José Baselga, MD, PhD :: Profile
Physician-in-Chief, Memorial Hospital
Memorial Sloan-Kettering Cancer Center
New York, New York
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 am a third-generation physician. My dad was a doctor, my mom is a nurse, and my sister is a doctor, so medicine always surrounded me. From very early on, I felt a sense of "destiny" that I was going to become a physician myself. Frankly, I never thought there was going to be any life outside of medicine.
Now, how I came to breast cancer research is an interesting story. I wanted to do oncology. I felt that the field was challenging, and that things were going to happen in oncology. When I was in my early 20's, oncogenes, or cancer genes, were identified, and it was clear that cancer care would change for the better. I was a fellow at Memorial Sloan-Kettering Cancer Center and worked in the lab of Dr. John Mendelsohn, (who since went on to lead MD Anderson Cancer Center and was a BCRF grantee until his retirement). At the time, we were beginning to work with the first anti-HER2 breast cancer therapies, to treat HER2-positive (HER2+) breast cancer.
As a fellow, I helped to conduct the first clinical trials on what later would become Herceptin® (trastuzumab). I saw with my own eyes the first responses of patients with advanced HER2+ breast cancer to trastuzumab. It was a magical moment. It was clear that this drug was going to help many people. At the same time, and this is critically important, a prestigious breast oncologist joined Memorial to lead the breast cancer group. His name is Larry Norton. I became one of his first fellows.
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: We have learned that the limiting step of any cancer therapy is resistance. When we apply a new therapy, patients either do not respond from the very beginning or initially benefit from the therapy but eventually develop resistance. With BCRF support, my group had previously identified that mutations in the PIK3A gene were responsible for resistance to anti-HER2 therapies. This information has allowed researchers to develop novel drugs, called mTOR inhibitors, which target the PIK3A gene pathway.
In our current project, we thought, let's get ahead of the game and identify from the get-go the mechanisms of resistance to therapies. Our idea was that if we could identify these mechanisms now, we could probably develop strategies upfront that would prevent resistance. Specifically, we are using combinatorial approaches that is, a treatment "package" of more than one therapy, as a way to target the cellular pathways involved in resistance. The validity of our idea was first tested and confirmed in the lab and then transferred to the clinical setting. This work culminated in several studies, two of which were reported in December at the 2011 San Antonio Breast Cancer Symposium, the world's largest annual breast cancer meeting, and published in the New England Journal of Medicine. These two studies, named BOLERO-II and CLEOPATRA, were large-scale international clinical trials examining the efficacy of combining existing medicine with new agents for women with metastatic breast cancers. (Read more about BOLERO-II and CLEOPATRA here.)
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: Since our BCRF grant was approved, something very remarkable has occurred - our scientific theory was validated in clinical practice through clinical trials. Based on earlier studies funded in part by BCRF, we were able to design and develop clinical trials of existing therapies to see if various combinations of them would produce improved results for patients. Through BOLERO-II and CLEOPATRA, we have shown new treatment options for women with advanced hormone receptor positive (HR+) and HER2+ breast cancers.
A few months ago, the question was if combinatorial therapy would be useful. As predicted, it was, and our data demonstrated that. The next development would be a long-term study of women in these studies. In addition to effectively managing these cases of metastatic breast cancer, we want to minimize any negative side effects that may result from therapies.
Also, our project has become even more important, because we now face the challenge of identifying ahead of time who will benefit from these combinatory therapies. Our research focus has shifted towards answering that question.
Q: What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?
A: I think in the next ten years, it's all going to be about personalized cancer care. What this means is that we will be able to design therapies directed against specific "drivers" fueling the formation of different types of breast cancer. This requires that we examine the genetic mutations present in every tumor, so we will need to routinely sequence tumors, or decode their DNA, in the clinical setting - not just as a part of a research project. We could create a catalogue of mutations that are present in every type of breast tumor.
With information from the tumors' DNA, we are going to be able to predict, with more or less success, which driver mutations are triggering the growth of tumors. This knowledge will allow us to estimate better the prognosis for patients but, more importantly, to develop more precise targeted therapies - well beyond what we have now.
Right now in breast cancer care, we have anti-estrogen and anti-HER2 therapies. In the next ten years, I think we will have a variety of new anti-HER2 drugs, as well as targeted therapies for other forms of breast cancer, including the PI3kinase mutant tumors and AKT mutant tumors. The list goes on and on. As new targeted therapies become available, we are going to need less chemotherapy and reduce the toxicity of therapies. The ultimate goal is to produce greater clinical benefits for patients with fewer negative side effects.
Q: What other projects are you currently working on?
A: We just announced the building of a new center for targeted therapies at Massachusetts General (MGH). Fully committed to the vision of personalized cancer care, we are expanding our genotyping facilities, increasing the number of new compounds tested in the clinic, as well as looking at compensatory pathways that may be activated through adjuvant therapy triggering drug resistance. We are working very hard to identify which compensatory pathways they are and how we can intervene.
The other project I'm truly excited about is collaboration with fellow BCRF grantee and director of the cancer center at MGH, Dr. Daniel Haber. We are studying whether certain molecular biomarkers within circulating tumor cells (CTCs) can provide an early sign of response to therapy. Dr. Haber's team recently developed a new way of isolating CTCs, which we believe have a role in cancer metastasis, in the blood. Based on this work, we could theoretically determine whether a tumor is responding to a given therapy and either continue or switch therapies faster. If successful, we will, for the first time, be able to examine routinely what is truly going at the molecular level.
Q: How close are we to preventing and curing all forms of breast cancer?
A: Personally, I think we could be closer than we think. A few years ago, the prognosis of patients with HER2+ breast cancer, which is one of the most aggressive forms of breast cancer, was not very good. Now, if you diagnose a patient early on with HER2+ breast cancer and if you treat her cancer appropriately, the cure rates of early disease are close to 90%. In less than ten years, we have witnessed a disease that can be cured in close to 90% of patients.
I am optimistic. I think what we know today is amazing. If we apply all of the knowledge we have and do it efficiently, I hope that in 20 years, breast cancer will no longer be a major cause of death in women.
Q: In your opinion, how has BCRF impacted breast cancer research?
A:It's not an opinion. It is a fact that I would not be here today without BCRF. I returned to Barcelona initially after my fellowship. Because BCRF was one of the first breast cancer foundations to fund work outside the US, I was able to use this support to run my lab and clinical research. BCRF has been, to me, a long-term companion, a tremendous partner in our research. I have said numerous times that I would not be here as a scientist without BCRF.
Read more about Dr. Baselga's current research project funded by BCRF.