267 ‒ The latest in cancer therapeutics, diagnostics, and early detection | Keith Flaherty, M.D.

1. 0:00 – 0:40

   Intro

   1. KFDr. Keith Flaherty0:00

      All of these advances are converging in a way that if we keep talking at four-year increments, the pace of progress is gonna be like substantially greater per unit time. We've already witnessed that. I mean, it's-- there's no question that four-year increments over my career, that's, that's been true. Um, it's reflected just in, in approval of drugs by the FDA, uh, for cancer. But, but now the convergence of diagnostics and therapeutics, um, that's what's finally coming into view. Um, that, that, that, that piece has really, I would say, been largely missing.

   2. PAPeter Attia0:29

      [upbeat music] Hey everyone, welcome to the Drive podcast. I'm your host, Peter Attia. Hey Keith, great to be

2. 0:40 – 4:55

   Keith’s interest and expertise in cancer

   1. PAPeter Attia0:40

      back with you again. Hard to believe it was, uh, almost exactly four years ago that we sat down in Boston to, uh, do what will be part one of this discussion. Um, but you know, we've got a lot more listeners now, and, you know, it's not like some of that content, uh, isn't still relevant today. So we'll, we'll probably talk a little bit about some of the things we spoke about then. But there are a number of things that I am excited to discuss with you that we haven't talked about, um, and I suspect that will make up the lion's share of our discussion. So thanks again for making time.

   2. KFDr. Keith Flaherty1:12

      Yeah, thanks Peter. It's a great pleasure to talk with you again. And yeah, you're right. Four years, a lot has happened. Um, you know, in therapeutic development, maybe you could have said four years ago that some of the things that have played out would have played out. But on the diagnostic side, that's-- I think that's probably where, um, I, four years ago I, I was, I didn't quite have the crystal ball vision as to how things would, um, would develop there. So, and of course, those two areas are like tightly related in oncology, so excited to dig back in.

   3. PAPeter Attia1:45

      Well, let's just start, maybe give folks a, a, a short background, a little bit about, about what you're doing and, um, you know, why it is that you're, at least in my view, in a great position to, to kind of talk about cancer in a way that is, uh, more than just an inch wide and a mile deep, which is the general nature of the field, but, you know, several inches wide maybe [chuckles] and, and, and-

   4. KFDr. Keith Flaherty2:07

      [chuckles] Right

   5. PAPeter Attia2:07

      ... and, and several, you know, and a mile deep. Like what, what is it about you background?

   6. KFDr. Keith Flaherty2:10

      Yeah. Right. Right. I'll try to hit some highlights here that, uh, uh, make that point. So, um, yeah, so I'm a medical oncologist. I've been in the field now for twenty-three years, um, which is a, a, a relevant number because of the fact that, um, the first translation of molecular insights, you know, specifically genetic insights into cancer biology, you know, really became therapy starting that year. That's when Imatinib or Gleevec like was first in patients and was, you know, kind of a revolutionary moment. Um, so my, my, my career, you know, kind of, you know, started right then and there, um, myself interested as a medical oncologist in trying to translate science to medicine in a, in very much that way, like taking insights in terms of the genetic makeup, like the mutations, um, and the sort of mutational architecture, if you will, of cancers and trying to translate that understanding into therapy. So I've been doing that for twenty-three years. Uh, like anybody in the academic medical world in oncology, um, I had focused on like specific cancer types, so melanoma and kidney cancer. And both of those I chose because of, because of the molecular insights that existed at the time that felt like they were, um, at least beginning to be ripe, uh, for translation. Uh, so I did that work for about a decade at University of Pennsylvania, moved to Mass General, um, part of the Harvard, uh, University, uh, you know, kind of umbrella, Harvard Medical School, um, to build a clinical program focused on therapeutic development much more broadly across cancer. Um, and then I think as we'll talk about this interplay between therapeutics and, and molecular understanding and ultimately diagnostics, basically built, um, a translational research group or, you know, surrounding therapeutic development, um, what I refer to as bedside to bench translational research to sort of understand, um, mechanisms of action, mechanisms of resistance, in other words, when drugs work, why? And if they don't work, you know, why not? And use those insights to try to kind of accelerate or drive the whole process forward. And then I'll just like, you know, throw in, um, also that over the past ten years, um, I've co-founded now a handful, uh, a little bit more than a handful of biotech companies, uh, with Loxo Oncology being the first ten years ago, and that was acquired four years ago, and Scorpion Therapeutics being the most recent. Um, and I'm actually sitting in the offices of Scorpion Therapeutics at the moment. Um, and so, uh, yeah, like basically that, you know, it's, it's, uh, through those channels, um, I guess I would say it's my job to keep, you know, a, a steady eye on like new therapeutic concepts that, you know, could be ready for prime time, um, to move forward, and then again, trying to translate molecular understanding into, you know, the tools that we can actually use for real patients, AKA diagnostics.

3. 4:55 – 10:33

   Cancer deaths by decade of life, and how cancer compares to other top causes of death

   1. PAPeter Attia4:56

      And, and Keith, I think, you know, it's, it's always worth repeating to folks what it is about cancer that's, um, as far as the big four chronic diseases, I call them the four horsemen in my book. There's something about cancer that's particularly damning, which is when you look at the other two chronic diseases that are huge killers, which are cardiovascular disease and neurodegenerative disease, they increase in their severity, uh, exponentially as you age. And they don't really become a dominant source of mortality until people are in the seventh and eighth decade of life. And that's not true for cancer. Um, [lip smack] in fact, I, I have a little table in front of me that I had one of our analysts pull together that I think is just-- we'll put it in the show notes. It's very powerful, right? So it's sort of looking at people in ten-year increments, so it's from twenty-five to thirty-four, thirty-five to forty-four, et cetera, all the way up to, you know, north of eighty-five. And it lists the percentage of people in each age category that die in response to cancer. And here's what's interesting is that number peaks in the middle, right? So at twenty-five to thirty-four, it's six percent 35 to 44, it's 13%. Think about that for a minute, right? That, that is a staggering number for people so young. By the time you get up to 45 to 54, it's 23%. 55 to 64, 30%. 65 to 74, 31%. And then paradoxically, it begins to come down after that because those other diseases are taking off. Another way to look at this is where does cancer rank in cause of death for all causes by decade? And if you go in those same buckets, starting at 25 to 34, it goes from third, third, second, first, first, second, third. In other words-

   2. KFDr. Keith Flaherty6:45

      Mm-hmm

   3. PAPeter Attia6:46

      ... it's always first to third. There is no other disease that always ranks in the top three cause of death for every age. That's it, full stop, period. It's cancer. And so, you know, it's, uh, it's the second leading cause of death overall. We could talk a lot about those stats, but there's nobody who's listening to this podcast whose life has not been affected by cancer. That wouldn't be possible. I, I don't, I don't think you could come up with an example of someone who doesn't know someone who's at least had cancer, uh, and very likely died as a result of it.

   4. KFDr. Keith Flaherty7:20

      Yeah, no, that's a good reminder. I mean, you know, one interesting thing, maybe just to, um, break that data down a little bit is, you know, people, you know, think of pediatric cancers. Um, of course, those are like, you know, if, if you, if you, if your life has ever been touched by a kid, um, with cancer, there's like, there's like just almost nothing more jarring, uh, you know, almost seemingly unjust, if you will, about a child, um, being diagnosed with cancer. For children, it... cancer's quite rare. So like, it, it really occupies a enormous amount of mind share. But then as you go into the decades that you were, um, summarizing, you know, what's interesting is to reflect on the cancer types, uh-

   5. PAPeter Attia8:00

      Mm-hmm

   6. KFDr. Keith Flaherty8:00

      ... you know, that kinda lead the way, um, right? So brain tumors, leukemia, uh, melanoma, the one, you know, this-- the most dead-deadly form of skin cancer, one, you know, one of the cancer types I mentioned that I've been focused on my career, uh, career long. Um, you know, that really jumps up. You know, in those 20s, 30s, 40s, um, those cancer types kinda lead the way in kind of the younger population. Um, and there's some interesting implications there in terms of like, well, what causes those cancers and, and why are, you know, some people, uh, you know, so vulnerable to them? Um, and then, you know, carcinogen-induced cancers, well, melanoma of course is... there's a carcinogen called ultraviolet, uh, light that's a carcinogen for skin cancer, including melanoma. Um, but like smoking related cancers, for example, you know, those really start to jump up, um, in later decades. Um, and then you've got, um, so like, you know, the-- just e-everyone's aware of this, but obviously lung cancer leads the way there. But there's, there's a, a smoking footprint for a bunch of other cancer types that people don't think about so much. Head and neck cancer is one that I think is, you know, relatively not top of mind for people. But, you know, even when you get to bladder cancer, which you'd think, oh, how does smoking cause bladder cancer? But... and it's not the sole cause, but it's certainly a, a big contributor. Um, you know, these sort of smoking related cancers, um, they do-- they take exposure, right, obviously, and, and a bit of time, um, to accumulate their population impact, um, ultimately. And I guess the other, just one other thing that I would kind of throw in there, because I'm sure we're gonna talk about like, you know, the really population prevalent cancers like so breast cancer, prostate cancer, lung cancer, colorectal cancer, the big four. Um, so breast cancer and prostate cancer are not related to, well, obviously ultraviolet light or smoking so much. I mean, a little bit of smoking influence on, on breast cancer risk, but, um, but there it's, um, you know, this really interesting interplay between, um, you know, these, these hormone receptors, uh, you know, k-kind of being hijacked or co-opted in a way. Um, and you think about the way in which those cancers form, I think it, it best fits your, um, you know, kind of this age, like, you know, cardiovascular disease and neurodegenerative disease, I would argue, like there's, there's something at play there that's similar to these hormone-driven cancers, which are very age-related. So breast cancer and prostate cancer really pick up in those later decades of age. Um, so it's just kind of interesting to reflect on, you know, kind of the how and why different cancers kind of feature, um, in those, uh, different decades of age. And that, that has tons of ramifications in terms of how we think about screening, which I'm sure we'll get into.

4. 10:33 – 18:42

   The relationship between hormones and cancer

   1. PAPeter Attia10:33

      Yeah, for sure. So let's add a little more color to that, Keith. So you mentioned the big four, right? So, uh, lung being number one. I, I think a breast and prostate is kind of number two, and colorectal number four. And then if you add a fifth in pancreatic, you now account for a little over 50% of all cancer deaths. So-

   2. KFDr. Keith Flaherty10:52

      Right

   3. PAPeter Attia10:52

      ... you know, we'll talk about incidents, but we're gonna talk about mortality. And at the end of the day, just five cancers account for half, a little over half of all cancer death in the United States. That's one point I'd make. Second point I'd make that's very interesting when it comes to breast and prostate is on the one hand, we have this clear understanding of the role of hormones, and yet as you point out, the implicated hormones are actually at their lowest levels when these cancers typically come on board, right?

   4. KFDr. Keith Flaherty11:18

      Yeah.

   5. PAPeter Attia11:19

      So we talk about the relationship between testosterone and dihydrotestosterone, DHT, and prostate cancer, and yet when men have their highest levels of these hormones in their 20s, in their 30s, and even in their 40s, that cancer is never to be found. [chuckles] That cancer shows up only when those hormones are long gone. I mean, you know, not gone completely, but of course greatly diminished. And the same is true with breast cancer, right? We see the incidence of breast cancer going up, but it's not necessarily hitting at the peak level of estrogen in women. There's more complexity to it, but again, it speaks to just how much is going on beyond the surface, uh, and the first order of thinking.

