Antonio Wolff, MD :: Profile
Professor of Oncology
Breast Cancer Program
Sidney Kimmel Comprehensive Cancer Center
Johns Hopkins University
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. Medicine is something I've thought about pursuing since elementary school, even though everyone in my very large family is in either business or high education. From Rio de Janeiro, Brazil, where the university educational system is very similar to Europe's, I found myself at age 16 applying to medical school. I therefore later on had to create my own "liberal arts curriculum" to round out my scientific education and took advantage of my love for reading and my curiosity about the world we live in and its history. While in medical school in Rio, I mostly used American medical textbooks as sources, and so it was natural for me to decide to come to the US in the late 1980s for my post-graduate training. I had a six-year plan, and this was 24 years ago.
When I first came to Johns Hopkins in 1992, I was almost instantly attracted to breast cancer because of two major convening factors: one was the incredible number of scientific discoveries in breast cancer coming to fruition at the time, many with immediate relevance to the care of patients; and the second was the many role models I met at Hopkins and elsewhere. Before the 1990s, most scientific developments in cancer were happening in hematologic malignancies, or blood cancers, partly due to the ease of collecting and studying blood and bone marrow tumor specimens from patients with leukemias and lymphomas, and this attracted a lot of smart people to those fields. With the identification of the tumor suppressor genes (e.g. p53 and the breast cancer susceptibility genes, BRCA1 and BRCA2) in the 1990s, we began to see breast cancer as a perfect example of how improved understanding of the major drivers in tumor growth had implications for not only diagnosis but also treatment.
Also, giants in breast cancer, such as Bernard Fisher, MD (who received the BCRF Jill Rose Award in 2003), and Gianni Bonadonna, MD, to name just a few, started in the 1970s and 1980s to change our understanding about not only surgery but also the role of treatments like chemotherapy following surgery (called "systemic adjuvant therapy"). Their work and that of so many others illustrated that adjuvant systemic therapy was effective in reducing the risk of recurrence for those with early-stage breast cancer. Until then, to maximize the reduction in the risk of recurrence and metastasis, surgical oncologists used to remove large sections of both cancerous and healthy breast tissues. However, by then we had finally learned that excessively removing otherwise healthy tissues beyond those affected by the disease was not only unnecessary and debilitating in many ways, but sometimes detrimental too. Today, lumpectomy (also called "breast conservation surgery") accompanied by radiation has become an appropriate and equally effective alternative to mastectomy for most women. In addition, we were also developing ways to individualize risk, so that we could offer women at greater risk adjuvant systemic treatments, such as tamoxifen and chemotherapy early on and so much more since. These developments truly revolutionized the way we approach breast cancer. I was very fortunate to be at the right place and at the right time in the 1990s, and to have easy access to so many of the leading thinkers who were generous with their time and who continue to inspire me.
Q. Briefly describe how BCRF funding has affected TBCRC as an organization and its research agenda. What are some laboratory and/or clinical experiences that led to the creation of TBCRC? What are the primary objectives of current TBCRC research?
A. Building on the work of so many and in many ways standing on their shoulders, the Translational Breast Cancer Research Consortium (TBCRC) may well be the next step in the evolution of "team science." Established in 2005 by an initial grant from BCRF, TBCRC is a collaborative effort by a multidisciplinary team of laboratory scientists and clinical researchers and pursues focused clinical trials that integrate clinical and laboratory studies in an effort to accelerate progress in breast cancer. Uniting the efforts of 17 major academic breast cancer programs in the US, TBCRC has activated 24 clinical trials, including 10 that had reached their accrual goals by January 2012. Thus far, almost 2,000 breast cancer patients have been part of TBCRC trials, including about 700 of them enrolled in prospective studies. There are currently 13 clinical trials open to patient enrollment, and several other clinical studies are under development.
Preceding these efforts and starting in the mid-1980s, clinical trials were expanded so that each included hundreds or thousands of patients often across country borders. Parallel efforts led by investigators in Oxford, England to pool the findings from separate but similar clinical trials as part of a multinational effort allowed us to recognize that small improvements in percentage points could translate into enormous, absolute number of individuals who could potentially benefit from new treatments. For instance, more than 230,000 US women are newly diagnosed with breast cancer each year. If a new intervention is shown to be effective in 1% of newly diagnosed women, you're talking about 2,300 lives just in one country. A lot of individual, small baby steps — such as improved detection, better local therapy with surgery and radiation therapy, and systemic treatments — when combined will result in an enormous impact on the lives of individual patients.
