 We are not going to solve the problem of cancer without concentrating on the bottom of the pyramid, which is to prevent cancer from occurring in the first place. And I will talk a lot more about it because we know much more about that bottom of the pyramid than we knew before. The middle of the pyramid would be a broad category, but we might call it secondary prevention or early detection, finding cancer in its early phases and removing it so that it does not spread and metastasize in the body, because of course for most cancers it's metastatic cancer that kills you, not the primary tumor generally. The top of the pyramid is cancer treatment. So again, prevention, early detection treatment, vast amounts of resources and a vast amount of national attention and international attention is paid on the top of the pyramid. And there's a good reason for that, for treatment. And of course immunotherapy is one example of that. It is the capacity to treat cancer using the immune system. But it's important to remember that it's the bottom of the pyramid that deserves attention in the next decade or so. And it's important to remember that all these three parts communicate with each other. These are not isolated silos. So let me talk a little bit about prevention and we can come and talk more globally about treatment in a second. What do we know now about cancer prevention as the landscape has evolved? Well, number one, the one surprising thing and one disturbing thing about what we know about the bottom of the pyramid is that for the last decade or so, and this is going to be a provocative controversial statement, so push back, push back on it. That's what we want, yeah. For the last decade or so I would argue we have not found removable human chemical carcinogens of substantial impact. Our capacity to find removable human chemical carcinogens of substantial numerical impact has gone down dramatically. That does not mean that they don't exist. Of course tobacco smoke is rampant, it's a huge carcinogen, but we've known that since the 1980s, 1950s, 1960s you might say. Big carcinogens that really we haven't been able to find. When people ask me what do I do in my own life as an oncologist to avoid cancer, I'm not doing anything different in 2017 that I wasn't doing in 1997, fundamentally speaking. So there are three possible reasons for this. Reason one is that we aren't finding them because we don't have the right tools. Reason two is that they do exist, but they're death by a thousand cuts. So there are many of them, they have impact, they're somehow additive, they're adding themselves up in the body. And reason three is that maybe they don't exist in the way that we think they exist. In fact, some or a fraction of cancer is the result of changes in DNA that are acquired when cells divide and make mistakes. Now that is not to say that there aren't carcinogens that we should not be tackling at the double negative. In other words, that is to say that there are carcinogens that we should be tackling. Human papillomavirus, tobacco smoke, and other viruses that are rampant across the world which you can vaccinate against. Other forms of carcinogens. But the point is that we need to learn much, much more about the bottom of the pyramid and that we are learning a lot more about the bottom of the pyramid. So I'd like to concentrate as we move along in the panel at what we know now about the bottom of that pyramid. So I definitely want to do that, but Julia, if you'll forgive me, said I want to go to the top of the pyramid for just a second. And that's because, so you work for MSD, which is part of Merck. Merck has been a pioneering leader in the case of immunotherapy for cancer. But you've also been in the previous life the head of the Center for Disease Prevention and for CDC, control end prevention. And a huge part of that is the bottom of the pyramid. So you've had some experience on both. My question is, do you think that the progress we're making at the top of the pyramid is substantial enough to make a difference given what you know about the ongoing challenge of the burden? First of all, thank you for including me on the panel and thanks to everyone who's here to listen and learn. You know, you really said yourself at the beginning, if we have 18 million new cases of cancer a year, we are not succeeding at the bottom of that pyramid. So clearly we have a lot of work to do in that area. There are drivers for those numbers. One of the biggest drivers, of course, is the aging of our population because, as you said, the accumulation of our duration on Earth also accumulates changes in our DNA that probably predisposes to cancer. But we're also living in an environment where there are enormous disparities in the incidence of cancer, not just geographic disparities but socioeconomic disparities and exposure disparities in some cases. But I think the third thing that we're learning is that we really can bend the curve. So we have pockets where we are seeing relative success in cancer prevention and control. And I'll just mention a couple, tobacco in countries that really have implemented comprehensive tobacco control programs, the curve is bending on lung cancer. And that is a tremendous public health success. Granted, it took decades to get there and we still have a long way to go. But, you know, we can change the shape of that pyramid. I think the other that you mentioned in terms of HPV as a carcinogen, we're seeing