Eli Y. Adashi, MD, MS, CPE: Hello, I am Eli Adashi, Professor of Medical Science at Brown University and host of Medscape One on One. Joining me today is Dr. Harold Varmus, Director of the National Cancer Institute (NCI) of the National Institutes of Health (NIH). A 1989 winner of the Nobel Prize in physiology or medicine, a former director of the NIH, and until recently President of Memorial Sloan-Kettering Cancer Center, Dr. Varmus is hardly in need of introduction.
Harold Varmus, MD: Thank you.
Marking the 40th Anniversary of the National Cancer Act (The War on Cancer?)
Dr. Adashi: It's wonderful to meet you after all these years of observing you from afar. December 23 will mark the 40th anniversary of the National Cancer Act and the initiation of the war on cancer. Can you give us an overall sense of what we may have accomplished over the last 4 decades?
Dr. Varmus: First of all, I think we've changed the metaphor. It's inaccurate, in my view, to think of a war on cancer as though cancer were a single, individual enemy, nor is the metaphor of war exactly right. We now understand that cancer is actually a constellation of diseases, many different diseases arising in different tissues. Indeed the number of diseases that cancer represents has only multiplied over the last 40 years as we understand more and more about how cancers arise. Second, we understand that cancer is an outgrowth of some fundamental principles of biology, how genes control our development, how development goes awry, how different genes can influence the initiation and progression of cancer.
The consequence is that we have a much deeper understanding of cancer in the sense of a byproduct of the way life is organized, and we have a sense that there are many puzzles to be solved. When we think about progress, which is the question I'm always asked, yes -- we've made enormous progress against some diseases. We've made much less progress against others. The challenge for us is to define the problem more clearly so we can begin to make more rapid progress against some of the diseases against which we have prospered very little.
Reforming the Clinical Trial System
Dr. Adashi: Upon taking the helm [of the NCI] you outlined 5 priorities for improving the cancer research program. Among those, you proposed to reform the clinical trial system. What concerns were you hoping to address, and how is this effort going?
Dr. Varmus: There were 2 major issues. The first had to do with what frequently happens to a complicated system that's been in existence for a very long time, namely that its organization is no longer well suited to the kinds of trials we are trying to run. With the help of one of my chief deputies, James H. Doroshow, Director of Division of Cancer Treatment and Diagnosis at NCI, the clinical trial system has been dramatically reorganized. The new number of groups will be reduced from roughly 10 to 5. Many of the groups that had a rather singular focus are now embedded in much more complex organizations. This helps with the process of getting trials going, carrying out trials, deciding when trials should be finished, and making sure that we're not losing the proper speed of responding to new advances in science.
The second big issue is one of incorporating more scientific thinking into the way trials are conducted so that trials are not simply tests of whether a drug works, but they're tests of biological principles; when the trial does not work we learn something about why it failed that's actually instructive in the next trial. We think that can happen and we've got the leaders of the clinical trials group more closely aligned with clinical center directors and other investigators in the scientific communities to be sure we're collecting the right samples and carrying out the trials in a way that is consistent with new developments and oncological science.
Dr. Adashi: In a sense, this was the other priority you outlined: developing new questions and new scientific agendas that you wanted to pursue at the time.
Dr. Varmus: But that's not the way we're putting that into place. The latter part of this is very important to me, and that is to get the scientific community engaged. And by the "scientific community" I mean everyone -- not just those people who work at laboratory benches, but the clinical scientists, behavioral scientists, other folks who are working on the cancer problem from an epidemiologic point of view, from a medical viewpoint -- to begin to define what aspects of cancer science are still deficient in knowledge.
The questions that come out of that kind of exercise we have called provocative, and over the last year we have compiled an interactive Website that people can go to ask cancer-specific questions; you will see that we tried to answer what we considered to be the 24 best questions so far. We've received close to 1000 letters of intent from experts who have applied to answer these questions, and we think this is a very novel way to use our resources in an effective fashion at a time when, quite frankly, budgets are not only not increasing, they are decreasing.
Genome Project: How Is it Helping Cancer Diagnosis and Treatment?
Dr. Adashi: Much has been made of the hoped-for impact of the Human Genome Project on both the diagnosis and treatment of cancer. Are we reaping some benefits, and are we hoping for more?