These incremental advances are particularly significant in breast cancer, and we now have the tools to increasingly look at individual patients to expand on the gains mentioned above. This is a disease comprised of several phenotypes or subtypes, like estrogen receptor positive (ER+), HER2 positive (HER2+), and triple negative. Not all breast cancers have the same triggers and drivers, and not all respond to treatments the same way. Therefore, there is a critical need to individualize decision-making for each patient, and consequently to design studies that also no longer approach breast cancer as a single entity. Today, there is even better understanding that not all ER+ breast tumors respond equally to endocrine therapy, and the same can be said about HER2+ disease and response to anti-HER2 therapies like trastuzumab (Herceptin®), and about triple negative breast cancer and chemotherapy.
With these insights, it also means that there is a plethora of new drugs and ideas. We as scientists and physicians have an enormous responsibility when thinking about new large randomized trials involving thousands of patients. Clinical trial participants are entrusting us to design appropriate studies and ask the right questions. In many cases, these individuals are facing a very challenging time in their lives for themselves and for their families. So, these studies must be based on solid evidence. We also need to ensure that the studies are asking meaningful questions and are appropriately powered to do so, and the need to collaborate with statisticians specializing in clinical trial design, patient advocates, laboratory scientists, and experts in pathology and cancer imaging has never been greater. We must also do these studies in a reasonable amount of time, so that we will have relevant answers in a timely fashion, then must disseminate these answers to change clinical practice in a meaningful way and benefit patients.
Even though there were mechanisms to help facilitate large-scale clinical trials involving multiple institutions and thousands of patients, many of my colleagues and I realized that we were trying to re-invent the wheel each time we had to put together smaller and complex clinical trials that relied on matching clinical data on outcome with tumor specimens from these patients for lab studies. These are complex studies that cannot be done by a single institution, and they often require biopsies to be taken at different times during treatment and access to fresh tissue. Researchers are trying to detect very early on changes in tissues that may ultimately correlate with which patients are most likely to benefit or not from a specific intervention. Furthermore, collecting and storing tissues is an amazing investment, but it is very difficult to attract funding, because sometimes there is not an immediate scientific question to be answered.
Recognizing all these challenges, I had the privilege to join forces with several BCRF grantees to come together to form a consortium and we named it the TBCRC. This would allow us greater intellectual independence and flexibility to conduct studies that were scientifically necessary but sometimes not of great interest to individual pharmaceutical companies, and sometimes too small and too complex to be done through more traditional and established research mechanisms like the National Cancer Institute clinical trial cooperative groups. Our goal was and continues to be to have a more nimble process to design and activate studies, while eliminating many of the barriers commonly associated with clinical trials.
Q. What is the structure of TBCRC? How has the organization evolved?
A. TBCRC is essentially "a center without walls" and operates with a very small infrastructure. To keep overhead at a minimum so that all the funds could be channeled towards research support, TBCRC operated for many years with only two part-time staff: our business manager Cindy Morin and our program manager Robyn Burns, PhD. I have served as its Executive Officer since 2006. My own institution (Johns Hopkins) realized early on the potential of this new idea and generously provided pro bono administrative and contracts management support for the TBCRC member institutions. Since then, TBCRC has grown to 17 institutions with over 200 faculty and staff individuals participating in its activities, and we recently hired two full-time staff to help oversee the development of research studies and to handle contracts among the TBCRC institutions and with its foundation supporters.
Most importantly, we realized early on the critical intellectual and patient assets we had and the need to engage them. TBCRC emphasizes multidisciplinary research and care. Our members include medical oncologists, surgeons, radiation oncologists, basic scientists, and imaging specialists. With the wealth of scientific wisdom and bubbling ideas, we soon created smaller working groups that meets by phone monthly and in person at least twice a year. Working groups in disease subtypes were established: endocrine resistance; HER2 resistance; and triple negative disease. We also established a correlative science working group to support these disease-oriented working groups. Since patients are the primary reason for all we do, each TBCRC member institution identified a patient advocate to represent them and their patients in a patient advocate working group. Finally, as nothing happens as if by magic, we asked the institutions to identify research coordinators and contract managers to band together in their own working groups. It is a lot of people, but much of their work is done by phone and via e-mail to expedite things and minimize costs. Also, a nice side benefit has been the establishment of common processes across institutions, which in many cases have benefited their own efforts outside of TBCRC.
