Introduction

Dr. Siddhartha Mukherjee: Over one and a half million Americans will be diagnosed with some form of cancer in 2011 and more than 560,000 will die from the disease. Cancer is responsible for 1 out of 5 deaths, killing over 1,500 people per day in the US alone. Recent discoveries reveal that the disease is much more complex than originally thought. Hundreds of genes contribute to cause cancer and for all the promising advances of the past decades a cure for many cancers remains elusive. Nevertheless, a new era of cancer research is dawning. Leading researchers now believe that existing treatments, including cutting or burning out cancer with chemotherapy and radiation, will soon be replaced with more precise, less harmful and more successful therapies and prevention.

Welcome to Breakthroughs: Cancer, the third in a three-part Big Think series on the major diseases of our time, Alzheimer’s, autism and cancer. This series made possible by Pfizer focuses on cutting edge medical innovations in our efforts to fight these major diseases and disorders.

I am Dr. Siddhartha Mukherjee, assistant professor of medicine at Columbia University. I'm joined by Dr. Harold Varmus, director of the National Cancer Institute and former director of the National Institutes of Health. In 1989 he was awarded the Nobel Prize with Dr. J. Michael Bishop for the discovery of the cellular origins of retroviral oncogenes. Next is Dr. Doug Schwartzentruber, a surgical oncologist with the Goshen Center for Cancer Care. His work pioneering cancer vaccines earned him a spot on the Time 100 in 2010. Next is Dr. Deborah Schrag, a medical oncologist at the Dana-Farber Cancer Institute in Boston. She specializes in gastrointestinal cancer. And finally Dr. Lewis Cantley, professor of cell biology at Harvard University. His work has revealed key enzymes that contribute to cancer growth.

***

What Is Cancer?

Dr. Siddhartha Mukherjee: The term cancer covers over 100 different diseases. Starting with the biological definition what is cancer, what characteristics do these diseases share, Harold?

Dr. Harold Varmus: Well cancer is indeed a disease that can arise in virtually any of our tissues and virtually every cancer that arises is somewhat different from another, but there are commonalities and the most obvious is the fact that cancer represents a derangement of growth. Cells grow too much and they grow in antisocial ways. They cross normal tissue boundaries. They invade. They can grow in other places where they shouldn’t be growing. They often fail to differentiate the way normal cells will. There are my characteristics of cancer cells that have been identified in different tissues in which cancers arise, but the basic finding is a derangement of growth and a derangement of the normal ability of cells to stay in the places where they should be growing.

Dr. Siddhartha Mukherjee: Recently there has been an enormous degree of research on cancer. Has this definition begun to change of what cancer is?

Dr. Harold Varmus: The definition hasn’t so much changed, but the- but we’ve enlarged our sense of what cancer is about and we understand a great deal more about the basic mechanism that drives cells to behave inappropriately, to grow too much, to fail to die, to fail to differentiate, to fail to respond to signals all around cells that normally tell them to restrict growth and we now understand that many of those failures that cells exhibit when they become cancerous can be traced to mutations or to changes in the way genes are expressed, so we’ve enlarged dramatically our sense of what cancers are and we’ve changed our means of defining a cancer. A cancer is not simply a lung cancer. It doesn’t simply have a certain kind of appearance under the microscope or a certain behavior, but it also has a set of changes in the genes or in the molecules that modify gene behavior that allows us to categorize cancers in ways that is very useful in thinking about new ways to control cancer by prevention and treatment.

Dr. Lewis Cantley: Yeah, I can expand a little bit on that. So we say there is a hundred different cancers. That is based on pathology, what you can see in a microscope and even back in the 60s pathologists began to do what we now call molecular pathology. They don’t just look- stay in the tissue and look at it by eye. They look at chromosomes for example and so leukemia has broke out from a single leukemia to dozens of leukemias that are defined differentially based on what chromosomal change can be seen in a microscope and so we’re now taking it to an even deeper level where we can go in and sequence the entire genome of the cancer and these mutations keep giving us more and more subtypes, so breast cancer is going to be hundreds if not thousands of subtypes of breast cancers once we get to the actual molecular events that are going on, so it’s I think in a way this is good. It’s bad, but it’s good and the good thing about it is it kind of explains why no one type of cancer gets completely cured by a given drug or it’s relatively rare. You have some cured, some are not. They probably don’t really have the exact same disease and our previous classifications were not really detailed enough, so we can use the approach of divide and conquer, but it also means we need many more therapies than we currently have. 

