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Read the full transcript of the latest episode of BCRF’s official podcast hosted by Chris Riback and featuring Dr. Shelley Hwang

Chris Riback: Dr. Leone, thank you for joining me. I appreciate your time.

Dr. Jose Pablo Leone: Hi, Chris. Thanks for having me. I appreciate the invitation.

Chris Riback: So with Father’s Day in the air, would you give us the context and the realities around male breast cancer because many people are not even aware necessarily that it exists? So how does it occur, and what are the risk factors?

Dr. Jose Pablo Leone: Yes. So breast cancer in men is overall a rare disease. It happens in about 1 percent of men, and it’s also 1 percent in the United States of the number of breast cancer cases that are diagnosed annually. Risk factors for breast cancer in men include older age. It includes sometimes exposures to estrogen or testosterone previously, hormonal differences in the balance between the estrogen and testosterone, some genetic conditions such as Klinefelter syndrome, for example. There’s also risk factors associated with prior exposure to radiation or carcinogens that can be seen as well.

Chris Riback: More so that radiation or carcinogens, is that more of a percentage-wise risk factor with male breast cancer than other breast cancers, or like other cancers, I guess, I should say, it also is a risk factor here?

Dr. Jose Pablo Leone: It’s a great question. To my knowledge, the evidence that is out there is not supportive that the carcinogens for the risk of breast cancer in men specifically have a higher relevance than in other cancers.

Chris Riback: Got it.

Dr. Jose Pablo Leone: In fact, we see breast cancer in men with all sorts of factors, including the carcinogens, but also in general as well.

Chris Riback: The others that you mentioned. So in preparing for this conversation, I read this from Dana-Farber in a piece that you medically reviewed, though I don’t think you necessarily literally wrote it, but I think that you reviewed it, that over the past 30 years, outcomes have improved dramatically for women in breast cancer. There are many new treatments including hormone therapies in CDK4/6 inhibitors. In contrast, there has been no improvement in the outcomes for men with breast cancer, and current guidelines don’t support the use of newer therapies in men. No improvement in 30 years. Why is that, and how is that?

Dr. Jose Pablo Leone: So that is a study that we did a few years, a couple of years ago actually on a study that we published in the Journal of the NCI, of the National Cancer Institute where if we think about the history of breast cancer and the treatments that we have had for breast cancer, the majority of men are treated with mastectomy, and they are offered Tamoxifen. Those are treatments that we have been using in the treatment of women with breast cancer for more than 30 years, and so if we keep doing the same thing, we will probably continue to have the same results.

With that hypothesis, we did an analysis of SEER data to try to see whether outcomes for men with breast cancer have changed in the last 10, 20, 30 years. So we went back all the way to 30 years, and what we found is that outcomes have not improved, unfortunately, for men with breast cancer during that period of time as compared to the outcomes that we know have improved in women over that period of time.

We did notice, however, an improvement in overall mortality in men which is consistent with the improvements that we have seen in the healthcare overall and in the survival overall. So the longevity of the male population has gone up over time as it has been the case for the female population as well. So we have seen that, but we haven’t seen the improvements in the outcomes for breast cancer specifically. So looking at breast cancer specific mortality, those have not improved.

Chris Riback: So I will ask you, of course, about your ETHAN study, but before we get there, more of the context and the description around this because, again, I think it’s a topic that people don’t hear enough about and don’t think enough about. Why is it so challenging to treat breast cancer in men?

Dr. Jose Pablo Leone: So there are several aspects that are challenging. One is the fact that the disease presentation is overall uncommon, and when a disease is uncommon, it’s harder to gather high-level evidence on what to do. So, in our field, the highest level of evidence comes from randomized controlled trials, and those trials usually require a large sample size. It’s hard to get a large sample size of men with breast cancer to randomize them as we would normally to try to find out what is the best treatment option for the given question that we’re trying to answer, and that is one of the biggest challenges.

Chris Riback: I was struck as well by the line that the treatment of male breast cancer, which is almost always estrogen receptor positive, remains challenging because there is virtually no data on the optimal endocrine therapy to use in men. I know we’ll start to get into your research in a moment, but first, why is there virtually no data on the optimal endocrine therapy to use in men? Is it because of what you just said a moment ago, and why aren’t they getting some of the newer therapies and other treatments that are standard for women?