Q. What direction(s)/trends do you see emerging in breast cancer research in the next 10 years?
A. I see three main trends: 1) therapy individualization; 2) further refinement of tumor subtypes driven by specific interventions; and 3) improved public understanding of the need for tissue repositories. This combination of trends can dramatically improve patient outcomes.
One of the most remarkable examples of therapy individualization is the availability of anti-HER2 therapies, and the development of improved predictive markers of treatment benefit. Trastuzumab was quickly brought to patients' bedside in the late 1990s. Improvement in standard pathology measures and testing of new measures like gene expression profiling in the 2000s were largely due to studies using tissues collected from earlier clinical trials. Through patient tissues, we can assess the regulation of genes, look at gene expression, and the activation of cellular pathways (like ER, HER2, and PI3 kinase), and better understand how all this comes together so that we can gradually further develop techniques and treat patients with truly individualized care. But, if we are going to individualize care, we must also make sure we have excellent pathologic testing for markers that will influence treatment decisions, so that we can recommend the right treatment to the right patient, and this has been a focus of my personal work since 2005.
Also, I see in the near future therapy individualization beyond the major subtypes of breast cancer we now have, and this will allow us to further refine treatment decisions in a meaningful way. Like everything we do today, this can only be achieved through the collaborative interaction of experts with very diverse backgrounds, including clinician researchers, laboratory scientists, epidemiologists, biostatisticians, and bioinformaticians. In other words, this is a very large village and organizations like the BCRF have played a key role to help bring us all together.
The large-scale studies from the 1980s made us realize the importance of prospectively collecting tissue specimens from patients. We may not be able to fully understand all the data embedded in these tumor specimens now, but as technology evolves our understanding will evolve too. Also, these tissue blocks become incredibly valued over time as we learn about the clinical outcome of the patients associated with them, especially if these are patients who first presented with early-stage breast cancer. Therefore, in this partnership between researchers and patients, we must engage them and explain the critical nature of efforts to collect tissue and blood specimens for present and for future use.
Q. How close are we to preventing and curing all forms of breast cancer?
A. We cannot promise the public — those affected by cancer and those who support cancer research — that we will be able to cure cancer in just a few years. However, we can promise that we will further improve on the gains of the last few decades and continue to improve strategies to reduce risk, methods of early detection, and treatments to further reduce the morbidity and mortality of this disease. We will further understand what drives the development of cancer, who are the patients at greatest risk for developing cancer for the first time, and who are those at greatest risk for disease recurrence. By individualizing treatment, we help avoid exposing patients to unnecessary treatments and wasting limited resources. We now better understand how truly complex cancer is and I think the public understands this too. Therefore, we must act responsibly, engage the public, treat them as equal partners, keep them informed along the way, and translate new discoveries into clinical practice as soon as feasible.
Q. In your opinion, how has BCRF impacted breast cancer research?
A. What the BCRF leadership and scientific advisors have done is absolutely unique. They have ultimately identified a large number of productive and committed individuals who believe in what they do. BCRF provides investigators with resources that are otherwise not available to pursue new ideas and partnerships. Researchers have used BCRF grants to complement funds from the National Cancer Institute and from other organizations to test new concepts and pilot innovative studies. By bringing all these individuals together and putting resources on the table, BCRF has fostered scientific collaborations and cross-fertilization of ideas that have directly impacted the lives of many women.
BCRF has also taken other critical steps to help communicate, engage, and educate the public on what scientific research is and on the critical role the public can have. What we learned from the HIV and breast cancer fields is that when scientific investigators engage and collaborate with patient advocates, foundations, and community organizers, we raise awareness. This awareness translates into momentum, into political and social will, and ultimately into additional resources that are especially critical in difficult economic times. Therefore, organizations like BCRF have helped groups come together to overcome major obstacles to discover new knowledge, implement new clinical trials, analyze results, translate them into clinical practice, and ultimately improve the outcome of so many women diagnosed with breast cancer or at risk of developing it. It truly takes an enormous village to have an impact, and I am honored to be a part of it.
Read more about Dr. Wolff's current research project funded by BCRF.