now that a combination of vaccination and screening for HPV disease and hopefully early and better treatments really can essentially eliminate cervical cancer. At least it's technically possible to have that conversation. Again, massive disparities and we have a long way to go to get there. And the last thing I would say is just in terms of the science of the situation, the biggest curve bender ahead of us really relates to the breakthroughs in the science that we now have at our disposal. The tools in our toolbox. You mentioned the CART T therapy or the gene therapy for a child with leukemia minister, but there are so many new modalities now that we really, this is the time to have the decade against cancer because we do have the tools in our toolbox. Julie, let me follow up on some of these bending curves. So in the case of cervical cancer, we have made tremendous strides in the developed world, but in sub-Saharan Africa, it's still a major killer of women. And what was frightening is the latest report from the World Health Organization showed that lung cancer rates globally were rising in women in large part because of a lack of tobacco control programs in much of the world. You know, this is a challenge of when we talk about cancer, we're talking about hundreds of diseases and we're also talking about huge disparities in terms of the kinds of people who get it and where they are and how they're being treated. Even in the developed world, we see dramatically different rates in survival between black Americans, for example, and white Americans. And so how do we begin to address these disparities with the structure that we have? Well, one way of thinking about it is to remember that the pyramid that we're talking about does demonstrate that the biggest value comes from addressing the base. And prevention on a per capita basis is much cheaper than any treatment that we have at the tip of the pyramid. So we do need to think differently about how we prioritize our investments. And the prevention investments are always, if not cost savings, cost-effects. So if you prevent cancer, you're reducing both ends of the cancer burden, the new cases and the deaths, as opposed to just the mortality. Mickey, this is, you know, we talk sometimes in these big statistics, you have a statistic of one, which is why you got into this. Talk a little bit about the experience with your father being diagnosed with pancreatic cancer. Yeah, yeah. So to self my self a little bit, I'm an internet entrepreneur. I started my own company, Rockton, two years ago. And, you know, when nobody really believes anybody will buy something on the internet. So I'm kind of disruptive, crazy entrepreneur, but kind of survived for the last 22 years. If you look back on probably Amazon and ourselves, only two companies survived this long. And then we, a family, found out my father had a pancreatic cancer six years ago. At that time I didn't have much knowledge about the cancer, to be very honest. But I love my father and I'm kind of crazy enough to start my journey, exploration to find the most advanced cure against pancreatic cancer. So at least I traveled all around the world. I went to Stanford, UCSF, UC San Diego, Columbia, Harvard, Paris University, many universities in Japan. And the conclusion was other than very, very toxic combination therapy, there was no, you know, good cure. And, but interesting enough, my friend, who is a client of my business, called me, and he was also friend of my father, Tom Hamicky. My cousin is doing this very interesting research at NCI, his Japanese. And he's, what is it? And he said, he's using lights to cure the cancer. Using light to cure the cancer, yeah. I said, give me a break, right? How can you cure the cancer with light? But I was desperate. So, and he said, by the way, President Obama mentioned about this project in his inauguration speech. I said, oh, I better go and check it out. So I met a meeting with them and it was, you know, kind of, my chin dropped and eye opening, you know, opportunity for me. What it is, basically, we create a conjugate of antibody with some special chemical and which certainly react only to certain type of lights. And they were just trying on the animals at the time. I saw it. And when I spoke with my doctor friends about this, 99% of them said, hey, Mickey, those kind of things work on animals, but it never works on humans. But I was immature enough. No, no, no, this is going to work. It doesn't, because we're not talking about chemical reaction or biological action. We're talking about cause-triggering the chemical reaction using lights. Being targeting and specifically destroying the cancers. I didn't know about the side effect or, you know, what would be the ongoing immune response at the time. But I thought this should work. And that's, I think, strengths of damages. Everybody in this industry for a long, long time, you know, are kind of trapped or, in my opinion, paranoid. But I have fresh eyes. And now we're in a, you know, we completely face the trial. And the result has been very, very amazing. So that's exciting. Sid, you know, as somebody who, again, coming back to your role as historian and doctor, you know, we've had these moments of optimism. Now we're talking about immunotherapy. But back in the 1900s, we were talking about radiation therapy as the great cure. And then combination chemotherapy, which in the early cases of the cures of leukemia and