Mitch Dowsett, PhD, BSc
Head of the Academic Department of Biochemistry
Professor of Biochemical Endocrinology
Professor of Translational Research
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 never seriously considered another career other than one involved in science. In fact, I can recall even before the age of ten saying that I wanted to be a scientist. I had a book given to me as a Christmas present, Science and Discovery, which grabbed my imagination. So that really turned me onto science in general, and as I progressed through school, I continued to feel an empathy with science. The thing that really turned me onto biological sciences and still astonishes me is the genetic code, which was unraveled not that many years before I was in secondary school. I am fascinated and find remarkable that the makeup of not just humans but any biological living being was actually coded for in some chemical form. That really sparked my imagination so I took a degree in Zoology, which was actually a mixture of different biological sciences with a twist towards biochemistry and genetics.
The thing that got me involved with cancer and breast cancer was a course run at Imperial College, where I was studying, by the nearby Institute of Cancer Research. I was particularly attracted by the idea that one could begin to use some of this genetic information in relation to clinical treatment. As a result of that course, I applied to the PhD program at the Institute of Cancer Research, with which I am still associated. My dissertation was on trying to understand the mechanisms of why breast cancer interacts with bone and causes it to break down when the cancer metastasizes to that region. I got involved in what we call "translational research" very early where we would take small breast tumor biopsies from the next-door Royal Marsden Hospital and put them into culture with small pieces of bone and try to understand how they interacted. So, I have had a pretty longitudinal career where I started working on breast cancer very early all the way through to the present.
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: Our work in general relates to exploiting the biomarkers which change in breast cancer during pre-surgical exposure of patients' tumors to a variety of different agents. Specifically, our BCRF-funded project of the moment builds on some observations we made a few years ago that if we were to expose hormone receptor-positive breast tumors to an aromatase inhibitor in situ, or other endocrine agents, we saw a profound fall in the proliferation of cancer cells, which is measured by a marker called Ki67. We rationalized that the degree of fall might be indicative of the benefit that the patient will get from that specific treatment. So, Professor Ian Smith and I set up a clinical trial called IMPACT, which showed firstly that those changes in Ki67 did indeed predict the outcome of patients in the ATAC trial, a much, much larger study comparing the effectiveness of the endocrine therapies, aromatase inhibitors and tamoxifen, after surgery. Based on the IMPACT results, we believe that generally one can use Ki67 as an intermediate measurement of treatment effectiveness for an individual patient.
I was inspired to work with Ian on the IMPACT study, because of my involvement with the development of the ATAC trial. ATAC was the first trial conducted and reported on the comparison of aromatase inhibitor versus tamoxifen, versus the combination of these two drugs. It was the first big clinical trial that I was involved with, and I was struck by just how enormous the trial had to be. ATAC eventually required over 9,000 patients to be randomized and to be treated for at least two and a half years before we had any indication of whether one treatment was better than the other. And the measure of that success was based on approximately 900 patients having to relapse with their breast cancer before we knew whether one or the other was better to restrict that relapse. These difficulties seemed to be something that we should be able to improve upon by designing clinical trials that use markers, such as Ki67, to predict patient benefit. And that is where the IMPACT trial came in. IMPACT involved just 330 patients and three months treatment duration. In fact, because we took biopsies after two weeks, we could show changes in Ki67 at the very earliest stage, and were able to show that the combination of aromatase inhibitor and tamoxifen was actually poorer than just the aromatase inhibitor very quickly. So the ATAC experience was something that really did stimulate or inspire my work on IMPACT. Currently, Professor Smith and I are again co-PIs on a new trial called POETIC, which builds on IMPACT to find whether giving patients an aromatase inhibitor prior to surgery and then measuring their Ki67 level may allow us to better predict during routine care the outcome of those patients in the long term.
With BCRF funding, specifically we are doing a study in premenopausal women, on whom you cannot use aromatase inhibitors because they are ineffective and cause significant adverse effects. But we thought the way around the problem was that we might be able to use the changes in hormonal stimulation of the breast tumor, occurring as a result of the menstrual cycle in these premenopausal women. We thought it might be possible to allow the menstrual cycle, instead of a drug, to stimulate certain genes in these women's breast tumors and indicate their responsiveness to treatment. We have some background data on our study, and a paper has just been published in the journal Breast Cancer Research and Treatment. These data were also presented at the 2012 San Antonio Breast Cancer Symposium. We have also launched a prospective trial to test this with colleagues in the UK and Vietnam.
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: The studies I mentioned are based on fairly standard technologies. The POETIC study, however, requires us to implement a collection of tissues essentially as soon as a patient is diagnosed and then again at the time of surgery, which in the UK has required a certain amount of change in the infrastructure. The POETIC trial involves 120 centers, and we just reached our targeted recruitment of 4,000 patients.
In terms of the future, including our work using the menstrual cycle to stimulate the effectiveness of breast cancer drugs, we are using high throughput multiplex molecular technologies, to search a larger number of genes to see whether we can get better signals of response to therapy than what we have gotten so far. Also, we just started doing next generation sequencing on some of the samples from the POETIC trial to identify any mutations existing in those tumors related to outcome. So, we are embracing these new molecular technologies and are beginning to apply them in our studies.
