Ian E. Smith, MD, FRCP, FRCPE
Professor of Cancer Medicine
The Royal Marsden Hospital
Institute of Cancer Research
London, United Kingdom
Q: Tell us about yourself as a scientist and how you became interested in breast cancer research. Did you ever seriously consider another kind of career than that of the sciences?
A: I decided at a fairly early age that I wanted to go into medicine. I trained at the University of Edinburgh, where I sometimes had to look after patients with leukemias or lymphomas. Cancer became an absolutely fascinating challenge to me. From that experience, I decided to go to the Royal Marsden Hospital in London, which is the main and one of the very few stand-alone cancer hospitals in the UK. For me, as a young doctor, the Royal Marsden was an extraordinary stimulus, because there I found clinicians not only treating cancer but also working alongside scientists in laboratories on the same campus. I remember we used to sit together in the evenings and talk about the challenges of cancer treatment and the underlying biology. That was when I decided that I wanted to be a cancer specialist and to take a scientific approach working with scientists to tackle what were very challenging problems.
Now, did I consider any another profession? The answer is "Not really." I had considered studying English literature, which I enjoy very much, but I did not have a very good answer for what I would want to do after graduation. And that was why I went into medicine, because then my path was much clearer.
Q: Briefly describe your BCRF-funded research project. What are some laboratory and/or clinical experiences that inspired your work? What are your primary goals for this research?
A: My interest in my current BCRF work really began more than 20 years ago, long before the Foundation was formed, when we started doing what is called "neoadjuvant" chemotherapy, or chemotherapy before surgery, for large breast cancers. We use that approach to try to shrink tumors so that mastectomy can be avoided. We did pioneering work on neoadjuvant chemotherapy at the Royal Marsden and then began applying the same approach with endocrine therapy, using tamoxifen and subsequently aromatase inhibitors including in particular letrozole. And we saw some excellent clinical results with good tumor regressions.
But what really began to interest me was how we could predict in advance which patients were going to benefit from treatment in the long term. Clinical measurement, we discovered, was a rather crude, inaccurate tool. So, working with my laboratory colleagues, we began to look at molecular markers, also called biomarkers, and particularly Ki67, which measures proliferation. A molecular marker is a biochemical test on a tumor that helps to characterize some aspect of its behavior. There are prognostic and predictive molecular markers. A prognostic marker helps to define a cancer's characteristics and its outlook, whether it is likely to behave in an aggressive or an indolent fashion. But what I think is more interesting and more important clinically are predictive markers, which tell you whether a cancer is going to respond to a treatment or not. The best example of a predictive marker is the estrogen receptor. It has been known for many years that if a breast cancer is estrogen receptor-positive, as most of them are, then there is a good chance that they will respond to endocrine therapy but if they are estrogen receptor-negative, then they will not.
In our work, we discovered that when you treat breast cancers with drugs, and in particular with endocrine therapy, the cells in many of these cancers stop proliferating within two weeks of starting treatment and "switch off." Therefore, we thought that measuring the change in the proliferation marker Ki67 might then give us a more accurate way of predicting which cancers were going to respond well to treatment. This has been one of the central tenets of our research and an area of research that BCRF has supported very strongly over the years.
Now, another component of my research that excites me is changing the traditional way of using these molecular markers. Standard practice dictates that you look at the molecular markers before you treat a cancer, use them to predict effectiveness of therapy, and then the surgeon removes the tumor prior to starting adjuvant medical therapy. But what we have been doing, based on our original experience with neoadjuvant treatments, is that instead of immediately removing the cancer, we start with a short course of preoperative medical endocrine treatment with tamoxifen or an aromatase inhibitor, and then remove the cancer two weeks later and look at how these molecular markers are behaving. It is our hypothesis that measuring changes in markers after treatment will predict the likelihood of the therapy working more accurately than if this test was done before beginning treatment. In other words, applying the marker test after treatment has started and after surgery gives us a measure of not just the biology of the cancer but of the sensitivity to the treatment we are using. Now if we can do that, it means that for each individual patient, you can tell very early on whether it is worth giving someone five years of an aromatase inhibitor, five years of tamoxifen, and such. Hopefully, although we are not quite so far ahead in this, we can also tell after one course of chemotherapy whether six or eight courses are going to beneficial or not, because if it is not going to work, the sooner you stop that treatment, the better. Conversely if the chemotherapy is going to be beneficial, it is so much better to be able to say to the patient, "Look, this treatment is unpleasant but we know from the molecular markers after your first course that it's going to work and we know it's got a high chance of cure." At the present, despite all the developments in cancer research, a lot of the medical treatment of early breast cancer is still guesswork. Our research is to overcome that guesswork.
Q: Are there specific scientific developments and/or technologies that have made your work possible? What additional advancements can help to enhance your progress?
A: There certainly have been developments in laboratory technology and my colleagues who work in the labs are the ones to elaborate on these. But for me, what is just as important is changing the mindset on clinical strategy. We spent many years thinking that everyone with breast cancer should have a mastectomy, but it turns out that was completely wrong, and we have changed that mindset. Now we need to change the mindset again, and to have surgeons, and indeed all the team looking after patients with breast cancer, thinking of using medical treatments first rather than rushing to surgery so that we can do these predictive molecular tests. To test our hypothesis, we set up a very large trial, in fact involving the whole of the UK, called POETIC. In POETIC, we aimed to recruit 4,000 patients who would be randomized to two weeks of preoperative endocrine therapy versus going straight to surgery.