Hodgkin's disease, which I'm actually standing here as a beneficiary of that early cancer chemotherapy in the 1970s. And then we had anti-angiogenesis drugs. These were drugs that were going to choke off the blood supply. And then we had the targeted, molecularly targeted medicines like Gleavec, which were the smart drugs in cancer. And in fact, even before this, we had immunotherapies, super-drugs like Interleukin-2 and Interferon, which we put on the cover of Fortune in 1985. You know, we've been through this before. How real is, what's different about the immunotherapy revolution that we're in now? Well, first of all, you have to think of our armamentarium against cancer, not as individual therapies, but as the possibility of combined. These are things that are additive. So in other words, cytotoxic chemotherapy, the kind of therapy that we use, is great at reducing tumor burden. It kills cells and brings down your cell burden from billions of cells to hundreds of cells, thousands of cells. But of course, it often doesn't cure. It cures some cancers, but doesn't cure many cancers. And those 10,000 cells that are left, 100,000, 1 million cells, then grow up again. And it's like beheading the monster and comes right back. Targeted therapies allowed us to use Achilles' Heels like concepts to now go after even those 10,000, 1 million cells that were left and attack them with their particular vulnerabilities. Immunotherapy is yet another iteration in this. But here's what's different, and it's very important, is that most of the cancer therapies that we were developing thus far were seed therapies. And this is an old concept that goes back to the 1800s. And it is to imagine cancer as the seed and the body as the soil, or the host as the soil. The seed, of course, this concept comes from the great surgeon, Padgett, who asked a very simple question. I mean, if you read Padgett, I make my students actually go back and read Padgett's paper. 1898. So it's an incredibly important paper in which Padgett just asks a simple question. He says, the spleen is about the same size as the liver. It has a similar kind of blood supply. The liver is a vastly disproportional site of metastases. The spleen barely ever gets the metastases. He gives a second example. He says, breast cancer metastasizes to the bone, but who's ever heard of a finger metastasis of breast cancer? You've never heard it metastasize to the axial skeleton, but not to the distal skeleton. It's the same bone. So why is immunotherapy different? Immunotherapy is different because it uses the soil to attack the seed. And why is that important? That is important because now we're beginning to understand that cancer is an interaction between seed and soil and that we know have to understand much, much more about the soil. I'm going to give you two studies that were published recently that are very important. One is a study in which they biopsied the esophageal cells from patients with elderly patients with and without smoking. Smokers are non-smokers. What's important is the following point, which is that even within the non-smokers, but especially within the smokers, you can see cancerous changes in cells but no frank cancer. In fact, if you look at the esophagus of such a person, there are what would be technically called cancer cells, but they're not cancerous. They're not invasive. Something about their body, something about the physiological state of the body, whether it's the immune system, whether it is the metabolic milieu, something is controlling or putting a back pressure on the development of cancer. So what I think is important about immunotherapy is actually two things, one of which has been widely appreciated. The widely appreciated thing is that it's a great treatment for cancer. It allows us to understand how to use the immune system against cancers that were previously very refractory to treatment. But the second thing that has been less appreciated is that it begins to open up the box of the soil. And when you open up the box of the soil, you actually find a kind of wormhole as it were from the treatment down to prevention. You can ask questions like, why is it that some people are not getting cancer? Is it because there's something special about their immune system? Is it something about their soil that we haven't previously identified? So it breaks, it finally, I hope, we are hoping, all of us, that it will allow us to break through this kind of impasse that we were in cancer prevention by identifying states or identifying people who are at higher risk and thereby beginning to sort of coordinate this pyramid from the bottom up to the top. It's a soil therapy and I'm very excited about soil therapies because they are a change in the way we think about the paradigms of cancer. I think that's very helpful, the seed and soil hypothesis of cancer. Julie, you said something really important before, which is you said as we age, we accumulate mutations in our DNA. Lots of accidents happen. Some of them are assaults from the outside in the chemical world or the physical world. Some of them are internal in terms of radicals, free radicals that happen and then go into the body of oxygen metabolizing chemicals that interact with DNA. And as this happens, you know, this accumulation of DNA mutations, sometimes it happens in just the wrong way and all the fail-sapes fail and you start to get cancer. Are we human beings at an inevitable, you know, is