   6. KFDr. Keith Flaherty11:57

      Well, yeah, no, that's a great point. And actually, you know, you're-- it's kind of very tempting to insert here kind of a, you know, sort of deep cancer biology, uh, you know, uh, principle. If you look at other cancers than breast and, and prostate The, you know, the cancer types where we've really gone the deepest in our understanding of what causes them to become cancers in the first place, um, and, and even in terms of translating that in terms of therapies, it's really been around the growth factor receptor, um, and downstream of growth factor receptors, like so on the surface of cancer cells-

   7. PAPeter Attia12:32

      Right

   8. KFDr. Keith Flaherty12:32

      ... and then inter-internally. Um, that's where the, that's where the action has been, right?

   9. PAPeter Attia12:37

      Yep.

   10. KFDr. Keith Flaherty12:37

       And, and, and here's the point which you just made about the hormone receptors, um, is that basically cancer cells, quote-unquote, "figure out" how to become independent of the actual growth factors themselves, right? So they basically turn, you know, they... through genetic mutation or alteration, they turn on these, um, surface receptors or the immediate downstream, um, signaling molecules from those surface receptors. It's mutations there. That's the absolute like nidus, if you will, the hotspot, um, of where most cancers, not all, but where most cancers actually get their kind of, you know, kind of oncogenic drive, um, you know, the mutations that, that, that drive cancer. Again, it really analogous, um, to the comments you, you know, or, or the, the reality and the comments you made about, um, prostate cancer and, and breast cancer in terms of the, uh, you know, the basically that the circulating hormone levels, um, at the time those cancers manifest are low. What's happened is cancer cells have wired themselves in a way to be sort of autonomous or independent of those ligands, but still using the receptors and their downstream consequences to drive.

   11. PAPeter Attia13:39

       Yeah, and I, and I wonder if there's a parallel between the following observation, which is a test-- a, a, um, a prostate cancer that develops in the presence of low testosterone, all things equal, is a worse prostate cancer. So there's that paper in The New England Journal of Medicine, God, it's probably been fifteen years now, that demonstrated very clearly that the lower the testosterone at the time of diagnosis of prostate cancer, the worse the outcome. Very counterintuitive, right? Everybody thinks testosterone is causing prostate cancer when in, in fact, what we're seeing is if... I mean, what-- the way-- So I wouldn't interpret that to mean testosterone potentially has zero role or that high testosterone is protective, although some have argued that. What I would argue is your point, which is the cancers that grow without the hormone are worse. And-

   12. KFDr. Keith Flaherty14:25

       Yeah

   13. PAPeter Attia14:25

       ... therefore, the parallel, if you will, is the ER/PR negative breast cancers are worse than the ER/PR-

   14. KFDr. Keith Flaherty14:33

       Absolutely

   15. PAPeter Attia14:33

       ... positive breast cancers. Those cancers, those typically hormone sensitive or driven cancers that proliferate, whether it be the initiation or proliferation without their respective hormones, tend to be the, the harder ones to, to combat.

   16. KFDr. Keith Flaherty14:47

       That's right. It, it-- Yeah, I mean, it's basically, um, so in those instances, those cancers have actually figured out how to essentially replace the function, uh, by virtue of acu- Well, you know, I, I use language like they figured out 'cause I'm, it, I, I think you might remember from our conversation four years ago-

   17. PAPeter Attia15:02

       Yes, we like to anthropomorphize cancer.

   18. KFDr. Keith Flaherty15:04

       Exactly. [chuckles] I was just gonna say, I, I love anthropomorphizing cancer. It's just, it's, um, um, actually from a therapeutic development perspective, it's like the easiest mindset to sort of adopt in terms of thinking about how cancers solve the problems that they need to solve to become cancers, right? It's not like... It's kinda scary language to use, I realize, but, but when you're trying to then like reverse that or intercept that, it, you know, kind of be- becomes a little bit useful. So anyway, the point is that there's a constellation of mutations that can be, that can turn on, um, essentially the downstream pathways, uh, from, you know, for example, um, estrogen receptor, uh, so that, so that, that what's driving then a so-called triple negative breast cancer, so lacking hormone receptors and lacking HER2, which is a, you know, well-established surface target, a growth factor, um, uh, receptor on, uh, on normal cells and, and on ca- on cancer cells, including breast cancer cells. For cancer, breast cancers that have figured out how to become bre- breast cancer, what you see in their, um, genetic makeup is that they basically still are, are dependent on the same sort of cellular processes. They still have to kind of, you know, regulate the same, um, downstream programs. They just do it through a variety of means, and ones that become very challenging to directly target, I mean, to like to intercept those. And so the point you're making about breast cancer, I'll just kind of maybe complete a little bit this way, which is you emphasize that their prognosis is better, right? So in other words, before ever talking about therapy, that like those breast and prostate cancers that, um, you know, form and stick with breast cancer 'cause that spreads across younger ages, you know, a bit more than prostate cancer does. Their prognosis is better, so before even coming to the issue of treatment, but their treatability is also far greater, right? Because we've got drugs that block-

   19. PAPeter Attia16:42

       Yeah, way more targets. Yeah

   20. KFDr. Keith Flaherty16:43

       ... the... Exactly. And, um, and, and intercepting those, um, uh, you know, what are we-- you know, hormone receptors specifically, which are by the way inside of cells, just a little nuance to, um, separate from the comments I made about sort of those surface growth factor receptors. Those drugs, we, we've had them for a long time, but also like serious advances have been made applying new chemistry strategies to developing even better and better versions of those. So, so we're actually-- So what we're witnessing, um, let me just make this point in relation to pancreatic cancer, which I'm glad you called out, is that, um, we have u-- I might have used this term four years ago. We have this scenario in cancer where there's kind of a distribution of haves and have-nots. And what I mean by that is we have patients whose prognosis to start with is better and whose therapy advances are really accelerating and like making certain cancers, and hormone receptor-positive breast cancer is a quite a good example of this, where like additional drugs now have been successfully developed as combinations since we spoke four years ago even, now FDA approved and on the market. Um, and so the outcomes of those patients just continue to be distanced from cancers like pancreatic cancer, where first off, the lethality of pa- of pancreatic cancer, right? Like per case diagnosed, um, the case fatality rate, so-called, um, is far higher than these other cancers, right? So it doesn't even come close in terms of number of cases diagnosed to breast and prostate, um, or lung for that matter. But it, but it, but per case diagnosed, the likelihood that it's going to be fatal ultimately is inordinately high. Um, and so that's both a That's a prognostic issue. Those are aggressive cancers, but also our therapy advances have been like really quite minimal, which is to say all we've got are the what I refer to as classical chemotherapy drugs of kind of the pre-2000 era, which have a modest impact at all. So talking about haves and have-nots, pancreatic cancer unfortunately remains very much in that kind of have-not end of the spectrum.

5. 18:42 – 23:40

   The link between obesity and cancer

   1. PAPeter Attia18:42

      Yeah, a couple other points to make just on the broad sort of contours of cancer. One of the other carcinogens we haven't really discussed, which is essentially the second most prevalent environmental trigger of cancer after smoking, is obesity. And we can certainly debate whether it's obesity per se, which I don't think it is. In other words, I don't think it's adiposity. I think it is inflammation and growth factors that come with obesity, namely insulin, probably IGF-1, not to mention the inflammation that is part and parcel with that, which I assume is in some way impairing the immune system and things of that nature. So that's another example where you have a lot of these cancers. Let's think of those top five, breast, prostate, pancreatic are clearly linked, colorectal as well. I'm not sure about lung. So lung might not be as related to obesity as the other four. But there are also many other cancers that fall outside of the top five lethal where we do tend to see this relationship. To my last count, I think there are about 25, 26, maybe 27 cancers that have a pretty tight relationship to that. So that's not only something that's increasing in terms of societal prevalence, but you might argue that that also takes a while to sort of kick in.

   2. KFDr. Keith Flaherty20:04

      Yeah, so that's totally right. Thank you for inserting that because it really is. It's so easy to think about ultraviolet radiation and skin cancers, so easy to think about smoking. I mean, now that we understand when we sequence an individual cell or a population of cancer cells, sequence their genome, and we can now see the footprint, if you will, the damage that those types of carcinogens induce. Obesity is unquestionably another, really that third highest ranking quote-unquote carcinogen, but the way it does it is certainly more complicated. And it is, as you're saying, sort of it's systemic. I really do latch on to that literature that you alluded to regarding insulin signaling, kind of like sort of the body's metabolic response to obesity. I mean, even you can study this just in like a fed versus fasted state, like in kind of a short-term setting. But when someone is obese, basically there are metabolic adaptations, if you will, that the body sort of attempts to make. And I would draw the analogy to where we started with the hormone receptor-driven cancer, so breast and prostate. It's a different phenomenon to a degree, but basically insulin growth factor, IGF you alluded to, and then its receptors on cells, which are sort of ubiquitous on all cell types, and certainly the cell types for which we've got epidemiologic evidence that those cancers are more common in the obese population. Basically what you can say from laboratory data is that the signaling that happens through insulin signaling in cells, it's tightly tied to what we have kind of talked about already, which is that sort of growth factor receptor pathway. I mean, it really is ultimately part of that sort of same biology. There's a pathway that connects those surface receptors into cells that then regulate sort of how the mitochondria act as sort of the power stations, if you will, inside of cells to the so-called PI3 kinase pathway, well described as being a driver in cancer. That pathway is basically being chronically driven in that setting of high insulin levels, high insulin growth factor circulating levels. So exactly what threshold level poses risk and over what period of time, I would say those dots haven't been fully connected, but the epidemiology is undeniable, and I would say the laboratory data that supports that connection is also undeniable. So I think there's something about that kind of pushing, that driving. It's like chronic inflammation, as you cited, which itself, by the way, of course, is a direct causal factor for certain cancers. So like an organ site or a tissue site where there's chronic inflammation, well described that cancers can arise in that setting. It's a similar phenomenon, basically. They kind of keep whipping the horse, if you will, in a way, and cells will ultimately, through genetic alteration still, basically respond to that environmental stress and cancers ensue.

6. 23:40 – 35:19

   Current state of treatments for metastatic cancer and reasons for the lack of progress over the decades

   1. PAPeter Attia23:41

      So I remember in January of 2000, I'm in my last year of medical school and I trek across the country from California to Bethesda to go and spend four months as a medical student rotating on the immunotherapy service with Steve Rosenberg. And this was the opportunity and dream of a lifetime for me. I had read his book, The Transformed Cell, many, many times as a medical student and wanted to basically go and learn what I could. And I look back at that, I think I was there from January until April of that year. I mean, literally one of the most You know, joyful examples of pure bliss. I, I had d-- I, I've told this story before.

   2. KFDr. Keith Flaherty24:28

      [laughs]

   3. PAPeter Attia24:28

      But I, I think I told this story when I had him on the podcast. You know, I had, um, found a friend I could stay with in Bethesda, but it turned out in the four months I was there, I was probably only there eight times. Um, I, I didn't leave the hospital. I literally had a cot where I slept, and I just didn't want to be out of there, and I wanted to be kind of as, as close to the lab, as close to the clinic as possible. But I'll never forget one of the most, um, you know, insane things that he said in the first week that I was there. [lips smack] He said, "Looking back over the past thirty years, we have basically made no progress in the long-term management of metastatic epithelial cancers." Uh, translating that into English, if you had a solid organ tumor that had spread to a distant site in 1970, the chance that you were gonna be alive in ten years was the same-

   4. KFDr. Keith Flaherty25:25

      Mm-hmm

   5. PAPeter Attia25:25

      ... in the year 2000, and that was basically zero. Now, there were a couple of small exceptions, and they happen to be the cancers that you and he are both interested in. There were about ten to fifteen percent of patients could achieve a solid, durable remission at the time to, uh, high-dose interleukin-2. But that was not appearing to be the case for any other epithelial tumor, and w-- there was still absolutely no sense of why that wasn't the case for the other ninety percent of patients who had metastatic renal cell carcinoma and melanoma. How are we doing today, twenty-three years later? Um, do you have a sense of w- w- how much bigger that number is? So if we went from zero percent ten-year survival in 1970, and I'm using ten-year to really try to get out some of the-

   6. KFDr. Keith Flaherty26:10

      Yeah

   7. PAPeter Attia26:10

      ... median survival extension stuff. But if we were zero percent survival for solid organ tumor in 1970, call it one percent in the year 2000 on the back of the, you know, few cases of RCC and melanoma, what are we at today?

