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Investigating Breast Cancer: Unraveling Metastatic Breast Cancer

Dr. Martine Piccart talks to us about the power of collaboration in metastatic breast cancer research
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Metastasis, the spread of cancer cells from the breast to other sites in the body, is responsible for nearly all breast cancer deaths. Approximately 150,000 men and women are diagnosed with metastatic breast cancer each year. Today, BCRF is the largest private funder of this critical area of research.

Dr. Martine Piccart is passionate about metastasis research and the vital role that international collaboration plays in her work. A BCRF investigator since 2004, Dr. Piccart’s research aims to better understand the origins of metastatic breast cancer and how it evolves. Through the Breast International Group (BIG), she oversees the AURORA-EU study, the Belgium-based arm of the Evelyn H. Lauder Founder’s Fund for Metastatic Breast Cancer Research. Named for BCRF’s founder, the Founder’s Fund is a multi-year, international collaboration. In 2019, AURORA-EU presented findings on the molecular differences between metastatic cells and other tumor cells, revealing a new avenue of research including the potential for targeted treatments.

Dr. Piccart is Professor of Oncology at the Université Libre de Bruxelles, Belgium, and Director of Medicine at the Institut Jules Bordet. She is also the co-founder and chair of BIG, which unites 55 academic research groups from around the world, running over 30 trials, and developing numerous research programs.

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Read the transcript below:

Intro: I’m Chris Riback. This is Investigating Breast Cancer, the podcast of the Breast Cancer Research Foundation and conversations with the world’s leading scientists studying breast cancer prevention, diagnosis, treatment, survivorship and metastasis.

We frequently discuss metastasis, which, of course and unfortunately, is directly related to the overwhelming and challenging role it plays in cancer broadly and breast cancer specifically.

Which is only part of what makes the goal that today’s guest has set for herself so audacious: To understand the origins of metastatic breast cancer and how it evolves.

Why would someone set such a standard? As Dr. Martine Piccart explained to me: She’s frustrated. She is grateful for the advances that have been made to date, for sure – the trials, drugs, therapies, approaches. She also wants more. Like everyone else, she wants the metastasis to end, and to get there, she wants a molecular understanding of the disease. In this outstanding conversation, she explains her passion and how she plans to get there.

More about Dr. Piccart: She is Professor of Oncology at the Université Libre de Bruxelles, Belgium, and Director of Medicine at the Institut Jules Bordet.

She also is co-founder and chair of the Breast International Group, which unites some 55 academic research groups from around the world, running over 30 trials, and developing numerous research programs. As you’ll hear, AURORA – a study to better understand metastatic breast cancer – is the most ambitious of these.

Dr. Piccart is President of the European Cancer Organisation, past-president of the European Organisation for Research and Treatment of Cancer, immediate past-president of the European Society for Medical Oncology and has served on the ASCO Board. She is author or co-author of more than 470 peer-reviewed publications, and among her awards includes the Jill Rose Award, William L. McGuire Award, Umberto Veronesi Award for the Future Fight against Cancer, the 2013 David A. Karnofsky Memorial Award, among others.

Chris Riback: Dr. Piccart, thanks for joining me.

Dr. Martine Piccart: Thank you for giving me the opportunity.

Chris Riback: Can we start with your career goal? I read that it is to understand the origins of metastatic breast cancer and how it evolves. Now what really interests me about that is for most of us, but perhaps too many of us, our goals usually center on the end of the journey, rather than trying to understand the beginnings. Your mind or at least your approach seems to work differently, why is that?

Dr. Martine Piccart: Okay. Let me try to explain to you what is behind. I have been treating women with breast cancer now for 30 years, and I am still very frustrated that we are unable to offer cure for women whose disease relapses in distant organs. Clearly I've seen progress in the disease with the development of some great medications. These drugs help patients to live longer and live better many times with the disease. But at the end of the day, we don't cure any of these women. My frustration comes from the fact that we basically understand nothing about metastatic breast cancer. We don't know why the disease in some patients, for example, comes back in bones and stays there for several years and suddenly one day, it will go to the liver, the lungs and obviously become life-threatening. Then in other patients, the disease will immediately attack different organs at the same time.

These patients will present with disease in the liver, in the lungs, sometimes in the brain and in the bones. Our molecular understanding of this disease is minimal and the clinical trials run today, the most efficient ones, are run by pharma. Pharma is of course, taking metastatic breast cancer as a kind of laboratory to test new drugs. This is good, this is essential because this is also why we've better drugs certainly today than the ones available when I started my career 30 years ago. But what I think is clearly missing is the molecular understanding of this disease. We do have fantastic technological tools to try to understand what's going on, but we have never applied them in a consistent fashion and on very large number of patients. Because what complicates the job is that breast cancer is not one disease but several very different diseases.

