#62–Keith Flaherty, M.D.: Deep dive into cancer—History, novel treatments, & the exciting future

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [upbeat music]

2. 0:04 – 7:41

   Why the podcast runs on listener support, and the guest introduction

   1. PAPeter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] Hey, everybody. Welcome to this week's episode of The Drive. I'd like to take a couple of minutes to talk about why we don't run ads on this podcast and why instead we've chosen to rely entirely on listener support. If you're listening to this, you probably already know, but the two things I care most about professionally are how to live longer and how to live better. I have a complete fascination and obsession with this topic. I practice it professionally, and I've seen firsthand how access to information is basically all people need to make better decisions and improve the quality of their lives. Curating and sharing this knowledge is not easy, and even before starting the podcast, that became clear to me. The sheer volume of material published in this space is overwhelming. I'm fortunate to have a great team that helps me continue learning and sharing this information with you. To take one example, our show notes are in a league of their own. In fact, we now have a full-time person that is dedicated to producing those, and the feedback has mirrored this. So all of this raises a natural question. How will we continue to fund the work necessary to support this? As you probably know, the tried and true way to do this is to sell ads. But after a lot of contemplation, that model just doesn't feel right to me for a few reasons. Now, the first and most important of these is trust. I'm not sure how you can trust me if I'm telling you about something when you know I'm being paid by the company that makes it to tell you about it. Another reason selling ads doesn't feel right to me is because I, I, I just know myself. I have a really hard time advocating for something that I'm not absolutely nuts for. So if I don't feel that way about something, I don't know how I can talk about it enthusiastically. So instead of selling ads, I've chosen to do what a handful of others have proved can work over time, and that is to create a subscriber support model for my audience. This keeps my relationship with you both simple and honest. If you value what I'm doing, you can become a member and support us at whatever level works for you. In exchange, you'll get the benefits above and beyond what's available for free. It's that simple. It's my goal to ensure that no matter what level you choose to support us at, you will get back more than you give. So for example, members will receive full access to the exclusive show notes, including other things that we plan to build upon, such as the downloadable transcripts for each episode. These are useful beyond just the podcast, especially given the technical nature of many of our shows. Members also get exclusive access to listen to and participate in the regular Ask Me Anything episodes. That means asking questions directly into the AMA portal and also getting to hear these podcasts when they come out. Lastly, and this is something I'm really excited about, I want my supporters to get the best deals possible on the products that I love. And as I said, we're not taking ad dollars from anyone. But instead, what I'd like to do is work with companies who make the products that I already love and would already talk about for free and have them pass savings on to you. Again, the podcast will remain free to all, but my hope is that many of you will find enough value in, one, the podcast itself, and two, the additional content exclusive for members to support us at a level that makes sense for you. I want to thank you for taking a moment to listen to this. If you learn from and find value in the content I produce, please consider supporting us directly by signing up for a monthly subscription. My guest this week is Dr. Keith Flaherty. Keith is a physician scientist at Massachusetts General Hospital in Boston, where he's the director of clinical research as well as targeted therapies. His research focuses on the understanding of targeted therapies in cancer. And if that term is a bit nebulous to you, don't worry about it. We define it quite clearly. Uh, and he focuses on the development of responses and predictive biomarkers to define the mechanisms of action and resistance of novel therapies. He's researched a lot of stuff in immunotherapy, so this is really the first podcast that I discuss immunotherapy in, which for me is super exciting because I've been looking forward to discussing this topic for quite some time. And, uh, you'll see why when we get into it, because immuno-based therapies are basically the most exciting recent development in cancer therapy. And we talk quite a bit about these checkpoint inhibitors for which actually the Nobel Prize in Medicine and Physiology was awarded last year. He's been a PI in too numerous to count first-in-human clinical trials using novel therapies. What else can I say? He's a professor of medicine at Harvard Medical School and serves as editor-in-chief of the journal Clinical Cancer Research. Overall, Keith is really a wealth of knowledge in cancer. We talk about a bunch of stuff. Now, honestly, the first twenty minutes we're just talking general life, medicine. We don't even touch on cancer. So if you're short on time and you really just want to get into the stuff on cancer, definitely jump ahead to twenty minutes into this stuff. We talk quite a bit about the history of chemotherapy, what its successes were, why they asymptoted. Same with radiation therapy, surgical therapy, and ultimately what took place and what didn't take place, maybe more to the point, in the Period of time between when the War on Cancer was declared in 1974 and the sequencing of the entire human genome about 25 years later. And then we talk about what took place in the two decades since that time. And you'll see that, well, at least even for me, I think you'll tell, I was actually learning quite a lot here vis-a-vis how some of those changes took place. And, uh, again, for that reason, this was a highly enjoyable experience, even if not one person listens to this podcast. I got a ton out of it. We, you know, basically got into this notion of what's a different approach to cancer. And again, clinically, I found this very helpful because this is a problem I think a lot about. So I, I do think people will, will enjoy this. We talk a little bit about liquid biopsies, even touch on roles of, you know, potentially CRISPR and over-hyped with respect to cancer therapies potentially. Even at the end, talk about stem cell therapy, vitamin D, melanoma, sun exposure, the list goes on. This is a pretty long episode, so hopefully we talk slow enough that you can listen to it at a slightly higher speed. And the show notes, as always, will contain a ton of information, not just links to the studies we talk about, but a lot of the semantics. I wouldn't be discouraged if you find this topic, in particular this episode, to be somewhat challenging based on how technical it gets at times. I think we both do a pretty good job of remembering that we're not just talking with each other, and I try to ask questions to bring us back thirty thousand feet and focus on the big stuff. But in many ways, I think this will be probably the deepest podcast I've done to date on cancer, though certainly not the last. So without further delay, please enjoy my conversation with Dr. Keith Flaherty. [upbeat music] Keith, thank you so much for letting me intrude in the middle of your living room on a rainy Monday afternoon.

   2. KFKeith Flaherty7:40

      My pleasure, Peter.

3. 7:41 – 16:43

   Boston weather, Flaherty's upbringing and the path into medicine

   1. PAPeter Attia7:41

      Is this normal Boston April weather? It must be, right?

   2. KFKeith Flaherty7:43

      This is the wet season, mud season as they call it, but it's a welcome break from winter. Hasn't been a particularly harsh one, but yeah, it's a good, good transition time. It was brown last week, so everything's just finally waking up.

   3. PAPeter Attia7:56

      [chuckles] Now, you've pretty much spent your whole life from basically Connecticut to-- or actually Connecticut south of Boston, right? So-

   4. KFKeith Flaherty8:06

      Right

   5. PAPeter Attia8:06

      ... so sort of basically Boston to Baltimore-

   6. KFKeith Flaherty8:07

      Yeah

   7. PAPeter Attia8:07

      ... this has, has been most of your life, yeah?

   8. KFKeith Flaherty8:09

      That's right. Born and raised in Baltimore, broke away to boarding school in Massachusetts for four years, Connecticut for college, four years, then back to Baltimore, four years of medical school, Boston for the first time, three years of residency, and then Philadelphia for nine years, which was both medical oncology fellowship and my first faculty stint. And now 10 years ago, I moved back up to Boston to Mass General, so this fall will be 10 years. But as you say, Northeast Corridor through and through.

   9. PAPeter Attia8:37

      Yeah. Well, you get your seasons, right?

   10. KFKeith Flaherty8:39

       Yeah. That's always my defense of the Northeast to Californians is I need the seasons, and certainly during my educational years, I always thought if I had San Francisco, LA, or God forbid, San Diego weather, not sure I really would have been able to keep my nose to the grindstone.

   11. PAPeter Attia8:54

       [chuckles]

   12. KFKeith Flaherty8:54

       The seasons are good to kind of force you inside and, uh, take your breaks when you need them.

   13. PAPeter Attia8:59

       Well, I think there's something else about it that I sort of lament. Both my wife grew up in Baltimore, I grew up in Toronto, and there is an intestinal fortitude that comes from being in a climate that is not particularly hospitable.

   14. KFKeith Flaherty9:09

       Yeah.

   15. PAPeter Attia9:09

       Um, you get a little tougher as a kid, I think, when it's... You have to pay attention. Like, if you forget your gloves, like, you're hosed.

   16. KFKeith Flaherty9:15

       Yeah, you're gonna pay for it.

   17. PAPeter Attia9:16

       Yeah.

   18. KFKeith Flaherty9:17

       I suppose that's true. I think resilience comes from a few parts of one's upbringing, but climate is probably, you're right. It's at least a bias of mine that, that it's a good thing to have. Even as the years keep passing and I think about, well, where would I want to spend the next ten years, twenty years beyond, I love it up here. I mean, for me, it's really the-- it gets just brutal enough in the winter, but not Canadian brutal.

   19. PAPeter Attia9:38

       Although Boston is its own little-- Boston and Toronto are not that different.

   20. KFKeith Flaherty9:42

       Oh, okay. Yeah.

   21. PAPeter Attia9:43

       Yeah. Montreal might be worse, but yeah.

   22. KFKeith Flaherty9:44

       Yeah. I just have more-- figuring latitude drives harshness of winter. I have more respect for Canadian winters, but maybe it isn't that different. I feel like, again, just gets harsh enough, and then in the summertime, get the payoff for the flip side, which is just so pleasant, but not like Baltimore burdensome in terms of the heat and humidity.

   23. PAPeter Attia10:00

       So you're kind of one of these guys who was exposed to medicine throughout, right? But I know your father was a physician. Your mother was as well, right?

   24. KFKeith Flaherty10:06

       Yeah, that's right. My father was a academic cardiologist for twenty-five years, and then almost an equal stint in industry, pharma and biotech. And my mom was an academic psychiatrist, actually really still is at the age of now seventy-- will be seventy-six end of this month. Very different career in psychiatry versus cardiology, but an academic career nonetheless. So a bit of research, a lot of teaching, mentoring, and that bit continues. She has incredible stamina for staying connected with her field. She's retired from patient care good long time ago, but couldn't give up the rest, and so continues to haul herself off to conferences and oral examinations that are still required for, for psychiatric boarding and so on. So kind of a inspiration in terms of longevity in the field.

   25. PAPeter Attia10:51

       You knew pretty early that you wanted to go into medicine, or was that not even clear when you went off to college?

   26. KFKeith Flaherty10:55

       Yeah. No, it wasn't clear to me at all. I mean, I honestly would have to admit that I didn't really understand how my parents' worlds turned. They were perfectly transparent and happy to talk about their careers. I just didn't know to ask the questions. I had two older brothers who then and now had no interest in science or medicine. I guess all that I could say from a young age, maybe by the time I was in boarding school and going to college, was that some way, somehow I wanted to help people. This is a phrase that I recall saying, but I had no idea what that might mean and what the different versions of it were. As years passed, I got more and more of the sense that a lot of how the world turned was kind of transactional business transactions, I suppose, people making careers on some version of transaction. I had this aversion or developing this aversion to that idea that I didn't want to be involved in what I broadly construed to be business. Now, we'll come back to this later, but-

   27. PAPeter Attia11:53

       I was about to say the irony, but okay.

