Breakthroughs in Targeted Therapies for Breast Cancer Are Improving Patient Survival Rates
A Conversation with José Baselga, MD, PhD
The dream is to bring precision medicine forward in breast cancer, and whenever possible, to think about reducing the use of chemotherapy.
—José Baselga, MD, PhD
For more than 20 years, José Baselga, MD, PhD, has devoted his medical and scientific career to caring for breast cancer patients and the development of novel molecular targeted agents to treat the disease. From 1996 to 2010, he was Head of the Oncology Department of Vall d’Hebron University Hospital in Barcelona, and from 2010 to 2012, he was Chief of the Division of Hematology/Oncology and Associate Director of the Massachusetts General Hospital Cancer Center in Boston. In January, Dr. Baselga began his new position as Physician-in-Chief of Memorial Sloan-Kettering Cancer Center in New York, where he is leading a staff of over 900 attending physicians and overseeing the institution’s clinical and translational research programs.
Dr. Baselga’s laboratory investigations of growth factor receptors as targets for breast cancer therapy were instrumental in the development of several molecularly targeted agents, including trastuzumab (Herceptin) and lapatinib (Tykerb). More recently, Dr. Baselga led the clinical development and clinical trials of two new drugs, pertuzumab (Perjeta) in the treatment of HER2-positive metastatic breast cancer and everolimus (Afinitor) in the treatment of advanced hormone receptor–positive HER2-negative breast cancer. In 2012, the therapies received FDA approval in the treatment of advanced breast cancer. Today, Dr. Baselga is focused on the clinical investigation of the next generation of PI3 kinase inhibitors for patients with mutations in the PI3 kinase alpha gene.
A Past President of the European Society for Medical Oncology, Dr. Baselga has served on the Board of Directors of ASCO as well as the American Association for Cancer Research (AACR) and has received ASCO’s Young Investigator and Career Development Awards and AACR’s Rosenthal Family Award.
The ASCO Post talked with Dr. Baselga about his goals as Physician-in-Chief, his latest studies of PI3 kinase inhibitors, and the advantages of the team approach to research.
What are your goals as you begin your new role as Physician-in-Chief of Memorial Sloan-Kettering Cancer Center?
This is a time of great opportunity in cancer research and in improving patient care. We have plans to expand our clinical programs, and we will be creating additional research and clinical space. Our goal is to bring precision cancer medicine to the forefront.
Being at Memorial is also like coming home for me. I completed a medical oncology fellowship here and was a young faculty member, so it is a very pleasant feeling to be back at such a fantastic institution with so many colleagues at the cutting edge of the field, and with such a strong commitment to advancing cancer care for our patients and worldwide.
Do you see progress being made in treatment advances for every cancer?
Yes, in every cancer. And we need to be open-minded about the possibility that even the tumors that seem to be the most difficult to treat might be targetable at some point.
Just a few years ago, melanoma was very complicated to treat and nothing seemed to work. Now we have amazing data with the checkpoint inhibitors, particularly the anti-CTL4, PD-1, and PD-L1 monoclonal antibodies, in addition to targeting the BRAF pathway in patients with mutations. At Memorial, for example, Jedd D. Wolchok, MD, PhD [Associate Attending Physician], and colleagues are combining checkpoint therapies, including anti-CTL4 and anti-PD-1, and they are seeing unprecedented activity.
We need to be open to the possibilities in all kinds of cancers. We are making progress in some of them rapidly, and I’m terribly excited about the research going on in breast cancer, lung cancer, melanoma, and leukemia.
In your phase III trial of pertuzumab for metastatic breast cancer, adding the drug to trastuzumab and docetaxel increased median progression-free survival by 6 months. How significant was that result?
It was very significant because not only did the study show an improvement in progression-free survival, which is important, it also showed an improvement in overall survival. In the initial New England Journal of Medicine paper,1 we showed improvement in progression-free survival. Sandra M. Swain, MD, FACP [ASCO President and Medical Director of the Washington Cancer Institute at MedStar Washington Hospital Center], later presented data at the San Antonio Breast Cancer Symposium showing a remarkable improvement in overall survival as well.