Dr. Harold Varmus: It’s probably good to understand though that while the subdivision is absolutely correct and every cancer has its signature there are commonalities and in many cases you can say yes there are hundreds of different cancer types that look the same. They look different genetically, but frequently there are commonalities that can be points of attack, mutations that act as drivers of the cancer behavior.

Dr. Lewis Cantley: Yeah, so hopefully we won’t need a thousand treatments. 

***

Why Cancer Attacks Some Tissues—And Not Others

Dr. Siddhartha Mukherjee: As you mentioned there are some parts of the body, some tissues where cancer is more infrequent and other tissues where cancer is more frequent. Dr. Schrag, give us a sense of why cancer often occurs in certain tissues and rarely occurs in other tissues.

Dr. Deborah Schrag: You know we don’t know the answer to that. We do certainly know that lifestyle factors are extremely important and have an enormous influence in terms of where cancers occur, so we know that exposure to hormones and the hormonal environment that people are exposed makes an enormous difference. This is true for breast cancer, prostate cancer. These remain two of the most common cancers among men and women. Of course smoking is also- remains an important issue. Now we know that we can’t- if we could modify folks lifestyle factors we would not be able to eradicate cancer, but just as Dr. Varmus was talking about how there are certain commonalities, there are certain common molecular mechanisms that go awry frequently, certain key patterns. We also know that with respect to behaviors, lifestyle, exposure there is certain commonalities, not enough exercise, too many calories and we have to work to exploit these and we really have to work to understand the interactions between the molecular events at the cellular level and the environmental exposures and lifestyle choices people make and how these factors interact. 

Dr. Harold Varmus: Could I just add one point to that? The question you raised about some organs not having cancers. For example, the heart, that is what I would call a provocative question. Why shouldn’t there be a cancer there and it leads you to think about what cells in any organ are at risk of cancers and it’s very likely that the incidence of cancer in different tissue types, prostate versus heart for example, virtually every adult male at the age of 90 having some prostate cancer and heart cancers being virtually unheard of probably reflects how many cells are at risk of becoming a cancer in any single organ and the likelihood that those cells are exposed to some kind of oncogenic stress, whether it’s tobacco smoke or hormonal influence such as Debbie is referring to, but to me the remarkable variation not just among organs, but among organ types in different environmental settings, different locations represent one of the great challenges that I don’t think the cancer community has completely grappled with yet and to me this is an area of provocative research that we ought to be paying more attention to now that we have better tools for looking at genetics. 

Dr. Deborah Schrag: So an interesting example that comes up for me all that time that I just don’t understand. We’re all born with 25 feet of small intestine, but yet we see only fewer than 5,000 cases a year in the United States. 

Dr. Siddhartha Mukherjee: Contrast that with the large intestine.

Dr. Deborah Schrag: We contrast that with colon cancer, which remains one of our top cancers. Well you know there is 6 to 9 feet of large bowel and we have 150,000 cases per year. When we look at these cells under the microscope it’s all epithelial cells. I mean an intestinal cell in the small intestine and in the large intestine is molecularly not that different. The large bowel cells are a little bit more engaged in reabsorbing water than they are in reabsorbing nutrients, but we do not understand why there is this dramatic difference between the incidence of cancer in the small bowel, which there is more of and the large bowel. We haven’t answered that. 

Dr. Harold Varmus: It brings up a very interesting new theme in cancer research. What is the role of the microorganisms we carry around with us? What is now being called the microbiome and of course the large intestine has trillions of bacteria and the small intestine has much less. That may well be that that is a driver of oncogenic change and of course the small intestine tumors, many of which you- as you mentioned, there are some. They are very frequently sarcomas, that is cancers of connective tissue as opposed to being epithelial and that is a very interesting example of that contrast.

***

How the Genomic Revolution Affects Cancer Research

Dr. Siddhartha Mukherjee: Tell us a little bit about what the Cancer Genome tells us about the genetics of cancer and what we have learned from the human Genome Project followed by the Cancer Genome Project. Do you want to start and then we’ll go around?