Q: What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?
A: The big thing that has been happening over the last few years is the application of next generation sequencing and massive parallel sequencing to identify genetic mutations and then to profile mutations in tumors. This work has revealed some surprises, such as that there are numerous mutations but with relatively low prevalence in any particular population of breast cancers. This "diversity" creates a real challenge as to how we can bring that information to clinical benefit. But trials are now being designed to see how we link those mutations to the applications of some targeted therapies. There is a real challenge, recognized by many people, in the heterogeneity of those mutations within any single subtype of breast cancer. This may mean that there are "escape routes" or populations of tumor cells that either do not contain those mutations or have additional mutations that make treatments ineffective. We must address those issues as we move forward.
The thing I would really like to see come forward in a big way is the measurement of tumor DNA in the blood, because I think that could be a game-changer in terms of the way we manage breast cancer. This essentially would be a very sensitive, highly specific tumor marker which would reflect whether or not after surgery significant amounts of tumor cells continue to reside in the patient and therefore need additional medical treatment. At the present time, we are treating patients after surgery essentially blind of whether they have residual tumor, and blind to response of that tumor. If we had had a marker of the sort, it would radically change the way we direct our therapies. I think the prospects for that occurring are good but probably a few years away.
Q: What other projects are you currently working on?
A: The POETIC trial is one of our major efforts. We will have in the laboratory all the tissue samples from the 4,000 participants, which is an enormous resource for trying to work out the mechanisms of resistance to endocrine therapy. This is a unique set of materials to help us to truly understand tumor heterogeneity and the different mechanisms of resistance to endocrine therapy and the degrees to which these are important in any patient.
Another project that we are working on is predictors of late recurrence in estrogen receptor-positive breast cancer (late in this case being defined as after five years of the patient being free of breast cancer). We have just submitted our first manuscript on this and presented data for the first time late last year at the European Society of Medical Oncology (ESMO) meeting. The observation was made a few years ago that the risk of breast cancer continues for many years in the estrogen receptor-positive patients. The convention up until recently has been to treat these patients for five years. Work has now shown that continued recurrence after five years can be markedly reduced by the introduction of further endocrine treatment at the end of five years. But the challenge is to identify which patients really need that continued treatment. Five years is already a long time to be taking treatment and recommending it to be taken further is not to be made without serious consideration. And there are some markers that are coming through that we should be able to bring to bear. But specifically trying to identify molecular markers that could be useful in that scenario is a recent research development. The markers that we have been testing out so far and have valuable prognostic or predictive characteristics have been found to have some prognostic value for late recurrence but were "discovered" in a way by chance, rather than by design. We expect to be able to improve on these by dedicated research in this area.
Q: How close are we to preventing and curing all forms of breast cancer?
A: That is a tough question. If we think about "cure" at least in terms of preventing death from breast cancer, data show that we are making substantial progress. Some twenty years ago, 16,000 women were dying of breast cancer in the UK each year, and the most recent data from two years ago were that 12,000 women died of breast cancer each year. These survivors would have been diagnosed several years prior, so going forward patients diagnosed nowadays have much better prospects, including better treatments that would lead to much reduced risk of breast cancer mortality. So in terms of reducing mortality, I think the chances are that few patients will be dying from breast cancer twenty years from now. I believe breast cancer will become a disease that is much less feared than it has been as we move through the next two decades.
I do not think that the approaches we are presently taking are likely to lead to major increases in prevention over the next few years. First, detection is not the same as prevention. Being able to detect breast cancer earlier does allow doctors to treat patients earlier and gives the patients a better chance of surviving the disease. But early detection is de facto not geared towards prevention. My optimism is more directed to thinking that the disease will be managed much, much better, such that the fear will be taken out of the diagnosis of breast cancer. Prevention is likely to have some importance by being targeted at those at highest risk.
Q: In your opinion, how has BCRF impacted breast cancer research?
A: I think BCRF has had major beneficial impact. The direct effect is, of course, in the provision of funding to investigators who already have either shown some promise or with established careers and trusting those people really to spend that money well. BCRF is not bureaucratic, which means much more of the money and time can be spent on the research itself rather than with people having to spend their time and effort on reports. I think the trust that BCRF has in its grantees is well-placed and that trust imposes a degree of responsibility on the investigators.
BCRF funding has also produced some indirect benefits. For example, the types of projects that BCRF enables one to do are those sometimes considered high risk but high pay-off, and I think the study that we are doing trying to establish whether or not we can use the menstrual cycle as a probe for the hormone responsiveness of the breast tumor is very much along those "high risk, high reward" lines. If it works out, it will be a major benefit and a terrific advance, but it is high risk. The data we have derived so far supports us moving forward, and it is decreasing the risk as we move forward. I think it would have been difficult to secure funding from another agency for this project.
Another thing I might say about BCRF is the genuine feeling of family it creates amongst the investigators. At the meeting in October, the interactions are very warm, and our meeting at that particular time is welcomed by all of us. We all travel to New York and I think we both enjoy and get reward from interacting with the advocates and the fundraisers. This meeting really does stimulate people and creates a patient-orientated focus in the participants' research as well.
Read more about Dr. Dowsett's current research project funded by BCRF.