Dr. Jose Pablo Leone: So it’s a great question, and part of why we have very limited to no data in some of the newer treatments is in part because for some of the treatment options, we continue to do what we have known has worked best so far. For example, the use of Tamoxifen, for example, or the use of mastectomy as a surgical approach. Because we keep doing the same thing, we do not generate data or enough data on alternative options for men. At the same time, for newer treatments such as CDK4/6 inhibitors or other targeted therapies that have come to the front line in the treatment of breast cancer in recent years, there is the problem that either some of those therapies excluded men or they do not have enough representation. Therefore, the level of comfort that we may have about some of them may be less.

That said though, there is certainly the possibility of extrapolating with caution many of the findings that were generated in trials that enrolled primarily women to the treatment of male patients if we do feel comfortable about the biologic mechanism of how those treatments work, particularly for endocrine therapy options and if we don’t worry about differential toxicity profiles between men and women when we use those agents, and that does happen. So, for example, there have been several smaller studies that have reported the use of, for example, CDK4/6 inhibitors for the treatment of men with breast cancer despite the fact that virtually, no men were enrolled in the first generation of trials of CDK4/6 inhibitors for metastatic breast cancer.

Chris Riback: “Extrapolating with caution.” What a phrase that is. On the one hand, yes, of course, it’s part of the scientific process and research that one takes data from one set and one set of results, outcomes, and tries to extrapolate to other circumstances. But as you just said, it has to be done with caution, with a bit of uncertainty, and I’m sure that it’s the goal of you and people like you to do the best you can to take that uncertainty away, to bridge that gap as much as possible for patients and people to come. So you and your team are now trying to address portions of that, so let’s talk about ETHAN. What is ETHAN? What’s your hypothesis? What’s the current status of your work?

Dr. Jose Pablo Leone: So the ETHAN clinical trial is a clinical trial that we are running in very close collaboration, and thanks to the support from BCRF through a cooperative group called TBCRC which is the Translational Breast Cancer Research Consortium. The ETHAN trial is a trial that is enrolling men with operable breast cancer stage 1, 2, 3 with hormone receptor-positive disease and is randomizing them to different endocrine therapy options of which Tamoxifen is the control arm because Tamoxifen is our current standard of care for the treatment of male breast cancer that is hormone receptor-positive.

We are comparing the Tamoxifen arm, the control arm to other options that have been known to be successful in women, including aromatase inhibitors alone as well as aromatase inhibitors with [inaudible 00:10:38]  suppression, and with and without the use of CDK4/6 inhibitors specifically on the studies, the use of Abemaciclib. So on the study, we’re trying to catch up with, essentially, 40 years of drug development in endocrine therapy for breast cancer which is what we know today for women with breast cancer, and we’re trying to use drugs that we know have been successful to hopefully be able to provide, at minimum, additional treatment options for men and at best, treatment options that actually improve outcomes for our patients.

It’s interesting because these medications, as it’s well-known for women with breast cancer, they have side effects, and the toxicity profile is different between endocrine therapy for a woman versus a man. For example, Tamoxifen can cause erectile dysfunction in men. It can cause blood clots both in women and men, but men have a baseline higher tendency of blood clots than women do. So it’s side effects like this that makes us wonder, “Could we use a different option?” The use of an aromatase inhibitor in men, for example, on the toxicity profile, can be quite attractive because aromatase inhibitors do not have a risk of blood clots as much as Tamoxifen does. They don’t appear to cause the same degree of erectile dysfunction as Tamoxifen can cause in some men.

Aromatase inhibitors can cause a risk for osteoporosis in postmenopausal women, but this is lesser of a risk in men, the risk of osteoporosis. So it’s an option that may be very appealing to men, particularly men who are having side effects. Yet, we don’t use it routinely in clinic because we actually don’t know whether it works or not, and so we’re hoping that the ETHAN trial will be able to give us the answer to that question as well as to try to understand whether the best endocrine therapy options that we’re thinking about for men should be different than the ones that we’re using currently. So the trial opened at Dana-Farber [Cancer Institute] last October, and so far, it has enrolled four patients. We also have the study currently open at MD Anderson Cancer Center, at Mayo Clinic in Rochester, and at Georgetown as well. We’re hoping to open it to three more sites in the very near future in the next couple of months as well. So we’re very excited about the study and looking forward to seeing the results.

Chris Riback: Why the multiple locations? Is that to get an increase in the end and make sure that you get to a sufficient number of participants?

Dr. Jose Pablo Leone: Yes. So I think the multiple locations will help us with several things. One is with the speed of enrollment, hoping that we will be able to enroll the patients faster, and finish the study sooner, and provide the results to the population sooner than if we did it as a single center. Another thing that we think will be helpful on the multi-centric approach for the study is to have, hopefully, more diversity of the participant populations and also, to give access to the study to populations that otherwise will have to come to, for example, Dana-Farber if the study was to be run only at Dana-Farber.