We need therefore, to do the study on relatively large subgroups of patients. When I had this idea that it was time to do something better for these women, I was extremely lucky that I could very easily convince the Breast Cancer Research Foundation that this was a very worthwhile research project. But you know when you get money to start something, it helps you to convince other organizations to help you.

Chris Riback: Of course.

Dr. Martine Piccart: The project is the following one. We want to study at least 1000 women presenting with metastatic breast cancer. What we are going to do for these women, and by the way, the program has already entered more than 800 women, so it's moving very nicely forward. We want to go back and recuperate the primary tumor, the original tumor in the breast. Then we want to collect tissue from a metastatic lesion, in the liver or in the lung.

Chris Riback: So the place to where the cancer has traveled?

Dr. Martine Piccart: Exactly. Then there is this other fantastic opportunity which is to just take blood, isolate plasma and there with these new technologies look for genetic material that the cancer cells are releasing in the circulation. Now we can of course detect this genetic material, distinguish the material from the genetic material that normal cells are also spreading in the blood. We can then study this genetic material in-depth so we can find aberrations in the genetic material like mutations. What the program has, which is really unique because there has been several attempts already to confront the analysis of the primary tumor with the analysis of the metastatic lesion using Next Generation Sequencing, that has been done by several teams. But what all BCRF funded program overall does, which is unique, is to follow these women to all their sequential therapies to collect the information on whether or not these therapies have been helping or have not been helping.

Essentially, we followed all these women until the end. At each disease progression, we sample blood once more. We do sequential sampling of plasma to look at the evolution of the genetic material that the cancer cells are spreading. Of course, our hope there is that by studying the longitudinal evolution of the molecular landscape of breast cancer, we might get a better understanding of which changes are driving this metastatic process. Possibly and that's my dream, we could even design strategies to even prevent the metastatic disease to take place. For sure, we are going to find more intelligent ways to treat women with metastatic breast cancer, I'm confident in this. But we might also go one step further and start thinking about some clever preventive strategies. You know that today to prevent the cancer from coming back, we gave to many women chemotherapy or endocrine treatment, or some targeted treatments.

But here, I'm thinking that we could become even more specific and that's what is so exciting about this program. I can tell you that when we ask women whether they are willing to participate, they are all enthusiastic. Even though very often they understand that they might not necessarily benefit from the knowledge that you are going to acquire to this program. But they fully understand that it could help possibly their daughters if they get the disease. It's a very exciting program that was very difficult to initiate because it's a European-based research program, where we have the analysis centralized and we have currently over 60 hospitals participating across 12 countries. At the beginning of course, it was difficult. The physicians got a little bit discouraged because sometimes when you do a biopsy of a metastatic lesion, well, you don't do it well and then the tissue you get is not usable.

Dr. Martine Piccart:  Anyway, there were a lot, a lot of barriers. But after two years, finally the program started to run smoothly. Today, we have every month, 20 fully evaluable patients entering the program. We are not even thinking that we might try to go a little bit beyond 1000 women. Again, because breast cancer is complex and is divided in different entities. Of course, we want to get solid knowledge about each of these entities. That's where we are today. The program is clearly not finished. We have already done an in-depth analysis of the first 381 patients entered in the program, and we are now working on studying the next 300 in-depth because you have to realize that we are not only looking at genetic aberrations. We want to go beyond that, we want to look at the stages of the immune system. So we want to study the microenvironment of the cancer cells in the metastatic lesions. We are also collecting frozen material to do RNA sequencing.

It's going beyond just DNA and trying to finally, perhaps, I hope understand better what is going on and what we can do these women and to offer them hope. Call the program AURORA, because it refers light in the darkness, a program that will offer hope for the future.

Chris Riback: That is an excellent, excellent overview. I understand why you have the end dream that you have and perhaps you will get there. I understand as well the steps in between that you hope and frankly it sounds like expect to reach. There's so much that I want to follow up with you on so many of the things that you just discussed. One of them is your use of the word evolution, because that was the image that was coming to my mind as you were discussing the progression and how you are looking at that initial tumor. Then you are looking as well at the lesion, the metastasis that has occurred someplace else in the body. Then you're continuing to look as the disease progresses hopefully does not progress of course, but as the patient continues to go forward. That sounds like an evolution, and I can imagine that folks may be wondering.

So you can describe in a sense how metastasis works or that it works. You can describe what happens, the cancer travels from one part of the body to another. I think that folks can understand that you don't have a cure for that yet, obviously, that's the work that you're doing. Why is it so challenging scientifically to understand the why? If so many, and you talked about that frustration, if so many people are looking at this and thought about it, and it is such a tremendous challenge, why is the why so hard? Even if we can't fix the why, scientifically, why is it so hard to get that handle on exactly why the metastasis occurs?