Dr. Varmus: Well, that always goes without saying. But the fact is that people, at first, probably oversold how quickly genomics was going to lead to changes in medicine. Then there was a reaction, which I think was very unfortunate, of people having the kind of dubious tone you had in your voice, because, in fact, the Human Genome Project has, first of all, dramatically accelerated cancer research on many fronts. Second, it actually has already transformed the way we think about cancer. When I said earlier that there are many more categories of cancers than we knew before, it's because of using the tools of modern genomics, and through DNA sequencing and cloning we have subdivided cancers by the nature of the lesions. It's a little bit like how at one time we knew there was pneumonia, and then we were able to identify specific bacteria and say there was E coli-induced pneumonia and pneumococcal pneumonia and tuberculosis pneumonia. The same thing has happened in the impact of genetics on cancer. Whereas once there were 4 histologic types of lung cancer, now we know that we can say that for adenocarcinoma of the lung, there is a type that is dependent on EGF receptor mutations, a type that's dependent upon ALK gene fusion, there's a type that's dependent on Kirsten ras (Ki-ras) mutations, and on and on, because there are actually quite a few categories, some of which actually are prognostic indicators. And, more important, some of them are now treatable -- not totally successfully treatable, but at least with partial success with drugs that inhibit the specific proteins that are mutated as a result of the mutations that I've mentioned.
Dr. Adashi: You're personalizing the treatment.
Dr. Varmus: We're making it more precise. I think that's the better term. "Personalized," to me, is a kind of euphemism; it's not very specific. My father practiced personalized medicine. We're trying to be more precise and I think that's an incredibly important issue. It's the way in which genomics in particular, but also other kinds of science, plan to transform diagnostic categories over the next 10 years, not only in cancer but in many fields of research.
A report from the National Academy of Sciences recently indicated that all of our nosologic classifications are going to change, but in cancer it's already happening, and those changes affect what we call a cancer, what we think will happen to the patient who has it, and how we're going to treat the cancer, and it may even begin to affect how we prevent it. Certainly it's going to influence how we screen for it.
Bringing More Innovative Cancer Therapies to the Table
Dr. Adashi: From where you sit, how well are we doing as a nation in bringing innovative therapeutics to the cancer table?
Dr. Varmus: It's slower than one would like given the fact that we now have so many potential targets identified. But, as the US Food and Drug Administration recently pointed out, they've approved more new drugs this year than in recent memory. Most of those drugs are cancer drugs, and in my own field of cancer research and therapy there are some tremendously positive hits. We're clearly far from being able to treat in a curative fashion as many cancers as I'd like, but there are many for which we now have important drugs with anticancer properties. It's also important to point out that we have much better ways to control some of the side effects of cancer, better control of nausea, pain, and of bone marrow toxicity. Sometimes this gets forgotten in our lust to control the cancer, but making cancer a disease you can live with and go to work with... and increasingly, as I learned during my time at Memorial Sloan-Kettering, we had many, many patients with lethal cancers who are actually feeling pretty good and are working full time and enjoying their families. As long as their symptoms can be kept under control by radiotherapy and drugs that control symptoms and other modalities, we're doing right by our patients.
Mortality Trends in Cancer
Dr. Adashi: One way to measure our progress of success is by monitoring the national mortality cancer rate. What's the latest in terms of the trends that we are monitoring or surveying nationally?
Dr. Varmus: The overall trend is good. We have been seeing roughly a 1% decline in age-adjusted mortality overall for all cancers, and for men and women, over the last 10 years or so. Some important signposts have been passed. For example, we expected to see decline in lung cancer mortality for women because they are now starting to stop smoking, whereas 30 or 40 years ago they started to start smoking; just in this last couple of years we've seen the beginnings of declines in lung cancer mortality for women. One of the things that we learned from such registration data is that some cancers are declining faster than others with respect to mortality rates. Some are increasing, and we have to pay special attention to those where our efforts to control the cancer are not as fruitful as they have been for others.
Most Promising Cancer Clinical Breakthroughs
Dr. Adashi: If you had to pick 1 recent highly promising scientific or clinical breakthrough in the cancer arena, what strikes you as particularly exciting?