Chris Riback: What’s your expected timeframe for the study? I know it’s impossible to say because it all depends initially, I guess, on getting the adequate number of participants, but what’s your expectation?

Dr. Jose Pablo Leone: So we’re hoping to finish the enrollment in three years total for the study.

Chris Riback: Wow.

Dr. Jose Pablo Leone: I think both the collaboration that we have had with advocacy groups on this as well as the support from our colleagues we’re hoping will help us to deliver on this.

Chris Riback: I’m sure that you do, and yes. I mean, it’s a lot of outstanding organizations that you’re working with. Yes. I assume that that’s obviously hugely significant to be able to get a wider, more diverse range of types of patients and participants from different backgrounds, and socioeconomic classes, and races, et cetera. I assume that that’s part of your goals. I wonder, is there any extent to which people in those different locations also have different lifestyles. Maybe some are more urban. Maybe some are more rural or other factors. Is that something also that you will get to factor in or you can’t really look at that because you want to stay focused on the various attributes that you’re looking to study?

Dr. Jose Pablo Leone: So it’s a great point, actually. The sample size of the study, which is a total of 60 men, is unfortunately small to be able to look into more specifics of the different types of patients that we will be enrolling. However, we’re hoping at the same time that the type of patients that participate in the study will be hopefully diverse enough at minimum on clinical characteristics in terms of age of diagnosis, the type of breast cancers that they have in terms of the stage and presentation, hopefully different backgrounds, and as you said, different lifestyles. That, hopefully, will give us a sense of comfort in that the information that we’re getting will be applicable to the male patients that would normally be seen in the community.

Chris Riback: I want to just talk with you about another key part of interest and work of yours because it was very interesting to me, and that relates to brain metastasis in breast cancer patients. I know you wrote a paper, I believe it was just last November, titled Survival Analysis of Patients with Brain Metastases at Initial Breast Cancer Diagnosis Over the Last Decade. How did those disciplines get connected for you?

Dr. Jose Pablo Leone: So that is a very good point, actually, because there are topics that at first glance, they appear to not have much in common. So, in my case, when I was in fellowship, I became interested in brain metastasis because it was a very challenging area. The prognosis back then was extraordinarily poor, and I just couldn’t believe that we couldn’t do any better.

Chris Riback: Yes.

Dr. Jose Pablo Leone: It was frustrating to me that we had no better options, and that got me interested into that topic. The male breast cancer interest for me started when I started my first job, actually, at the University of Iowa and the VA Hospital at Iowa City when I started seeing male breast cancer patients, and I felt embarrassed that I felt I didn’t know enough about the treatment as I did for female breast cancer. It got me interested in trying to understand more the disease, and as I was learning more, I was even more interested as how do we know these things, and hoping to contribute to the field to increase our knowledge, and therefore, doing research to try to fill the many gaps that we have in the case of male breast cancer.

Chris Riback: Why do you say that breast cancer is many diseases in one?

Dr. Jose Pablo Leone: Because there are very different presentations and also, very different courses that breast cancer can have. There are patients who have breast cancer who will never have any recurrence or any problem whatsoever. The cancer will never metastasize even if the cancer is on the larger side at the beginning, if the stage of presentation is higher. Contrary to this, there are situations where patients will present with smaller tumors, and the tumor may develop a relapse in a very short period of time. That relapse may not only be short in time, but also may be to visceral organs that are of critical importance. Then, there is a question of, “Why does one situation look so different than the other?” It almost looks like two different types of cancer altogether. At the same time, when we do the treatments for breast cancer, we see that the responses to the treatments that we have are very different depending on the number of characteristics of the tumor and the patient, and it also makes it appear that not all the tumors are all the same.

Chris Riback: Is that ultimately frustrating to you, or perhaps is it hopeful to you? Is it frustrating that there’s so many factors, and permutations, and outcomes, and possibilities, and reactions, and each person is different as you just explained, or is there hopefulness to you in that that, “Well, there are people who obviously have very challenging outcomes, but there are others who have less challenging outcomes. Maybe there’s something about the less challenging outcomes that we can learn and apply to the more challenging?” How do you balance frustration and hopefulness in what you do every day, I guess?