this just an inevitability of being human, of getting cancer over time? Is this just another, you know, breakdown of the body as it were? I think there's some plausibility in your theory, but clearly there's so many exceptions to that rule that I don't think we can say it's an inevitability. But, you know, when you were talking about the seed and the soil, I was thinking when I was very young and starting out my career in biology, I was told by an important professor that if you understood syphilis, you would understand medicine. Then we came an intern and we had the HIV epidemic and I was told, well, if we really understand HIV and how it's interacting with the body and how it's evolving and the opportunistic infections and cancers that follow it, we will understand medicine. And now I'm really beginning to think that if we understood cancer, we would really understand medicine and particularly the psychoneurobiologic access, which these days even includes the biomes, because there's so much information exchange going on in our bodies all the time. It's not just a static process of DNA eventually making too many mistakes. There are problems and then there are corrective factors and humors and small molecules that are speaking to our immune systems all the time, and we simply don't. There are so many of these systems. There was the genome which was supposed to give us the code to life and there's the proteome, which is the proteins that are encoded by these genes and then there's the metabolome, which is all of the metabolic things and the bacterium, all the bacteria that are synergistic and so on. And as we've come, there's just so much data to process. And I think another dimension of this is the dogma has always been that as you age, your immune system gradually deteriorates so that part of the susceptibility here is the accumulation and the other part is the fact that our defense systems wear down. But one of the interesting things that we see and some of the patients who are responding to immunotherapy is they're really old. And so it tells you that when you turn their immune system back on, there's enough immune system there to basically cure their cancer. Now, how could that be? I mean, it defies our traditional dogma about immune senescence. So, Mickey, you know, when I was talking with you earlier before this session, you know, it was clear that you were talking about antibody conjugates and this, you know, EGFR receptors and all of these, the sort of the conversation of modern cancer and biology that you've seemed to have mastered in a short time. And you're suggesting that as yourself described, crazy technology disruptor that six years ago, before your father's illness, you didn't know any of this stuff. How did you start to teach yourself about the sort of the cancer biology? Well, of course, when we learned that my father had a pancreatic cancer, I, you know, visited and had a talk with the, you know, top scientist and oncologist and everybody. And during that course, I learned the basics of cancer cells and immune system and so forth. And then I, of course, began to invest it. I was so engineer-invested to this photomereotherapy project, as a matter of fact. I funded like 95% of it so far. And, definitely, I'm in a board meeting. I wrote notes about the, everybody's talking about what are they talking about, right? And go back and Google it and it really works. And I'm not saying I'm completely understand, but my approach is not really super targeting any DNA or RNA. And I think the reason why I could have an understand approach is coming from a totally different angle compared with other therapies. So I want to jump into that because, you know, there's so many tech entrepreneurs now who are getting into cancer and there is this, they're bringing a mentality of quote, fail fast into the cancer research world and development. And they're really pushing the envelope in some cases into new science, into places that traditional science hasn't gone. Sometimes they're just faster in terms of creating genomic sequencing companies or others, you know, the tools, the technology of the world. What is it about the tech world, what can the tech world bring to the cancer research world? Well, first of all, including my project. Although this is for profit business, most of the codes is coming from kind of philosophical mindset. So I put in $30 million. I think this is going to be hugely successful, but even if you fail, we don't care, right? Because this is like bringing the money back to the society. The second, the good thing about this kind of philosophical approach is bringing in the mentality of entrepreneurship to drug development. And of course it's totally different field, but you know, entrepreneurs, we care about the reality, right? And then of course in this cancer academic society, there are all sorts of ongoing long talk, talk, talk approach. Let's just test and see. Let's just explore. So I think mentality approach are a little bit different and of course we cannot do it by ourselves, but we can be a great partner to the great scientists. So Julie, you know, the minister, minister Spahn said earlier about the cost of some of these drugs. You work for a drug company, a big one. Just to put this in perspective in the last five years in the United States, the cancer drug costs have doubled in just five years. They're predicted to double again. In 2017, the average drug that came out that