a dramatic way. So, we have discussions every week at the leadership level of will grants continue to exist? Will funded grants be paid? We have examples where they have been withdrawn, right? I happen to know if somebody who was offered a cancer job at a prominent, stable, large, old academic institution withdrew the offer because they were uncertain about future budgetary issues because of the changes in grants. I've never seen that happen in my 35 years of being a faculty member. So, clearly a change in the world. you start thinking about the job that we have, this drug development and new discoveries. How will we go forward? Let's say I'm industry. How can I reliably continue to invest in this front? When I'm not sure how things are gonna go. If I'm an investigator based at an academic institution, how do I decide that that's a logical career path forward for my brain and my intellect if I don't know that there'll be this source of funding to do the research, to set the standard, to change the standard of care? 

In many ways, what we're hearing is that the United States is becoming increasingly irrelevant and untrustworthy for sure. The whole point of what we established in establishing the National Institutes of Health and the National Cancer Institute was to be the gold standard, to be the rock that was always going to be there, to be the constant stream of new data and new resources that will the actual improvements in many diseases, not just cancer. We know that that's why people would come and want to train here. So, the best brains on the planet would wanna come and train and be trained by us here in the United States because of this resource. And, of course, all of this is going away.

The Georgetown University faculty, my daughter, who is my sage. Yesterday, that our faculty, I somehow missed the memo, is now gonna hold a weekly vigil for one of our graduate students who was deported because according to the federal government, his visa status was not right. But really, we know it was because the research he was doing was not in line with what the current administration feels is important.

I don't know if you saw this, but the New England Journal editor in chief received what was perceived to be kind of a threatening letter basically accusing them of not publishing "competing viewpoints." A randomized clinical trial. Patient got treatment A versus treatment B, and the accusation is that the authors may be misleading the readers. So, is this an assumption that the science was fraud? Is it an assumption that there's a counterpoint to their hypothesis that was not listed in the science? I don't know. I don't even know where it comes from. So, this is where we are, is that the federal government is trying to undermine the veracity, the solidness, stableness of the data being presented by the New England Journal of Medicine, one of the journals that we have in highest regard, and it is their strategy, of course, right, is to doubt, to cause doubt, in things that we hold, to be the solid base and the truth, if you will.

Now, you all know that, talked about before on Oncology Unscripted this, this concept that the federal government sent Harvard a letter, which we talked about already, that basically said, we're freezing your funding. So, $2.2 billion of funding to Harvard has been frozen with an additional billion dollars in grants. And basically, threatening the education of international students. They're talking about removing Harvard's tax status.

And, of course, Harvard is the one group that has quite publicly stood up and essentially said, look, you don't have the rights to do this. And their president, Harvard's president, wrote this response, and I do wanna read it to you in specific.

It says the consequences of the government's overreach will be severe and long lasting. Research that the government has put in jeopardy includes efforts to improve the prospects of children who survive cancer, to understand at the molecular level how cancer spreads throughout the body, to predict the spread of infectious disease outbreaks and to ease the pain of soldiers wounded on the battlefield. Opportunities to reduce the risk of multiple sclerosis, Alzheimer's disease and Parkinson's disease are on the horizon. The government's saying, "no, we don't wanna know that." And the victims, will be the future patients, so writes their president. And their loved ones who will suffer with a heartbreak of illness that might have been prevented or treated more effectively.

So, this indiscriminate slashing of science, medical technology research is essentially undermined our role and our ability to help, not just Americans, but people around the world. The accusation, again said by Alan Garber, who's the president of Harvard is that this was the government's reaction to the university, Harvard being antisemitic Alan Garber is Jewish and American, and he basically says, look, we understand our role in all of this. They take their work very seriously, and they'll continue to fight hate with an urgency that it demands. And they will comply with all their obligations under the law they say, he says, it's not only their legal responsibility, it's their moral imperative. Such a strong pushback counter statement to that.

But then, you know, our Secretary of Education? No, you don't know who that is, but She's become famous really for a couple of things. One, she was at an AI meeting. She kept referring to it, because she can't read the teleprompter as A-one. Which of course the reason you know this is that every steak sauce joke in America comes from this statement, statement, this lack of understanding of even where she was.