   8. KFDr. Keith Flaherty26:29

      Yeah, I think fifteen percent is a conservative number. Um, you know, some would make a case for twenty percent. I think the problem is there that, uh, you need a little bit, we need a little bit more time. Some of the, some of the newest therapies, you know, are only-

   9. PAPeter Attia26:40

      Yeah, yeah, we don't have the ten years

   10. KFDr. Keith Flaherty26:41

       ... you know, on the, on-

   11. PAPeter Attia26:41

       Yep, yeah.

   12. KFDr. Keith Flaherty26:42

       Yeah, we don't have the ten years. Um, but, but if you track their five-year-

   13. PAPeter Attia26:45

       Yeah

   14. KFDr. Keith Flaherty26:45

       ... uh, you know, three and five-year outcomes, if you will, you'd like to think that, you know, they're, they're gonna get us to, to twenty percent. Um, so that's, you know, again, just to, uh, just to clarify what we mean by, um, using this term metastatic. Um, so like clinically overt detectable metastatic cancer means that you're picking it up radiographically or clinically. Like that's, right, that's what, that, that's what that term means. Um, now the fact is that cancers are found, when they're found at what's thought to be an early or localized, um, uh, you know, site, uh, basically it's, you know, it's very, very common that cancers will have spread to so-called regional lymph nodes, like through lymphatic channels to the closest lymph node basin, uh, wherever that may be. Um, this is not true for all cancers, but it's certainly true for the common epithelial cancers you're, um, uh, you know, focused on in this question. And so basically, um, the point to emphasize there is that spread to lymph nodes is properly called metastatic, right? But we just don't use that jar- it's a j- it's a jargon term. Right? We just... we, we don't actually... we don't talk, think about that, um, [chuckles] as being metastatic.

   15. PAPeter Attia27:47

       Yeah. So the, sort of the analogy, right, i, is like, um, you know, when people leave a city in an airport and go to another airport that's in another city, we don't call it spread until they leave the airport and go to the city proper.

   16. KFDr. Keith Flaherty28:02

       Right. [laughs]

   17. PAPeter Attia28:02

       Even though they've clearly demonstrated the capacity to go from their house to the airport, hop on an airplane-

   18. KFDr. Keith Flaherty28:08

       Exactly. [laughs]

   19. PAPeter Attia28:08

       ... go to another airport, and once they step foot out of customs and collect their bags, well, now we can say they've really spread.

   20. KFDr. Keith Flaherty28:15

       Yeah, that's right. And, and I'll, uh, the other point I was just gonna quickly make is that it's feasible to surgically remove regional lymph nodes along with the primary, um, site of disease in, you know, the vast majority of cases. And so w- because of that, you know, sort of historical standard, uh, practice of, you know, surgical resection, including regional lymph nodes, um, we think of surgeries that can encompass all of that as, you know, basically being, you know, one, one treatment, and then those patients are, you know... Well, we're gonna come to this, I think, probably [chuckles] a little bit further along in the conversation, but, you know, they are thought to ha- not have metastatic disease. But what I mean by that is, you know, overt, so, like, you can detect it clinically or radiographically. Um, how do we know that some of those people actually have metastatic disease, right, at that time? Well, by following them five and ten years. Well, not even that long. I mean, one, two, and three years is, in fact, enough for most of the aggressive cancers. Um, they w-- you know, you do the surgery, you clean the slate, you do scans, you know, of various kinds, you f- you see nothing. Um, and basically a substantial fraction of those patients, depending on the cancer type and depending on how much, you know, the features of their primary tumor as well as lymph node involvement, a substantial fraction of those patients, let's go with thirty to fifty percent, you know, kind of a typical range, um, over those few to several years of follow-up will manifest metastatic disease. Well, they always had it. They had it, they had it from before the surgery was ever done. Um, and as you said, basically they, actually cancer cells, this, or the analogy of the traveler, left the airport, and they actually, they, you know, they did, they lodged in a, you know, distant site. Uh, we just didn't have the methods, you know, to find it. So time would, would tell, um, that, that in fact in retrospect they had had it. Um, this is where actually some huge advances have been made in terms of, um, blood-based detection, um, of those instances. Uh, we're not, we're not perfectly good at that now, but there have been substantial improvements in the technology for detecting particularly circulating, um, tumor DNA, um, in instances where people have only microscopic metastatic disease. That's, that's the, that's the term I wanted to kind of insert in this conversation is microscopic metastatic disease And we'll come back to this, but let me, let me just, you know, uh, pick up on this theme again, you know, for, for evident overt metastatic disease where you can see it on scans or, or clinically to, um, witness it. Uh, that's where those numbers pertain that we're talking about, like, you know, getting in this, you know, 15 moving towards 20% range. Um, 10% on an absolute scale. So, so like let's, let's go with the idea that we're on the path with available therapies that have just, you know, recently been introduced included towards that 20% number. Half of that advance has come from one therapeutic modality, PD-1 antibody-based immunotherapy. A single approach, um, has accounted for half that number. It's astounding. And then what about the other half? Um, that has come from a, a repertoire of these so-called molecularly targeted therapies that intercept, you know, those, um, you know, genetically altered drivers that I alluded to some minutes ago, um, these surface receptors and their downstream signaling molecules. Um, but you know, tho- those have p- those individual drugs have picked off, you know, as small as 0.2%, you know, of the cancer population, um, in the kind of rarest inst- instance up to, you know, a couple few percent, right? And then, but you add them all up, and those have produced, um, you know, also, uh, you know, long-term survivors now, I mean, by, by historical standards. So that 10 nu- 10-year number is like it's an astoundingly long survival by historical standards because metastatic cancer will prove fatal, um, in nearly everybody if un- untreated, um, you know, within that timeframe, even the most, quote-unquote, indolent cancer.

   21. PAPeter Attia31:49

       Yeah. So let's just kind of go back and, and restate the important part of that. So, um, basically 1970 to year 2000, zero progress has been made. 2000 until now, we've probably been able to, um, you know, make a small dent in that. Half of that dent has been on the back of Keytruda.

   22. KFDr. Keith Flaherty32:10

       Right.

   23. PAPeter Attia32:10

       How many, how many drugs are in the other half of that? Like, so we mentioned Gleevec a minute ago. That was probably the first.

   24. KFDr. Keith Flaherty32:17

       Yeah. There've been 52, fi- there've been, yeah, 52 FDA approvals, but, um, but that's against 19 unique mechanisms.

   25. PAPeter Attia32:25

       Mm.

   26. KFDr. Keith Flaherty32:25

       Right? So there's a lot of me- a lot of me tooism, um, in... I mean, this is true in all therapeutics-

   27. PAPeter Attia32:29

       Yeah

   28. KFDr. Keith Flaherty32:29

       ... not just oncology. Um, and so that's, so look, like I, I tend to c- then go down to that number, right? So like 19 unique mechanisms. Um, and, uh, and even there, frankly, there's not, there's some, there's some overlap, um, you know, so like different molecular targets, but like for the same population, like within a given pathway inside a cell, there's instances where we've actually successfully drugged like one component and its immediate downstream component and the immediate downstream component yet again. That would then count as three on that list of 19, but really they're very overlapping. So if I were to really boil it down, you know, I would s- we're, you know, kind of in the 10 range, um, in terms of, you know, truly unique-

   29. PAPeter Attia33:10

       Yep

   30. KFDr. Keith Flaherty33:10

       ... uh, mole- molecular targets. Uh, and, and Keytruda does have company, so this, I would, you know, the, the, so the, the target of Keytruda, just for those who are trying to keep up with the jargon [chuckles] as they do their g- their Google searching on any of these topics, the target of Keytruda, um, is P, capital P, capital D, hyphen one. That's a surface receptor on certain immune cells, um, particularly on these CD8 positive T lymphocytes that can kill tumors directly, but there are other immune cells that, um, express PD-1, and so, and that's a brake on those immune cells. So the antibodies that block that brake are the so-called PD-1 antibodies. There are five of them that are FDA approved, and Keytruda, Keytruda or pembrolizumab is, that's the dominant one that made it to market, um, well, first and also in the broadest number of cancer populations. Um, but there's, you know, uh, when I said me tooism before, like there's like lots of me tooism in that space.
7. 35:19 – 44:29

   The interplay between the immune system and cancer cells

   1. PAPeter Attia35:19

      Yeah. I, I think it's probably worth just sort of explaining immunotherapy again. Uh, again-

   2. KFDr. Keith Flaherty35:24

      Yeah

   3. PAPeter Attia35:24

      ... I, we have an entire podcast dedicated to that when I sat down with Steve Rosenberg. You and I spoke about it briefly four years ago, but I think given that the immune system is, uh, [chuckles] I was about to make a joke that wasn't intended to be a joke. I was about to say it's not innate as in our understanding. [laughs]

   4. KFDr. Keith Flaherty35:41

      [laughs]

   5. PAPeter Attia35:42

      But of course, it is innate in, in its-

   6. KFDr. Keith Flaherty35:43

      Right

   7. PAPeter Attia35:43

      ... in its physiology. Um, but, but given that I think that, you know, people don't necessarily, you know, completely understand the nuances of the immune system, given that, um, it's played such an important role in cancer, uh, optimism over the past two decades, and given that it's probably about to play more of an important role-

   8. KFDr. Keith Flaherty36:04

      Mm-hmm

   9. PAPeter Attia36:04

      ... as we go forward, I, I think it's worthwhile for the listener and viewer to understand how the immune system works with respect to cancer because when we talk about TIL, when we talk about checkpoint inhibitors, which we've already touched on, uh, I don't want people to be lost. Uh, so unfortunately, this is one of those moments in this podcast where you gotta buckle your seatbelt up a little bit. Um-

   10. KFDr. Keith Flaherty36:24

       Yeah

   11. PAPeter Attia36:24

       ... but it, it, but it pays dividends, um, because you become a very educated consumer of, of how these drugs work.