was released in the market was averaged $100,000 as an average cost. In fact, there was no drug in 2018 that was below $100,000 when it was released. If you're thinking about it as Sid said, it's additive, the treatments. We're going to be combining a lot of these drugs. How can even developed western countries afford this, let alone the developing world? We've got to get our hands around this, don't we? We do. And at the same time, having cancer is very expensive. If you need treatment and chemotherapy and radiation therapy and surgery and all of the other modalities that come into play, the cost of cancer care is expensive. What we really need to find are the ways that we can precisely identify patients who are going to respond to a given set of tools and recognize that the aim here is cure. Curing cancer is going to be a lot less expensive than spending a lot of money over an arc of time in treating it enough and repeatedly treating it. And we don't think of cancer medicines as investments in cures. If you just look at the cost of the medicine, yes, it's a large number. But if you look at what's the cost averted when you're able to treat with highly effective cancer medicines, you can see that innovation is really worth it. And I just kind of go back again to the HIV environment when we were beginning to launch HIV drugs, we had the same conversation. Those drugs were expensive when they first came out. Of course, over time and as the period of exclusivity ends, drugs are now widely available in every part of the world at a price that is affordable. But the incredible cost of care of HIV disease in 1980 really justifies the investment that we're made in the industry. It counts for the rise though because in 2013, I mean, this has been happening for a while, you can go back and see this really kind of extraordinary rise. In 2013, the WHO estimates that global spending on cancer drugs, just on drugs, was $96 billion in 2013. In 2017, just four years later, it was $133 billion and it's projected to go again by that same slope upward. I mean, I understand why it's expensive, but why is it getting so much more expensive so fast? There are a couple of reasons for I think the rapid increase. One is that the drugs are working, so we're using them and a lot more patients, particularly the current and hopefully future generations of the immunoncology drugs. I mean, MSD has one of the immunoncology drugs and we are having 900 clinical trials with this drug in 30 different tumor types and we already have survival advantage in several. So, we're seeing the investment increase because the drugs are working and they're working much more broadly than we imagined. Yeah, I mean, I think that's true and I think it's important to say that the numbers are a little scary in terms of the fact that even now, only about a third of people respond to these immunotherapies in the specific cancers and melanoma, which is the most, the cancer, probably most receptive to immunotherapy, initial response rates are about 60%, but over a three-year period, it drops to about 40 or 30%. And so, this brings us back to the conversation you and Sid were talking about, which is that bottom of the pyramid. By the time we get to that state, it's kind of, it's not always too late, thankfully, and it's getting, again, possible to cure cancers later on, but we really have to address this earlier, Sid. There's no doubt about it, but the important feature of this is that, as I said in the past, the three levels of the pyramid, by the way, the middle level is, as I said, early detection, were dissociated from each other to a large extent. There were people who were working on prevention who thought of the total sum of cancer money or the total sum of resources as a zero sum game. Every piece of money that goes to treatment is taken away from prevention. That's less and less true, because we are being informed by what is, the biology is informing us in every direction. As I said, we now know a lot more about immunotherapy. We hope to learn a lot more about obesity. Obesity is a great example. In fact, I made the provocative idea that we haven't discovered a carcinogen since the 1990s. We actually have, although it's not technically a carcinogen in the standard sense. It does not damage DNA as we understand it, but what it does is it might create human states, physiological states, that might be inflammatory, that might be otherwise linked to obesity, that somehow or the other increase, clearly increase the risk of certain cancers, but not other cancers. You're talking about sugar, right? Sugar is one of them. We're running, actually, we ourselves, we've got a big study on this. It was just published in Nature. We're running a big study on this, starting very, very soon changing the diet to make it more receptive to chemotherapy. That's our study. What we're finding out is that if the ecosystem would work correctly, we should be able to find trapdoors or real insights between these three aspects of the pyramid, and that will move the clock forward, because clearly something is, we cannot afford to treat hundreds of millions of patients with extraordinarily expensive drugs, especially if the responses are not doable. In a minute, I just want to open it up for questions. If you have a question, please raise your hand and we'll get a microphone to you, hopefully. I think we've got microphones. Just a second. We're calling you just a second, but I