   28. KFKeith Flaherty11:55

       Absolutely. I'm laying that right out, right out there for you. There's so many ways in which I turned on that. There's a, I mean, in a good way, have turned on those initial principles. But yeah, any case, I thought this idea that I needed to find a path where I felt like I was very directly helping people was gonna be the most sort of satisfying career and something that would get me out of bed in the morning without having to really try. That part I'd say really did work out. So I think that's probably the one piece that I think I did get from my parents. So I didn't know exactly what they did when they got to the hospital.

   29. PAPeter Attia12:27

       But you had some sense that it involved people, and they were in a probably a more direct way of helping. I mean, you could argue most people are helping people-

   30. KFKeith Flaherty12:34

       Yeah
4. 16:43 – 25:16

   Medical education, investigation and the accelerating pace of oncology

   1. PAPeter Attia16:43

      And medicine still may be one of the slightly easier places to do it because the path to, quote-unquote, "academic success," non-academic clinical success, it's still relatively unperturbed from so many other paths, right, outside of medicine, or is that not even true anymore?

   2. KFKeith Flaherty16:58

      I don't see it that way, but I'd be interested in your perspective as a surgeon 'cause I think maybe we have a different angle on that, being in medicine versus surgery, which obviously culturally have always had some real differences, not just culturally, sort of skill sets. So a thing that I've been deliberating on, let's say this, I've had a 20-year oncology career, almost 20 years, a few months away from that. Um, so I divide my career up into these two decades, and I've watched technology advance and the field-wide body of knowledge accelerate in a 2000 to 2010 interval and then these past 10 years. And this is true in so many areas of technology advance, but in biomedical research and in cancer, which my only area of any expertise, I thought 2000, 2010 was mind-blowing.

   3. PAPeter Attia17:41

      Mm-hmm.

   4. KFKeith Flaherty17:41

      And I thought we were gonna spend time catching up with the mind-blowing advances. That was my talking point coming into the field in 2000 that I thought we've got this huge wave of molecular insights, mostly genetic insights in terms of cancer that had built up but hadn't been transformed in medicine. That was my unbelievably naive, simple-minded pitch as I was entering the field, and I said I wanna make myself useful in that translation of science and medicine. Anyway, 2000, 2010 then you could say were the first chapter of translating molecular insights into medicine. in oncology. Well, 2010 to 2020 makes that first decade look unbelievably slow and where it was every two years there was maybe a monumental event, whereas now it's like six at a time. So that's in terms of like crossing the finish line. But in terms of data generation, ability to produce high dimensional data, analyze it, try to make sense of it, raise hypotheses, test hypotheses, yeah, the cycle time is changing a lot, and the constituents that we now need to interact with are totally different. The point I'm coming to, to answer your question is, I see medicine now as this terrifying arena in which to try to assemble a multi-decade long career. Like, how do you keep yourself relevant in a, let's say, 40 year arc? Here I am at 20 years and feel like I'm an absolute dinosaur. Mentoring is the thing that I think I can still do with some relevance to the younger generation. And in mentoring them, I tell them, "Look, you need to learn how to talk to a bioinformatician, computational biologist." I couldn't have even imagined 10 years ago that I'd be telling my mentees that, much less that I would have this notion that I need to understand the world from that degree of mathematical modeling complexity. But it's having now mentees who are in computational biology myself, I've come to realize that it's, I didn't have the skillset at the dawn of my career. Is it possible for people, broadly speaking, to actually retrain themselves and grow a new lobe of their brain? It's possible, but it's gonna force a totally different paradigm in terms of how one thinks about taking breaks, taking sabbaticals, gaining that knowledge base.

   5. PAPeter Attia19:48

      So I was actually thinking of something different, but what you're bringing up is more interesting, so I want to double click on that before we jump into the meat of what we're going to talk about. Based on the way you're describing it, Keith, I would say doctors coming out of training are hosed because medical school, and I'm going to really make a lot of enemies by saying this, but I guess it's my podcast, I'm allowed to say this. I think medical school might be one of the most anti-intellectual forms of higher education that exists. I mean, when you contrast it with even the experience that many people have in college where you really get to think creatively, you really get to problem solve, you really get to explore the limits of what is known and what is not known and ask questions. Not having gone to law school, but my brother did. I got to see my brother do that in law school. Having more friends than I can count who did PhDs in everything from the humanities to the sciences, they got to do that. Well, I went to a good medical school, but that's not the way my education was, and I'm not sure it's that much more like it today. In other words, I'm not sure medical school teaches you how to be a thinker or a problem solver or even, and maybe, again, I hope I'm wrong, but if you don't learn how to learn, and God forbid the people who go into medical school as pre-meds, so then they've missed out on at least taking an engineering degree or taking a humanities degree where you would have got some of that stuff. So, so yeah, then I think you're in real trouble.

   6. KFKeith Flaherty21:04

      I totally agree with you, and the word that you didn't use that I'll use is investigation. That's not taught. And at best, it's taught in a retrospective field wide introspective way, and by that I mean like diagnostics. I mean, thinking about how to diagnose illness in medical school is the beginnings of teaching that concept.

   7. PAPeter Attia21:24

      I actually tell people the one type of statistics that physicians get very well trained in without explicitly being told what they're doing is Bayesian statistics, because that really is clinical medicine. Clinical medicine is pure Bayesian statistics. It is learning how to update your pretest probability with new information over and over again. And the reality of it is that doctors get very good at that. It's never codified and formalized such that they understand that that's actually what's being taught.

   8. KFKeith Flaherty21:49

      Yeah, although contaminated by bias, as in recency bias, right?

   9. PAPeter Attia21:52

      Yeah. Oh, yeah, yeah, yeah.

   10. KFKeith Flaherty21:53

       So this is a huge issue in the practice of medicine that you're so clouded by the last few outcomes, your pretest probability is not as accurate as it could be if you were able to eliminate that. Going back to that point that medical school, it teaches information as fact. It teaches the known. That known unknown divide is exactly, it's my pitch in academic medicine, at least talking to people about cancer as a career. I tell them, "Look, it's so simple to find the boundary between what's known and not known. There's so much out there we don't know." And in any area of trying to understand physiology, pathophysiology in the mode of cancer, you will so quickly get to that frontier. And then how do you operate in that frontier? Once you're there, how do you help the patient in front of you, the next wave of patients that are coming in the not too distant future, and then like a full generation out? How do you help across that gradient? Well, investigation is the only way you can pose yourself as being helpful, and that, I didn't get that in medical school, sadly, even though I was at a fantastic environment for learning the archival version of medicine.

   11. PAPeter Attia22:54

       That's a great way to distinguish, right? I mean, you go to a place like Hopkins, you're going to get the best archival education imaginable. You're walking through the halls where the actual profession came to North America.

   12. KFKeith Flaherty23:06

       And I actually, it was one of the things I cherished when I was there and the few books I brought with me out of medical school, surrounding myself with books that are not medicine as a general sport, were the history of medicine. I mean, Osler particularly I thought was absolutely an Aristotelian figure. So I thought those are the roots and we have to figure out how to reimagine ourselves like those great builders of the medical discipline. So anyway, it was very retrospective and it wasn't really honoring the notion that everybody in the field, particularly these big academic centers that are given tons of resources to investigate, can and should see themselves as being absolutely on the frontier. It's a more dynamic frontier now than ever before, mostly because the sensing technology to be able to actually understand what's wrong in the system and when you perturb the system with the therapy, how the system responds. Cancer is such a great example of this. Our sensing technologies have just gone berserk in terms of the acceleration So there's just so much more that one can learn. But again, this is the concept that only, even in my oncology training, I didn't get that. My oncology training was the same notion of learning about how we got here over decades. Well, my talking point going to oncology was that I was right at this end of the conventional chemotherapy era, as I was calling it, and the beginning of the so-called molecularly targeted therapy era, but it hadn't happened yet. And so I wasn't interested in learning about the past.

   13. PAPeter Attia24:27

       So in other words, you could see that the futility of chemo, which basically had made minimal progress over 40 years.

   14. KFKeith Flaherty24:32

       Well, it reached an asymptote, right? So you basically, if you blindly develop drugs against cancer cells to find out what's poisonous to them, and then you filter those in mice to see what kills the mice at equal concentrations versus what doesn't quite kill them, and you call that your possible therapeutic, what will you get out of that? This is one of my first lectures that I used to give to medical students about cancer therapeutics as I was trying to outline a path forward, is that basically what you get out of that is all these agents that tangle the DNA and some microtubule stabilizing and destabilizing drugs. And the blind approach only gave those types of therapies. Those types of therapies then thrown at cancer cure a good fraction of testicular cancer, a respectable fraction of lymphomas and leukemias, and cure almost nothing else.

5. 25:16 – 37:14

   Why chemotherapy, radiation and surgery hit an asymptote

   1. PAPeter Attia25:16

      Let's pause there for a moment because we're going to just dive right into cancer. But in the spirit of being true to the history, let's just reproduce what you said. So let's take a step back. Many people listening to this certainly hear the terms chemotherapy, radiation therapy. It might be a bit of a fog beyond that. So what you just described was chemotherapy, and what you just described was an arbitrage that must be true. Chemotherapy, it's not hard to kill a cancer cell. It's actually very easy to kill a cancer cell.

   2. KFKeith Flaherty25:44

      Yeah, bleach does a fantastic job.

   3. PAPeter Attia25:45

      Yeah, bleach, formaldehyde, go to Home Depot, most things on the shelf kill cancer perfectly. Problem is they kill everything perfectly. So the arbitrage you describe eloquently is it has to kill cancer and almost kill, but not kill, not cancer. So that's a narrow subset of things. And as you described it, they're targeting DNA for the most part, which is why they're targeting things that grow, which is why when most people think of a patient on chemotherapy, the first thing they think about is their hair's fallen out. They've got sores in their mouth.

   4. KFKeith Flaherty26:16

      Yeah.

   5. PAPeter Attia26:16

      Their nails are brittle. And if you look a little deeper, you'll understand that their gut is really falling apart. What's common to all those things, right?

   6. KFKeith Flaherty26:23

      In their bone marrow cells.

   7. PAPeter Attia26:24

      Yep.

   8. KFKeith Flaherty26:24

      Yeah, rapidly dividing bone marrow cells. That's exactly right. So the analogy I u- oftentimes use with patients about talking about chemotherapy is it's a bicycle going down the road slowly, one bike going very quickly, one going very slowly. So the cyclist in this case being the determinant of that. And you're standing between two cars with your broomstick, and you come out to throw your broomstick in the front wheel of those two bicycles. One of them goes ass over tea kettle, and the other one looks at you and says, "What, what are you, what are you trying to do here, punk?" And it's that fast-growing cell concept. It's that filtering system of what can kill a fast-growing cell. That's what generated those hits. We could have come up with other hits potentially if the chemical diversity of probes that were used were broader, maybe other hits could have been found.

   9. PAPeter Attia27:11

      For example, we didn't really look at metabolic distinction between them beyond DNA. That Warburg's stuff left behind, we'll come back to it later. But you're right.