   12. KFDr. Keith Flaherty36:32

       Yeah, so let me, let me kind of layer the onion this way, um, which is I, I, I find it most useful, and I'd say this even in talking to patients, um, so they're, you know, my, my lay audience, uh, if you will, uh, to start with, um, you know, the concept that, that the immune system needs to find levers that it can grab onto, as in differences, things that are fundamentally different, um, than normal cells. Uh, we, we... Our immune system is trained, um, in fetal development, um, to, to do exactly that and, and, and quote-unquote only that, um, except for the fact that we unfortunately hold on to self-recognizing immune cells, and those can cause autoimmune disease, which is not the topic of our conversation today. Um, but basically, um, it... So when you consider, you know, what's, what's different about cancer cells and what, you know, what have we learned over the decades on that topic, there are a variety of differences. Um, now s- I'll, I'll, you know, start here because it's kind of gives a little bit of chronology in a way. Uh, we, we, we began to understand some time ago that, um, a lot... A common feature of cancer cells is that they behave, um, like they're, uh, sort of progenitors or precursors. Like in development, right, all mature cells in the body come from a, you know, a, well, a stem cell of, you know, of a, of some sort. Um, and there's lineage and different, different lineages and different types of stem cells. Uh, but ultimately, you see cancers actually adopt sort of a biological behavior that's like backing up, if you will, in the developmental, um, process. Um, and this is part of the, just a co- consequence of the genetic alterations or the combination lock, as I often refer to it, of genetic alterations that can lead to cancer, is that that's one of the programs, um, that they typically adopt. And it turns out that developmental cells, um, have surface, um, you know, proteins, uh, surface, you know, markers, if you will, that are not expressed in, in, uh, uh, fully mature tissues. And the immune system can see those, um, so that's well documented. And Steve Rosenberg's early successes actually were, were, you know, uh, identifying, uh, those immune cells that existed in people that could recognize, uh, you know, those, those types of antigens. So, so these are referred to as cancer-testis antigens, so just think of that as kind of this developmental sort of biology. Turns out there are also, interestingly, some what we refer to as lineage antigens, so like, you know, uh, surface markers that, you know, kind of tag a certain, you know, cell type that the immune system interestingly can recognize, even though we think of those as being more like self. Um, but, you know, we, we ha- we, we, we see the, we see evidence that, that the immune system reacts, uh, to those, and that there are, you know, cell therapies, um, as you were alluding to before, um, that also take advantage of that. The, the big discoveries of the recent, you know, several years have been that carcinogens cause mutations, um, in genes that then, you know, the, those genes encode first RNA and then proteins and, and the altered amino acid sequence of the protein, that can be recognized. So those are intracellular, almost always, um, those, those proteins, but we have a machinery in our cells, all, all cells in the body, um, including those cells that go on to become cancer, that basically breaks down those proteins as they age, um, and will present a representative set, if you will, of those broken down protein fragments or peptides, um, to, uh, you know, present them, meaning on the cell surface in the context of these, um, uh, you know, molecules we refer to as major histocompatibility, um, you know, receptors, as they're, you know, uh, kind of alluded to. But the idea is that they're, they're, they're trying to show the wares, if you will, the, the in- inner contents of a cell to the immune system, um, because we think that because of that is that, that virally infected cells, you know, have an infection inside. Um, we think this is how this, you know, machinery, um, was ever, uh, uh, you know, how it ever evolved in the first place. And so kind of showing the inner contents, if you will, is a way of being able to, like, let the immune system know that there's a virally infected cell. Well, that same machinery exists again in every cell. Um, and by the way, if cells stop doing that, there's a branch of the immune system, stop, stop presenting antigens at all, um... So antigen's a new word. I meant to, um, introduce that. Antigen means a difference, like a, a protein fragment that's being presented and seen as different. We call that an antigen, and it can come in these different categories that I'm talking about. Um, so basically if a cell, if a cancer cell w- were trying to hide itself, if you will, by not expressing, um, these receptors to present antigens, then there's actually a branch of the immune system that's basically, you know, natural killer cells, as they're called. They're very primordial immune cells. They're supposed to just, you know, swoop in and, and kill those cells. And, and we have evidence that that does occur.

   13. PAPeter Attia41:12

       So, so let's just, let's just pause here, Keith, to make sure people are following the anthropomology of this. Um, so basically you have a row of homes, and each person in their home is responsible for demonstrating the contents of their home. So they reach inside, and they pull out various items from their home, and they leave them on the curb. And the, you know, the military is coming down the street inspecting the contents on the curb. And they're just making sure that it's all stuff that we've pre-agreed is safe.

   14. KFDr. Keith Flaherty41:47

       Yep.

   15. PAPeter Attia41:47

       Right?

   16. KFDr. Keith Flaherty41:48

       That's right.

   17. PAPeter Attia41:48

       So what they know... They don't know the entire repertoire of what could be presented, but they have a very clear list of what is acceptable.

   18. KFDr. Keith Flaherty41:55

       Mm-hmm.

   19. PAPeter Attia41:55

       And they're basically just identifying anything that is not on the acceptable list.

   20. KFDr. Keith Flaherty42:01

       That's right.

   21. PAPeter Attia42:01

       And if anything shows up and it's not on the acceptable list, the house is destroyed. Furthermore, if you leave nothing on your curb, either because you're too incompetent or you're nefarious and you're trying to hide what's in your home, there's another branch of the military that comes along and just blows up your house. So failing to play the game [laughs] results in a, in a loss of home.

   22. KFDr. Keith Flaherty42:23

       That's right. Yeah, well said. So that, so that's the beginning, right? I mean, it's this kind of sampling, if you will, like you said, of the, of the i- inner contents. Um, uh, and, and so that, that's important to recognize because, you know, if you kind of put start with this core principle that cancer is a, quote-unquote, "genetic disease," meaning that mutations that happen in key genes that, um, disable cells' ability to repair DNA damage, um, as a common, um, you know, a feature of cancers, for example, or mutations that activate some of those surface receptors or downstream signaling molecules that we talked about before. Um, those, uh, mutations we've learned in recent years can be seen as different. Um, so they, like, you know, kind of begin to, you know, increase the kind of the toolbox, if you will, um, uh, of handles that the immune system can latch onto. So if you think about it that way, the cancers, you know, um, you know, begin to form potentially, uh, if they're witnessed, uh, by, you know, the immune cells as having a difference early, uh, we have lots of evidence that they can be eliminated. Um, and I mean, and there's actually kind of the, I guess, you know, uh, indirect, uh, you know, negative evidence, if you will, that people who have profoundly compromised immune systems will pop up with cancers. I mean, if you give people, you know, seriously, you know, high-dose immunosuppressive medication for various other medical conditions, you will see cancers just kind of sprout up, um, you know, quickly and then certainly over time as well. Um, this immune surveillance concept is, you know, inordinate amount of evidence, um, in support of this idea that at... if at least keeping them down, you know, cancer, proto-cancers down, if not outright eliminate them, is that's just part of life on, on planet Earth, um, you know, sort of in the cosmic storm, if you will, with UV radiation as being, you know, one carcinogen I mentioned. Well, actually gamma radiation [chuckles] coming through the atmosphere is, is also a, a cause of DNA damage. We have to kind of, um, you know, try to repair those, uh, you know, that damage, uh, inside of cells. I mean, when I say we, I'm, I'm again using the anthropomorphic inside of a cell's, uh, inner workings here. Um, and, but, you know, but if the repair can't happen, we have this other mechanism of immune surveillance, uh, basically to wipe it out. So,

8. 44:29 – 59:30

   Different ways cancer can suppress the immune response, and how immunotherapy can combat cancer’s evasive tactics

   1. KFDr. Keith Flaherty44:29

      I, what I... The reason why I wanted to just kind of spend enough, you know, kind of words, uh, you know, on this concept is that basically people have to understand that by the time they're diagnosed with cancer, something's gone wrong, right? [chuckles] Basically, right, like the, the, the system didn't work, um, to detect, you know, in this surveillance mode, um, the forming cancer. It didn't eliminate it. Um, how can that be? Well, it turns out [chuckles] that there, um, you know, for every, you know, kind of process that activates the immune system in response to an infection, just go with it, idea that that's like kind of, you know, the primary function of the immune system in terms of how it is that we ever kind of got out of the swamp in the first place evolutionarily. Um, there's a break on the immune system. Like, you can't just elaborate immune response, you know, indefinitely. I mean, imagine having the flu forever, like just dumping cytokines or immune system hormones into the bloodstream, you know, cranking up, you know, body temperature, you know, and, and consuming a ton of metabolic resources in fighting infection and feeling bad as a consequence when you have the flu. You can't do that, like, you know, indefinitely. You gotta stop, you know, immune responses. Um, and so we have, you know, mechanisms to do that, like a, turns out, very elaborate set of mechanisms to do that. And cancers have just ever so craftily figured out, [chuckles] uh, how to basically kind of reach into the genetic code, the blueprint, uh, and co-opt mechanisms that will basically impede immune system recognition and response. That's the PD-1, PD-L1 story. So PD-1 we've talked about. That's the target of Keytruda. But what cancers do, it's a nasty little trick, um, is they've figured out how to... Not all cancers, but, but the ones that are most responsive, um, to Keytruda, they have figured out, um, how to express on their surface, uh, the, the, the foot that presses on the brake, okay? So that's called PD-L1, so Programmed Death-L1, Ligand 1, which basically reaches across to PD-1 on T cells and tells them, "Shut down," basically. The, like, mission accomplished. Don't, don't [chuckles] need to do anything here. Um, and so, you know, a, a, a lung cell, an alveolar lung cell, um, that ultimately becomes cancer is not supposed to be expressing that, that, that, that protein on its surface, right? It's not supposed to be regulating the immune system. That's like, that's not the, the natural job of a lung alveolar cell. Um, but a cancer that arises from that cell, uh, in many instances basically, quote-unquote, "figures out" how to express, um, that protein. And so then blocking, you know, the interaction of the foot with the brake, like, that's the magic. That's... There, there it is. Um, now that's just one mechanism, but as I said, it's actually produced a bigger incremental benefit in the cancer population than any single mechanism we've ever discovered in all of cancer biology research and therapeutic development history. So it's a pretty powerful one, but I'll just conclude with this statement, that there are other mechanisms by which the immune system can be suppressed. Um, in fact, there's entire cell types in the immune system repertoire that are, uh, have a dampening effect on immune system response, and cancers can recruit them into their so-called microenvironment and create this very adverse environment for the T cells that could otherwise attack and kill. So it's like almost like assembling a force field by virtue of inviting in these non-cancerous cells, right? They're, like, this is like ca- the cancer cell is recruiting in, um, these suppressive immune cells. So this is some of what, what we're up against. I mean, I just wanna make it clear how kind of complicated it is. Um, yes, we've, we're super grateful to have had this, you know, kind of eureka moment, um, with, you know, the success of PD-1 drugs. Uh, but, but cancers have co-opted multiple mechanisms by which they defend themselves in terms of, you know, trying to close the gap then and use this immunotherapy concept much more broadly, and cancer is gonna require us to develop the understanding of, okay, well, which tricks are being pulled and how to be able to, you know, really target those very specifically. We can't disable people's immune systems, [chuckles] right? Like, that's not okay. Um, and so you, we, we do need a fair amount of precision and, um, you know, and, and figuring out kind of the sweet spot, if you will, in terms of what mechanisms cancers, uh, are using, uh, for this purpose.

   2. PAPeter Attia48:43

      Of all the things that, um, Steve talked about when, when I interviewed him last year, the one that I was most blown away by, which spoke to my time away from the trenches, you know, time away from what you're doing day to day, was that roughly 80% of epithelial tumors had novel neoantigens. Now, again, if you said that at a party, that would go over everybody's head and it wouldn't-

   3. KFDr. Keith Flaherty49:11

      [chuckles]

   4. PAPeter Attia49:11

      ... resonate as a particularly insightful thing to say. But in light of what you've just said, let's, let's make sure people understand what that means and how shocking that is relative to where we were 20 years ago. 'Cause 20 year... Like, just to put this in context, right?

   5. KFDr. Keith Flaherty49:27

      Mm-hmm.

   6. PAPeter Attia49:27

      So when I finished my time at the NCI and went back to finish medical school and applied to residency, you know, you talk, in residency interviews, you're talking about what you're obsessed with and what you're interested in, and I talked a lot, I mean, that my time at NIH was such a formative part of my education, and I can't tell you how many people I interviewed with that just laughed in my face and said, "This immunotherapy stuff is nonsense."

   7. KFDr. Keith Flaherty49:54

      [chuckles]

   8. PAPeter Attia49:55

      Like, "It's totally irrelevant." Like, "What are you talking about, kid? Like, this, you're gonna sell yourself to us as an interesting person that we should let into our program, and you're talking about that crap? Like, it literally means nothing, okay? It works on melanoma. Who cares?"

   9. KFDr. Keith Flaherty50:11

      Right. Right.