Dr. Lewis Cantley: Sure, well, as I said earlier the first thing the Cancer Genome is beginning to tell us is that there are many, many more subdivisions of cancers than we previously could predict based on pathology alone and I think that is going to be extremely informative. The goal now with target therapies as the genome is- First of all, it’s telling us what genes are likely driving the cancer, so if you find that in lung cancer 30% of the people get a particular mutation in a gene called Ras, 90% of pancreatic cancers have exactly that same gene and you see that those are exactly the subgroups that don’t respond to any of our existing therapies then you realize that we need to have drugs that target Ras in some way and we don’t know. All the approaches we’ve made thus far have failed for that particular target, so people are trying to figure out ways to target. It turns out to be a difficult gene to target, so the first thing that is going to come out and has already come out is the identification of what we call drugable oncogenes, things that are mutated in the cancer EGF receptor lung cancer for example and so those opportunities hopefully we already know a lot about those and drugs are being developed and we’re hoping to get a lot of success out of that. In some ways I think on the other hand it has been somewhat disappointing in that most of the things we’re finding from the cancer genome sequencing are things that we already knew. In some ways retroviruses that cause cancers in mice and chickens, things that Harold actually worked on as a post doc and helped develop the field they’ve essentially done the experiments in other animals and identified the oncogenes for us, so we’re finding relatively few oncogenes that we didn’t already know about from these mutational events, but I think it’s still going to be extremely valuable. 

Dr. Siddhartha Mukherjee: Do you share the disappointment about the Cancer Genome Project Harold?

Dr. Harold Varmus: No, but I would point out a few things building on what Lou just said. First we knew about the Ras genes of course well before the Cancer Genome Projects, but we knew about Ras genes and the mutations that arise in them very frequently in pancreatic, lung and colon cancer even before there was a Human Genome Project because we knew about that in the early 80s, so I think it’s useful to remind people of that because here is a tremendously attractive target for developing drugs, even for thinking about ways to diagnose cancers early and we really have had a hard time capitalizing that over the last 30 years and that is a good reminder of how difficult this all is.

The second point I’d make is that yes, I agree that we have of course rediscovered in the Cancer Genome Atlas Project and other efforts of genomics of cancers that the oncogenes we knew about because they’re relatives of the retroviral cancer genes sure, they’re involved quite frequently as our well know so called tumor suppressor genes, but we’re having a much- getting a much better picture of what the real complexity of cancer might be. Secondly, there are new methods that extend our ability to analyze a genome well beyond just looking for small mutations. There is some very important rearrangements. We were talking earlier about prostate cancer and one of the things that I think is a pretty good indicator of the danger of a prostate cancer can be seen by finding a rejoining of chromosomes that generates a new gene that seems to be a driver of prostate cancers and that is the kind of thing that would have been very difficult to discover without this concerted effort that is going on.

Third, there are actually changes in the genome that are not mutational. They affect the way DNA is modified by chemical processes and the way in which DNA is expressed because of changes in the proteins that coat DNA and allow genes to be expressed. Very recently there have been a surprising set of mutations that govern what we call the methylations, a kind of chemical addition to DNA that governs gene expression that is regulated by a series of enzymes and coated by genes we would historically have thought of as oncogenes and it’s clear from some recent work about an adult leukemia called acute myeloid leukemia that these genes are playing a very important role in that disease and represent another kind of target for therapy and a way to think about diagnosis, so I think there are a lot of rather surprising things that are coming out of this and the picture, the full picture of genomic change is really very dramatic and quite wonderful.

Dr. Lewis Cantley: So if I could just add one additional thing. I don’t want to leave the impression I'm disappointed or we shouldn’t have done that, the Cancer Genome that was- and of course the mutations that Harold was talking about I think are very exciting. It really has opened up the field, but it’s still a relatively minor subset of cancers that are involved in gliomas and AMLs.

Dr. Harold Varmus: Well I think we don’t know yet.

Dr. Lewis Cantley: Well there is- Yeah, anyway, that is definitely helping us out, but I think the other thing that we’re going to get from this is biomarkers that will allow us to do much smarter clinical trials, so that we do a clinical trial and 15% of the patients respond. If the trial is not- if it’s not- if you don’t have thousands and thousands of patients it’s hard to prove that that 15% is actually relevant and the drug may fail to be approved even spite of a huge investment in the trial and many, many years and there is examples of that that we know of where it was very clear to the clinicians the drug was working, but it still didn’t get approved, so if we can design trials where we tease out early on who is going to respond and who isn’t then that 15% becomes the 100% because you only do the trial on them. They’re defined by their mutational status, the so called biomarkers that- these are biomarker driven trials, so I think that is going to be a tremendous advantage coming out of this.