   10. KFKeith Flaherty27:20

       How to manipulate it particularly was the completely lacking. This concept of you take cancer cells, you establish this mind-blowing ability to grow them outside of a patient and create so-called immortalized cancer cell lines, Henrietta Lacks cervical cancer being paradigm example out of Hopkins, but eventually dozens to hundreds to now thousands and hundreds of thousands of these cell lines, which ones take in plastic versus which ones don't? Well, there's definitely a fast versus slow cell growing just by cancer type. And then within the cancer cell population, which is always heterogeneous, you've got faster and slower growing varieties there too, and the ones that take are these hot rod cells. And if you then use that as your filtering mechanism to ask, "Well, what will kill them?" What you come up with are these toxins to, to rapidly dividing cells. That's exactly right. So that caps... The term chemo, when I use it, is always to describe these things. Now, an important piece of nomenclature is that people will still always say that, well, a cancer therapeutic is a chemotherapy.

   11. PAPeter Attia28:14

       Right. But no, I favor the way you think about it. I like to think of chemo as that type of chemical. Immunotherapy is used chemicals, but they're totally different, right? Metabolic therapies, PI3K inhibitor, I'm not really considering that chemo. But I want to put a point on what you said because it's, it's sad, but it's just the reality of it. So when Nixon declares a war on cancer, it's what? It's about '72, '70-

   12. KFKeith Flaherty28:35

       '74.

   13. PAPeter Attia28:36

       '74.

   14. KFKeith Flaherty28:36

       Yeah.

   15. PAPeter Attia28:37

       Okay. If you look at 10-year survival for metastatic solid organ tumors, so I'm going to just take out leukemia and lymphoma, and as you pointed out, we have seen success in some of those, and we'll come back to it. From a solid organ metastatic perspective, from '74 until 10 years ago, isn't testicular the only success, maybe, and GIST?

   16. KFKeith Flaherty29:01

       Yeah. Yeah, GIST was an early targeted therapy success from-

   17. PAPeter Attia29:04

       So testicular, basically seminomous testicular tumor.

   18. KFKeith Flaherty29:06

       That's right. You could cure with doublet chemotherapy. You could cure the large majority, greater than 90% even.

   19. PAPeter Attia29:11

       But if a woman had metastatic breast cancer in 1974 and a woman had metastatic breast cancer 40 years later-

   20. KFKeith Flaherty29:17

       Shockingly little difference.

   21. PAPeter Attia29:18

       I mean, we had median survival extensions of maybe six months, 12 months.

   22. KFKeith Flaherty29:22

       Yeah, per new therapy that might come along at best, and then you could stack a few of those in a disease like breast cancer. So what actually kills the population of cancer, breast, colon, prostate, and lung, and then pick up some other notables that are still refractory to this day, like pancreatic cancer and so on, in terms of number of deaths. But the common cancers, they are perturbed at best a little bit by these agents. So some subpopulation of those cells will slow down and die with conventional chemotherapy, but many of them are pre-wired. They were hardy to begin with. They got there through a hard-earned evolution under selective pressure of the immune system and adverse metabolic environment, and they used all the tricks up the sleeve of a cell, of a normal cell, to reprogram themselves to be able to survive in these harsh environments. You throw in another harsh environment reagent in the form of chemo, and not surprisingly, that these things were already basically hardwired to be able to survive yet another insult. But that's chemo.

   23. PAPeter Attia30:18

       That's an interesting way you explain that. I think that that's important, I think, for a listener to understand is a cancer cell has to overcome a heck of a lot to get to be clinically relevant. So how many, I used to remember all the numbers and the growth rates, but A clinically relevant mass has how many billion cells in it approximately?

   24. KFKeith Flaherty30:33

       Yeah. Well, clinically relevant that you can find on a scan-

   25. PAPeter Attia30:35

       Yeah, like something that you could see, like a one by one by one centimeter cancer.

   26. KFKeith Flaherty30:38

       No, you're in a billion cells already at that point.

   27. PAPeter Attia30:39

       Yeah, you're at a billion cells. So just to get a billion rogue actors, you have to evade T cells, you have to grow your own vascular supply, you have to overcome, as you said, adverse metabolic conditions. These things are evolutionary warriors by this point.

   28. KFKeith Flaherty30:56

       Yeah. I mean, I usually start... You're absolutely right. These are the fil-

   29. PAPeter Attia30:58

       I mean, it starts much smaller though

   30. KFKeith Flaherty30:59

       ... these are the filters. Yeah, no, no, but I start with the analogy, there's like a random spinning of the combination lock where mutations are being acquired over time through a variety of insults, or not even necessarily insults, just bad replication, uh, technology, if you will, where the detection of errors and the correction of errors is not perfect. Anyway, we accumulate mutations over time, some of which we could limit and control, some of which we can't. The combination lock is just spinning, spinning. The combination has to be dialed in the right sequence, just like when you're opening your gym locker or you don't get cancer. You've got to get your tumor suppressor early and in the right order before your activated oncogene comes along. You're randomly spinning the lock, you're picking up lots of passenger mutations, not just true drivers, so these incidental mutations that happen here and there. So as that's happening, you finally click important components of the program, but along the way, some of those are actually mutations that are seen as foreign by the immune system, and if they're too visible-
6. 37:14 – 45:57

   The genome era: drivers, two-hit hypothesis and the hope for an AZT of cancer

   1. PAPeter Attia37:14

      So let's take stock of where the world was 25 years after the war on cancer was declared. It's the late '90s. The scientific community is on the cusp of fully sequencing the human genome. At this point, we know a number of things, right? I mean, that's when I was in medical school. We certainly understood that cancers are initiated by genetic mutations and everything you alluded to with respect to genes that suppress tumors and genes that promote tumors, the relationship there is pretty well understood. If you refresh my memory, I also think people understood that virtually all of those mutations were somatic. Did anybody have a hope that the Human Genome Project was going to give us a whole bunch of germline mutations-

   2. KFKeith Flaherty37:57

      Yeah

   3. PAPeter Attia37:57

      ... that cause cancer? No, I don't think we believe that, right?

   4. KFKeith Flaherty37:59

      No, that's right. You're right, the spinning of the combination lock concept, the right sequence, Bert Vogelstein innovation in colorectal cancer initially, that was in hand by the late '90s, that, that basic concept. Now, what was left to be sorted through and a justification for doing whole genome sequencing in cancer was that we didn't know what that sequence might look like across cancer. We didn't know what the spectrum of genetically simple to genetically complex cancers was, and I mean that at the individual cell level, not talking necessarily about across all cancer types. So what I'm getting at is, do you need three mutations to get a cancer? Is eight somehow better a number? By that, I guess, I mean, just look at a distribution of, quote-unquote, "true drivers".

   5. PAPeter Attia38:41

      So wait, 'cause I sort of know the answer today, but I, I never actually thought about this then. In 1999, did we know if the average breast cancer had three versus 30 versus 300 mutations?

   6. KFKeith Flaherty38:51

      No, and most importantly, how many-

   7. PAPeter Attia38:54

      How many were drivers?

   8. KFKeith Flaherty38:55

      ... true drivers? I mean, I'd say true drivers 'cause that term driver is thrown around a bit and true driver... What are the essential building blocks? And we'll come back to what essential ultimately means, 'cause I think that has to do with therapeutic vulnerability. But any case, yeah, this idea of how many hits did you really need? Remember that Knudson described this, you know, the two-hit hypothesis, right? And it seems reasonably clear that in very simple tumors, two hits actually might be enough. Now, probably then, I think it fair to hypothesize-

   9. PAPeter Attia39:25

      Explain for the listener what two hits-

   10. KFKeith Flaherty39:27

       Oh, sorry

   11. PAPeter Attia39:27

       ... means in that situation, 'cause that's a great teaching example.

   12. KFKeith Flaherty39:29

       Yeah, so two hits, I mean, as it was initially construed, really was the combination of the inactivation of a tumor suppressor gene, tumor suppressor gene being, by definition, a gene when its function is disabled, cancer becomes more likely. Nearly all of the genetically inherited cancer types that people are familiar with come from having a inherited alteration that partially or completely disables a tumor suppressor gene. We know very few of the opposite, which is the activation of another gene. Oncogene could just mean cancer gene, but in the field, most people think of oncogene as the thing that gets activated and tumor suppressor gene as the thing that gets inactivated. That's the simplistic version of the two-hit hypothesis.

   13. PAPeter Attia40:08

       So you're born with two copies of each gene and one of them is not working, of a tumor suppressor gene.

   14. KFKeith Flaherty40:12

       Yeah.

   15. PAPeter Attia40:12

       And later on in life, just from a stochastic process, you only have to hit it once, not twice, which is far less likely, and that's why these are patients that are getting cancer in childhood and adolescence.

   16. KFKeith Flaherty40:23

       And multiple of them over time, new unrelated cancers, sometimes in the same organ. I mean, a patient with-

   17. PAPeter Attia40:28

       Yeah, multiple colon cancers. Yeah.

   18. KFKeith Flaherty40:29

       Exactly. They keep starting new cancers over and over again. Now, even in the most genetically simple cases, I would just quickly assert that we have plenty of evidence now that suggests that you get these genetic alterations that can dial the combination lock in the right way. But the simplest genetic defined cancers almost certainly have then a, quote-unquote, "epigenetic," as in not hardwired mutation alteration change as well, so a so-called state change, where they occupy a different state of development basically compared to their normal cell counterparts. So if we're talking about a pancreas cell, endocrine cell in the pancreas becoming a cancer, it moves away from its differentiated, fully mature neighbors and does so in a way that's important in terms of its cancer biology. It makes it more hardy, makes it be able to survive insults, makes it be able to adopt programs that it's not supposed to have, like traveling, as in becoming metastatic. More and more evidence to suggest that, yes, a lot of that work is done by mutations, but then the mutations in some cases actually make the cells more plastic, make them more able to read parts of the genome and use parts of the genome that that cell type isn't normally supposed to have access to. This is an insight that I think has only come-

   19. PAPeter Attia41:45

       Yeah, we didn't know that 20 years ago.

   20. KFKeith Flaherty41:47

       No, we didn't know in the late '90s. This is my argument in retrospect about what it is that The Cancer Genome Atlas really uncovered for us. A criticism is that we just relearned a lot of the same things we already knew. We already knew that RAS mutations occurred in 25% of all cancers, and we knew then and pretty much know now that we can't drug them directly, so that's an inconvenient reality. The point being that the catalog of activated oncogenes had actually been largely resolved one by one by one from the mid '80s going up to the late '90s. This was the catalog I was looking at when I was saying, "I'm gonna go into the field and try to figure out how to take this information and turn it into some version of first therapy." I was a student at Hopkins When HIV was absolutely uncountered with any therapies at all, I did a second sub-internship on the service where the HIV patients were cared for as inpatients, usually-

   21. PAPeter Attia42:39

       That was on the Osler service, wasn't it?

   22. KFKeith Flaherty42:41

       Exactly right.

   23. PAPeter Attia42:41

       Yeah.

   24. KFKeith Flaherty42:41

       And AZT was in humans in clinical trials for the first time. It was talked about actively on that service because it was definitely a research-minded service. So by the time I got finally in through my medical training into oncology, a few more years had passed.