   10. PAPeter Attia50:12

       Okay. Why is the fact that 80% of epithelial cancers have novel neoantigens a, a, a totally staggering feature that had people understood that 20 years ago, uh, you know, maybe more than just a handful of people would have found immunotherapy to be-

   11. KFDr. Keith Flaherty50:28

       Yeah

   12. PAPeter Attia50:28

       ... a, a very promising field?

   13. KFDr. Keith Flaherty50:30

       Yeah. Right, right, right. So let, let's, uh, like, let's break that down a little bit, um, you know, kind of the biology behind this. So mutations accumulate in a cell that's gonna become cancer. Fair number. I mean, we're talking, you know, never less than dozens in the, you know, the, quote-unquote, "most genetically simple ca- um, cancers." But you're typically into the hundreds and thousands. Um, and basically, you know, the, like, not all of those have a consequence, um, and h- and to the point about these, uh, antigens. So some of them are in parts of the genome that don't even encode proteins, right? So, like, in which case they're not gonna ever become, you know, the, the k- types of antigens you're alluding to. The ones that are translated into proteins, again, those proteins age, they get, you know, uh, sort of, you know, broken up in the, uh, proteasome presented in the context of these MHC molecules that I referred to before on the cell surface. But that's done differently in each of us. And so basically they're... Like, we don't show our entire wares. We show kind of, you know, selected, um, uh, representation of them. In other words, these MHC molecules, you know, you inherit kind of half of your set from your mother and half of your set from your mother- father. Um, they have a ability to grab just certain protein fragments, um, and present them. Uh, when I say grab, they're, like, actually loaded onto those, um, by a, like, cellular machinery that's quite, uh, elegant. Um, and so the point is, we have this, um, you know, this repertoire of showing inner contents, and so only certain mutated, well, genes that translate into, let's call them mutated proteins or, you know, just altered proteins, um, only certain of those can actually be presented out of the very large number of mutations that actually exist. Um, but what is astounding is that, that as you say, 80% of... So when you use epithelial cancers, just remind people like breast, colon, prostate, lung-

   14. PAPeter Attia52:14

       The big ones

   15. KFDr. Keith Flaherty52:14

       ... pancreas, these are all-

   16. PAPeter Attia52:15

       Yeah, yeah

   17. KFDr. Keith Flaherty52:15

       ... these are all epithelial-

   18. PAPeter Attia52:15

       It's basically, it's not leukemia and lymphoma-

   19. KFDr. Keith Flaherty52:18

       Yeah

   20. PAPeter Attia52:18

       ... it's basically, it's, it's e-

   21. KFDr. Keith Flaherty52:19

       Or, and brain, and brain t- and brain tumors.

   22. PAPeter Attia52:20

       Yeah, yeah, yeah.

   23. KFDr. Keith Flaherty52:20

       Right, yeah, not leukemia, lymphoma, or brain tumors. Uh, and so, uh, and yeah, and mel- melanomas, we mentioned before, those, those actually come from melanocytes, which are of neural crest origin, which are actually, um, share common features with brain tumors. But basically, just to be complete, it's all the rest of cancer. Um, what's astounding is that basically you can find evidence, um, that these mutated proteins are being presented, um, in the vast majority of these common cancers. And here's the point. We are born with T cell receptors, um, well, born and during early fetal devel- or early, um, uh, uh, development after, after birth. We elaborate this, this very, uh, impressive repertoire of T cell receptors that, you know, sit on the surface of T cells that can recognize exactly these altered proteins, like with just one amino acid substitution-

   24. PAPeter Attia53:09

       Hmm

   25. KFDr. Keith Flaherty53:09

       ... uh, present, um, in the, the, uh, the peptide fragment. Um, we've got that repertoire, and you can... So this is the, you know, the proof that these antigens are antigens. I mean, like, to meet the definition of antigen, you have to find in a human being [chuckles] that the immune system can actually see it, um, in the context of it being presented on these MHC complexes. And, and it turns out that, like, this, it's kind of a lock and key concept, essentially, um, that, that it has to structurally work out that the pro- pep- protein fragment is being presented, you know, in the T cell receptor docking in, um, and seeing that version but not the unmutated version, right? Like, where that difference is enough to basically tell the T cell, "Go," like, "Kill." Um, yeah, so these exist. I mean, this, like, this first began to be described in earnest, mm, about a decade ago. Um, and then, you know, of course we were sequencing cancer genomes, um, you know, a, a ton at the time, and we figured out as PD-1 and CTLA-4 were being clinically developed, we began, like, looking then in retrospect and seeing, you know, it's these tumors that have a ton of these mutations. Um, they're the ones that are responding, like, much more likely than other cancer patients/cancer types. Um, and so guess what? It's the ultraviolet radiation-associated cancers that have, like, just enormous amounts of mutations, like, in total, and the presence of actually significant numbers, usually oftentimes dozens of these mutated neoantigens. That's the jargon term that we're, we're, like, coming towards here. Um- And so that explains why the response rates are so high in those cancers. Smoking-related cancers then account for just about all the rest of where PD-1 has been efficacious. So it, like we didn't know this when PD-1 and CTLA-4 antibodies were first being developed, that like there was this interplay that, um, we could then like just add one drug that, you know, kind of blocks this foot on the brake, as I mentioned before, and bam, you unleash these preexisting T cells against these presented, um, antigens. But that does explain a ton of the benefit that we've, um, covered already, uh, with this, um, so-called immune checkpoint antibody approach. So, so that's fascinating, but I, I think, you know, what you're coming to is, well, then, then what, what else can we do with that information, right? And, and so what Steve, I'm sure, talked about with you is, well, we can actually engineer immune cells [laughs] to attack these things, um, and, you know, basically potentially overwhelm other ways that the immune system tries to... or that, that cancers try to protect themselves from the immune system, um, which is what cell therapy, um, of various kinds can do. Uh, so, you know, basically, we're still in the early days of elaborating this understanding, um, that, that, yes, the vast majority of cancers, um, have these, you know, mut- alterations that the immune system can actually recognize. Let me just finish with this one very nuanced point. We have learned that some mutated new antigens are much more, uh, will cause a much more robust immune response than others. In other words, they're not all the same in terms of the sort of type of immune response, um, that can be elicited. And there's an argument that many have made in terms of thinking about cancer biology and evolution and coexistence, you know, of this immune surveillance, um, system, that basically the mutations that we end up seeing in diagnosed cancers are ones that aren't particularly well-recognized. They don't produce powerful immune responses. The ones that produce powerful immune responses, well, guess what? Those cancers never became cancers in the first place. They got wiped out.

   26. PAPeter Attia56:30

       Yep.

   27. KFDr. Keith Flaherty56:30

       Um, right? So there's this notion that like, basically, you have to be able to fly under the radar, [laughs] uh, you know, right? And, and you can, you can build yourself as a cancer cell with cer- a certain repertoire of mutations, provided that none of, none of them are powerfully immunogenic.

   28. PAPeter Attia56:44

       Yeah. I m- uh, we could talk about this forever. I'll say a couple more things on it so that we can move on to talk about T cell therapies, where I think we're going next. But I, again, I think to put a bow on this, the way I think about this is that, you know, through all of recorded human history, there have been very, very rare reportable incidents of spontaneous regressions of solid organ metastatic, you know, these epithelial tumors, right? Where, you know, Steve Rosenberg writes about one, which was the, the patient who got him to completely change his career. It's the 1960s. He's a resident at the Brigham. A patient comes in who 10 years earlier had been sent home to die with metastatic gastric cancer throughout his liver. You know, they took his stomach out to palliate him and the, you know, he should've been gone in three months. He shows up 10 years later with a gallbladder that needs removing, not a shred of cancer.

   29. KFDr. Keith Flaherty57:39

       [laughs]

   30. PAPeter Attia57:40

       Clearly a spontaneous remission. There's an example of someone who made not so much and so significant of an antigen that it got wiped out before it got anywhere. This one actually got all the way to the promised land, but somehow at that point the immune system said, "I recognize it, and there are enough of us that recognize it-"
9. 59:30 – 1:10:15

   Elimination of a substantial portion of cancers through immune cell engineering faces challenges of specificity, cost, and scalability

   1. PAPeter Attia59:30

      so, so what does that look like?

   2. KFDr. Keith Flaherty59:32

      Yeah. Well, it's, I mean, just, you know, just to, uh, you know, connect the dots from early versions of cell therapy to where we are now, um, I mean, you know, Steve Rosenberg's work was, you know, so-called adoptive T cell therapy. Let's not focus on that jargon term so much. But basically doing a surgery to remove a single site of cancer, metastatic cancer, um, removing the immune cells that had found their way into that cancer, um, which turns out actually is some of them are seeing antigens that they're specific for. Others are just trafficking through, and they're kind of bystanders, as it turns out. Um, but any case, immune cells, you know, don't traffic in high numbers through all cancers, but certain, quote-unquote, "immunogenic cancers," yes, they do, melanoma again being, you know, near the top of the chart there. Um, and what Steve Ver- what Steve was doing, um, through the '90s, um, and certainly by the time you got there, was taking those immune cells, isolating them from that patient's tumor, and simply expanding them, right? Not, not, not, not picking them-

   3. PAPeter Attia1:00:27

      Nothing, no, no genetic anything

   4. KFDr. Keith Flaherty1:00:29

      ... not, yeah.

   5. PAPeter Attia1:00:29

      It was just grow these tum-

   6. KFDr. Keith Flaherty1:00:30

      Exactly, yeah.

   7. PAPeter Attia1:00:31

      Yeah, grow these TIL.

   8. KFDr. Keith Flaherty1:00:31

      Yeah, t- to a number that when he infused them back was, could then, you know, systemically, could then traffic through the body and destroy, um, you know- people's cancers. Um, not, not all the time, but a significant minority of patients could be cured that way. Uh, that's still true today. And, and, and by the way, we are right on the verge of that, just that approach alone, no genetic manipulation becoming an FDA-approved therapy finally for melanoma-

   9. PAPeter Attia1:00:56

      Mm-hmm

   10. KFDr. Keith Flaherty1:00:56

       ... which is where, you know, uh, Steve had had the most consistent success back in those years. Uh, he, he's tried it in many different cancer types. Now, what's been learned along the way, um, is exactly what we've already summarized, which is this, you know, this idea of antigen specificity that you can find basic- you, you know, this kind of, you know, what is it that the immune system is seeing, um, these infiltrating immune cells in tumors? What are they, what are they looking at? And then taking that knowledge to basically now begin to engineer, um, immune cells. Generally starting with the patient's own immune cells, um, so not coming from tumor anymore, right? But just basically collecting them from the blood. Um, you need a fair number of them. Uh, but because of genetic engineering advances, cell- cellular, um, genetic engineering advances, you know, we can now basically, you know, swap in, swap out, you know, s- essentially whatever we like. And in these immune cells that, you know, um, we want to direct against cancers, uh, we can basically introduce, you know, the, the, the, the recognizing piece, if you will. Um, so if we, if we sequence a patient's cancer, uh, which we do just as part of routine standard of care these days, but you do it this, like, a little bit deeper, a little bit more, um, uh, in, yeah, kind of a, a systematic, thorough way. Uh, basically in, uh, in, let's go with that number, 80% of patients, you know, we can identify a mutated, uh, antigen that will only be in the cancer cells and introduce into the, their immune cells a surface recognizer, if you will. I'm just being vague about the term and to not get lost in too much jargon all at once. Um, and then basically just, you know, dial up that number of cells in the laboratory and then infuse them back like a blood infusion, which is how cell therapy's given. Um, and, and that's, that's the approach that, like, translates, you know, connects the dots that we've, that we've covered. We are not doing that today, to be very clear. The cell therapy advances beyond just simply expanding, um, the, the tumor-infiltrating, um, immune cells or lym- lymphocytes. Uh, beyond that approach, the engineering that's being done right now are against surface lineage markers, um, so on B cells for l- lymphoma primarily, but some leukemias and now multiple myeloma as well. Basically, we are wiping out the cancer cells that arise from that population and the normal ones, [chuckles] okay? Just to be clear. Like that, like, so what, what, what we're, what we were talking about is, you know, a very elegant, you know, very tumor-specific, um, cell therapy strategy, which you can, like, readily envision, uh, sort of taking the field, if you will. Uh, but where we are right now in cell engineering is going after common surface markers in cell populations that we can, quote-unquote, "afford to get rid of." So eliminating B cells is actually not a great long-term thing, [chuckles] but you can actually survive without your B cells. These are an- uh, antibody-producing cells, uh, for those who don't, you know, track immunology.

