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Investigating Breast Cancer: A Cross-disciplinary Approach

Dr. Antonio Wolff talks to BCRF about how collaboration is key in the fight to solve breast cancer

It takes a village to understand and solve breast cancer. In this case, the village is more like an innovative network of research labs, scientists, patients, funders, and more. In other words, something like the Translational Breast Cancer Research Consortium (TBCRC) led by Dr. Antonio Wolff. The TBCRC is a collaborative group founded in 2005 to conduct innovative and high-impact clinical trials for breast cancer.

In this episode, Dr. Wolff shares how collaboration across disciplines, institutions, and countries is key to attacking the disease. Dr. Wolff’s work, along with others, has helped design, implement, analyze, and report clinical trials. The goal of these trials is to provide insight into the development of more effective and individualized treatments for breast cancer. Results provide crucial insights that guide personalized treatment for various subtypes of breast cancer.

The numbers are impressive: TBCRC is comprised of 19 clinical sites and five working groups that have launched nearly 50 studies. These breast cancer investigators share information, data, successes, and even obstacles, as they frequently coordinate their efforts toward their common goal.

Dr. Wolff, a BCRF investigator since 2007, is a professor of Oncology at John Hopkins University and a member of the Johnson Hopkins Kimmel Cancer Center in Baltimore, MD. He received his medical degree at the Universidade Federal do Rio de Janeiro in Brazil and trained in medical oncology at Johns Hopkins. He is an associate editor of the Journal of Clinical Oncology, chair of the ECOG-ACRIN Breast Cancer Committee, and chief operating officer of TBCRC.

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Read the transcript below:

Chris Riback: ​Dr. Wolff, thanks for joining me. I appreciate your time.

Dr. Antonio Wolff: ​It's so good to be with you, Chris. Thank you for the invitation.

Chris Riback: ​So of course, you're a globally renowned cancer and breast cancer expert, and I'm really looking forward to getting to talk with you about that. But in researching you, I'd like to point out, not only are you a top scientist, you also can do a pretty mean Twitter, with a not unimpressive following. How do you do that?

Dr. Antonio Wolff:​Well, I'm actually impressed that you did your homework, and you noticed that. How do I do that? I actually try to think about things that would be interesting to me or to people like me or to people that would be interested in what we scientists do day to day, on a day to day basis, and what it might mean for them. And so I try to be as conversational as possible. You have to be succinct, you have to be short, and you have to be to the point, to capture the essence of the message. I began doing Twitter, actually registered for Twitter probably 2009, and that's probably why I have an easy Twitter handle.

Chris Riback:​ Yes, you do. You were first in. You were first in on Twitter.

Dr. Antonio Wolff: ​I think Twitter started in 2007, and I joined probably in 2009 but I can tell you that I did nothing with it for a while and I was doing the proverbial lurking, looking around. And then I realized that what Twitter does, and I think you could be said the same social media, it really allows us, scientist, to communicate directly to the public. And at the end of the day, this is what it's all about. There is no question, we all went into science because we were curious. We went into science because we want to find out how things work and then many of us, like me, we into the medical field and into research because we wanted to help people. And so we do a great job in speaking complicated and writing complicated and whether it's a paper or grant, but at the end of the day, whether we are communicating with the public with the grant agency, we need to speak plain language and plain English.

And so Twitter has been, I find it awesome. Because it gives it us the opportunity to reach out to the public directly and it forces us to be sharp in our thinking. So I will say that actually Twitter and other forms of communication and I can tell you, I use Twitter professionally. I don't use it for personal uses––it forces me to more clear in my communication and the feedback we get gives you the opportunity to better understand if what you as a researcher think is interesting really matters to the people for whom this should matter the most. It's a great platform.

Chris Riback: ​It's an excellent platform, and you are excellent at it. So look, if the whole medical science research thing doesn't work for you, you always can apply for an entry-level job as a social media editor at a start-up in Silicon Valley.

Dr. Antonio Wolff: ​Hey, there you go.

Chris Riback:​ So in your plain language, maybe a little bit more than 140 characters, but in ways that the rest of us can understand, what is the Translational Breast Cancer Research Consortium?

Dr. Antonio Wolff: ​The TBCRC as we call it, and by the way the TBCRC does not yet have a Twitter presence. This is actually something that we've been discussing among us exactly for all the reasons that we just mentioned, but I'll come back to that in a moment because we have other ways to remain relevant. And then the other funny thing is that the handle @TBCRC already belongs to someone else who does something that has nothing to do with breast cancer, so we now need to come up with a nice Twitter handle for TBCRC, but we'll get to that.