But then she also was, in theory, the signatory or author of a response to Dr. Garber at Harvard for his letter that he had just sent, that I quoted there. And if you haven't seen this, this has been getting a lot of social media press just because of the quality of writing. You would think that our Secretary of Education could write a letter, particularly if you're writing it to somebody at Harvard that at least is grammatically correct, if not at least readable and understandable. But as you can see, and as I'm sure you have seen on social media, the people in charge aren't up to the game.

And that's how they're doing this. They're undermining education. They're undermining those sources that are our foundation of knowledge of truth, So, that we can get on with curing cancer or whatever it is that our cause is. But by undermining us, causing doubt on us, they can then bring their agenda forward.

And I want to restate what I've shown you before is that there is an ad out there. claiming that the current administration under the President's leadership will cure cancer by 2029. why does it matter what we do? Why does it matter where truth resides? Because the real truth is gonna come forward over the next four years, and we will no longer have to worry about cancer.

In the meantime, I hope to see you at ASCO in Chicago, and I hope you continue to do the right thing, to build truth, to build for the future because we know it's gonna be back on our shoulders soon, and in fact, the load will be heavier when it's back on our shoulders. So, be in shape, get ready because it is gonna come back to us to solve the problems.

John Marshall, Oncology Unscripted.

The Fellows’ Forecast: What First-Timers Expect at ASCO

John Marshall, MD: Hey everybody, John Marshall for Oncology Unscripted. We are getting all ready to go to ASCO and we thought it would be really interesting to talk to some people who are going to ASCO who have never been. I was thinking back, my first ASCO was in a year that started with 19, just to give you an idea, and it used to rotate around different cities. Been at Chicago, same place, same bat channel every year for many, many years at this point.

I was actually able to coerce some of our fellows who are making their first trip ever to ASCO to come on and for a quick interview, introduce themselves, give us some thoughts about what they're anticipating, and then if they're nice enough, maybe we'll grab 'em after ASCO to see what they learned and what was different than what they were expecting. So, listen in folks for what, you might reflect back as to what you thought before you went to your first ASCO.

Tina, introduce yourself and maybe give us one word of what's ringing around your head about what you're anticipating for ASCO.

Tina Roy, MD: Hi, I am Tina. I'm one of the second-year fellows at Georgetown, second year hematology oncology fellow. I did med school back in Scranton, Pennsylvania at Geisinger, and I did residency and now fellowship here. The one word that, I think of is, overwhelming because of how packed it is.

John Marshall, MD: That one's gonna come true. That one's gonna come true. Christian, introduce yourself. Give us your thoughts.

Christian Agbisit, MD: I went to med school in the Philippines, but then my residency in Illinois, and then ended up in Georgetown for fellowship. And my word is something big is at ASCO.

John Marshall, MD: Good. I think big, it will feel that way for sure. And last, but not least, Nikita.

Nikita Chintapally, MD: Hi everyone. My name's Nikita. I went to medical school in India at Kasturba Medical College, did my residency here in DC, and happy to be at Georgetown. I'm a first-year heme/onc fellow. My word for ASCO, as I'm a baby fellow, I still like to think of, is just ready to get inspired, I guess.

John Marshall, MD: That's awesome. And, let me tell all of you out there listening, and these are three of the smartest people. It's such an honor to work with these folks who have dedicated their entire lives and they know so much more than old people know, and I'm dependent upon them. And they're great partners for us, and they're nice enough to spend time with us. Actually, I snuck them out of somebody else's clinic right now to do this, so, I'm in trouble with their current clinic mentors. But anyway, let's get right into it.

Tina, let me pick on you first. When I first went to ASCO, I thought it was all about fun. I wanted a hotel with a good pool, in the, in the range of fun versus work. Where do you think this is gonna be? What's your impression of what it's gonna be?

Tina Roy, MD: I think it's going to be in the middle. Work because there's so many different events to go to. I've tried to make my schedule multiple times already and I can't decide for some of the sessions which ones to even go to. So, I think I'm going to even have to watch some, like on demand after. And then fun, there's a bunch of dinners planned already. I am planning on getting deep dish pizza, So, I think there'll be, it'll be fun too.