Dr. Jose Pablo Leone: Yes. So I will tell you I share much of that sentiment that you just said because when we see a patient who does very well is very encouraging. To see somebody get cured of breast cancer is one of the most happy moments you can see as a doctor for me personally. Yet, you could have had the exact same approach, the same treatment recommendation to a different patient, and that patient, unfortunately, does not do as well, and that is very frustrating when we see that. Another part that is very frustrating is that we don’t always know why that happens. In fact, I would say most often, we may not know why that happens, why that is so different between the two patients. It’s an area that needs a lot of research to be done to understand not only why those differences exist, but also, how do we make them disappear? How can we actually cure all patients with breast cancer, the ones who were destined to do very well, but also the ones who were destined originally to not do so well? Hopefully, we have a treatment that will change that destiny to a cure.

Chris Riback: So let me ask about you. How did you get into this? I mean, going back as a child, did you grow up in Argentina, or is that where you did your studies? Obviously, you wanted to work in an environment with a similar climate, so you ended up in Iowa which is very well-known to have temperatures just as warm as Argentina. I’m sure you didn’t miss at all, but how did you get it? Was it always science for you even as a kid or other interests?

Dr. Jose Pablo Leone: So I come from a family where my father was a doctor, and I’m sure that influenced my decision somehow. Also, my sister is a doctor, and both of them, oncologist. In fact, I’ve worked with them very closely over the years. To me, personally, what got me interested in medicine first is the ability to help others and to help others who are in need at a moment where they need to improve their health, and oncology is an area where although it’s very specialized and is only getting more and more specialized, you still have the opportunity to think about the patient as a whole. So similar to what you would do if you were a primary care physician.

So I like the approach of general medicine. I do like to focus on a specialty, and I see oncology as an opportunity to combine both into taking care of a patient who, when the patient comes back to clinic and has a symptom, we have to think about what could the diagnosis be, whether it’s a recurrence of the breast cancer or a different condition. Then, on a scientific level, oncology, in general, is a field where there is a tremendous opportunity to do research from clinical trials, newer treatments, also, a lot of new information coming in from genetic and genomic alterations that can make a big impact, and it’s a field where it’s always something to look forward to for improvement which, to me, is very interesting.

Chris Riback: Had you ever experienced anything like in Iowa winter before landing there?

Dr. Jose Pablo Leone: No. Never in my life before.

Chris Riback: Oh, it’s cold. I’ve been in Iowa in the winter. It can get really, really cold. To close out, Dr. Leone, BCRF. What role has BCRF played in your research?

Dr. Jose Pablo Leone: So I’m forever grateful for BCRF and for all that what they do and for the support that they have provided me. Without the support from BCRF, the ETHAN trial would never have happened. Before getting the support that we received from BCRF for the ETHAN trial, we had applied for support from other sources including industry, and we, unfortunately, would not be able to get the support that we needed to conduct the study had it not been for BCRF efforts. I just want to highlight that because this is something that many people will say that, “Had they not been funded by X organization or X resource, their research would not have happened.”

That is true in my particular case as well, but I want to highlight one thing that I think is more important which at least for me is that the research that we’re doing which we’re hoping to help the patients, particularly patients who do not understand how do we not know more for their treatment, which is specifically men with breast cancer, is research that virtually not many other places will want to support. BCRF has looked aside from the reasons of why other places would not want to support those studies and has yet provided the support, supporting the idea behind the study, and believing that this was something that can be impactful and that can be helpful to our patients. I have seen that from BCRF not only for my particular area of research, but also, many of my colleagues and investigators that have had their ideas and their projects supported by BCRF who are projects that are incredibly important and that otherwise would not happen.

And another thing that BCRF has been incredibly helpful with is a program that they have which is a drug collaborative research program where BCRF has partnered with different industries to bring a bridge of the availability of newer therapies and the academic interest in finding the best patients who will benefit the most from those treatments. I think that’s incredibly helpful, actually, because what happens is that BCRF has an enormous amount of knowledge about what is scientifically helpful and also valuable from a patient perspective from the various people that collaborate with these patient advocates, scientists, scientific advisors. So they will connect with industries to partner with them, and then hear proposals from scientists so that the collaboration can happen in a much more integrated way where otherwise it may not happen at all because the industry partners may not see the value that BCRF is seeing and is making possible. It all comes down to making it possible which is what BCRF is facilitating, and that is, I think, immensely helpful.

Chris Riback: That’s wonderful. Well, thank you, and most importantly, thank you for your time, and thank you for the work that you do, and the studying, and the care of patients every day. Thank you on all.

Dr. Jose Pablo Leone: Thank you very much, Chris. I very much appreciate it.