   25. PAPeter Attia42:54

       So wait, you nadir, I mean the nadir, meaning the nadir of despair, the peak of hope would've been '96 when HART was introduced, right?

   26. KFKeith Flaherty43:01

       That's right.

   27. PAPeter Attia43:01

       And that's when you were starting medicine.

   28. KFKeith Flaherty43:03

       So I was graduating from medical school at that time.

   29. PAPeter Attia43:06

       Yeah, I mean, starting your medicine residency-

   30. KFKeith Flaherty43:07

       Yeah, that's right
7. 45:57 – 46:03

   Bcr-Abl, imatinib and the first targeted therapy success

   1. PAPeter Attia45:57

      So you did your residency at the Brigham and then your med-onc was at, uh-

   2. KFKeith Flaherty46:02

      At Penn

   3. PAPeter Attia46:02

      ... at Penn.

   4. KFKeith Flaherty46:03

      Yeah.

8. 46:03 – 1:07:07

   Immunotherapy, checkpoint inhibitors and tumor immune visibility

   1. PAPeter Attia46:03

      Was Carl June there at the time?

   2. KFKeith Flaherty46:04

      He was.

   3. PAPeter Attia46:04

      So let's take a detour into immunotherapy for a moment.

   4. KFKeith Flaherty46:07

      Yeah. [laughs] Yeah.

   5. PAPeter Attia46:07

      Because there's part of me that just like wants to do this temporally because of how much we know today, and I don't want to lose stuff that we now take for granted, but at the time was so important. So there were a couple of cancers... Well, uh, let's go even further than that. Based on everything you said a moment ago, it's pretty clear that we need systemic therapy. We've reached the limits of local therapy, so surgery and radiation work pretty darn well when they work, but there ain't a lot of ways to make it better.

   6. KFKeith Flaherty46:37

      Yeah, you can minimize their, uh, adverse effects.

   7. PAPeter Attia46:39

      That is exactly right. You can make them less harmful, but they're about as efficacious as they can be. We take our first type of systemic treatment, which is chemical chemotherapy, and as we basically saw from twenty five years of '74 to '99, we basically cured one additional cancer. Somewhere along the way, there's another idea for a systemic type of therapy, and you alluded to it earlier, which is, look, I mean, you didn't say it explicitly, but I'm just going to put words in your mouth. Once the mutations happen to cancer, they cease to be purely self. They start to display a little bit of non-self characteristic.

   8. KFKeith Flaherty47:11

      Yeah.

   9. PAPeter Attia47:11

      And we have this branch of the immune system that is, I mean, staggeringly effective at eradicating non-self things, namely viruses. So, uh, we don't have to go back to Cooley's toxins, but basically if you just go into the '90s, you've got guys like Allison who are working on things called checkpoint inhibitors, which we're going to come back to. You've got Steve Rosenberg at the NIH, who's having limited success in melanoma and renal cell carcinoma. You've got Carl at Penn and a number of people around the country that are starting to show little cracks in the armor of cancer, and these results... Well, I want to talk about the durability of them, but just for a moment, explain what cancers were we seeing this in, and what did we know by the late '90s about immunotherapy?

   10. KFKeith Flaherty47:58

       Yeah. So what you just described, one way of rephrasing it is that you had people recognizing this idea that there's, uh... Let me back up a step. What had been recognized pathologically decades before was that there are some tumors that at the time of surgery are evidently visible to the immune system because you can find a ton of immune cells infiltrating into them. I mean, I like to go back to melanoma. Many instances, there's a good entry in there because melanoma is the cancer type that I have focused on throughout my career. Fortuitous for a couple of reasons, that choice, but any case, it definitely useful for this discussion. So what's useful about melanoma in this discussion, let me just remind listeners that melanoma harbors just about the largest number of mutations per cell of a tumor that makes it, if you will, to succeeds in becoming a cancer and isn't eliminated-

   11. PAPeter Attia48:44

       It flies as high as possible beneath the radar.

   12. KFKeith Flaherty48:46

       That's right. There's a few other cancers out there, but it's a simple reality that they're picking up so many mutations, these melanocytes, the precursors to melanoma from ultraviolet radiation, the vast majority of which we think are useless to the formation of a cancer.

   13. PAPeter Attia48:58

       What's the typical number of mutations in a metastatic melanoma cell?

   14. KFKeith Flaherty49:00

       It's high thousands, so you can have in the tens of thousands, but high thousands. There's a distribution and a limit to that distribution.

   15. PAPeter Attia49:08

       Aren't there only about 20,000 genes?

   16. KFKeith Flaherty49:09

       Oh, I mean individual-- Oh yeah, you'll find multiple mutations per gene in a melanoma. So on mutations per megabase, and then scale that out to the-

   17. PAPeter Attia49:16

       And how many of those do we think are playing a functional role? We don't know.

   18. KFKeith Flaherty49:20

       Five, six is a rough estimate based on real functional evidence now. So you have this huge onslaught of mutations which are useless to the cancer's purpose, probably adverse for the purpose of immune recognition, and so it's an outlier. It's not a completely separate, but it's at the far end of the spectrum in terms of cancers that aren't cleared and eliminated by the immune system and survive with all of this mutational abnormality in them, a lot of non-self. So that's a cancer that at the time of initial diagnosis, a superficial melanoma on the skin, you will find, not in all cases, but in the vast majority, a robust amount of immune recognition, infiltrating immune cells and T cells that are the variety that can clear a virally infected cell and can kill a cancer cell when they see that the internal content's being presented on the cell surface by the so-called MHC complex have enough difference from self, then that's the cell population that you will witness in those tumors. And it had been described in the '60s that a melanoma, notably other cancers by the '80s, you looked at a spectrum of melanomas, those that had the most robust immune cell infiltrate were going to be least likely to be life-threatening to the patient after adjusting for other factors.

   19. PAPeter Attia50:30

       In other words, was the experiment ever done when you took 100 patients who had a local resection, normalized them for depth, so they're all Breslow five, and you add up the TIL, tumor infiltrating lymphocytes, and you get a prediction of who's going to be alive in 10 years?

   20. KFKeith Flaherty50:47

       Precisely. That's right. Powerful. Very powerful, that prediction, and then that was just replicated across the rest of cancer, that finding. Colorectal cancer has its own distribution in that regard, and some that are wildly mutated, immunogenic-

   21. PAPeter Attia51:00

       Has anyone commercialized this today as a diagnostic at the time of therapy diagnostic or predictive tool?

   22. KFKeith Flaherty51:07

       To a degree. So Immunoscore is a commercial assay that's been developed that is about more complex version of immune recognition than just these T cells. But we can unpack this more deeply now, cataloging the success, the huge waterfall event in the immunotherapy development era when PD-1, PD-L1 interactions were discovered and then leveraged as a therapeutic. That fraction of cancer patients who are one drug away from clearing their tumor with a PD-1 antibody, which is the largest impact we've had with an immunotherapy of any kind by a long shot in terms of numbers of patients helped. These are those patients. Yes, their cancer succeeded, but they had the immune system nibbling at their heels at every step of the way. So yes, they developed a true bonafide cancer.

   23. PAPeter Attia51:50

       We just had to block this one checkpoint inhibitor.

   24. KFKeith Flaherty51:53

       This one break on the immune system where the foot was being expressed by the tumor cell and literally reaching across the divide and repelling or making quiescent a T cell that had succeeded otherwise in making it into the environment. That's a swath of cancer.

   25. PAPeter Attia52:07

       Now, it's interesting too when you go, like I'm much more familiar with CTLA-4 because that was the work, what I was doing when I was doing my time in the lab, both in medical school and, and later in residency. It was interesting the amount of autoimmunity you saw as well, suggesting that, boy, when you took the brakes off the immune system, it didn't just want to kill cancer, it actually wanted to kill a bunch of things.

   26. KFKeith Flaherty52:27

       Yeah. So this reminds people these systems were not created purely to survey for cancer and eliminate it, right? So the purpose of dampening effects on the immune system are that you don't just mount an immune response and have it just take over your body, which is what a CTLA-4 blocking, uh, well, transgenic experiment will produce, is lymphoproliferative overdrive that kills the mouse. So the idea that these breaks exist for a reason, I think is, is intuitive if you think about the fact that basically we, we live in a complex system. We're exposed to pathogens. You talk, we were talking about viruses, but we're being exposed to microbial pathogens that are trying to infiltrate all the time. You wipe out someone's immune system with chemotherapy or a bone marrow transplant, and those bacteria that are living in the gut and in a-

   27. PAPeter Attia53:10

       Seemingly harmless in symbiosis.

   28. KFKeith Flaherty53:12

       Oh, exactly. They will then infiltrate. They're right at the margin to begin with. They'll infiltrate, they'll take over. This is a really active border zone that's being policed all the time. You give a CTLA-4 antibody, and where does the most life-threatening chaos erupt? It's at the gut. You've unleashed this preexisting force that's at work all day, every day in this very immunologically active environment, and it starts attacking normal colonic tissue and can perforate the colon from which patient then dies. It's the leading cause of death from that therapy, as rare as those events are, but, but it's a very powerful sign of how this sort of gas pedal and brake component is at play. Play back the conversation to talking about chemotherapy and this notion of therapeutic index. Well, here's the issue with unleashing the immune system systemically with these types of therapies.

   29. PAPeter Attia54:00

       Yeah, the early days of this in the '80s when Steve Rosenberg and his colleagues were using mega doses of interleukin-2, you saw that flip side, right? Which was the systemic inflammatory response syndrome was As life-threatening as the cancer, you were teetering between the patient dies of what looks like sepsis-

   30. KFKeith Flaherty54:20

       I was going to say, yeah
9. 1:07:07 – 1:12:03

   Epigenetic plasticity and resistance across therapies

   1. PAPeter Attia1:07:07

      But you said something earlier that I want to repeat because you've alluded to it twice, I believe. It's a bit of a scary concept, right? Which is some of these mutations may have no obvious immediate targetable quality, but they enable epigenetic change that itself is the problem and much more difficult to target. Is that a fair assessment?

   2. KFKeith Flaherty1:07:31

      That's right. I dropped that thread from before. I meant to finish a thought previously that The Cancer Genome Atlas project, like whole genome sequencing of large numbers of cancers, what did it teach us? Well, it retaught us what we already knew in terms of the common tumor suppressor genes and activated oncogenes. The big discovery was how commonly you will find across cancer driver genetic events, so like causative genetic of alterations in genes whose protein product regulates chromosomal wellbeing, so epigenetic regulators as they're oftentimes thought of. So chromosomes are complicated. They're dynamic in normal cells, and they're definitely dynamic in cancer cells. Think of it as a folding and unfolding of the blueprints. Basically, certain cells in the body only need to read one segment of the blueprint to be able to do their job. Cancers, generally speaking, like to open up the blueprints. That's a fair generalization, and you can reflect that even at just the entire chromosome level. Literally, chromatin is open and being read more actively. It's the only way that a lung cell can figure out how to travel like a white blood cell ultimately, is you have to open up the blueprint and see that part of it. It's these epigenetic regulators that are being-- that now were really discovered by The Cancer Genome Atlas project, so going back now, I guess 10 years ago is when it really kind of these insights first began, about five years ago. That era taught us how widespread these types of genetic alterations were. That was not known before that campaign was launched. So yes, you have these activated events, these tumor suppressor genes that are eliminated. Many of them have to do with DNA repair mechanisms and talk about other common tumor suppressor genes. But anyway, in the middle are these epigenetic regulators that themselves are activated or inhibited through genetic alteration. That was just a big aha moment in the field because it showed how essential, well, A, how cancers do it, that they create this so-called plasticity, this ability to basically go from being a differentiated lung cell into a less differentiated lung cell that's not now able to do things that its normal lung cell is not supposed to do.