Dr. Harold Varmus: If I can make one comment about the clinical trials because this is of great interest to the public. One reason we were so successful with pediatric cancers, developing chemotherapies that cure a large fraction of pediatric cancers is because virtually every kid came to a cancer center, was entered in a clinical trial and over the course of many years a lot of disappointments, heartache and a lot of loss of life because these cancers are very, very difficult to treat and finally emerged with a set of principles and operating procedures for treating these kids effectively. We’ve been much less successful with adult therapy and one of the reasons I think is because the heterogeneity of the tumors as Lou is describing. The Cancer Institute is currently reorganizing its clinical trial system in a way that is designed to take advantage of the point that Lou is making. For example, in treatment of lung cancer we know that a small fraction are susceptible to inhibitors of mutant kinases and one of the drugs erlotnib just barely squeaked through its first clinical trial because they were enough patients with that mutation in their tumors. Another very similar drug didn’t squeak through because it had too many people who didn’t have that mutation and now that the Cancer Genome analysis is giving us the tools to so called stratify these patients I think all of us believe there can be much smarter trials set up, faster trials, trials that give us much more effective information about how to treat.

***

How Carcinogens Cause Cancer

Dr. Siddhartha Mukherjee: So we’ve talked a little bit about the Cancer Genome. We’ve talked about the genetic changes, but I want to take one step back even before these genetic changes arise. Dr. Schwartzentruber, tell us what we know about how carcinogens cause cancer.

Dr. Doug Schwartzentruber: Well that is a challenging question because there are multiple ways for carcinogens to cause cancer and I probably should defer to some of the other panelists as well who have studied that much more than I have, but the obvious first step is how the environment which from the minute we’re born begins to interact and create feedback to say our normal cells that could then potentially be cancerous and maybe I'll stop at that point and lead into others.

Dr. Lewis Cantley: Well I can. I mean most carcinogens we think cause cancer by mutating DNA, but there are examples of carcinogens for example, forballesters [ph] which can cause skin cancers that almost certainly are to working through mutating DNA directly, although in the long run you always end up getting mutations in DNA. They are rather probably causing cells to grow at a higher rate and the higher the rate cells grow the more frequently they get mutations in DNA. Basically a cell has to go through a division cycle and make a daughter cell in order for a mutation to get locked in and that- But most really do it by directly damaging DNA, UV light, radiation directly damage the nucleotides in the DNA and many other chemical carcinogens interpolate into the DNA and at the time of cell division interfere with proper base replacement. 

Dr. Harold Varmus: No, I agree entirely with this, but I would like to add two important points. First we as individuals grow up from a single cell and through many, many rounds of cell division many errors are going to occur because the ability to copy and distribute the three billion base pairs of DNA into daughter cells is an inherently error prone mechanism. We have ways to try to correct it, but nevertheless damage will occur and over the course of many cell doublings there will be damage that can be carcinogenic, so you don’t need to have external factors for cancer to arise. Cancer is probably part of our heritage. Genetic change is a good thing at the species level because we generate diversity throughout living systems. The other point I would make is that not all carcinogens are UV light or radiation. Some of them are viruses and it’s very important to keep that in mind. It has been estimated that in developing countries for example maybe a third of cancers are caused by viruses. We actually have vaccines that are effective against some of those viruses. The human papillomavirus vaccine, the human hepatitis B virus vaccine can prevent a very large amount of cancer in those countries if the vaccines are made available, brought to patients, made affordable in poor countries. Cervical cancer is largely controlled in this country by pap smears, by early detection, but and we only have about 3,000 deaths a year in this country, but in my parts of the world, India for example, in large parts of Africa cervical cancer is the most common cause of death from cancer among women and we now have the potential to reduce the incidence of that cancer by two-thirds using human papillomavirus’ vaccine.

***

Will We Cure Cancer By 2015?

Dr. Siddhartha Mukherjee: The former NCI director, Dr. Andrew von Eschenbach estimated that- he established an ambitious goal of eliminating the suffering and death due to cancer by 2015. Dr. Varmus will this happen?

