BCRF sat down with Dr. Matthew J. Ellis to discuss his current work and interest in breast cancer research. Read on to learn more.
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 have always known that I wanted to do medical research. As a young doctor in training in London, Oxford, and Cambridge, I was struck by the number of patients with metastatic breast cancer. When I approached my mentors about a career in cancer, they largely discouraged it and suggested instead gastroenterology or cardiology as "more promising" medical specialties. There was still the pessimistic attitude in the '80s towards cancer that it was a disease we could never understand and therefore it was hopeless to treat.
But yet as I cared for these women, seeing them respond to chemotherapy and endocrine (or anti-hormone) therapy, I got the impression that breast cancer was not hopeless at all. Inspired by the discovery of "cancer genes" (oncogenes), I decided to also pursue a doctoral degree focusing on fundamental molecular biology. I hoped that by marrying knowledge on disease etiology with clinical aspects of breast cancer, I could make a difference. When I finished my PhD, I met Dr. Marc Lippman (a BCRF grantee since 1995), who has become one of my lifelong mentors, and he encouraged me to come to the United States to work with him at the Lombardi Comprehensive Cancer Center of Georgetown University in Washington, DC.
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: Well, breast cancer is a complex set of diseases, so it made sense to focus on one subtype. I zeroed in on the estrogen receptor positive (ER+) subset. The majority of women with breast cancer are ER+, which also means that the majority of women dying from breast cancer die despite targeting ER with tamoxifen or estrogen-lowering agents (aromatase inhibitors). In the late 1990s, I developed a new treatment protocol for patients with ER+ breast cancer: instead of operating on them immediately, we gave them a few months of endocrine therapy before surgery, which resulted in shrinkage of the tumors, making it possible for patients to avoid mastectomy and instead undergo breast conserving surgery.
We also preserved the patients' generously donated tissue samples, so we could study them in the lab to get at fundamental issues, for example, why some women with ER+ breast cancer respond well to endocrine therapy but others do not. In 2004, through the National Cancer Institute-designated cooperative group ACOSOG, now part of the Alliance for Clinical Trials in Oncology, we opened a neoadjuvant trial comparing the effectiveness of the different aromatase inhibitors, a class of endocrine therapy. More fundamentally, we were trying to understand why there was such a great variability in the response to treatment. BCRF funding gave us the means to collect the highest-quality specimens at different treatment intervals so we could apply genomic techniques to see exactly how these breast cancers were re-coded as a result of all the mutations that occur during the genesis of a tumor. Federal funding for clinical trials remains inadequate for this kind of longitudinal specimen acquisition.
Recently, we applied "whole genome sequencing" on these specimens, which consisted of both healthy and cancer tissues from patients. This means that we sequenced entire genomes of tumors and compared them with the genomes of healthy tissues from the same person. So far, we have completed 46 cases and have also used partial genome sequencing techniques with data currently complete on 77 cases in total. Now, we have a list of all the common and rare mutations that occur during the development of cancer from a normal cell. We also have begun to relate the presence of these mutations with the clinical behavior of the tumors and look at responses to therapy, histological growth patterns, and whether the mutations occurred in pathways that could be targeted. A paper describing this work will be presented at the Annual Meeting of the American Society of Clinical Oncology in June and printed in Nature magazine later this year.
During the course of this work, we have discovered entirely new genes involved in the development of ER+ breast cancer. We were not only able to describe genes that were involved in coding aggressive ER+ breast cancers that became resistant to aromatase inhibitor therapy but also families of genes that are associated with slow growing, indolent types of breast cancer. The genetic basis for these slow growing ER+ breast cancers was understudied previously, because the sequencing of cell lines, ER negative tumors and cruder genomic techniques missed this important biology. So our BCRF supported study really did, I think, contribute in a major way to our fundamental understanding of luminal, or ER+, breast cancers. The funding was visionary and critical for this work.
Q: Are there specific scientific developments and/or technologies that have made your work possible? What additional advances can help to enhance your progress?
A: Our research capitalizes on the new technique called massively parallel (or "next gen") sequencing. With this technology, we take tumor DNA and matched normal DNA from a patient and we break these DNAs into tiny fragments and sequence them at random. Computer programs are used to map the sequences to the human genome and to spot differences in the normal and the cancer DNA (mutations). Using this approach, we can identify not only the gene mutations but also the frequency at which these mutations occur. Having access to this type of technology was the primary reason for my move to Washington University in St. Louis. What we have found is that tumors are often quite complex and in the process of evolution, both rare and common mutations are present. The challenge is to determine what changes are biologically relevant and therefore useful for patient stratification and treatment. In terms of the next step, we are beginning a huge effort to maximize the value of next gen sequencing. Discovery using this technology will be largely completed within the next two to four years. Literally thousands of breast cancers are going to be sequenced. We now need to figure out the clinical application of these techniques.