want to follow up on this issue of whether we are doing enough in the science systematically to have an effort in the prevention effort. In other words, are we finding biomarkers that can warn us of a cancer state or cancer progression? You mentioned the fact that we really haven't found a single percentage of significance that we can identify as, yes, this is causing cancer even though they may be part of a slew of chemicals that are damaging DNA. How do we change the cultures that we do shift a little bit more towards that bottom pyramid? I think one of the ways is to have very strict criteria. I like Mickey's comments about entrepreneurship, but on the other hand, the criteria for judging whether a drug works or a therapy works or a prevention mechanism works are and have been very clearly defined. We can't keep changing the goalposts and the FDA has been very thoughtful for a long time and CDC has been very thoughtful for a long time about making clear that if you shift goalposts, things go horribly wrong. So there is a process by which any therapy or any experimental modality is evaluated through a phase one, phase two, phase three study. The endpoints are created so that we're looking for survival and mortality. Mortality is a very important end point because there are endemic biases in response rates and survival rates and so forth. We can talk about them extensively studied. So you need to have hard endpoints. You need to follow the rules and so on one hand, the entrepreneurship is very helpful because it breaks and disrupts the ecosystem. But on the other hand, there's also important pushback from organizations that know that by changing goalposts and making language slippery, it actually doesn't help. So there has to be a push-pull dynamic here and that's very important. Fantastic. We've got a question from Seth Berkeley, CEO of Gavi. Thanks, Cliff. I love your Sid soil kind of way of thinking about this. I want to build on what you just talked about and it's interesting. I would argue exercise is an example of something that improves health in multiple ways, probably prevents cancer. So there's an example of something that can be recommended. But what we've also done in the past is we've had these crazes. We all remember Linus Pauling with vitamin C and then it was selenium and it was vitamin E and vitamin D and one of the challenges, I think when you do that, it's the right idea, you know, how do you build the immune system up by giving it nutrition. But the problem is that when you put that intervention in, you change all the loops and you down-regulate things and up-regulate things. How do we get to an understanding of those interventions? And one of the problems with those is very hard. If you have hundreds of millions of dollars to be made for drugs, you have an incentive. What's the incentive to do those simple manipulations, do the large-scale trials that are necessary to get us, you know, simple things we can use globally on the prevention side? Yeah, that's a great question. I think once that had been done, you should take the first step at that since you've been involved in a more global sense. You know, it's not an easy answer, obviously, or we would have already figured it out. But as we begin to look at things like single-cell genomics, we can tease out the relationship between a perturbation here and the downstream or upstream effects of that. It's going to take a lot of time, but as I said at the beginning, we have the tools now to begin to probe these things. And I think, as you were saying earlier, the discipline and the science that needs to go into being really clear about the endpoints that we're looking for, it's systems biology. And so whether you're talking about an inexpensive intervention or a complex intervention, we still have to go through the same processes. Well, so the simple interventions, I wouldn't say simple. So it's interventions that are not pharmaceutical in their fundamental nature, such as diet. Or exercise. Exercise, diet, the reduction of obesity, etc. These fall very much within the category of national institutes. So the NIH, for instance, is now funding large epidemiological studies and large dietary studies. We actually were part of them. And these are really important epidemiological studies. So you begin by, first of all, being disciplined, not moving goalposts. And number two, relying on federal institutions, such as the NIH, such as European institutions, to fund studies where the incentives are not pharmaceutical. You have to empower them to be able to do that. You have to empower them with money. You have to empower the scientists to do them, the epidemiologists. And you have to arm them with the right language to do that. And then, simultaneously, you allow the pharmaceutical universe, starting with academic laboratories who work on this, including my own, to move along. Drugs that will treat, prevent, and potentially cure. It's very much interesting. Seth, who represents GAVI, the vaccine alliance, so it reminded me, we do have some preventive approaches to cancer. One is the HPV vaccine. Another one is the cervical cancer vaccine, which has not been as widely endorsed as it should be. And there are others that, just from a vaccination standpoint, we could be reducing a tremendous amount. Julie, do you? One of the dimensions of this is rarely discussed, really, is the success in drastically reducing the incidence of hepatitis B-related