Dr. Harold Varmus: You’re putting me in a different position. Politically I don’t want to bash a previous director, but I will because this was a claim that just has no reality. The argument was we’re going to banish death and suffering from cancer, not that we were going to abolish cancer, but that is just not going to happen in such a short timescale and it creates first of all, a false aspiration, one that we clearly cannot succeed in achieving and secondly, it provides too much optimism in a setting that is as you’ve heard around this table, a very complicated set of diseases and we are not going to conquer all those diseases and prevent death from them in such a short timescale.

Dr. Lewis Cantley: Yeah, I completely agree and I would add that I'm optimistic because I think with these target approaches and as we break cancer into more and more sub fractions we figure out how to cure the sub fractions that every year we’re going to see another few percent get if not cured, at least have treatments that allow people to live without extensive chemotherapy approaches and so if you do that, if you project it and say we’re only going to cure 2% this year well if we started curing 2% in 1970 today we’d be almost finished because in 50 years at 2% we could get them all.

Dr. Siddhartha Mukherjee: I'm reminded of the advertisement that came out in 1969 which said, “Mr. Nixon, you can cure cancer.”, in the New York Times and the Washington Post and of course the advertisement says you can cure cancer as if it was one disease and of course the word cure and the goal was by- in fact, the goal was set at that point of time by 1981 and 1981 has long passed as you know. 

Dr. Harold Varmus: Yeah, I think the discussion though needs to be enlarged slightly so we remind ourselves that while it’s attractive to think about curing an advanced cancer with drugs that there are many other things we can do to reduce the burden of cancer. One of course is to prevent it and we’ve had some brief discussions about that, but we can make great- in fact, most of the reduction in mortality from cancer in this country is due to smoking cessation. Secondly, I would point out that drugs are only one of many things we do to treat cancer and perhaps the most effective thing we can do is remove a cancer, so surgery is a very important tool here, surgical methods, not much talk about, have improved. When we detect cancer early before it has spread we can cure it more frequently, so early detection, prevention and conventional therapy used early on very important steps.

The other thing I would go back to is Dr. von Eschenbach’s term "suffering."  We tend to forget that while cancer is still a terrible disease we have reduced suffering from cancer already dramatically, much better pain control, control of nausea and vomiting. Chemotherapy has gotten more tolerable. We can restore bone marrow function fairly quickly with really very superb science using hormones to stimulate the way the marrow functions after chemotherapy. These are major changes.

Dr. Deborah Schrag: And the fact that it’s no longer something that people need to keep a secret, the fact that there are many public figures who have cancer who are open about their cancer diagnoses and the numerous strategies people use to cope.

Dr. Doug Schwartzentruber: I think our strategy somewhat has changed. Yes, we continue to search for a cure, but the other C word, control and so many of our trials right now that are publishing results talk about cancer control as opposed to the term cure and getting that disease to stabilize and not progress and if we can do that it becomes an elegist to some of our other chronic diseases.

Dr. Siddhartha Mukherjee: Dr. Schrag, can lifestyle choices alone prevent cancer?

Dr. Deborah Schrag: Lifestyle choices alone can’t prevent all cancers, but they can enormously decrease the incidents, particularly of some cancers, so lung cancer would be the best example. Some of the things Harold was talking about, getting vaccinated for hepatitis B, getting vaccinated for the human papillomavirus, getting 11 year-old girls- we could probably eradicate or come close to eradicating cervical cancer. The challenge is here we’ve got a cancer that is caused by a virus and we know that just as our genes are changing and evolving so are the genes of viruses, so right now we have a vaccine that seems to work against most strains, but is it possible that we’ll have new viral strains that this vaccine will no longer work? Absolutely, that is probably, so this is going to be an ongoing process.

***

Why Cancers Recur Despite Treatment

Dr. Siddhartha Mukherjee: So this goes back a little bit to the cancer stem cell theory. Scientists have discovered that some forms of cancer such as leukemia have their own stem cells and may be able to regenerate themselves and this might be one reason that they relapse after chemotherapy. Tell us about the cancer stem cell theory and what is known and unknown about it. Anyone.

Dr. Harold Varmus: You answer that.