John Marshall, MD: There is a lot of fun. There is booze involved at ASCO. Sleep is not one of the big things. Christian, work-fun. Where are you in this balance? Here? 

Christian Agbisit, MD: Yeah, I think it's gonna be both. Basically, because I'm graduating and going into a community practice, I wanted to kind of soak in all the new stuff. 

John Marshall, MD: I wanna come back to you maybe afterwards about the community practice piece because you'll notice just that there aren't many community practitioners who go to ASCO but do get a feel for that when you're there. As you look at that, because it becomes not worth it to community docs to go to ASCO, which is always one of—and they go to best of ASCOs on a Saturday somewhere, later. So, I'd be interested in your feedback on that of the value that you see, as a rising community practitioner, in the future.

Nikita, where are you? Work fun.

Nikita Chintapally, MD: I am hoping it's more on the spectrum of fun for me. I'm hoping to, you know, do maybe meet some people, meet other fellows, happy to just branch out, network in any way possible. I'm really excited to see more people do like oral presentations. I think it'll be really inspiring, and it'll be a good way to get a sense of how people present their work in an effective way. So, I think that's what I'm looking forward to the most.

John Marshall, MD: One of my partners and good friends, and one of your mentors, Dr. Isaacs, is giving a. Big oral presentation, you gotta show up for that and see what it's like. Because it is, it does make you nervous when you get up there in front of, what is the largest room you will ever be in for a medical meeting. So, just so get ready for that is one piece of it.

Christian, let me pick on you. Have you thought about packing yet? Carry on. Are you gonna check? I mean, it's what, three, four days, right? So, what are you gonna do?

Christian Agbisit, MD: Well, basically just gonna pack like some shirts, and shoes, comfortable shoes for walking. 

John Marshall, MD: That is such a boy answer, isn't it? Mm-hmm. let's talk, I, you know, I'm a married man. I know about packing that it's different by gender, although some boys are more about their packing than others, but ladies, have you thought about it? 

Tina Roy, MD: Comfortable shoes.

John Marshall, MD: Heels? Let's start there.

Nikita Chintapally, MD: I'm doing sneakers.

John Marshall, MD: Sneakers. 

Tina Roy, MD: Definitely practical shoes.

John Marshall, MD: Okay.

Tina Roy, MD: I also am going for a day extra because I have a lung cancer event to go to beforehand, so I actually have thought about how many outfits, and I think I might need to go shopping this weekend. 

John Marshall, MD: So, it's remarkable. I will wait to see what is going on this year, which is how dressed up people are. This is just a warning. particularly when we see people from other countries, they tend to, there's a lot of heels when you and to Christian's point you, you know, you, you put a lot of steps on, right? I mean, you, you, one meeting to the next could be a quarter mile, in terms of just distances. So, practical shoes is a good piece of advice. Nikita, do you have a particular, have you already put it out on the bed? Know what you're gonna take? 

Nikita Chintapally, MD: I'm probably just gonna need to pack maybe like a blazer or some layers, because I know conference centers can get super cold.

John Marshall, MD: Cold. It's totally true. It's totally true. And you don't sleep by the way, just so you know. So, you, you party until late and then. You get up early because the next session that you really feel like you should go to is at 7:30 AM. And by the way, you're gonna be taking a bus with a bunch of other nerdy oncologists from downtown Chicago to the convention center sipping coffee. Don't spill it on yourself because you had to be careful with your pack, right? This is just advice, To go out there. it is a contact sport ASCO. So, you're also gonna see for the first time, Nikita, I'll start with you. It's like we've all been to meetings where pharmaceutical companies display stuff, right? So, I don't know if you've been to a big meeting before, but they have these halls where they have their booths and their maps, their actual maps. And so, any idea about what that's gonna be like?

Nikita Chintapally, MD: I have absolutely zero clue what that's gonna be like. I'll probably see the, you know, drug names that we use in clinic, and that'll be the extent of my excitement, but maybe I'll be, it'll be different. 

John Marshall, MD: Have you all had, have you been to one of these meetings where you've seen this kind of huge booth? 