Chris Riback:​ @therealtbcrc

Dr. Antonio Wolff: ​I like that. So anyway, what is TBCRC? The TBCRC is actually something that a number of us, including some of my seniors at that time, individuals like Dr. Larry Norton, Dr. Nancy Davidson, Dr. Eric Winer, and a few others, the TBCRC was started to occupy a niche that did not exist in the middle of the 2000s. Breast cancer is a discipline that involves a group of investigators. It has been extremely cooperative and collaborative, going back to the 1970s and for that, I give a huge amount of credit to all the individuals that came before me.

​I am not that young, but I'm also not that old, so I occupy a niche in my development that I really have gotten to know many, if not most of the breast cancer investigators. I would call them from the second generation of breast cancer researchers, individuals that finished then training in the late 1960s, 1970s and were extremely active in the 1980s in developing a lot of the evidence, leading studies in the 1990s and then in the 2000s they were beginning to occupy a role and a position that today, I am fortunate enough to be in that role, where I can also now be in a position where I can train the next generation of investigators, which is really a lot of fun and one of the main things we do in TBCRC.

​So my colleagues, my then seniors, began, they noted how difficult it was to bring together like-minded individuals, many of these studies done in the 1980s and 1990s were relatively small studies, no more than a few hundred patients, but some smart statisticians and epidemiologists began to realize the opportunity to bring all of those studies together and do what we call a systematic review and meta-analysis, concept of the big data but pulling together not real-world evidence but rather a collection of well-conducted clinical trials and trying to see if those large, putting together all these data the patient level could then allow us to begin to observe patterns that were not clear if you're just looking at an individual trial.

And these meta-analyses proved to be incredibly helpful to allow us, for instance, in the mid-1990s, it took us a long time to begin to realize that as one concept, adjuvant endocrine therapy, the use of a drug called Tamoxifen for women with estrogen receptor-positive disease and till 1995, there was a belief that these medications, Tamoxifen did not help women with early-stage breast cancer, did not help improve their survival. It was only after one of the Oxford Overview Meta-Analysis published in 1995, doing exactly what I just described lumped in together a lot of similar sized studies that the effect became obvious and that changed clinical practice.

We, the NCI, with the war on cancer in the 1970s and many key investments in the 1980s was funding in the US a number of what we call cooperative groups. At that time SWOG, NSABT, CALGB, ECOG, and a few others, NCTTG, as well, and these groups were doing a lot of studies, especially, the adjuvant study, many studies, a study of disease as well. These were studies that required several hundred patients and many went on to change the clinical practice in breast cancer in early stage in advanced disease. But the amount of funding available at that time allowed many more ideas coming from these friendly competitive groups where you'd kind of nudging each other, challenging each other to do better and better because your best friends are also competing with you.

NCI always very supportive of us doing these types of studies, but they were time-consuming, took a long time, but also allowed a whole generation of investigators to be trained and to become very good at designing, implementing, analyzing, and reporting clinical trials and improving more and more their ability to communicate with the public, which goes back to what we discussing moments ago.

Chris Riback:​ You've called it a Center Without Walls.

Dr. Antonio Wolff: ​We try to keep our infrastructure as nimble as possible and one of the things that began to happen in the late 1990s and early 2000s is that the level of funding coming from the National Cancer Institute began to decrease in order to support the infrastructure and the number of ideas we had in the cooperative group systems. We also had a number of single institutions, many of them major academic press programs in the US, with great ideas able to do smaller studies that at the same time were smaller but also we had the capability of doing studies that were more as I call them, biospecimen intensive.

What I mean by that, we had the ability to do more blood tests, collect more blood samples from patients on trials. We were able to potentially do research biopsies. So someone with early-stage or metastasize, we would ask patients to volunteer to donate a tissue sample, to allow a research biopsy of breast tissue or a site of metastasize in an organ like the liver or lymph node. These are more costly. These are more time consuming, and it was becoming difficult to do these types of more bio-specimen intensive trials within the cooperative group systems because the level of funding available for those types of bio-specimen collections was simply not available.