I am also increasingly excited about new developments in proteomics. Our ability to identify proteins, analyze them, and reliably identify modifications of proteins has been rudimentary. But now, faster, more accurate, and computationally better supported proteomics machines are coming online. These "mass spectrometry" machines are going to make the deep impact that the introduction of massively parallel sequencing made two to three years ago. Creating a comprehensive approach that includes both DNA/RNA and protein analysis will get us to the next step, which is an understanding of how the recoding of the cancer genome alters protein function. When we can understand that, we will gain a much clearer picture of how to treat individual patients in a very precise way because we will be able to zero in on the most critical changes that drive the disease outcome.
Q: What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?
A: What our sequencing efforts are already telling us is that breast cancer is a very heterogeneous disease. It may be as heterogeneous, or even more so, than all the different types of leukemia. Breast cancer will fracture into many subsets, beyond luminal A and B, HER2 positive (HER2+), and triple negative. By using our understanding of the underlying biology of breast cancers, we will be able to determine whether or not certain classes of drugs will benefit patients.
For example in our studies, we found rare activating mutations in genes such as HER2. These tumors are labeled "HER2 normal" because they do not have gene amplification but functionally they are HER positive. Hypothetically in these cases, tumors are likely to be sensitive to such anti-HER2 drugs as lapatinib. But currently these patients would never receive lapatinib based on our standard definition. These HER2 mutations are infrequent, occurring in perhaps 1-2% of breast cancer patients, but because breast cancer is so devastating common, we may be talking about more than 2,000 patients a year in the US alone. These cases are, therefore, a very significant subset to recognize because there may be a treatment already available to help them. The only way to find these patients is through the prospective use of sequencing technology. In reality, most targeted therapies dramatically affect only a relatively small population of patients. However, because of the large numbers of targeted oncology drugs available, I predict there will be increasing numbers of patient subsets who will benefit from improved diagnostic approaches.
Q: What other projects are you currently working on?
A: We are a part of the National Cancer Institute's new program called Clinical Proteomic Technologies for Cancer (CPTC) initiative. This is a consortium of sites working on cancer proteomics. We are beginning to place mass spectrometry-based cancer protein identifications into the context of our knowledge of RNA and DNA, from the next generation sequencing studies, to create a comprehensive approach that includes parallel analysis of DNA, RNA, and protein in each cancer sample.
Another thing that I'm very interested in is taking these genomic approaches and improving the therapy for ER+ breast cancer through the use of combinations of endocrine drugs with targeted therapies. We are studying the combination of endocrine drugs with signaling inhibitors, such as PI3 kinase inhibitors, that can cause rapid activation of cell death programs in cancer cells. The problem with ER+ breast cancer all along has been that endocrine therapies unfortunately are only partial therapies. They suppress the cancer by making tumor cells dormant but in many patients they do not cure. Because these drugs do not get rid of tumor cells entirely, the cancer cells can reactivate and develop secondary mutations, making them resistant to drugs that were formerly effective. The only way to deal with that problem is to find therapies that cause complete regression of a tumor right at the beginning, right at the time of diagnosis.
Q: How close are we to preventing and curing all forms of breast cancer?
A: I think we have already made massive progress in some breast cancer subtypes, for example using trastuzumab (Herceptin®) on HER2+ and third-generation chemotherapy on some forms of triple negative breast cancers. In the ER+ group, I think there are definite possibilities around endocrine drugs combined with other signaling pathway inhibitors. Going forward, I think we need to determine therapy in a "genome forward" way, meaning using the tumors' mutational profiles prospectively to create testable therapeutic hypotheses for each patient. A cure for everybody is our goal, but I think it requires us to completely rethink the way we do clinical trials. We cannot continue to do trials that produce a 4% improvement in survival in a study involving 4,000 patients; the sums don't add up. Prospective identification of subset of patients who would benefit from individual drug approaches involves a lot more diagnostic work, a lot more sequencing, a lot more organization but I don't think it's beyond the wisdom and power of my colleagues to achieve this little transformation. BCRF will be absolutely essential to the effort.
Q: In your opinion, how has BCRF impacted breast cancer research?
A: I think the vision shared by BCRF's co-founders, the late Evelyn Lauder and Dr. Larry Norton, is fantastic. They have created a different and very smart model for research funding. The alternatives, one of which is the competitive grants model, require you to spin a story and propose an "exciting" but self-contained piece of work is cumbersome and slow, as the time from application to delivery of the dollars is typically over a year. Also, clinical trials are an example of the type of study not always amenable to the competitive grants process. For instance, you may need funding to collect, ship, and store tumor specimens, which may sound mundane but is absolutely critical because you cannot do an experiment without these samples. Our work could never have been done without BCRF funding. Another thing is that BCRF invests in individuals and individual groups. With a non-bureaucratic approach, through Larry Norton's vision BCRF has created an "academy of breast cancer researchers." At our annual faculty-only retreat preceding the October Symposium & Awards Luncheon in New York, we get to have interesting and very worthwhile conversations. These opportunities foster camaraderie and collaboration. In our research, BCRF became a critical cog in a very complicated machine to actually achieve the experiment.
Read more about Dr. Ellis' current research project funded by BCRF.