Dr. Lewis Cantley: I'll start on it and then you can correct whatever I get wrong, but so the cancer stem cell really I think emerged from observations of liquid tumors, leukemia, lymphomas where it was clear that the cancer was emerging at a partially differentiated stage of the tumor and in tracing back what antigens are on the surface one could determine that there was a subset of those tumors that had antigens that looked like a normal lymphocyte stem cell and that that subpopulation could continually self renew while the somewhat differentiated descendants of those cells would ultimately quite dividing, so the bulk of the total number of leukemic cells were not actually capable of indefinitely propagating and I think the data for that is extremely strong and so the- some of the therapies that look like they’re working beautifully because you reduce the total number of cells by 98% or so, but you’re not killing the ones that are actually keeping this tumor going, so that is why there has been so much excitement about this. If we look at- and so we need to get therapies that hit the cancer stem cell, not just the ones that are descendents of it.

As we look at other types of cancers like melanomas on the other hand it looks like almost every single cell is a stem cell, that they are all capable of self renewing, so the stem cell idea is very important to understand and certain- some therapies and other therapies it’s probably not really relevant.

Dr. Siddhartha Mukherjee: So once again we have a heterogeneity problem.

Dr. Harold Varmus: So the problem has been- One of the reasons there has been so much controversy here in my view is that stem cells of course ignites public excitement and even excitement among scientists. The real issue and I think Lou described this fairly is we know that cancers can recur. The question is can any cancer cell lead to a recurrence or are there subsets and if there are subsets that is obviously of great therapeutic importance because you really have to eliminate the cells that will generate the cancer and it’s not enough to measure the total bulk of the cancer cells and I think the evidence, as Lou has said, is that some cancers virtually any cell going into the right environment, the environment make a big difference here, can regenerate and the tests are very hard for doing this and you have to know that when you’re introducing cancers back into an animal host, is that the appropriate animal host for testing. Frequently these are human cancer cells going into animals. What is the immune system of the animal like? What is it respecting and not respecting? So I think these are- The concept is very important because we need to know if cancers are heterogeneous it goes back to their ability to recapitulate a cancer. We’ve got to know how to address the cells that are responsible for regeneration.

And the other thing, just to introduce a concept we haven’t talked about, drug resistance. Frequently it’s thought that those are cells that are resistant to therapies and in other words, one facet of so called drug resistance, which is a huge problem in cancer therapy today.

***

The Link Between Cancer and Aging

Dr. Siddhartha Mukherjee: Here is another provocative question. Some cancers such as prostate cancer are age related clearly, whereas other cancers are not. Acute lymphoblastic leukemia arises in children. Why is it that only some cancers are age related and other cancers are not age related, Dr. Schrag, Dr. Schwartzentruber, clinicians?

Dr. Doug Schwartzentruber: I don’t have a good answer for you. We do know that the immune system is differently developed at various stages in life and that may be one clue that now the host factors, as you deposit a tumor or a cancer in that patient may behave differently through ages, but I’d look to epidemiologists to give us an answer.

Dr. Deborah Schrag: We don’t know. I mean we know that for example, for some types of leukemia as you well know folks are born with predisposing mutations and there is sort of the idea of there being a second hit or multiple additional hits and these exposures may occur at different points in the lifestyle, so at different points across the lifespan, so for example, if hormonal environment is very important. Perhaps it’s not a surprise that we don’t see prostate cancer in adolescent boys. We never see prostate cancer in adolescent boys, so that right there is telling us something, but there is more here that we don’t know. Epidemiologists try to figure this out, try to understand this. We know that Hodgkin’s disease; there is a few diseases that have two peaks, testicular cancer and Hodgkin’s disease. Both have what we call a bimodal distribution. They’ve got a peak around the teenage years and then there is another late peak in the 50s and 60s. The diseases sort of look that same at the moment under the microscope, but are they really the same? Probably not, we’re not quite there yet, but there is some tantalizing clues.

Dr. Harold Varmus: I think there is- it’s worth thinking about one problem that most scientists have not focused on. That is, what is the cell in any organ? Every organ is made up of cells in lineages, stem cells and intermediate stage cells and the most mature, highly functional cells and we don’t know in the vast majority of cancers which cell is actually the target cell for developing a cancer. If we knew the abundance of those cell types and the number of cell divisions they go through and the likelihood they’re exposed to mutagenic events I think we begin to get a better picture. For example, one way to think about this is a disease called retinoblastoma, largely a hereditary disease that requires one additional mutation is only seen in kids up to the age of six and we know the target cell for that disease, the retinoblast disappears in the eye, so there is no target cell anymore and that is why the disease occurs early in life. You could argue that in contrast a disease like prostate cancer arises in an organ that has a certain number of stem cells throughout life and you’re just waiting for mutations to accumulate as they continue to do throughout life and the disease gets more frequent with increasing age.