The NCI would provide us for the most part with resources to run the study, to test new treatments but we always had to go elsewhere to figure out how to collect the specimens. So we had a situation, why did we do the TBCRC? We had a situation where we had the cooperative system was allowing us to do, still very important and practice-changing trials by asking simpler questions and we had a lot of new ideas that required a bigger dive into the details as I mentioned with correlative studies, using blood and tissue specimens. And we figured out that we needed something in between instead of doing the large studies, we had to cooperative groups, or the much smaller trials and more intensive with one or two institutions.

We realized that we actually needed to have something in between where we could bring together three, four, five, six, up to 10 institutions at a time, joining a study where we could do what we were doing within each of our institutions but in a larger scale with more patients and taking advantage of the broad expertise that we all have to design the best possible studies and I think that this is one of the critical things about TBCRC ... the ability to give junior investigators the opportunity to present, propose their ideas to more senior investigators, hone their skills, improve the quality of their proposals and design the best possible studies, so that we could continue to develop the pipeline of junior investigators that one day would become senior investigators and I with others am a perfect example of individuals that grew up in that system.

Chris Riback: ​Yes, cross-discipline, cross-generation, cross border is what I'm hearing from you.

Dr. Antonio Wolff:​ Cancer is one example. It's going to touch on all of us, all of us at some point in our lives will be affected by cancer. We will have a loved one who's affected by cancer. We will know someone in our social, professional circles, so it is an equal opportunity challenge for us all. The way TBCRC is organized is exactly to take advantage, to be ready, and to take advantage of opportunities as they developed.

Chris Riback: ​You’re bringing together so many institutions. I think 19 institutions, maybe it's grown since maybe it's slightly more than that, but my interpretation is you are creating that very infrastructure so that we're at a continual high pace in terms of research.

Dr. Antonio Wolff:​ That is absolutely true. So the TBCRC was started with about 11 or 13 institutions and then gradually, got to the number we are today, where we don't have all of the best institutions but we have among the most experienced breast cancer academic research programs in the US. So individuals that have expertise in clinical trials, individuals who have expertise in laboratory research, and many of us who can bridge both camps, be it clinical arena, taking care [00:30:00] of patients, as well as the more fundamental laboratory studies that could potentially have clinical relevance.

What we have done, and we are as you said a center, we function as a center without walls. We have been able with trying to keep us nimble without physical locations, but taking advantage of the tools available for communication, we have hired a couple of individuals who serve as business managers and program managers and protocol coordinators, who are individuals who help keep the glue together. Most of us are academic researchers with expertise in medical oncology, surgical oncology, radiation oncology, laboratory science, and then we bring the people who help. We, scientists, dream of the studies we want to do, but then we need individuals who are going to make it happen logistically so we have protocol coordinators. We also need individuals who have expertise in legal issues, contracting, and finances, because all of this takes effort and I often say, "No money, no mission."

Chris Riback:​Yes.

Dr. Antonio Wolff: ​So we have to be very careful that we put together studies that have, we are able to fund the studies we do. How many people it takes to change a light bulb? Unfortunately not just one person but a small army. But we function without a physical location. We are all based around the US in our academic institutions. Many of us don't receive direct funding from TBCRC, but we come together within TBCRC because it has given many people like me the opportunity to join together within individual working groups and we have monthly phone calls and they happen, usually about eight, nine times throughout the year and then we get all together twice a year in the spring and fall.

And just to give an idea, working groups, we have working groups focusing on Triple-Negative Breast Cancer, focusing on Estrogen Receptor-Positive Breast Cancer, HER2 Positive Breast Cancer. We also have working groups focusing on, we call it Loco Regional issues, so a number or surgeons and radiation oncologists and then recently, we also added an Immuno-Oncology interest group. We get together by phone. We have identified among us individuals with expertise in bringing people together, they function as co-chairs. We have a patient advocate represented in each of these working groups. We have a clinical trial methodologist, statisticians as well, and so we on a regular basis, we propose a new idea that we think could be an important idea in answering questions that we have about issues we are facing in the clinic. Anyone of us can bring a new question, a new idea.

Do we have something here that could potentially be addressed in a clinical trial? Then through an iterative process, an idea is discussed and we think about what would be the best clinical trial design to address that question. Usually, the person who proposes that idea becomes the champion and others begin to offer ideas and collaborate and through over a couple of months, very quickly we may have the opportunity to develop a clinical trial and I think it goes back to the points that we were making before, it is so important to have us more or less on standby.