   3. PAPeter Attia1:09:32

      It gives up some of its lung superpowers in exchange for greater pliability and, yeah, it's, [chuckles] I just, it's like a reality TV show you couldn't make up.

   4. KFKeith Flaherty1:09:42

      Yeah, exactly. It's diabolical, but it's using the whole playbook, right? I mean, I use that blueprint analogy, but it really is, you know, every cell in the body has the entire chromosomal content in it. It just doesn't use it. Like that discussion in neuroscience about how much of your brain do you use at any given time. Well, the normal cell isn't using so much of the blueprint to do its job. If it's gonna become a cancer, which is a, a cell doing many jobs all at once and to the detriment of the host ultimately, it really has to open up and maintain this open blueprint, not just wildly open, but very, you know, kind of strategically and purposely. So that happens, again, relatively recent insight. We are just at the beginning of actually developing tools, as in like chemical tools, to actually alter the function of these proteins to see, well, then what would happen? Can you actually restrict the blueprint reading? So go back to melanoma one more time. Melanocytes derive from the so-called neural crest. So the brain tissue and these pigment producing cells, like super weird developmental fact, come from the same tissue type. So in melanocytes, as people probably well know, distribute generally, uh, just throughout the sun exposed skin, although there's a few stragglers here and there, which can form melanomas. Any case, these guys are sparsely distributed in the skin, creating a little bit of a shield of sorts, but not a very effective one. Any case, they derive from the neural crest. That's where they come from. So what happens when you blast the hell out of a melanoma with BRAF targeted therapy and a PD1 antibody and you're shrinking tumors down but not eradicating the cells and things come back out? What do they start to look like? They look like neural crest cells. So they take a step back in the evolutionary developmental path, and in doing so, find hardiness mechanisms that allow them to survive an activated T cell repertoire, allow them to have their dominant driver activated oncogene largely disabled and be able to manage, not only survive, but ultimately then begin again growing and becoming life-threatening. This is a theme across cancers. I mean, this has been seen now lung cancer and breast cancer and other tumor types where there's been substantial advance in terms of therapies and real outcomes being achieved for patients. So these leapfrog moments that have been happening, common, common principle is this so-called epigenetic state change thing, and the genetic determinants of it, as I said, are really, it's within this past 10 years that we've gotten any insights into it.

10. 1:12:03 – 1:53:54

    Defining targeted therapy: HER2, EGFR and the oncogene landscape

    1. PAPeter Attia1:12:03

       When we talk about targeted therapy, it's a bit of a buzzword now, and I think for someone like you, it's worth maybe clarifying how do you define targeted therapy and what do you think is really our first great example of it?

    2. KFKeith Flaherty1:12:17

       Just to get right through the jargon and be able to keep chemo to one side and targeted therapy to the other. What I've always said is targeted therapy is simply that we knew what we were doing from the beginning.

    3. PAPeter Attia1:12:28

       [laughs]

    4. KFKeith Flaherty1:12:29

       Um, so we knew what we wanted. We knew what the specs were. The so-called-

    5. PAPeter Attia1:12:34

       It's Babe Ruth actually pointing-

    6. KFKeith Flaherty1:12:36

       [laughs] Exactly

    7. PAPeter Attia1:12:36

       ... at the wall.

    8. KFKeith Flaherty1:12:37

       Exactly.

    9. PAPeter Attia1:12:37

       Everybody can hit a home run-

    10. KFKeith Flaherty1:12:38

        No, just closing your eyes.

    11. PAPeter Attia1:12:39

        That's right. That's right.

    12. KFKeith Flaherty1:12:40

        Yeah.

    13. PAPeter Attia1:12:40

        But if you can actually point to where the ball's gonna go before-

    14. KFKeith Flaherty1:12:42

        That's right

    15. PAPeter Attia1:12:42

        ... you hit it.

    16. KFKeith Flaherty1:12:43

        So it's basically none of the conventional chemotherapy drugs were known to be DNA binding and designed and engineered to be them, but the target product profile, if you will, was specced out for everything that we call targeted therapy. Now, some people might take exception with that, including the first monumental success. So we actually had two versions of targeted therapy at work in the '90s, somewhat quietly, epidermal growth factor receptor and HER2, which is related in the same family, close-knit family actually, of epidermal growth factor receptors, plural. These two surface growth factor receptors had been kind of discovered and cataloged in terms of their biologic function in many cancers in the '80s, and then antibody that could reach the cell surface component of these receptors were engineered and were being investigated in clinical trials. They weren't causing heroic effects as had been hoped, but those were definitely targeted therapies. They did end up moving the needle and largely in combination with conventional chemotherapy, notably in the case of HER2 targeted therapies in breast cancer and EGFR antibodies, at least in colorectal cancer.

    17. PAPeter Attia1:13:46

        And before we leave HER2/neu, what's the success rate? So if a woman-- HER2/neu is used pretty commonly as an adjuvant now, right?

    18. KFKeith Flaherty1:13:52

        Yeah, but the naked antibodies produced a 10 to 20% response rate, so tumor shrinkage by the criteria that we use in clinical trial.

    19. PAPeter Attia1:13:59

        Yeah, so more than a 50% reduction.

    20. KFKeith Flaherty1:14:02

        Yeah, some notable benefit in a pretty small fraction of patients when given as monotherapy.

    21. PAPeter Attia1:14:06

        When given, and given in patients who still had disease.

    22. KFKeith Flaherty1:14:08

        That's right, initially in patients with overt metastatic disease, uh, overt versus covert metastatic disease. So that's right. So is that really an AZT-like moment to see that type of tumor shrinkage, um, depth/reliability or unreliability of tumor shrinkage in that low range, so to be debated with conventional chemotherapy, which itself had a 30, 40% likelihood of causing the same amount of regression, and then you are now in, in business 'cause you're producing 60-plus percent response rates.

    23. PAPeter Attia1:14:36

        Now, these are mostly PRs, not CRs?

    24. KFKeith Flaherty1:14:38

        Correct.

    25. PAPeter Attia1:14:38

        PR is partial response, CR, complete response.

    26. KFKeith Flaherty1:14:41

        And in every cancer type, it's true in leukemias or hematologic malignancies, as is true in solid tumors, the more you can beat down the tumor, the more likely that's gonna last for a while. So putting people, quote-unquote, "into remission," which is a leukemia term, actually has its solid tumor equivalent, so complete responses are the most durable, surprise, surprise. And amazingly, even our kind of stupid CAT scan technology, as much as we think, oh, I can only pick up a smaller than billion, but many, many millions of cells needed to be visible on a CAT scan. Turns out that actually that threshold, like clearing below that threshold of so-called complete response, actually does mean something very powerful in terms of patients' longish term outcome, maybe not cure, but still longish term outcome, even with certain monotherapies. So HER2 was an example where, yeah, it moved the needle to a degree in a subpopulation. With conventional stupid chemotherapy, it seemed to actually collaborate reasonably well and improve survival in big phase III trials when HER2 antibody was given with chemotherapy versus chemotherapy alone. That was a slow motion aha moment. What was the fast motion one was the, to me, kind of validating moment, which was in Bcr-Abl translocated chronic myelogenous leukemia, and then the same drug amazingly worked in gastrointestinal stromal tumor. But any case, that came a couple years later, that-

    27. PAPeter Attia1:15:57

        So what, explain what's a tyrosine kinase. What is that whole thing that you just said, and why does that matter?

    28. KFKeith Flaherty1:16:02

        Right. So the chronic myelogenous leukemia-

    29. PAPeter Attia1:16:04

        So there's four leukemias broadly speaking, right? There's-

    30. KFKeith Flaherty1:16:07

        Yeah, acute and chronic, myeloid and lymphoid leukemias.
11. 1:53:54 – 2:06:40

    From metastatic to adjuvant therapy: HER2, GIST and BRAF/MEK combinations

    1. PAPeter Attia1:53:54

       So time matters, meaning-

    2. KFKeith Flaherty1:53:56

       Evolution.

    3. PAPeter Attia1:53:57

       Well, yes, but also, like, if you catch CML and treat it early enough-

    4. KFKeith Flaherty1:54:01

       Oh, yes. Yeah

    5. PAPeter Attia1:54:02

       ... in theory, you're going to have a better response than waiting until the tail starts coming out of the dragon.

    6. KFKeith Flaherty1:54:09

       That's right. So the compensation that a cancer cell will be able to leverage by having now these built-in accelerants or more disabled tumor suppressors, like the ability to adapt and work their way around with de novo resistance or rapidly acquired resistance is absolutely a huge risk the longer you wait. That CML example, well, we've begun to map it out in, quote-unquote, "common solid tumors". So in breast cancer, if you look at HER2, I was beating up HER2 for its not aha moment efficacy. This is trastuzumab, the first naked antibody, but modified forms of HER2 targeted therapies have come along since. These more armed antibodies, if you will, that definitely have greater effect. But even just take trastuzumab, the naked antibody, its ability to help a metastatic breast cancer patient live longer for a period of time, well-cataloged, but measured in months, several months, let's say. Now you take that into the so-called adjuvant setting. So this is covert metastatic disease. So for those who have heard enough jargon and had family members deal with cancer, they know of two situations where the surgeon says they got it all, but the medical oncologist is telling them, "We're still worried there's still some cancer cells around. We're too stupid to know if they're there or not. CAT scans can't tell us 'cause they're too low resolution. We're not there yet in terms of actually measuring circulating tumor cells or circulating tumor DNA in a diagnostic and high resolution way, but we're just worried because we know that looking back a decade, if we had 1,000 cancer patients like you, we know that half of them are gonna show up with overt metastatic disease over the first few to several years of follow-up." So you know a time that someone had microscopic metastatic disease after their surgery with curative intent. So what I'm getting at is now that's the adjuvant setting, so the possibility but not certainty that microscopic metastatic disease exists. You give therapy in that situation, systemic therapy, to seek and destroy microscopic deposits. That's so-called adjuvant therapy. So with that jargon stated Adjuvant use of HER2 antibody, this was the first example of this is why I'm giving it its due credit, cures patients. Cures patients. You don't cure patients in the overt metastatic setting with HER2 antibody therapy. Like that's unheard of. So that was the first paralog in a common cancer that kills lots of women that this CML evolution concept reviewed earlier.

    7. PAPeter Attia1:56:26

       And remind me what the numbers were, because we sort of take it for granted today. You take two groups of women that have HER2 neu positive tumors that are NED, uh, meaning surgically, uh, resected down to having no evidence of disease as you described. Half of them get a placebo, half of them get the antibody in 10 years. What percentage are alive in each group?