liver cancers. Liver cancers, yeah. Many years ago, Merck Tech transferred our entire intellectual property for hepatitis B vaccine to China. And you can watch the incidence of liver cancer in China go down over the past several decades. So, you know, that's a cancer prevention vaccine. The same thing with HPV vaccine. The early data from Australia now just showing that not only are you preventing genital warts, but you're preventing the early stages of HPV-related cancer. It's also another dimension of the immunotherapy. But in fairness, these are cancers where the infectious disease etiology is known. I have a theory that there are other cancers that are probably infectious, and we haven't discovered that yet. But, you know, again, it's a technology that is improving, and we will be able to take some cancers off the table. That's exciting. We have another question right in front of us. Oh, this lady right here, yes. Do you identify yourself too? I'm Caroline from Belgium. On the level of prevention, I have a question. How much more do we know about cancer being in our genes, being genetic? Like we know a few genetic cancerous breasts, and we know a few known genes about that. Is there more research? Cancer is fundamentally a genetic disease. There's no way around that idea. Fundamentally cancer is caused by mutations that disrupt mainly growth, sometimes death, and, you know, things that feed into growth and death, including metabolism and the way cells differentiate and live and survive. We're getting around the fact that, fundamentally speaking, cancer is a genetic disease and it will always be a genetic disease. Now, the question is, there are about four or five ways that DNA damage can occur, thereby unleashing mutations. Number one is that you can inherit the damaged gene from your parents. So a classic example of that would be BRCA1 and BRCA2. So you can inherit that. We now know that the inheritance can be quite complex, and we're making dramatic advances in teasing apart the complexity of that inheritance. By this, I mean the following. If you take all the patients who have inherited breast cancer as a circle and ask the question how many of them can be explained by single gene mutations that they inherited from their parents. It turns out only 30%. 70% of the patients who have inherited breast cancer, breast cancer running in their family, mom had it, grandma had it, etc., etc., 70% we could not explain before, because their risk was carried not by one gene, but by hundreds and possibly thousands, possibly tens of thousands of genes interacting with each other. We are now using computational algorithms being able to predict that risk. Those women will hopefully be screened using various techniques, mammography being only one of them, and hopefully will be able to prevent cancer in those. So that's one, is that you inherit it from your parents. Number two, you can get it because viruses go and tamper with your DNA. There are many examples of this, cancer causing viruses. That might occur because viruses directly tamper with your DNA or they create inflammatory milieus that cause cells to divide and therefore make changes in their DNA. Number three, is that can cause bicarcinogens. So chemicals including radiation which go and damage DNA in its chemical form and thereby contribute to the alteration of DNA. And number four, and that's the worst one, accident. So when cells divide like all copying machines, they can make mistakes and when they make mistakes you can get mutations. So really speaking, there are four and you can say maybe a fifth inflammation four or five mechanisms by which cancer occurs and different cancers use different intersections of these four or five mechanisms to occur. But fundamentally speaking cancer is and always will be a genetic disease. So it's interesting because if you're talking about all the accidents that have to accumulate to create a truly malignant phenotype, one that's capable of proliferating and metastasizing, it's a billion to one shot but in a body with a trillion cells, a billion to one shot doesn't seem so small after all. We've got a question over there. Identify yourself please. I'm Makoto Swayamatsu from Tokyo, the president of the Japan Agency for Medical Research and Development and my question is I'm always dreaming of global data sharing and particularly in Japan that we are analyzing the genetics of the super centenarians and the semi-super centenarians and the young centenarians, they are all over 100 years old and they are expert to escape from any kind of stress and carcinogen perhaps but if we can shake hands with each other and correct these genetics data and compare with those who suffered from cancer so can you imagine if we can get some nice idea if it never happened before and making a new approach that is my question. It's a great question and we've got a researcher on the academic side and one on the drug side how do we improve our sharing capability? That's a tough question I am part of the National Academy of Medicine in the United States which is undertaking an effort to try to improve the processes for data harmonization and sharing and on the most advanced level that's a brilliant idea and we definitely need to do it but when you start getting down into the complexities of the governance and the interoperability and the ownership and the privacy issues it very quickly becomes complex and I think the opportunity in that space