We know that every month, on the same time, on the same day of the week, we're going to have a phone call and we have organizers and coordinators that help us with agendas and minutes so we know exactly what conversations that may need to happen in between conference calls. And we gradually, this gives an opportunity for junior and mid-career investigators to immediately get feedback without having to wait for a study section to provide feedback in a couple of months, but we almost immediate feedback of an idea, whether this is a good idea, not a good idea, or an idea that needs refinement and then we can take it to a steering committee of about 10 people with more senior individuals with a lot of experience and then we can figure out how best to make sure that the question we're asking is relevant and let's figure out how we're going to fund this through philanthropic funding or sometimes partnership with industry. Because in many cases, they have access or control individual drugs of interest and how ultimately, we make it all come together. It goes back to the same challenges we're having--we need to have people available and ready to handle a new challenge, rather than creating something that doesn't exist.

Chris Riback: ​And that real-time, near real-time feedback from folks who have gone through it before, from top researchers and scientists from around the world. That type of feedback is, has to be invaluable and I can only imagine what those phone calls and that feedback is like. Now, of course, for somebody like you, one full-time job just isn't enough, is it? Let's talk about quickly your own research. You focus on new treatment strategies, as I understand? The development and implementation of prognostic and predictive biomarkers, tissue, blood, imaging in a clinical practice, as well as how to improve the survivorship experience of breast cancer patients and their caregivers. How do those come together or are they unique paths? Although as I ask that, in listening to you, I assume that with you, everything connects, so explain to me how those all come together for you?

Dr. Antonio Wolff:​You're a good observer. I think you're absolutely correct, and so what you just, the list that you read, essentially, they could represent the career of many individuals and not just the career of one individual. I tell my colleagues, I meet with a lot of younger investigators and trainees and I joke that if they look at my publication record, they will have trouble identifying one specific theme. Even when we go around the table, sometimes in meetings and you spending the first couple of minutes introducing yourselves and people raise their hand, "My name is so and so and I'm interested in XY and Z." It got to the point that nowadays when we go around the table in an example like this, I usually raise my hand and say, "My name is Antonio Wolff, and I am interested in anything and everything that gets related to breast cancer." Which is true.

Chris Riback:​Yes.

Dr. Antonio Wolff:​And I think it reflects my background. I have a busy clinical practice. I see patients two days a week and I've been doing this, I finished my training in the mid-1990s, so I've been doing this for 20 plus years. I have patients that have been with me for a long time and I've seen them going through major health challenges, but also major, important life events. I think this is a perfect reminder of what this is all about. It's about people and even in my own personal life, I've had my own health challenges, and I think those are as we get older, we realize that at the end of the day, we are trying to help individuals and help them live their lives the best way possible.

That is the same answer I give to many people who ask me, "It must be so difficult to be a cancer specialist." My answer is, "I don't think I could have done anything different or anything better than what I do." Because that's part of the reason why I made a conscious decision in my training as I was doing, I was a laboratory researcher during part of my training, learning laboratory skills, and the challenges of doing science in the lab.

I very quickly realized I have, I like being around people. It is a privilege that patients give us. They open a window in their lives, in their most personal issues and fears and give us the opportunity to go in there and we have a responsibility then to help them the best way possible. So in this, the trajectory of being a medical oncologist as I am applies to any other medical discipline. The issues are, they cover a whole gamut, because it is, "Do we have the best diagnostic tools? So we can make the correct diagnosis."

So not until then will you find exactly what is going on and then you can come up with a plan of action and then you need to figure out whether the tests are appropriately developed and giving you accurate information and whether that is an imaging test, an MRI, a PETCT, whether this is a blood test, you don't have false positives and false negatives, and you make sure that the tests are really doing what they're supposed to do. Then we have treatments that we need to find out or is this new treatment going to really help or is this treatment going to just have toxicities, be its side effects, but sometimes also financial toxicities and cost.

Do they have not only efficacy but also effectiveness? Do they improve outcomes compared to other treatments, and then we have once you treat someone, I often tell my patients, especially patients with early-stage disease, "I am going to be your doctor for a while, but my hope is to become the doctor in your past so that you can finish your treatment for early-stage disease and I'll be able to help you move on with the rest of your life and hopefully, you will even come to the point that you forget that at one point you had cancer and you can move on and have your relationship with your primary care physician and do everything that you want to do and forget about me and forget about all of this."