    8. KFKeith Flaherty1:56:46

       Usually the way we think about it is like how many patients are saved, if you will, because it all depends on the level of risk of recurrence to start with.

    9. PAPeter Attia1:56:54

       Yeah. So what's the AR and RR?

    10. KFKeith Flaherty1:56:55

        Yeah, right, right. So whatever you start with, so it's depending on the trial, a third to a half of the recurrences that would have occurred don't happen by the addition. This is-- You're right to mention placebo, but by historical fact in this case, everybody got chemo.

    11. PAPeter Attia1:57:08

        Everybody gets the same... Yeah, yeah.

    12. KFKeith Flaherty1:57:09

        Yeah, chem-chemo plus minus, if you will. So the addition of the HER2 antibody or not, and this is now many subsequent studies and other cancer types have been done to try to show the same kind of benefit of treating only microscopic residual disease as opposed to overt metastatic disease. So a third to a half reduction in risk of relapse over long periods of time now, and stably so in the case of HER2, we have lots of data.

    13. PAPeter Attia1:57:30

        Do women take anti-HER2 neu for life now in adjuvant or how many-- It's five years?

    14. KFKeith Flaherty1:57:34

        No, no, no. The hormonal therapy is the long duration therapy in the adjuvant setting. So hormonally driven breast cancers, you're now complicating this, my attempt to make adjuvant therapy disease eradication sound simple. Hormonally driven cancers like breast cancer and prostate cancer in the so-called adjuvant setting, it is clear that the original data was a year of therapy, then three years of therapy, five years of therapy. It's clear even that 10 years of therapy is better than five years of therapy in a population, and hormonal therapy prevents relapse at least to a third to half standard analogous to HER2. But when you see an effect like that in series of clinical trials where longer durations of therapy to treat covert metastatic disease longer is better than shorter, it tells you you're not eradicating in everybody, you're suppressing in some people, and that's the story over and over again. In gastrointestinal stromal tumor, which was the first solid tumor big targeted therapy success where imatinib was being repurposed for the fact that it's a c-KIT inhibitor and c-KIT is mutated in two-thirds of gastrointestinal stromal tumors. That drug first showed benefit in metastatic patients, overt metastatic patients. Then in a series of adjuvant trials, one year, three years now ongoing therapy beyond that, incrementally better. Is there ev- reason to believe that some patients are being cured? Absolutely. But there's some patients where disease is just being suppressed and maintained in a micrometastatic state from which they will not die, at least in the foreseeable future. But this just goes to my point about, okay, is single agent targeted therapy a tumor clearing treatment for very many cancer patients, even when we use optimal next generation early detection methodology? Eh, that is going to be realized in a real fraction of cancer patients, but we're still gonna need combination regimens to dismantle tumors in their fully complex way. The BRAF example how-- has already now played out. So melanoma BRAF inhibitor monotherapy improved survival to the tune of a nine-month improvement in overall survival, which in melanoma, which is median survival used to be six to nine months, so on average six to nine months. So like getting a bump like that-

    15. PAPeter Attia1:59:38

        You're basically doubling the survival of patients with metastatic melanoma, but not curing.

    16. KFKeith Flaherty1:59:42

        Right. That was a big deal. Interestingly, BRAF inhibitor monotherapy was tried in an adjuvant trial, didn't meet its endpoint, so it, it apparently numerically reduced risk of recurrence, but marginally so and not enough to achieve statistical significance, so that trial was called negative. In parallel, I and others had been pushing hard in the metastatic setting to go from AZT to doublet... What was the first doublet HIV regimen? I'm blanking now, but in any case, a, a proteasome inhibitor. And so any case, in melanoma, we were treating with BRAF inhibitor monotherapy. We're seeing responses. Those responses would last on average six months. This is an aggressive disease. Again, patients would typically die within six months in the untreated state. So patients would respond, and those response would be maintained for a, a huge range of times, but the average was six months. We saw that basically the tumors were working their way right around the drug in the MAP kinase pathway. They were bypassing BRAF through CRAF most commonly. That was the easiest trick for them to use. They didn't need to develop mutations that resisted the drug itself, which is a theme in Bcr-Abl CML and in other oncogene-driven tumors that are treated effectively with targeted therapy and fusion-driven cancers in particular. Remember those genetically simple tumors? A very, very common theme is they need to mutate the actual gene that's being targeted because they need that thing back on. They don't have very many tools in the toolkit. They need that guy back on, and the only way they can evolve resistance is to basically repel the drug in the first place. Those are so-called gatekeeper mutations. So in BRAF mutant cancer, BRAF mutant melanoma, you don't see those mutations emerge because it's too easy for these cells to rewire their way past BRAF through CRAF. So we saw this happening in humans. So yes, in parallel in laboratory systems, but more importantly, we were seeing it in humans within the same year that we first documented responses in, in those patients because we were biopsying them serially for research purposes, which was then thought to be a crazy concept, but now it's not so crazy. In any case, we saw this bypass happening. We knew that there were available inhibitors of downstream MEK, M-E-K, the guy that BRAF turns on. Those drugs already existed. They weren't shown to be useful on their own yet anywhere in cancer. There were signs of life here and there in clinical trials. But MEK is right below BRAF and CRAF, and we said, "Oh, let's just put these two together, try to intercept this bypass." That worked. Like we went very quickly from BRAF inhibitor monotherapy to BRAF/MEK combination therapy, including overall survival improvements that were as big as the overall survival improvement of BRAF inhibitor monotherapy. I'm fast forwarding through my entire career here. Any case, BRAF/MEK combination in the adjuvant setting prevents relapse by 50%, and patients receive a year of therapy, stop treatment, and there's a persistent gap there in terms of cured patients. This is melanoma we're talking about, melanoma that will work its way around BRAF inhibitor monotherapy in, on average, six months. You can wipe it out in the covert metastatic state, microscopic residual disease, AKA adjuvant therapy, with that same regimen. So the point is there is some real kind of early detection, early treatment theme that is absolutely yet to be fully leveraged and realized because we're still working on the early detection technology, blood-based mostly, but it's coming. And then adjacent to that, even in some cases when we find cancers very early, they are already genetically complex. We have to have a toolkit that allows us to dismantle at more than one point, and that's its own long conversation. But the issue of adjacent to AZT, what does that armamentarium look like in terms of the next agents that we're presenting?

    17. PAPeter Attia2:03:17

        Right. Because with HIV, we think of it by class of drug. You basically have a toolkit of drug classes, and it seems to me that you've done a very eloquent job explaining this. There are basically some fundamental pillars in growth and some fundamental pillars in protection. And when the day comes that we have a toolkit that knows, okay, I've got these three things that can hit this pillar, three things that can hit that pillar, four things that hit this pillar, six things that hit this pillar, nothing that hits this pillar, and two things that hits this... I mean, that's-- You're in the golden zone when you can start stacking, because that's what HAART, highly active antiretroviral therapy, did. It basically put, whatever, three or four pillars together, and at that point, HIV was not cured, but it was chronic. You didn't have to die. You didn't have to get AIDS.

    18. KFKeith Flaherty2:04:06

        We can't keep hitting the same pillar and expect that we're gonna cure cancer. So we got away with it in melanoma because we, we kept hitting [chuckles] the same pathway, got away with it by hitting it twice and improving outcomes and actually improving side effects, which is its own weird story, but really cool story biochemically. The bigger point, just hitting some of the talking points that we touched on before, is we need the activators of the immune system. We need the inhibitors of the activated oncogenes. We need the drugs that target these epigenetic regulators. We need the metabolic switch regulators, which are emerging, I would say, just as we speak, very early days. Epigenetics and metabolism generally are the, what I point to, to say that these are the pillars where the tools are coming, but it's early. And I generally make the point that if we just flesh out those toolboxes and we're lacking still, um, some famous gaps would be like understanding how to wrestle down telomerase. This kind of like is a clock that exists in cells that allows them to basically measure their age.

    19. PAPeter Attia2:05:08

        Did you see the science paper last week? It was the science paper about the, the astronaut Kelly's time in space, the year in space.

    20. KFKeith Flaherty2:05:15

        I read a lay article summary of it, but yeah, go ahead.

    21. PAPeter Attia2:05:18

        You know, it's interesting. So twin brother, right? So one-- The... I only bring this up 'cause you mentioned, uh, telomerase. So the, uh, I could be having this backwards. I think the telomeres of the astronaut that was in space elongated significantly during his year in space, but within three days back on Earth, completely reverted to normal, which of course just made me question the importance of telomere length. It's an interesting point. So your pillars then, 'cause I wanna share with you my framework, which is purely a clinical framework. It's not a research framework. It's a, you're on the front lines, you're a primary care doctor, you're a patient, how do you think about cancer? Because while I think most patients, when you talk about the big diseases, most people are afraid of Alzheimer's disease above all else because of the phenotype. But when you think about probabilistically, most people are afraid of cancer because the likelihood of getting it is somewhere between a third and a half, depending on your gender. So you said epigenetics, metabolism, immune. Would those be your three fundamental pillars of cancer?

    22. KFKeith Flaherty2:06:18

        Yeah. I mean, growth factor receptors, which again are-

    23. PAPeter Attia2:06:20

        Well, within them

    24. KFKeith Flaherty2:06:21

        ... that was the original pillar because those are the first discoveries made, frankly, in cancer biology and cell signaling. But these others are clearly the other major pillars of normal cell programs that have to be co-opted by cancer for cancer to achieve its gains.

    25. PAPeter Attia2:06:34

        Yeah, so the epigenetic modulation, the immune stuff, the metabolic stuff, and of course the growth factors.

12. 2:06:40 – 2:18:10

    Why combination therapies aren't being tested: biotech fragmentation

    1. PAPeter Attia2:06:40

       So I usually tell patients, I think cancer is really hard. Like, atherosclerosis is inevitable, but we also know so much about it. Not everything, but we know enough about it, and we have enough tools that, look, if you really want to be aggressive, you can delay it so that you're not gonna have your first heart attack till you're 100. That's doable. That's totally doable if you start early enough. I'll save my soliloquy on Alzheimer's disease, but I say, look, cancer's the hardest one, and it's the one that I think most about in the sense of it's the one that I am least confident at our ability to reduce risk in. So I say, look, here's my take on it. Step one, try not to get cancer. Sounds like a dumb thing to say, but we know a handful of things that are increasing our risk for cancer, so let's keep those to a minimum. Luckily, most people have figured on that smoking is not a good idea, but right behind it is insulin resistance and obesity. And so there's something about that probably down... So if smoking was probably acting more on the mass genetic level, something about insulin resistance was acting on this growth sort of pathway. Okay, so we could talk about all the things we can do to not get cancer. Step two, which again creates a lot of enemies, especially depending on which side of the Twitter sphere you live on, is let's look for cancer early. If burden of disease matters, you can take the approach of women should never have a mammogram, just if a lump shows up in your breast, go see your doctor, but otherwise don't do anything, is one end of the spectrum. And then you've got coconuts like me on the other end of the spectrum that say, "No, I understand why you might come to that conclusion if you're trying to do it at a cost basis." And if you're only limiting yourself to mammography, which has such horrible sensitivity and specificity, but if at least theoretically you could say, well, in a world where costs become less ridiculous, i.e., not in the United States, if you took it out of the equation and you were willing to layer mammography, which will always be important to catch a calcified lesion with diffusion-weighted imaging MRI as an even superior technology to ultrasound, coupled with molecular screening, well, you can make the case that no woman should ever present with breast cancer. And in that situation, can we do better? And then you talk about looking at therapies that would go after multiple pillars simultaneously, not in serial, not waiting for one to fail and the other to go on. So that's my sort of Neanderthal approach to cancer. How would you make that more robust?