   11. PAPeter Attia1:03:48

       And, and so, so the, the poster child for this, of course, is CD19.

   12. KFDr. Keith Flaherty1:03:51

       Yes.

   13. PAPeter Attia1:03:51

       And as you said, every B cell is walking around with this marker on it, just, we don't have to get into why it's called CD19.

   14. KFDr. Keith Flaherty1:03:59

       Mm-hmm.

   15. PAPeter Attia1:03:59

       And when a subset of B cells go on to become lymphoma that is otherwise unresponsive to other treatments, lo and behold, you could, you know, wipe out... You could basically send in someone that's gonna target every CD19. Um-

   16. KFDr. Keith Flaherty1:04:13

       That's right

   17. PAPeter Attia1:04:13

       ... and, and you, you'll get rid of the bad guys, you'll get rid of some good guys, and on balance, it's, it's worth it, for sure. Um, but yes, what we're talking about here is a next layer of sophistication because, for example, if a patient has metastatic lung cancer, it's not an option to wipe out all of the lungs. Um-

   18. KFDr. Keith Flaherty1:04:37

       That's right.

   19. PAPeter Attia1:04:38

       But it's also a more complicated problem. Like, there are many cancers for which you could completely live without the organ. You don't need your colon, you don't need your breast, you don't need your prostate, you don't even need your pancreas. Um, you'd much... You're better off be-- I mean, I'll give you an example. I think you may remember this. I have a friend, um, with Lynch syndrome, and it was unbeknownst to him because he was adopted. Um, developed colon cancer, uh, in midlife. Again, a great surprise when you're 40 to develop a stage III colon cancer. Um, but later developed a pancreatic adenocarcinoma. Um, you know, I sent him to see an excellent, uh, doc who I had trained with, and he was inoperable. Um, so everybody who is familiar with pancreatic cancer understands inoperable s- you know, locally advanced, uh, pancreatic cancer is, uh, is a, is a six to 12 month prognosis. Um, but because he had Lynch, I mean, this was 2012 maybe, maybe 2013.

   20. KFDr. Keith Flaherty1:05:42

       Mm-hmm.

   21. PAPeter Attia1:05:42

       It was just around the time that a paper had come out in The New England Journal of Medicine that had mentioned, "Hey, if you have mismatched mutation genes-

   22. KFDr. Keith Flaherty1:05:51

       Mm-hmm

   23. PAPeter Attia1:05:51

       ... you might be a candidate for this new anti-PD-1" And this h- story has a happy ending in that sure enough, he got the anti-PD-1, went into a complete remission-

   24. KFDr. Keith Flaherty1:06:03

       Mm-hmm

   25. PAPeter Attia1:06:03

       ... but now needs insulin because the-

   26. KFDr. Keith Flaherty1:06:07

       Yeah, yeah

   27. PAPeter Attia1:06:07

       ... his immune cells destroyed every pancreatic cell in his body, not just the cancer-

   28. KFDr. Keith Flaherty1:06:12

       Mm-hmm, right

   29. PAPeter Attia1:06:12

       ... but the non-cancer. Do we, do we not have enough novel proteins on breast cells or prostate cells that we can, that the, that the CD19 approach-

   30. KFDr. Keith Flaherty1:06:23

       Yeah
10. 1:10:15 – 1:31:49

    Why TIL therapy isn’t always effective, and the necessity for multimodal therapy to address various aspects of the cancer microenvironment

    1. PAPeter Attia1:10:15

       Let's go back to TIL for a moment. You mentioned that they're on the cusp of, um, receiving an FDA approval for the treatment of metastatic melanoma. So again, just to bring people back to what that means, that means a patient with metastatic melanoma who presumably has progressed through all other non-cell therapies, um, and still has harvestable tumor, this is [laughs] a very important feature of TIL. You actually have to be able to surgically pull out a large enough sample of a tumor. So a patient, for example, has cancer that has spread to their lung. They have to actually undergo lung surgery and take out a wedge or lobe or whatever amount is necessary. That tumor is taken immediately to the lab where all the lymphocytes that are there are expanded and expanded and expanded, and I forget, I, it's been so long since I've been at it, I think they want to get to at least ten to the nine. Is that the-

    2. KFDr. Keith Flaherty1:11:05

       Right. That's right

    3. PAPeter Attia1:11:06

       ... order of magnitude?

    4. KFDr. Keith Flaherty1:11:06

       Yeah.

    5. PAPeter Attia1:11:06

       Okay.

    6. KFDr. Keith Flaherty1:11:07

       Yeah.

    7. PAPeter Attia1:11:07

       So you want to, you expand this to about ten to the nine cells, and they're reinfused, usually with interleukin, and again, you're, you're looking for this response. It sounds great in theory.

    8. KFDr. Keith Flaherty1:11:19

       Mm-hmm.

    9. PAPeter Attia1:11:20

       Why doesn't it work every single time? You've clearly identified lymphocytes that know how to go there, and presumably, that's half the battle. Why don't they, why doesn't this work every single time?

    10. KFDr. Keith Flaherty1:11:31

        Yeah. I mean, it's, it, again, it goes back to defense mechanisms to a degree. I mean, it's, so there's, there, you know, this, I, I talked about that kind of layering of the onion, [laughs] uh, metaphor before. Basically, there are layers of force fields. I mean, there, it, it is the case that there's actually direct mechanisms that can impede killing, um, at the tumor cell level, and I talked about like PD-L1 being expressed on cancer cell surface. Well, it turns out even intracellular, um, mechanisms, um, so, so the, the way in which interferon, which is an immune system hormone that like basically triggers cell death, it's part, part of the killing process, um, that when CD positive T cells are trying to kill a cell, it's like a virally infected cell, or in this case, a cancer cell. And, and it turns out that, that, and you know, to become cancers, you know, successfully become cancers in the first place, that you can find direct evidence, certainly in melanoma, of, of that cancer, that, you know, in- intracellular pathway itself being altered. So that like the, the, that the immune cells are actually unable to do the killing because immune, because that cell is no longer sort of sensitive, um, to immune cell mediated death, um, which is a very nasty little trick, and one that can't be overcome just by dumping in, uh, more immune cells. At least we don't have ev- direct evidence that it can. Um, this also can cause resistance to, to PD-1 antibodies, we've demonstrated, um, like in melanoma and a handful of other cancer types now. But that's the-- So you have to start sort of like inside the cell in terms of, you know, ways in which cancers have evolved an ability to resist immune recognition that is like that they're, they're kind of contending with. Um, but then you've also got, you know, that recruitment of, um, suppressive immune cells that I r- alluded to before, which like especially very antigenic cancers very commonly, you know, do that, need to do that. Um, and you can't overwhelm them just by introducing more CD positive T cells, uh, by and large. And so in those cancer types where those, um, so-called myeloid cells are, are very, very predominant, like this cell therapy has just not taken, you know, hold at all. Um, and then there are trafficking issues. Um, in other words, you know, so like there are basically features of cancer microenvironments, um, some of them related to oxygen tension, some of them related to nutrient availability, um, that make it very challenging for immune cells to, you know, persist, you know, multiply and, and do their killing work. Um, and so this is, you know, we, we, we've known for so, such a long time that cancers are, cancer cells are metabolically inefficient, um, that they're living in this incredibly harsh environment, um, like as in very low oxygen gradients and, and we just, you know, people didn't really understand like the why of that. I mean like, like what-

    11. PAPeter Attia1:14:13

        Right. Peop- people-- The, the-- Your, what you're describing, of course, comes, stems in part from the Warburg effect, which had always been-

    12. KFDr. Keith Flaherty1:14:19

        Exactly. Yes. Yeah

    13. PAPeter Attia1:14:19

        ... you know, people had always thought, well, it must be that cancers can't undergo oxidative phosphorylation-

    14. KFDr. Keith Flaherty1:14:25

        Right

    15. PAPeter Attia1:14:25

        ... and that's why they're doing this inefficient thing. But to your point-

    16. KFDr. Keith Flaherty1:14:28

        Yeah

    17. PAPeter Attia1:14:28

        ... between the substrate argument, you know, going through reams of glucose leaves you more building blocks, which is what they need more than ATP. Uh-

    18. KFDr. Keith Flaherty1:14:37

        Yes

    19. PAPeter Attia1:14:37

        ... and then on top of that, you're lowering the pH, you're creating this-

    20. KFDr. Keith Flaherty1:14:40

        Yes

    21. PAPeter Attia1:14:40

        ... incredibly harsh microenvironment. Uh-

    22. KFDr. Keith Flaherty1:14:43

        Yep

    23. PAPeter Attia1:14:43

        ... it seems like there's every reason in the world for, uh, from a, from a, from a, um, a natural selection standpoint for cancer to do that.

    24. KFDr. Keith Flaherty1:14:51

        Uh, this is my point, is that I think it's the, the why of it is that like, well, cancer cells like ultimately figure out how to sufficiently thrive, if you will, in such harsh environments. Well, who can't survive in that very harsh environment? Well, immune cells. I mean, and so this is the idea that this is all, much of this has to do with, you know, kind of creating, conditioning this harsh environment as a force field. Um, you know, this is another thing we are not addressing by virtue of just dumping in, um, more immune cells. And so, you know, my argument is, you know, that like when I talk about multimodality therapy for cancer, it's, you know, about targeting those mechanisms that we can address inside the cancer cell. It's about modulating the environment, um, metabolically, um, you know, kind of actually even fixing to a degree this oxygen, um, s- you know, uh, paucity of oxygen, uh, in the pockets, uh, you know, of that, um, as well as manipulating these other cell populations like immune cells. Um, and turns out even like fibroblasts, for example, like get recruited into certain cancers, most notably pancreatic cancer. Um, they seem to be part of the force field against the immune system as well. So we have to kind of knock down the force field. I mean, it's just, it's the Star Wars analogy, right? You've gotta take out that, the moon [chuckles] that generates the, the force field around the Death Star before you, um, you, you send in your fighters to actually try to destroy it. And so, you know, to me it's, it's, you know, we're, we're, we're on the verge of understanding, you know, kind of the hierarchy, um, of this biology and how to think about, you know, both diagnosing and then treating at this level. But, but the toolbox has to elaborate, you know, much more completely. It's just, I, in my strongly held view, it's not gonna be four therapeutic maneuvers all in column A, right? Or four in column D. It's like one from A, one from B, one from C, [chuckles] one from D. That's the type of four drug regimen that's gonna eradicate cancer, and it's not gonna be one cocktail for all patients.