Dr. Varmus: Give me at least 3. In the prevention arena, or perhaps "screening" is a better term, we finally have evidence that low-dose helical CT scanning can prevent death from lung cancer -- not simply detect a lung cancer and allow someone to live a long time. We have evidence from a very large-scale study that was ended just about a year ago, because we had reached the point of showing over about 8 years that by screening heavy smokers at an elderly age, between the ages of 55 and 74, we could reduce lung cancer mortality rates by about 20%. Now, that creates other kinds of problems we need to deal with: How do we actually implement the screening process in a way that's effective and affordable and acceptable to the community and maintain the high rates of reduction in lung cancer mortality that we've seen in a very highly controlled study? But it's very encouraging, because lung cancer is the biggest killer.
The second thing is that we've had some of the most impressive demonstrations of the effectiveness of immunotherapy that we've ever had. Of course we've had antibodies for a long time and that's a kind of immunotherapy, and antibodies like herceptin clearly have benefit. But seeing that an inhibitor of the activity of the immune system, a drug that's now called ipilimumab, in metastatic melanoma is a very significant breakthrough, and it makes us feel that we're on the right track in making substantial investments in the immunology -- the immunologic response to cancer.
I suppose a third example is the depth of knowledge that we're obtaining by systematically analyzing literally hundreds of tumors of each known histologic type for the genetic damage that characterizes those types of cancer. Through a very large project called the Cancer Genome Atlas that we're carrying out with the National Human Genome Research Institute, we have accumulated an incredible catalog of mutations that is, in a sense, the substrate -- that it's the material that we are going to be using to learn how to prevent and treat cancer more effectively in the future.
Reason to Believe Cancer Mortality Rates Will Continue to Decline
Dr. Adashi: About 600,000 or so Americans die every year of cancer, which would be second, I suppose, only to heart disease. At this time, going back to the anniversary we were marking earlier on, I know it's difficult to project, but if you had to guess, what figures might we be looking at on December 23, 2021?
Dr. Varmus: I'm not going to make that kind of projection. I do think there's every reason to believe that mortality rates will continue to decline. You have to remember that everybody dies of something. Cancers are, in general, age-related, so counting the total number of cancers is not the best way to analyze this problem. The way to analyze it, just as we do for heart disease, is to look at age-adjusted rates, and when we make that kind of calculation for heart disease we can see that over the past 50 years there's been roughly a 70% decline in age-adjusted mortality for heart disease, cardiovascular disease, and stroke. That is remarkable, but of course it's still the major killer, so we have to factor that in. But I do think that we will be improving the age-adjusted mortality rates for most cancers over the next 10 years.
Will we have major breakthroughs? Well, they're breakthroughs because we can't predict them. That's why we call them breakthroughs. So I don't make that kind of prediction, but we have an incredible amount of information. We have strong support. We have $5 billion a year to spend at the NCI and I plan to spend that well. I am optimistic because of the strength of the science that we do that we will make significant progress, but I'm reluctant to say what progress will occur or what the number is.
Dr. Adashi: Fair enough. On a personal note, what is it that drew you to this challenge at this time in your life?
Dr. Varmus: Do you think I'm too old to do this kind of work?
Dr. Adashi: Well, your wife may argue that it may be time to take it easy.
Dr. Varmus: I'm not somebody who takes it easy. She knows that, and if I try to take it easy that's not healthy. I was at Sloan-Kettering for 10 wonderful years, and we did a lot of great things there, but these jobs have a lifetime. When you're at an institution and you have ideas for it, you're going to get them done. You usually do that within the first 5-8 years, and I think I did that at Sloan-Kettering. As times became tight economically, I could either have retreated to my own lab and continued to work in my lab, which is something I enjoy doing, or I could have taken on another leadership position. Frankly, as I've said many times when I was here at the NIH as the director, I was frequently frustrated. The NIH director has very little money, has very little authority over scientific programs, is always pleading with the institute directors to follow his or her example. Running an institute always looked more fun, and indeed it is more fun. I'm running programs. I'm making decisions that affect science directly rather than making political judgments and simply interacting with what's now an increasingly refractory Congress. I love this job and am very glad I did it.
Dr. Adashi: Well said. Thank you. On this note, sincere thanks to Dr. Varmus and to you, our viewers, for joining Medscape One on One. Until next time, I am Eli Adashi.