    2. KFKeith Flaherty2:09:11

       Okay. So what we're missing is still components of the toolbox to be able to actually knock out pillars. So that's, I often say we, we still need to diversify our toolbox. Then it's the issue of marrying diagnostics with therapeutics, so understanding the assembly process of cancer in a patient-specific way and being able to deploy those therapies. That is an, an emerging hard task. I spend a lot of my academic time railing against the impediments that keep us from pushing drugs together in supervised settings, both experimentally and clinically in clinical trials. So this idea of getting to following the HIV example, we are chronically facing headwind in terms of getting there.

    3. PAPeter Attia2:09:51

       Is that because HIV killed patients so much quicker and there was more desperation that clinicians, IRBs were more willing to move quickly to stacked therapies?

    4. KFKeith Flaherty2:10:02

       Yeah. We have all the same regulations. The HIV advocates created-

    5. PAPeter Attia2:10:06

       It was the advocacy.

    6. KFKeith Flaherty2:10:07

       Yeah. They created regulations to cover life-threatening disease, and cancer is captured right in that. We have a amazing forward-thinking regulatory environment in the United States and increasingly in Europe. Because of the lead blocking that was done by the HIV advocacy community, we have the same benefit.

    7. PAPeter Attia2:10:23

       So the heavy lifting on that front was done in the '80s and early '90s.

    8. KFKeith Flaherty2:10:25

       Absolutely, and I've spent tons of time exploring whether there are remaining impediments there, talking with FDA leadership in particular, and I usually quickly sum up to say they are on our side, they are our friends, they have self-organized in a way that actually will be the accelerator, not decelerator of progress. The problem, if I were to put a finger on it, is the way in which companies that decided they could see a business model in HIV and basically decided they were gonna pursue it, could create the toolbox within their one company. Um, had it not been for that, we would not have seen doublet and triplet therapy.

    9. PAPeter Attia2:10:59

       And is that purely a simplicity of therapy and therefore an economic issue?

    10. KFKeith Flaherty2:11:04

        Precisely. And simplicity of the organism that you're targeting.

    11. PAPeter Attia2:11:06

        That's what I mean, yes. Simplicity of the opponent.

    12. KFKeith Flaherty2:11:08

        That's right. The number of enzymes that the thing has in its genome that you could then postulate as potential targets, massively smaller, and so within one umbrella of one company, you could see combination therapies being-

    13. PAPeter Attia2:11:19

        Right. So even though Merck or Pfizer could have a program under each pillar, that's typically not the way it goes, is it?

    14. KFKeith Flaherty2:11:25

        Here's how I generally draw out the math. So 60% of drugs coming in the cancer pipeline now come from small biotech companies. It used to be that big pharma was the driver, and the phrase I often use is that big pharma outsourced its R&D to risk-taking, venture-backed, highly specialized small biotech companies, not just in cancer, but here I'm, I'm sticking with cancer. So you've got this distribution of where drugs are coming from that is a huge swath of different firms, many of which have a single asset in the small biotech space, and at most they get to have two or three.

    15. PAPeter Attia2:11:57

        What's the sweet spot for big pharma? Is between phase two and phase three or between phase one and phase two? If you exclude the big aha moments.

    16. KFKeith Flaherty2:12:03

        Yeah, okay. So if it's an aha moment, then it's phase two. That's the acquisition moment, and if it's not, then it's randomized phase two/phase three. Optimal moment, as you said, kind of where's enough risk been taken off the table and where now you've got a commercialization opportunity, which is what big pharma is for us, in oncology at least. Yes, there's still innovation and incubation, new therapies coming out of big pharma, but as I said, it's, it's shrunk down to a small component. The basic science, as you well know, across all of public/private domain, is in the public sector, right? The basic science, the stuff where you can't guarantee any kind of return in terms of when you're gonna get an insight that you could turn into a potential therapy. So you've got this fantastic chaos of publicly funded biomedical research, the world's greatest biotech.

    17. PAPeter Attia2:12:45

        I was just about to say, by scale, when you look at the public domain, everything from, most of it, of course, being NIH, but also Howard Hughes and others, what percentage of the world's pure exploratory science is funded in the United States?

    18. KFKeith Flaherty2:12:59

        90%.

    19. PAPeter Attia2:13:00

        It's that much of an advantage?

    20. KFKeith Flaherty2:13:02

        Yeah. It's narrowing in Europe a bit with now central investment in cancer research in Europe. That number is dropping percent by percent.

    21. PAPeter Attia2:13:09

        Truthfully, if you said 50, I would have still thought that was impressive.

    22. KFKeith Flaherty2:13:11

        No, no, no.

    23. PAPeter Attia2:13:12

        If half the world's basic exploratory research was happening-

    24. KFKeith Flaherty2:13:15

        It's where the money is, the public investment in research, and then add the private.

    25. PAPeter Attia2:13:19

        Well, I'm adding the philanthropic on top of that, but yes.

    26. KFKeith Flaherty2:13:21

        Yeah. Well, we live in a philanthropic environment that's not known in much of the world, so that is a meaningful additional layer. So no, huge, huge, huge engine here is the public domain. Those discoveries then are out-licensed to small firms over large firms by a huge margin. Of course, I here live in one of the... Well, not one of. The world's biggest biomedical research engine vis-a-vis taking those discoveries into small firms, and the Bay Area for sure, and New York and San Diego are the kind of other major pillars of that. But so you have these hubs of activity of taking new discoveries, some of which come from outside the United States even, but then are incubated into companies. What I'm describing here is this very dynamic, very exciting, very purpose-driven, expertise-heavy biotech sector, which is great for so many reasons, but I'm bringing it up as a complaint, even though I personally have benefited from, [chuckles] from the ability to step into entrepreneurial roles and co-found companies and so on and so forth, and been enormously gratifying for so many reasons. I registered as a complaint because it's distributed our toolbox so widely, and we live in a world right now where 0.37 of rational combinations of two cancer therapeutics that are still in investigational territory are finding each other in clinical trials. I published a paper on this topic a year and a half ago. It is a terrible sampling, mingling rate. Terrible. So we make new discoveries all the time in the academic domain that would suggest a new combination. You've got patients dying every day of that addressable cancer by molecular subtype or whatever. The likelihood that you're gonna be able to launch a clinical trial to marry those two drugs when they exist in two firms is that small. That is a terrible problem. HIV didn't have that problem, but because of the complexity of human cells, and therefore human cancer cells, the toolbox is being chaotically distributed. We need a way to change that, and we need a way for drugs to be able to be married in life-threatening cancer in a rapid, rapid fashion, so it's not an inertia problem in the culture. It's not doctors, it's not patients, it's not academic medical centers, it's not the regulatory environment. It's not.

    27. PAPeter Attia2:15:25

        And it's a shame, 'cause some of those are a heck of a lot easier to solve.

    28. KFKeith Flaherty2:15:28

        You'd think. This is the least rocket science thing that I've put my shoulder into the past number of years now, novel, novel cancer therapeutic investigation, but it's the hardest to change. And to me, there's an obviousness in terms of focusing on this problem, but the, the obviousness in the entire ecosystem in terms of actually getting alignment and incentives aligned to allow this dabbling to happen, it is a major, major impediment. And I've been making the point that I think we need quadruplet therapy to dismantle most complex cancers if early detection's only gonna get us so far.

    29. PAPeter Attia2:16:02

        And ideally across four pillars.

    30. KFKeith Flaherty2:16:04

        Yes, exactly. And different ones, right? So going back to the P53-
13. 2:18:10 – 2:25:21

    Liquid biopsies and early cancer detection

    1. PAPeter Attia2:18:10

       You've alluded to it already, but are you pretty bullish on liquid biopsies?

    2. KFKeith Flaherty2:18:13

       For sure. There's several reasons why. The early detection piece, I think we've touched a little bit on.

    3. PAPeter Attia2:18:17

       Let's tell folks what they are. I use the term from time to time.

    4. KFKeith Flaherty2:18:20

       Right. So tumor cells, a primary tumor with no, let's go with the notion that we can have knowledge that there is no microscopic metastatic disease. It's just a primary tumor.

    5. PAPeter Attia2:18:30

       Right. You have a tumor in your colon. You have an adenocarcinoma in your colon, and we know that it's nowhere else.

    6. KFKeith Flaherty2:18:36

       And that thing will shed its genetic contents, DNA and RNA, which mutated genes will have their mutated RNA versions. You have mutated DNA and RNA kind of detection opportunities, if you will. So DNA is shed, we think from lots of cell types, but definitely cancer cells seem to disproportionately shed their DNA, which is chewed up a bit as it circulates in the blood, but you can find it. And with higher and higher resolution technologies, if you find a single copy even and can amplify that up and detect it as a signal, since we know what the genetic map is of all cancer, we can have those probes reasonably well in hand, and a lot of acceleration has happened in this space the past just few years now. I'll come back to my complaint on the impediment side when it comes to reimbursement of diagnostic tests, 'cause that's the problem I think we face there in reality. But from a public good perspective and from a science perspective-

    7. PAPeter Attia2:19:27

       Yeah, just, I mean, I'm just curious right now from a purely, like I'm thinking about this through the lens of cancer screening at the population level. And again, I'm always trying to make the problem simpler by taking away one constraint, which is cost. 'Cause in the short term, I think you have to start, if you try to solve this problem at a quality-adjusted life year perspective, one, you're inserting your morality into the discussion, and two, I don't know what the number is and it's too hard, so let's make the problem simpler. All we're doing is trying to reduce the risk of physical harm to a patient and psychological harm through false positives. So if you could layer liquid biopsy on top of diffusion-weighted imaging MRI, the best colonoscopy, the best mammography, boop, boop, boop, boop, boop, boop, boop, I, I mean, you can theoretically construct a point where you can catch every cancer prior to its clinical presentation.

    8. KFKeith Flaherty2:20:17

       Yeah. Let's just go with breast, colon, prostate, and lung, since that's 80% of solid tumor cancer deaths. So that would be, that'd be a good goal just to go after those. So the challenges are, so again, the DNA is shed

    9. PAPeter Attia2:20:28

       Do we have a sense of how big a tumor needs to be to even start shedding?

    10. KFKeith Flaherty2:20:32

        No, it has not been well mapped out, but certainly less than a centimeter. And, and this, you mentioned centimeter before as a radiographically findable and so on nodule. So if you go map out cure rates with surgery alone across common cancers, breast, colon, prostate, and lung, at centimeter-

    11. PAPeter Attia2:20:47

        Right, at centimeter below-

    12. KFKeith Flaherty2:20:49

        Yeah

    13. PAPeter Attia2:20:49

        ... the exceptions are few. I mean, pancreatic would still be-

    14. KFKeith Flaherty2:20:52

        Yeah, that's right

    15. PAPeter Attia2:20:53

        ... one of the few where even sub-centimeter, your odds of survival are less than 50/50.