    25. PAPeter Attia1:16:46

        So let's, let's dig a little deeper into that in terms of what the next five years might hold for us, right? So if we're sitting down again in five years to talk about the success of the previous five years, what's likely happened, right? So how much further have we gone in immunotherapy just in straight up activating T cells, either through adoptive cell therapy via genetic engineering to take peripheral blood lymphocytes and turn them into or engineer them into TIL? Let's put that as a category of therapy. Let's talk about other ways to identify checkpoints or, uh, checkpoint inhibitors and/or, um, combat the tumor suppressor cells. So call that the sort of tumor suppressing environment, go after it. How much of it is gonna be [lips smack] in the metabolic environment or the kind of interstitial microenvironment that's, and, and targeting the hostility? Um, and then how much of it is going to be inducing mutagenesis? So-

    26. KFDr. Keith Flaherty1:17:50

        Yeah

    27. PAPeter Attia1:17:50

        ... again, you know, w- you and I spoke about this g- uh, p- probably a couple of years ago, and I ended up, I think it, I think I was able to keep it in the book. I know there's always so much pressure. You're trying to chop stuff out of the book. So I don't remember if this finally made it in, but I at least referenced one study that had taken patients, I think, with lung cancer who were, you know, n- none of them had any PD-1 activity, and then a course of platinum-based chemotherapy all of a sudden rendered a subset of them to now be susceptible to it. In other words, using a conventional chemo increased immunosusceptibility even though the conventional chemo itself wasn't particularly responsive.

    28. KFDr. Keith Flaherty1:18:28

        Mm-hmm.

    29. PAPeter Attia1:18:28

        Um, so, so, a- and again, there's lots of ways to, to go about doing that.

    30. KFDr. Keith Flaherty1:18:32

        Mm-hmm. Mm-hmm. Yeah.
11. 1:31:49 – 1:38:36

    The challenge of treating metastatic cancer underscores the importance of early detection to improve survivability

    1. PAPeter Attia1:31:50

       Keith, I'm gonna change gears for a moment only because I know we have a very short clock today relative to how long you and I could normally speak, um, and I wanna talk about another very important topic. So to introduce it, let me share with you some stats that you know better than I do, but I'll let you interpret the stats for the listener. [lips smack] If you take a person with Stage 3 colon cancer, so this person has cancer in their colon, it's even spread to the lymph nodes of the colon, but to the visible eye, it has spread no further into... There's no radiographic evidence that it's anywhere else. [lips smack] You're gonna put that patient on a fancy regimen of chemotherapy. I don't have to spell out FOLFOX and all that stuff, but there's a, there's a regimen of chemotherapy you'd put that patient on. How many of those patients are gonna be alive in five years? 60, 70% of them?

    2. KFDr. Keith Flaherty1:32:39

       Yeah, that's about right.

    3. PAPeter Attia1:32:40

       Yeah.

    4. KFDr. Keith Flaherty1:32:40

       Yeah. I mean, it, uh, yeah, again, all depends on the size-

    5. PAPeter Attia1:32:43

       Yeah, yeah

    6. KFDr. Keith Flaherty1:32:43

       ... of the initial tumor and other features, but that's about right.

    7. PAPeter Attia1:32:45

       Yeah.

    8. KFDr. Keith Flaherty1:32:46

       Yeah.

    9. PAPeter Attia1:32:46

       Let's now take that same patient in a way, except he also has cancer that has spread to his liver.

    10. KFDr. Keith Flaherty1:32:55

        Yeah.

    11. PAPeter Attia1:32:55

        So you're gonna go ahead and cut the colon out, take those lymph nodes out, but on the CT scan, you're gonna notice that he's also got metastatic cancer. So one of them is Stage 3, one of them is Stage 4. We're gonna give that Stage 4 patient the same chemotherapy. We're gonna give them the same drugs. But in five years, somewhere between none and a few percent of those patients will be alive.

    12. KFDr. Keith Flaherty1:33:19

        Yeah, yeah.

    13. PAPeter Attia1:33:19

        And if you wait to 10 years, it's none.

    14. KFDr. Keith Flaherty1:33:21

        Yeah. Yeah.

    15. PAPeter Attia1:33:23

        What, what's a decent explanation for that observation? Which, by the way, if we had more time, we could tell the same story for every cancer, basically.

    16. KFDr. Keith Flaherty1:33:31

        Yeah, yeah. Like, in other words, what I refer to as microscopic residual disease. Like, why, why, why is it that we're actually able to eradicate microscopic residual disease with the same drugs that, that don't do the job, um, when you have-

    17. PAPeter Attia1:33:42

        Macro disease.

    18. KFDr. Keith Flaherty1:33:44

        Ugh. Yeah.

    19. PAPeter Attia1:33:44

        Yeah. Right.

    20. KFDr. Keith Flaherty1:33:44

        When it comes to-

    21. PAPeter Attia1:33:44

        And in other words-

    22. KFDr. Keith Flaherty1:33:45

        Yeah. Yeah

    23. PAPeter Attia1:33:45

        ... why does it work when you have hundreds of millions or billions of cells not all clumped together, but sort of diffuse?

    24. KFDr. Keith Flaherty1:33:52

        Yeah.

    25. PAPeter Attia1:33:52

        But when you have like 100 billion cells and they're like-

    26. KFDr. Keith Flaherty1:33:55

        Yes, exactly. Yeah, yeah

    27. PAPeter Attia1:33:55

        ... in big visible clumps, the same-

    28. KFDr. Keith Flaherty1:33:57

        Yeah

    29. PAPeter Attia1:33:57

        ... drugs just fail.

    30. KFDr. Keith Flaherty1:33:58

        Yeah. So there's, there's, there's, you know, I would say two prevailing explanations. Uh, th- they're, they're hypotheses, I mean, frankly, because we-- They're, they're, they'll become explanations once we actually [chuckles] you know, connect the dots and really, you know, prove that we can, you know, demonstrate our knowledge by curing more patients with this. Um, so one is basically just a clonal heterogeneity concept. So basically, as cancers evolve, um, we used to think that cancer cells were kind of identical clones of one another, like that, like they're, they're just like, you know, just a massive number of absolutely identical cells. Um, that, in the beginnings of cancer, that is largely true. Um, but as cancers continue to evolve, um, in our bodies, uh, they actually keep mutating. Um, and so you start establishing subclones. I mean, and, like you can have a dominant subclone. That's typically the case. Like that might even be, you know, 99% of the cells. Um, and then in that remaining 1%, you might have 10, 20 subclones. Um, we've like proven now that, that certain therapies actually are able to pick off the 99%. They leave the 1% or, and then somewhere in that 1% is a clone that has a resistance mutation, like already in it, to the drug that we're giving. Um, so there's a clonal heterogeneity, you know, um, you know, kind of, uh, hypothesis that I would say is, is quite strong at this point because of some of the evidence I just alluded to, that that's a big part of the problem. If you nip it in the bud, if you will, with of- offering the same therapy when there's not so much clonal heterogeneity, um, that's, that's, that represents a curative opportunity. And so when I was talking before about these, um, so-called oncogene-targeted therapies, which is not all of the targeted therapy successes we've had, but the ones that go after these mutated, um, activated, um, proteins, um, you know, those growth factor receptors and downstream ones in particular, um, it's very clear that you can't-- you can cure a trivial fraction of patients with overt metastatic disease, and you can cure a pretty substantial fraction of patients in the so-called adjuvant setting, so microscopic residual disease setting. And, and so, so we, we have direct evidence that this phenomenon occurs, but, but, but you're asking the why question. It's, we think, some contribution or some part explanation from having to do with, you know, lack of clonal heterogeneity. The other is the secondary immune response concept, right? That basically all successful curative cancer therapies actually do trigger immune recognition, um, through what's referred to as immunogenic cell death, so that you're killing the cells directly with your drugs. Um, but that basically the, with the mop-up work, if you will, of actually eradicating every last single cell is an, is the immune system's job. Um, it's a concept that was first, um, introduced, uh, when, when we had just the, these conventional chemotherapy drugs from the 1900s. Um, and, and now we actually have more and more evidence that our, you know, sort of more elegant molecular targeted drugs actually engender these types of, you know, like, you know, better immune system recognition phenomena, um, as part of their mechanism of action. And, and I- I-- and because we've de- directly demonstrated that, like better immune recognition in, you know, in patients who are receiving these therapies, looking at biopsies compared to, uh, pretreatment And that that happens rather quickly. Um, you know, I think it's reasonable to then s- you know, like overlay that on top and say, well, yeah, no, it, it, I mean it's, it's, you, it's extending your spontaneous remission, you know, kind of, um, starting point, uh, from a while ago in discussion, uh, that basically you're, you're allowing this kind of tipping point phenomenon to occur. Yes, you're directly killing cells with these drugs, that's true, but the eradication piece-
12. 1:38:36 – 1:49:21

    Liquid biopsies for early detection of cancer and determining the possible tissue of origin

    1. PAPeter Attia1:38:36

       it. Yeah.

    2. KFDr. Keith Flaherty1:38:36

       Right. 'Cause we're t- we're pretty terrible at that, uh, in, in, as, as it stands right now. Um, so, you know, as, as I think many, um, uh, of your audience know, basically we can only screen... We only have real direct evidence of effective screening for a few cancer types. Um, I mean, cervical cancer for sure, but we could also, like, hopefully eradicate cervical cancer by getting everybody vaccinated-

    3. PAPeter Attia1:38:57

       HPV vaccine. Yeah

    4. KFDr. Keith Flaherty1:38:58

       ... um, eventually. Exactly. Um, but, but cervical cancer screening, um, uh, you know, uh, absent a vaccine is, is quite effective. So, um, so that's one. Breast cancer for sure, we can cut the risk of breast cancer death by about a third, um, with mammography, but that's not, that's not a very inspiring number. I mean, I absolutely [laughs] suggest that e- everyone who's eligible who you care about, you should, um, you know, uh, strongly insist that they get mammograms. Colonoscopy, um, and other less invasive means of detecting colon cancer can reduce risk of colon cancer death by about 25 to 30% ballpark. I mean, the, the be- the most optimistic estimates would be about a third, um, also. Um, and I'd, there again, I'd say, well, that's, that's a real number. I mean, I, you know, I, I've had my first colonoscopy and I'll keep doing them. Um, but that's not, that, that isn't, you know, um, again, particularly inspiring. And despite, you know, lots of effort and of, let's say, lots of controversy, prostate cancer screening is, is really quite poor. I mean, really, it's like kind of a, it's a, [laughs] it's almost like just, you know, um, non-randomly assigning people to get prostate biopsies, right? As, you know, getting PSA tests, basically. It's, it's, it's not a great way of detecting, um, cancers and certainly not potentially dangerous prostate cancers.

    5. PAPeter Attia1:40:11

       But I would add something to that, Keith, which is that all of those three, the three last ones, which are three big cancers, right? Those are three of your big-

    6. KFDr. Keith Flaherty1:40:18

       Yeah. Yeah

    7. PAPeter Attia1:40:18

       ... five. Um-

    8. KFDr. Keith Flaherty1:40:20

       Yeah

    9. PAPeter Attia1:40:20

       ... they all have something in common. So if you look at mammography, infrequent colonoscopy, and PSA, I would make a case that all of those are not great screens by themselves.

    10. KFDr. Keith Flaherty1:40:32

        Yeah.

    11. PAPeter Attia1:40:32

        Uh, I'm sure you would agree, right? So in other words-

    12. KFDr. Keith Flaherty1:40:34

        Yeah, yeah, yeah

    13. PAPeter Attia1:40:34

        ... um-

    14. KFDr. Keith Flaherty1:40:34

        Yeah

    15. PAPeter Attia1:40:36

        ... people often confuse, and unfortunately this is true of physicians and policymakers more than it is patients, 'cause I think the patients are looking to those of us who think about this for input. Patients confuse, or policymakers rather, and physicians confuse the statistics you rattled off as proof positive that early screening doesn't justify the cost.

    16. KFDr. Keith Flaherty1:40:58

        Yeah. Yeah.

    17. PAPeter Attia1:40:58

        A different way to say it is, no, mammography used in isolation, which has its blind spots, is not a monotherapy.

    18. KFDr. Keith Flaherty1:41:10

        Yeah.

    19. PAPeter Attia1:41:11

        PSA by itself, as you said, is shy of a random number generator.