Then obviously for some patients, with advanced disease, we may not be able to cure their disease and allow them to forget about this, but we can hopefully improve not only their quantity of life but also their quality of life. So that they spend time with doing what is important for them, whether it is to work, to study, to retire, to see children graduating, growing up, and falling in love to live a full life as much as possible. For patients with an incurable disease who unfortunately will die from the disease, help them during that transition. ​

But the type of work that I do touches, as I said, I am interested in anything related to breast cancer. Anything that could in one way or another improve the quality of the work we do, improve our ability to help people, and that is one of the things, why being a researcher in breast cancer and being a part of this, one example is TBCRC, it is such a privilege because I am surrounded by smart people and it just kind as I often joke, it raises my IQ. Just being, surrounding myself with very smart people who are going to challenge me to do my best is almost like a sports team, a sport competition. We're going to be better, practicing together, training together.

Another point, even within TBCRC and in other groups as well, we have probably, we are one of the groups of the largest number of patient advocates in it. So within TBCRC and in other groups as well, we have probably, we are one of the groups with the largest number of patient advocates in it. So within TBCRC, we have 19 institutions, a criteria for membership is that we need to identify one patient advocate from each institution, to come and join us. When we get together, we have 19 patient advocates in the room. ​All the discussions have a patient advocate present. They split themselves within the various working groups so that, because they're volunteering their time, but they make sure that what we do matters. They keep us humble, as I often say and they call, when they see BS, they call it. When seeing that we are going down on a tangent and getting excited about an idea that may not be relevant to patients now or in the future or we are asking patients to do too much, they tell us. This has been, as I said, incredibly humbling because, at the end of the day, this is about helping people.

Chris Riback:​Listening to you, my estimation is that, well, perhaps at some point as you hope they can forget about having had the disease. I'm highly skeptical that they are able to forget about having had you as their doctor. That doesn't seem quite possible. Dr. Wolff, to close out this conversation, what role has BCRF played in your research?

Dr. Antonio Wolff:​ I am so grateful to organizations like BCRF because they play such a unique role in so many aspects of everything we do. The BCRF has been able to channel the energy and the interest of the public who begins to understand and do their best to try to understand what we do. There is a lot of goodness out there. There is, as I said, cancer, not just breast cancer, but cancer at large and I actually with that every single disease, lung cancer, prostate cancer, had the privilege of having an organization like BCRF and many of the other diseases and physicians are fortunate to have so.

The BCRF has been able to be a conduit by an incredibly talented, inspired, motivated group of individuals, some of them scientists, others not scientists, but individuals with the public good in mind, and to channel the work by volunteers, the work of philanthropists, the work of individuals, many of them who are very wealthy, others who are not. Individuals who are interested in helping, in figuring out, "How can I use my dollar, my resources, and potentially make sure that this is well used. So BCRF brings it all together and providing, developing resources, I often joke, "We know that every vote counts. Every dollar counts and it adds up very quickly."

And with its scientific leadership, people who can pay attention to many of the challenges and health issues and ideas challenge us, researchers, to think about new ways, novel ways in a manner that has not been done before, and with all of that, the BCRF is not simply writing checks and doing fundraising in their various events but they're spending a lot of time with us, listening to what we scientists are saying, doing what you're doing today as a non-scientist, trying to understand what we do and then wearing the hat of the public, helping us put ideas together, not only to explain to the public but also to make sure that the work we do has relevance.

​And so it is organizations like the BCRF are so unique and I think we researchers have an obligation to, as I often say, we need to help BCRF help us by helping BCRF communicate with the public what we do and I think that this is one of the best examples of a public, private partnership, and BCRF not only interacts with the public, they also interact with industry, because they often themselves want to further help researchers but they need to have a little bit of a wall separating their corporate interest from some of the public, scientific interest because of issues of conflict of interest. ​I could go on and on but I think it is absolutely amazing what an organization like the BCRF has been able to do over the past 25 plus years.

Chris Riback: ​Well, that's terrific and it's made up of the folks how described but also folks like yourself who are advancing things, bringing together researchers and scientists from around the world and as you described, working with patients every day. Dr. Wolff, thank you, thank you for your time and most obviously, thank you for your work.

Dr. Antonio Wolff: ​And I'm very thankful that you took the time to listen to people like me because it goes back to our earlier conversation about Twitter: Sometimes we can communicate in a minute, sometimes we need 10 or 15 minutes, but this all about us explaining to people why what we do is so important. So I'm very grateful that you took the time to speak with me today.

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