is where we need private public partnerships in some cases research institutes such as the one you're describing or academic consortium where there are a number of data sharing agreements going on now across networks of academicians and pediatrics in particular comes to mind where we're working out agreements for being able to do that but I think the dream of uniform data sharing is a long way off at this point in time and I think that the success of data banking for cancer genomes has been extraordinary the UK Biobank for instance achieved something that I mean I'm embarrassed to say that because of a variety of reasons the United States actually fell behind in appropriate biobankings the UK Biobank is a very simple idea it takes the genomes anonymized genomes of individuals and attaches to them a whole bunch of biometric data including how long they live whether they get breast cancer whether they get Alzheimer's disease and already we're finding from that UK Biobank extraordinarily important information this goes back to your question remember I said that 70% of those people who have familial breast cancer whom we couldn't before detect based on genetics because the genetics was complicated in fact from the UK Biobank data now we can find women 9 to 10 fold increase in breast cancer risk based on tens of thousands I think I would say thousands of gene variations that increase their risk I'll make one more point about this which is that in the UK it required a change of culture it required a change of culture where people said that yes there is a privacy risk there is a possible risk very deeply and we will only allow people who have signed lots of agreements etc are appropriately trained to have access to the Biobank information so it just doesn't become a kind of free for all in the centenarian database what's emerging is very interesting if among the centenarians among the super centenarians in fact although it's a small group people who live to 120, 180, 116 they don't seem to die of cancer they die of degenerative diseases their bones break they die of osteoarthritis and its complications they die of neurological diseases that are degenerative so there's a lot of information in all of these Biobanks and even though we might not be able to share it globally I think the UK Biobank has shown us very clearly that if you do put information into a Biobank and guard it safely and anonymize it there's a lot of important information in terms of exposure, genetics and risk yeah that's a great question and UK Biobank is great we've got a question right here let's know who you are Sam Ampta, I come from India I have had familial breast cancer I've been through breast cancer three times in my life I've lost my sister to breast cancer my question here is every time that I have gotten breast cancer it's a new primary it's never been a fantastic disease that one phenomenon I really can't understand that how can someone get three new primaries precisely because of the genetic risk of cancer which is being carried, I'm sorry in your case as a hereditary risk so I mean again there is a, I'm ignoring the soil component to this because we don't understand it there must be some soil component to this as well but as far as the seed component to this is the actual development of the breast cancer is concerned that is because there is clearly a hereditary risk and that hereditary risk exists in every cell in your body every breast cell in your body every breast epithelial cell in your body carries that hereditary risk and it's a stochastic phenomenon, a statistical process in which one of them is acquiring enough mutations to become a cancer cell I'm ignoring the soil aspect of this so the first two times the PR was negative and the third time was strongly positive that also I was but this is the kind of information that we're getting from complex genomic banks so I don't know if I don't want to talk about individual incidents but what I do want to say is that in the past a person like you if there were BRCA1 and BRCA2 negative for PR these other genes, 4, 5, 6, 7 genes we would not be able to know whether you actually carried risk or didn't carry risk we wouldn't know whether to screen you or not screen you etc now we do know we are beginning to know if the genomes of this audience were sequenced for breast cancer alone for familial breast cancer alone there would be one or two people who we would be able to identify and say that you have a 9 to 10 fold higher risk than the general population of having breast cancer this is a small study we generalize it across populations a European study, it's a white study it's a white female study there are many ifs ands or buts but there is definite progress on identifying women with breast cancer with higher risk my last question is that if I ever were to get cancer again would immunotherapy help me I mean you don't know my entire history but yet I mean it's a very random question we can't unfortunately dispense a medical device from the pistachio what we've learned in this last hour obviously that cancer is extremely personal that it affects people forget the statistics as we've learned from Mickey and his dad and from you it couldn't be more personal we've also learned how extraordinary and complex it is and if you had to find three people to help solve that complexity you couldn't do better with Hiroshi Mikutini Julie Louise Kerberding and Sid Mukherjee thank you very much