Many of our colleagues initially had said that we would not be able to do the POETIC study on a large scale. They said that you could do this at a specialist cancer center but to make this trial work on a larger scale, you have to change the mindset of nearly all the surgeons in the land. And the really exciting thing is that trial has worked extremely well. We have now reached our targeted recruitment of 4,000 patients. In the UK, we have caused a change in the whole mindset, a change in the attitude to approaching breast cancer, so that surgeons and other professionals agree to this concept of using medical treatments first as a means to determining for the individual patient in from molecular tests which is going to be the best treatment. And although that does not sound as clever as developing some new technology, nevertheless, I think it is really very fundamental to further progress in clinical breast cancer research.
Q: What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?
A: The most dramatic change in breast cancer over the last 10 or 15 years has undoubtedly been the appreciation that breast cancer is not just one disease. We know from gene expression studies and from many different areas of biological research that breast cancer is a series of different disease subtypes, each of which require very different treatment strategies. For example the most dramatic development in recent years has been the discovery of the HER2 biomarker on the cell surface of some breast cancers. Around 20% of breast cancers are of the HER2 subtype, and these respond very well to an antibody against HER2, called trastuzumab (brand name, Herceptin®), which has revolutionized the management of that particular subtype. HER2 has also made us aware of another subtype, called triple negative breast cancer, which is negative for three receptors: HER2, ER, and progesterone (PgR). And we know that for triple negative cancer we need to develop other treatment strategies. There are other subtypes as well and the trend of defining breast cancer on the basis of smaller and smaller subtypes, which all need more and more specific treatments, is going to continue. The fancy word for this is "personalized medicine," and we are well on our way towards that goal.
But there is another really important thing as well--the molecular markers that differentiate different types of breast cancer may also be targets, targets which differentiate normal from cancer cells and which may therefore be targets for new drugs. These might kill off the breast cancer but not damage surrounding normal cells, and trastuzumab is an excellent example. Chemotherapy also has made a major impact in breast cancer but it is a toxic, unpleasant treatment. As time goes on, we will gradually develop more and more of these targeted therapies for different breast cancer subtypes, and it is going to be so much better than the kind of blockbuster "one-size-fits-all" approach that we have had in the past.
Q: What other projects are you currently working on?
A: I have always been in interested in new drug development, which will continue to be a very important part of breast cancer. These new drugs are much more interesting than in the past, as drug development in the past largely was almost serendipitous stumbling on things that work. Now we are basing them on the molecular targets as I have described above.
I also have great interest in breast cancer in young women. For young women, breast cancer can be a particularly devastating disease. We have very good treatments, and patients can often be cured, but the cure comes with a price. Some of our treatments cause long-term infertility, which is a terrible thing for a young woman. Many of our treatments also cause suppression of ovarian function, so young women have very unpleasant side effects due to this highly unnatural state of premature menopause. This is an area that we have not really worked out properly, not so much in terms of research and treatment, but in terms of support, in terms of appreciating the particular problems, the psychological as well as the physical, problems. And it is an area that we have a lot of interest in at the Royal Marsden because young women tend to gravitate here since we are a specialized cancer center.
Q: How close are we to preventing and curing all forms of breast cancer?
A: In terms of preventing breast cancer, we may well be able to prevent some cases through drugs like tamoxifen, and possibly through lifestyle changes. But, I certainly do not think that we are going to be able to prevent all breast cancer in the foreseeable future and it will continue to be a major and very important disease in our society.
But in terms of increasing cure rates I am very optimistic, I think the last 15 years have been very exciting. Even though breast cancer incidence is rising, deaths from breast cancer are falling at a steady rate. A major reason for this has been the use of so-called adjuvant medical therapies given after surgery. Now, as I have described, there are new therapies and new concepts (neoadjuvant therapy being one of the most important) emerging, which are being applied across the board. As new drugs continue to emerge, there is every reason to believe that deaths from breast cancer will continue to fall. We are already in an era where only a minority of patients die of this disease, and I predict that in the next 10 years deaths from breast cancer will become very uncommon.
Q: In your opinion, how has BCRF impacted breast cancer research?
A: BCRF has had a dramatic and stimulating impact on breast cancer research. The funding itself is not just crucial but quickly accessible. This is important--it is very difficult nowadays to get large amounts of research money quickly through the more traditional sources. That is not to say that governments are unsupportive of research, quite the opposite, but they have limited budgets, and it is increasingly difficult to be able to obtain all the funds you need and quickly.
Another marvelous thing about BCRF is the community spirit that it engenders. BCRF brings all the top people involved in breast cancer research together, physically once a year and in spirit over the rest of the year. That leads to better exchange of ideas, and that is the way progress is made--not by people sitting and working in isolation, but by bringing large groups of people together. This is what makes BCRF so important and so valuable.
Read more about Dr. Smith's current research project funded by BCRF.