    20. KFDr. Keith Flaherty1:41:17

        Mm-hmm.

    21. PAPeter Attia1:41:18

        But that doesn't mean that adding ultrasound or MRI to-

    22. KFDr. Keith Flaherty1:41:22

        Right. Yeah

    23. PAPeter Attia1:41:22

        ... the breast surveillance program won't dramatically by stacking s- tests with different sensitivities and specificities, right?

    24. KFDr. Keith Flaherty1:41:29

        Mm-hmm.

    25. PAPeter Attia1:41:30

        Mammography, exceptional for small calcified lesions, uh, works poorly in hyperg- glandular tissue, right? The exact opposite is true [laughs] with the MRI. Uh, similarly with the PSA by itself, virtually meaningless, but PSA density, PSA velocity now adds much more, uh, specificity.

    26. KFDr. Keith Flaherty1:41:51

        Yes.

    27. PAPeter Attia1:41:51

        Uh, furthermore, you start to add things like a 4K, and if the risk is high enough, you get, um, you know, multiparametric MRI. I'll te- I'll tell you this, Keith, I mean, I'm not telling you anything you don't know, but I think again, just for listeners, in 10 years, I have not had one patient get a prostate biopsy that wasn't warranted. And I'm, I'm not a superstar. It's not like I've, I've got some-

    28. KFDr. Keith Flaherty1:42:13

        Right, right, right

    29. PAPeter Attia1:42:13

        ... no, it's just that-

    30. KFDr. Keith Flaherty1:42:14

        You just-
13. 1:49:21 – 1:57:21

    Commercially available cancer screening tests

    1. KFDr. Keith Flaherty1:49:21

       doing, you know, much of its job.

    2. PAPeter Attia1:49:22

       So what's the, what's the state of the, uh, uh, of the market today, Keith, in, in terms of, um, uh, tests that, that people listening to this can actually get as part of a, a, a, a cancer screening, uh, protocol? So, so-

    3. KFDr. Keith Flaherty1:49:36

       Yeah

    4. PAPeter Attia1:49:36

       ... so GRAIL has a commercially available kit.

    5. KFDr. Keith Flaherty1:49:38

       Mm-hmm. Yeah.

    6. PAPeter Attia1:49:39

       Uh, it's, you know, it's not over the counter. You need to get it through a physician.

    7. KFDr. Keith Flaherty1:49:42

       Yeah.

    8. PAPeter Attia1:49:42

       Um, what, what are some other tests out there? And in your view, how close are we to these tests being an imperative part of cancer screening?

    9. KFDr. Keith Flaherty1:49:53

       Yeah. I, I, I think we're not quite at the imperative point, but we're, uh, we're certainly at the point where I would say it's reasonable to get a test. I mean, right, if you consider yourself an early adopter- [chuckles]

    10. PAPeter Attia1:50:02

        Yeah

    11. KFDr. Keith Flaherty1:50:02

        ... and you know who you are, um, it's reasonable to get a test. Um, it's, you know, and, and, and just quickly to answer your question, uh, the first part of your question, uh, there's a test that was initially developed by a company called Thrive that was acquired by Exact, um, and they, they, they have a commercially available test as well, and then another company called Delphi, um, have a commercially available test, which are all, all have performance characteristics that are, you know, in the same realm, um, in terms of supporting, uh, you know, their, their current clinical use. Um, but here's the concern, um, that many people have, which is, um, that basically we're at a state in the field where finding people who are blood positive, blood test positive, um, could lead to a large degree of anxiety [chuckles] in terms of then you do, you know, standard, standard radiographic assessment, you don't find the problem, and that, and that basically the medical community, and because we're not talking about oncologists-

    12. PAPeter Attia1:50:56

        Yeah

    13. KFDr. Keith Flaherty1:50:57

        ... who are doing the tests, right? So, um, the medical community, um, really hasn't had time to really kind of work out the kinks of like, how do we manage this situation? And so you could almost argue that there need to be, you know, generalists who, you know, kind of really develop expertise, you know, kind of content knowledge-

    14. PAPeter Attia1:51:14

        Yeah

    15. KFDr. Keith Flaherty1:51:14

        ... have a network of specialists that they can work with to be a, you know, to be able to kind of catch these patients. Um, and these tests were launched, you know, before that was really created. So that, that's just my PSA-

    16. PAPeter Attia1:51:24

        Yeah, yeah

    17. KFDr. Keith Flaherty1:51:25

        ... my public service announcement in terms of, um, the fact that you just like, you know, if you just get a test and you're not in the hands of someone who can, you know, kind of manage, um, a positive test, um, I think that, that, that is at, at least anxiety provoking. But the, and the technology will, is, is, I mean, again, it's c- we, we've, uh, with collaborators of ours, uh, we've actually been doing like direct head-to-head comparison, uh, you know, kind of analyses like of how much lower can we go in terms of, you know, amount of, of, uh, tumor DNA in the blood that can be detected with, you know, what are currently R&D methods, but are readily scalable. Um, we're really at 100X better. I mean, it's like it, it, this is, it's, and you know, that it's-

    18. PAPeter Attia1:52:05

        At that point, you're talking about a finger drop of blood if you're 100X better-

    19. KFDr. Keith Flaherty1:52:08

        Yeah. Well-

    20. PAPeter Attia1:52:08

        ... than 10 ML, you mean?

    21. KFDr. Keith Flaherty1:52:10

        Well, yeah, but okay, that's true. [chuckles] You could take it in that direction, but we actually, we-

    22. PAPeter Attia1:52:14

        You would say no, stay with 10 or 20 ML-

    23. KFDr. Keith Flaherty1:52:16

        10 MLs, exactly

    24. PAPeter Attia1:52:17

        ... and we are way more sensitive.

    25. KFDr. Keith Flaherty1:52:18

        Yes. Oh, exactly.

    26. PAPeter Attia1:52:19

        Yes. Yes.

    27. KFDr. Keith Flaherty1:52:19

        Exactly.

    28. PAPeter Attia1:52:20

        Okay.

    29. KFDr. Keith Flaherty1:52:20

        I mean, right. So that, so that's the point. And, and then, and then do serial analyses, right?

    30. PAPeter Attia1:52:23

        Yeah.
14. 1:57:21 – 2:05:38

    How to address the disparity in cancer care, and the exciting pace of progress for cancer detection and treatment

    1. KFDr. Keith Flaherty1:57:21

       Exactly

    2. PAPeter Attia1:57:21

       ... diagnostic to therapeutic."

    3. KFDr. Keith Flaherty1:57:22

       That's right.

    4. PAPeter Attia1:57:23

       Keith, w- we're just about out of time, so I wanna kinda end with, with a, with a question that you may not be able to answer, but it's worth asking anyway. Um, you know, I think of you and, and, and people I know like you as the most remarkable, you know, oncology advocates, meaning I know that if one of my patients comes down with, uh, cancer, I can call you up and say, "Keith, I've got this woman. It's a very unusual breast cancer. It's, you know, it's, it's HER2 new positive, but ER, PR negative. There's something funky about it going on. Wh- who do you like? Who should she be seeing?"

    5. KFDr. Keith Flaherty1:57:59

       Mm-hmm. Mm-hmm.

    6. PAPeter Attia1:58:00

       Um, and, and, and, and, and, and let's say there's another situation where a traditional therapy is failing and, and you know, you're gonna point me in the direction of, um-

    7. KFDr. Keith Flaherty1:58:09

       Mm-hmm

    8. PAPeter Attia1:58:09

       ... of where to- where there's a clinical trial that's promising.

    9. KFDr. Keith Flaherty1:58:11

       Mm-hmm.

    10. PAPeter Attia1:58:11

        Not just a phase one-

    11. KFDr. Keith Flaherty1:58:13

        Mm-hmm

    12. PAPeter Attia1:58:13

        ... that's, like, probably got no hope, but here's a, here's a phase two that really has some hope. Okay. So, like, there should be an entire industry of Keith Flahertys who are there to be consulted by, um, families who find themselves in this, in this situation. Because again, we come back to how we started this discussion, there's nobody listening to us right now or watching us right now-

    13. KFDr. Keith Flaherty1:58:40

        Mm-hmm

    14. PAPeter Attia1:58:40

        ... who hasn't been touched or will not be touched by cancer. And even if it's a cancer that ultimately doesn't kill them, which again, in about half the cases it won't actually kill you, you will need help navigating the system, and the disparity in cancer care in this country, uh, and probably in most countries, is significant, and therefore it does matter who you know. It does matter which expert points you to the best treatment center. So because I can't clone Keith and a dozen other people that I know that I can pick up the phone and call, what, what does that look like? I mean, what, what can somebody do when they, when they get that bad news?

    15. KFDr. Keith Flaherty1:59:23

        This drives me crazy, uh, what you're talking about in terms of access to expert opinion, um, when you need expert opinion, and, and particularly for complex, unique, um, outlier cases, if you will. And, and, but we're... And y- you don't know as a patient or a family member whether you're, you know, um, dealing with a middle of the road case, right? How, how would you know?

    16. PAPeter Attia1:59:41

        Yeah.

    17. KFDr. Keith Flaherty1:59:41

        Um, and, and this is where, um, basically... So f- first off, like, we, we, we need to pool our insights, if you will, right? Like, like, like break down the silos of, you know, hospitals and centers and universities and whatever, um, and pool our, you know, kind of, you know, uh, opinions. Uh, that's kind of point number one. Point number two is we need to leverage technology for this purpose. Like, this is, I mean, this, uh, people get all excited about artificial intelligence-

    18. PAPeter Attia2:00:07

        Yeah

    19. KFDr. Keith Flaherty2:00:07

        ... in terms of its, you know, its in- how it's informing, you know, chemistry advances and, and the like. And, and, and you know, I'm excited about those things too, but, but... And, and in other aspects of, you know, biology discovery and all that. But this is the ob- this is the most obvious use basically, right? Is that you essentially, you, you start to, you know, like, build the database essentially of, of opinions, um, that, you know, that, like, I and others, you know, offer to specific cancer cases based on certain aspects of their diagnosis, right? And, and the patterns are, like, these, these are not hard for a machine to [chuckles] to figure out.

    20. PAPeter Attia2:00:42

        Yeah.

    21. KFDr. Keith Flaherty2:00:42

        I mean, a human could figure out.

    22. PAPeter Attia2:00:44

        No, it's just, it's sort of codifying what you do, what you do very easily as the-

    23. KFDr. Keith Flaherty2:00:48

        Yes

    24. PAPeter Attia2:00:48

        ... teaching set for the AI.

    25. KFDr. Keith Flaherty2:00:51

        Exactly. And what I'm getting at is within the 95%, you know, boundary of, you know, of, you know, kind of typical cases, um, basically you, you, I mean, you really could, you could h- the decision support can really be based on, you know, the last 100 cases that I and my, you know-

    26. PAPeter Attia2:01:07

        Yeah

    27. KFDr. Keith Flaherty2:01:07

        ... other melanoma colleagues have seen that are, you know, just like this. Um, and then the edge cases is where we need to apply our specific attention, right? And there, I think there are actually enough of us-

    28. PAPeter Attia2:01:16

        Yeah

    29. KFDr. Keith Flaherty2:01:16

        ... to handle the edge cases. Um, uh, the problem is that we, like the way our system works is, like, nobody knows what their complexity of their diagnosis is, so they're, right? [chuckles] So they basically are, are, like, everybody's seeking, you know, the same level of care and, and, you know, sort of decision making, um, without that understanding. And, and I, we can get way ahead of this and, and, and be transparent in explaining, like, look, you know, here's why we're saying you've got a very typical case. We have a ton of outcome data.

    30. PAPeter Attia2:01:41

        Yep.

Episode duration: 2:05:38