    16. KFKeith Flaherty2:20:56

        Melanoma happens to be measured in literally one millimeter increments, so huge metastatic potential, but any case, we have other strategies for that superficial tumor to find it early. But any case, you know, so coming back to your point-

    17. PAPeter Attia2:21:07

        I, I see your point, which is if you could decide no one ever shows up with a tumor bigger than one centimeter-

    18. KFKeith Flaherty2:21:12

        Exactly. Exactly

    19. PAPeter Attia2:21:13

        ... potentially doubled cancer survival, right?

    20. KFKeith Flaherty2:21:16

        So those guys are definitely shedding, so it should be detectable. If we need to use microvesicles or exosomes, which have RNA and some DNA in them as a way of being able to find scarce entities, these mutated gene products that are now, in this case, in the case of exosomes, why they're being transmitted around the body, we don't know, but, but it happens. Not just tumors, of course. Normal cells do this, too. So circulating tumor DNA, exosome or microvesicle packages of nucleotides, these opportunities for detection, as well as circulating tumor cells, but circulating tumor cells are based on available technologies, they're the hardest to find in a patient who has a one centimeter tumor nodule. So using that as a threshold. So already it's in sight that we're gonna have high resolution methods for shed DNA and probably same for exosomes, and circulating tumor cells I think could get there. The issue, to come back to your framing here of, like, false positives and anxiety provoking and so on, remember P53 mutations, 50% of cancer. Finding a P53 mutation in blood, what does that tell you? A, you might have cancer, you may not have cancer, and where is it? What part of the body is it coming from? Well, 53, 50% of cancer, it could be virtually anywhere.

    21. PAPeter Attia2:22:24

        Yeah, so how much of the effort in the liquid biopsy is going to be histology specific?

    22. KFKeith Flaherty2:22:28

        Exactly. This is where circulating tumor cells would be the favored approach.

    23. PAPeter Attia2:22:32

        The DNA will not offer tissue specificity.

    24. KFKeith Flaherty2:22:34

        You can get the whole fingerprint out of a circulating tumor cell and know exactly what the entity is that you're hunting for now in terms of organ type, and so you just survey that one organ with every imaging methodology yet to come. So there's reason to be hopeful there going from CTCs forward. What's really cool in the circulating tumor DNA and exosomal RNA field is lineage mapping. So turns out basically that the genetic blueprint, when it's folded up in a colorectal villous cell of, of the colon, the epigenetic alterations that occur in that cell are characteristic. So you can fingerprint cell of origin by looking at epigenetic marks. This is a realization that's now being ported into the blood detection world so that you can actually map where did that fragment of DNA or RNA come from. So this is work in progress as we speak. There's a ongoing collaboration between our group and the Broad Institute at MIT on this topic, but I know of other groups who are in this space. So there's a convergence of sort of cell of origin fingerprinting with genetic detection methodology that you could, you could readily see how we could get there in the foreseeable future, this idea of being able to say, "Okay, our imaging still isn't picking it up, but we know that you've got a breast cancer brewing, and now-

    25. PAPeter Attia2:23:47

        And in some cancers, for example, if you took a woman that was high risk to begin with, and now you had DNA proof that she had cancer, I suspect there are some women who would actually just say, "Without additional imaging, I might be willing to just undergo a mastectomy," or a guy would say, "Look, I'm willing to undergo a prostatectomy or whatever." Now it gets harder with lung cancer. [laughs] You can't have just bilateral lobectomies all day long, or pancreatic even. But that's a step in the right direction because as you said, maybe at that point we could justify even at the societal level, 'cause certainly at the individual level you'll do anything, but at the societal level we'd say, "Look, once you have that DNA test that points to that tissue, we're going all out-

    26. KFKeith Flaherty2:24:24

        Yeah

    27. PAPeter Attia2:24:24

        ... on scrutinizing that tissue."

    28. KFKeith Flaherty2:24:25

        Right, and, and your first instinct is to think down a potential upcoming surgical path. If not, if you can't see it now, you don't know where to cut, but eventually you will. But I'm actually, as a medical oncologist, leaping to the systemic therapy concept. Can we motivate an immune response against that thing when we know enough about its genetic fingerprint or an oncogene targeted therapy and monitor the response using the same method, right? So when you were talking about blood biopsy, a huge near term opportunity is to use it as a therapeutic monitoring tool to understand can you actually get people down to a minimal residual disease, no detectable evidence anymore by this blood method. So yes, it's an early detection tool, but it's also a therapeutic monitoring tool. So you can take a patient, you don't know where their breast cancer is, but you don't wait for it to emerge. You attack it when it's still genetically simple and monitor that effect in blood so you know when to stop treatment or you know when treatment's not proving effective and switch gears to something else because you've got a toolbox with, uh, different regimens in it.

14. 2:25:21 – 2:41:59

    Stem cell therapy, cancer's link to aging, and the vitamin D–sun debate

    1. PAPeter Attia2:25:21

       I want to switch gears for a minute. There's so many just sort of cancer questions that I get asked all the time that I don't know the answer to. So I have at least two patients who I guess somewhat against my recommendation are adamant that stem cells, intravenous stem cell therapy has played a enormous role in the improvement of their health. One patient in particular, there's no denying that his symptoms improved dramatically with IV stem cell therapy, and I don't want to represent that I have the hubris to suggest that it's not working. I just don't know. My bigger concern, because putting the cost aside and the immediate risk, like infections and sort of risks of the therapy, which are non-trivial, of course the risk on the other side, which is it's too successful in a sense and those stem cells acquire a life of their own. So is this something you spend much time thinking about?

    2. KFKeith Flaherty2:26:12

       I've thought about it. I just think that if they're wild type stem cells, I think they'll follow the rules. So this whole discussion has been about cells that basically, not through anthropomorphic spiritual means, but by through [laughs] you know-

    3. PAPeter Attia2:26:25

       [laughs] Right

    4. KFKeith Flaherty2:26:25

       ... random, random genetic alteration Basically are able to not follow the rules. I mean, this is this revolution that happens inside of our bodies that is cancer. It's actually, I usually use the term evolution. This is, this is individual cells following the preservation and success, organismal success instincts that allowed us to crawl out of the swamp in the first place and become the complex organisms that we are, this drive to continue evolving for selfish purpose. So using that mindset, to come back to your question, I think a truly wild-type stem cell will find its home and find its niche and its proper influences and behave accordingly is, is my assumption. Unless it were to become non-wild type through external manipulation outside the body where, when it's potentially fragile and capable of picking up aberrations that aren't corrected. But stem cells are, they are notably hardy cells that can survive insults remarkably well and correct. So a cell that survives a genetic insult, a stem cell is particularly capable of detecting the damage, repairing the damage, taking its sweet time in doing so, and not spawning daughter cells until it's got its house back in order. So its P53 detection program and DNA repair machinery is particularly robust. So this is why when people talk about cancer stem cells, notably, uh, which no one would want those, cancer stem cells are thought to be kind of the worst of the worst. They're these primordial cells in the cancer cell population within a given tumor that have found their way back in development towards a stem cell, and in doing so, have adopted these really hardy skills, survival skills. No, they can't proliferate and divide very quickly, so they don't have that, but they can survive almost anything. Whereas the avant-garde, highly proliferative, very dynamic population that will multiply and actually be the life-threatening leading edge of a cancer, those things are more vulnerable. So actually, if you look at what chemotherapy has done for us, it's fairly conventional chemotherapy. It's fairly clear that actually what it can do is it can prune this highly proliferative avant-garde population, leaving behind this more, quote-unquote, stem cell-like pool. And there's a whole field, it's a contentious field to a degree in cancer biology/therapeutics of how much true stem cell biology really exists there. But you brought it up more from the perspective of whether stem cells themselves could go rogue, and I would say unless they're perturbed in some significant and ultimately genetic way, I don't see how.

    5. PAPeter Attia2:28:51

       Now let's talk about another fundamental cancer question that's serves no real purpose other than unless there's some clinical application of prevention, I suppose. It's impossible to deny the age-related association between age and cancer. Certainly kids can get cancer, but for the most part, cancer rates rise monotonically until the ninth decade or so. I mean, there's a bimodal distribution because you've got the childhood cancers. If you're fifty versus sixty versus seventy, you leapfrog up in risk, right?

    6. KFKeith Flaherty2:29:21

       Almost exponentially, or at least quadratically. It's not just linear.

    7. PAPeter Attia2:29:24

       Consider two hypotheses. One is, as we get older, our genome is more susceptible to injury. Consider three. Two, as we get older and we've accumulated more of these, the probability that they can start to layer and stack and you get the phenotype that's not advantaged. Three, the immune system loses some of its steam and therefore the radar window in which you can detect cancer narrows basically, or the ability to detect all of the above, one of the above.

    8. KFKeith Flaherty2:29:59

       All of the above. You've just described very nicely what I des- what I call the inevitability of cancer. We've got too many stochastic events accumulating and surveillance systems that are breaking down. DNA damage repair and immunologic, those are the two fundamental most important components. And if you're allowed to go one log shift in mutation burden per cell and the immune system not see it and not clear it, that's it. I mean, there's no human that-

    9. PAPeter Attia2:30:27

       There's no immune system that's gonna-

    10. KFKeith Flaherty2:30:28

        That's gonna overcome that. So when I say inevitability, you connect the dots in terms of the per decade acceleration and appearance of cancers across the population, and I oftentimes say, if we all live to a hundred and thirty, we'd all have a cancer, quote-unquote, "real cancer." Let's not get hung up on benign growths that aren't cancerous. The definition of cancer for a totally lay person who doesn't think about cancer much is ability to travel and actually wreak havoc and kill. Yes, glioblastoma kills in, in its local site. But benign tumors, which are almost cancers, yes, those happen broadly across the population. There's autopsy studies that show at least fifty percent of people die with at least a benign tumor. So almost getting there, sure, that happens already. But I'm talking about fully getting there, a full, full-blown and will be eventually life-threatening cancer will emerge.

    11. PAPeter Attia2:31:15

        It's interesting, actuarially, by your tenth decade, your risk of cancer starts to go down. Although, and I discuss this with my patients a lot, my explanation for that is that atherosclerosis ratchets up faster than cancer, and it's not that cancer is going down, it's that heart disease is dominating. And that's my-- I say the same thing to patients that, that you do, which is whenever I get asked these questions that frankly kind of annoy me, which is like, "Aren't we just going to figure out a way to all live to be two hundred one day?" And I'm sort of like, "No. What are you talking about? You have to figure out a way to prevent age-related disease." And yes, there's lots of cool ideas and, "Oh, what if you could just maintain telomere length?" is like one I love hearing, and it's like, that's totally irrelevant because even if there were some benefit that came from that, you have to thwart atherosclerosis and cancer.

Episode duration: 2:57:28