Now we are developing other drug combinations that are equally exciting. We are also studying pertuzumab in the adjuvant setting, which could potentially further increase the cure rate in patients with early diagnosed HER2-positive breast cancer.
Could you talk a little about other targeted therapies being developed in breast cancer?
Another emerging target is the PI3K gene, the most frequently mutated gene in breast cancer, as we have learned from The Cancer Genome Atlas effort and others. Close to 50% of the estrogen receptor–positive tumors have a PI3 kinase mutation and it is also frequently mutated in HER2-positive breast cancer. We know that patients with PI3 kinase mutations, downstream of the HER2 receptor, respond less to trastuzumab, pertuzumab, and lapatinib, but now we have PI3K alpha-specific agents, including BYL719 and GDC-0032. We presented data at this year’s AACR Annual Meeting,2,3 in which we showed high responses in patients with PI3K alpha mutations.
The work done by others with CDK4/6 inhibitors is also very promising. In addition, initial data show that a significant proportion of patients with breast cancer have an overexpression of another receptor, FGFR1, and we are about to launch a clinical trial with patients with FGFR receptor alterations.
I can see a landscape in which breast cancer tumors will routinely be genomically sequenced as part of clinical practice. We are already doing that at Memorial. Sequencing not only helps you identify the best treatment approach, it also opens up the possibility for patients to take part in novel clinical trials with agents that are increasingly safe. The dream is to bring precision medicine forward in breast cancer, and whenever possible, to think about reducing the use of chemotherapy.
You are currently involved in several clinical studies of PI3K inhibitors as single agents and combined with PARP inhibitors. Please talk about those studies.
At the AACR meeting, we presented data on PI3 kinase inhibitors as single agents, which showed high activity. This again proved that if there is a driver mutation in a tumor, it is likely that targeting it will result in clinical activity. The next question is how are we going to amplify the tumor activity that we are already seeing? There are a number of approaches we can take. One that we are pursuing is to combine PI3 kinase inhibitors with HER2 inhibitors—for example, trastuzumab and pertuzumab.
Another approach we are working on is combining PI3 inhibitors with antiestrogen therapy, similarly to how we combined everolimus with an antiestrogen. A third approach is the out-of-box “Dream Team” approach being funded by Stand Up to Cancer (SU2C).
We are working in collaboration with Lewis C. Cantley, PhD [Director of the Cancer Center at Weill Cornell Medical College and New York-Presbyterian Hospital], Gordon B. Mills, MD, PhD [Chairman of the Department of Systems Biology, MD Anderson Cancer Center], and Gerburg Wulf, MD, PhD [Assistant Professor of Medicine, Harvard Medical School] on different mouse models combining PI3 kinase inhibitors and PARP inhibitors, and we all came together with the same data. Now the PI3 Kinase Dream Team is conducting a clinical trial with a PI3K inhibitor and a PARP inhibitor in five cancer centers.
Will the team approach to cancer research become the norm in the future?
This is a complex question. We need to find ways to work together and to learn from each other with everybody bringing their expertise to the table, while at the same time understanding that the power of individual investigators to work independently is critical to cancer advancements. So I guess it will be a combination of both. ■
Disclosure: Dr. Baselga has served in a consulting or advisory role for Novartis, Roche, and Chugai.
1. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.
2. Juric D, Krop I, Ramanathan RK, et al: GDC-0032, a beta isoform-sparing PI3K inhibitor: Results of a first-in-human phase Ia dose escalation study. AACR Annual Meeting. Abstract LB-64. Presented April 7, 2013.
3. Rodon J, Juric D, Gonzalez-Angulo AM, et al: Towards defining the genetic framework for clinical response to treatment with BYL719, a PI3Kalpha-specific inhibitor. AACR Annual Meeting. Abstract LB-65. Presented April 7, 2013.