Dr. Siddhartha Mukherjee: And breast cancer for instance, we know that the length of hormone exposure, estrogen exposure is critically important, so you need so many years of hormone exposure before you finally get your malignant cell.

Dr. Lewis Cantley: Yeah and I think the example I gave earlier of these rare heart cancers that appear even before birth, but then disappear, so I think those examples and probably the other examples we heard of where you get this bimodal event are probably driven early, the early event is probably driven by some hormonal environment, some growth factor hormone is peaking at that stage as you go through puberty for example and that is actually substituting for one of what would otherwise be a mutation required, so now you only need on mutation plus a high level of that hormone and that drives it at that stage. The older form is probably mutations that are replacing the need for the hormone coming up with age, so they’re less probable to take longer to appear, but ultimately result in a similar disease.

***

Are We Winning the War on Cancer?

Dr. Siddhartha Mukherjee: 1971 was the declaration of the war on cancer and 40 years have passed. There has been a lot of skepticism, a lot of optimism since that time. What have we done right and what have we done wrong and what happens next?

Dr. Lewis Cantley: I'll start then. I'm sure Harold will have—he's lived through this longer than I have, but I have my prejudices, so I will start. I think the biggest thing we’ve done wrong is we tried to put all of cancers in one basket and say here is the drug that is going to cure all cancers. We’re very dependent on pharmaceutical companies to develop these drugs. It’s extremely expensive to develop drugs. Clinical trials cost hundreds of millions of dollars, drug development for a single cancer and historically 98 to 95% of all those trials have failed and I mean that is a horrible success rate. If you think you’re going to spend 200 million dollars with only a 5% chance of success you wouldn’t want to go to Vegas with those odds and yet that is what pharmaceutical companies do and that is why they price the drugs so high, to pay for all the failures and so you might ask well why have they failed and I would say in part they failed because they’ve not been able to define the patient population. The preclinical models didn’t lead to enough knowledge about the disease to predict who should be on the trial and in some ways I think the pharmaceutical companies didn’t want to know because they didn’t want to label on the pill to say “can only be used for a 5% subset of one breast cancer”, right and so that- But now pharmaceutical companies have realized that even for these very narrow indications like chronic myelogenous leukemia or EGF receptor lung cancer you can still make a profit and you can get the trials approved, the drugs approved much more rapidly if you define the patient population upfront and so we’ve seen a tipping point in how pharmaceutical companies do their trials and that is a good thing, so I think the main thing we did wrong is we tried to treat all cancers the same way and blind ourselves to the differences between human beings.

Dr. Harold Varmus: And I don’t disagree with that, but I think that one has to think about the nation’s effort to control cancer as a much more multidimensional kind of approach that involves efforts of prevention and understanding the disease and treating it in a wide variety of ways through detection and surgery and other things and I think the one thing we did right with the effort that was initiated by Nixon, I know calling for increased expenditure on an important disease and of course cancer is not the only diseases that the nation pays attention to. We have the National Institute of Health that have 27 institutes and centers addressing many diseases and we made I would say even more substantial progress against some of those like heart disease where the mortality rates have fallen dramatically and if you look at overall mortality from cancer while there has been a modest, but persistent and real decline over years it’s very easy to say we’re not winning the war so there is some battle line that has to be crossed, but some right things were definitely done and one was to make general investments in basic research on cancer, and the fact that the government did not say let’s just give money to these pharmaceutical companies and ask them to make a pill, but instead said let’s spend money through the National Cancer Institute and other institutes at the NIH to try to understand this disease, let’s use the tools we have and some of the tools may seem crazy in retrospect. Why should we try to cure cancer by studying animal viruses for example, in chickens and mice or why should we be looking at other kinds of models or cell lines, but in fact, what we’ve learned is pretty remarkable.

When we look back 30 or 50 years from now we will say we went through a magical period between 1970 and 2020 or 2030 in which we took a disease that is very difficult to understand. We took the tools of modern science and learned what is wrong with the cancer cell and we began to diagnose cancers earlier and classified them more profoundly and add to traditional chemotherapy and radiation and surgery drugs that are precisely targeted and we have reduced the mortality from cancer by ten-fold or a hundred-fold and I think with time we will see that there is a great arc of progress here that is really quite remarkable.