Tina Roy, MD: I haven't seen huge pharmaceutical booths, but even some small ones can be pretty exciting. I'm expecting a, because I've heard about it, I'm expecting a lot, I think. 

John Marshall, MD: Well, one thing you'll notice, this is it'll freak you out—and you'll go, Dr. Marshall? The carpet is thicker, so they make fancier carpet to slow you down when you're on the booth. So that's one thing you'll notice. There are two sides, US and not US because there are different rules around regulatory, they hire people who are not real reps to stand on the corners to welcome you.

So, there's this big thing, the wildest booth I have ever seen. I'd be interesting if our listeners might chime in. many years ago, and it was a medicine for dry mouth, and they literally had a fountain flowing through a sand desert in the middle of this booth. So, when you all go, we always try to pick our favorite or maybe, worst booth that you, you went to go see. So maybe when we follow up later, you take a, share something with like, you were just like, whoa, that, that was, that was something.

Let's do something more important while we're really going. am, and maybe I'm back to Tina. So, what do you wanna learn? What are you expecting to learn?

Tina Roy, MD: I'm really excited about the trainee and early career lounge because of meeting other mentors, meeting other fellows. So, I’m hoping to learn a little bit more about the job application process. See different people in different practices. I am also really excited to see what interaction is between pharmaceutical companies, oncologists, what kind of atmosphere there is.

So, I think I'm kind of, of course, those big like plenary sessions, oral abstracts. I'm excited about learning the nitty gritty about what's happening, but also just like that atmosphere and interaction between the different groups that are there.

John Marshall, MD: That's great answer. Christian? 

Christian Agbisit, MD: Kind of same thing as Tina. How I can treat my patients, plenaries and which are the, well, the new stuff that comes out in.

John Marshall, MD: You know, if it's in the plenary, it's positive. So that's one of the things you can pretty much bank on, going forward. Nikita, what are you hoping to learn from all of this? That you really wanted to be a surgeon? No, no, no. Something different.

Nikita Chintapally, MD: Never, yeah, definitely similar to what Tina said about the early career and mentorship, as I'm going into second year, we have more research time, so hopefully trying to see, you know, you know, what could be feasible from my standpoint. Get some ideas and just again, big, big picture. Get really inspired, hopefully.

John Marshall, MD: I think you'll be surprised. By the number of people that you actually recognize. You'll, you'll cross paths, maybe, you know, through your training at other institutions or just you'll see people you recognize. And of course, it is when you're as old as I am. You recognize lots of people. I think. So that's one thing that is fun too, is that you connect to people that you don't see often or regularly.

It is time to connect, the internationalness of it is quite striking. So, you'll see people from all over the world. are certain countries that do not allow, or we don't let them in. To be blunt. And so, they will go to ESMO or other meetings so that you will notice the absence of certain people, maybe, you know, over time because their countries don't allow, or we don't allow their immigration in.

But very much of an international feel to it. It's both exhilarating, I think. But it's exhausting too because you are learning. There's a lot of new stuff you're drinking in. There is a lot of business that's transacted during the meeting, and a lot of new data that's unloaded on us.

And so, what we then try to do is take this information as say just a GI specialist and try to integrate it into how does it affect treatment on the Wednesday, when we get back on June 4th. So, from there. So, any last thoughts? Christian, you got a plane ticket,

Christian Agbisit, MD: Yeah.

John Marshall, MD: okay, you got a hotel? Okay, then those are the two most important things, Nikita, any thoughts?

Nikita Chintapally, MD: What are you most looking forward to, Dr. Marshall?

John Marshall, MD: Well, so my problem is, is that I'm overbooked and so, I, I, you know, which meeting will I actually go to, and will I actually go and see any data being presented? So, I'm at a place where I almost never go into the posters or to the presentations because I got too much other stupid stuff going on in my world.

It’s an enjoyable event because so much, it is our community. It is a celebration of our community. It's, it's an excitement. You all talked about being inspired and, you know, reaffirming what you do so you leave, you leave charged and ready to, to move on to cure cancer. 

Thank you, guys, very, very much. I know you gotta keep running. We'll get back together in a couple of weeks and see what you learned when you went to the 2025 ASCO.

John Marshall for 

Oncology Unscripted

Talk to you all soon.

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