Dr. Martine Piccart: Well, I will give you my personal opinion on this. If you look at the research currently done in metastatic breast cancer at all the hospitals, you will very quickly realize that this research is driven by the pharmaceutical industry. Pharma develop drugs and then they think about what is the clinical situation where my new drug can really show an improvement beyond what is available today. That approach means already in itself that you are not looking at the evolution of the disease from the beginning to the end. You are just studying with your new drug a certain clinical situations. For example, is my drug better than what is available today after patients have failed a first-line treatment for the metastatic disease? All the research is done in this way and it is supported by pharma. So investigators, clinicians of course, are desperate about new drugs. They want to go to participate into these trials and clearly, it's important, but the result is also that all the other aspects are neglected.

Nobody has been thinking, why are we seeing an evolution that is, at the end, little? Why is this evolution taking two years in some women and 17 years in others? These kind of in-depth thinking has not happened. Then even if it happens, who is going to pay for that? This is exactly the situation where foundations like BCRF, we could simply not do the work even if you are enthusiastic about the work. I think it's part of what I call academic initiatives without commercial interest, there is no obvious commercial interest, at least in the first place. I imagine that if we find some new things in this program, there could potentially be some commercial exploitation of the findings. But at first glance, this is a very cerebral program and I am not sure that too many commercial enterprises would be interested in supporting it.

I think it's understandable that we have not seen these kind of effort happening before. I've seen that some of my colleagues in the UK are doing a similar program for lung cancer. It's likely to happen for other cancers, but it just beginning. At least in breast cancer, I have not found a similar program yet in the world

Chris Riback: Well, I'm sure if there were one, you would certainly know about it.  Another area that you discussed that as I have read about you makes total sense that it's something that you would incorporate into a project such as AURORA. That is the coordination with multiple doctors and hospitals, and countries. Tell me the importance of that. You have a keen interest, it seems to me it's in fact part of your core philosophy that to make the advances needed in cancer and breast cancer in particular, this is going to be a global... I guess if not global, certainly a Pan-European or a Pan-regional, but it's going to be a global effort. It's not going to occur necessarily just with one person. That seems to be core to who you are and how you approach what you do.

Dr. Martine Piccart: Exactly. Well, I have two personal reasons for that. One is that, when I was 27 years old, so I was starting my studies to become an oncologist, my mother got breast cancer and there I suddenly became aware that they were very important questions regarding the optimal treatment of women with breast cancer that had no answers. I became impatient. I thought, "How is it possible that these essential questions have no answers?" Then the second reason is that of course I am based in Brussels, so I'm Belgian and Belgium is a small country. It is a small country, but it's very open to Europe as you know, because we have the headquarters of the European Union in Brussels. I immediately got interested in international collaboration. I started to work for several years with EORTC, which is a European Organization on the Research and Treatment of Cancer.

I could really feel the power of international collaborations. Of course it's difficult, you lose time at the beginning because it's cumbersome, the administration is very heavy to get all the countries aligned. But the time you lose at the beginning, you recover so efficiently after, you can really do things so much faster. I think patients today, they have not a lot of time to wait for us to become efficient in research. I am really enthusiastic about international research and I have indeed been looking for international collaboration during my entire career. You are right.

Chris Riback: Yes. It is evident in your history. I'm curious, when you were 27 and you got the news on your mother, were you already in science, were already a researcher, a scientist, a doctor?

Dr. Martine Piccart: Yes. I was starting, so I was a physician but I was doing my training to become a medical oncologist, and I was working in a lab to do a thesis on resistance to endocrine treatment. Yes, I was already involved. But I can tell you, I got upset because there were very important questions such as; how many cycles of chemotherapy should my mother receive, and this is a very unpleasant and toxic treatment. At that time, it was not known and in fact, my mother got a one-year treatment with chemo, which we never, don't do anymore today. Because it has been shown in clinical trials that six courses is enough. Then came the question about the duration of endocrine treatment. All these questions that are so important for women because of the burden of the treatment on your daily life, they had no answers. Then I looked and I found clinical trials of a few hundred patients here, a few hundred patients there. All these trials were completely underpowered to answer the question.

Anyway, that gave me the idea that I had to create a very large breast cancer network, which is the Breast International Group.

Chris Riback: Yes. Yeah, it's an extraordinary network. The last thing that I want to follow up with you on from your opening statement and just terrific description of everything that is happening. You talked about the women's willingness to participate. I can tell you, I have heard that in so many of these conversations, there's an all truism almost around the women and the men, the people who participate in these programs, in trials. It is very much a sense, nobody is unaware of the challenges, but it's very much about doing this for others. What is it about that community, what generates that? Do you believe now that you've looked at it for so many years, what generates that sensibility in that sense within that community?

Dr. Martine Piccart: That's an interesting question. Of course, I am not sure I can give a broad answer because I am only treating women with breast cancer so I don't know much about other cancers, in particular, cancers happening in men. But for the women, a clear motivation is of course that, if you get breast cancer, well, the risk for your daughter is there. It might not be a huge one if the disease is not genetic, but the risk is there. That to me easily explains that women with this little disease, metastatic breast cancer, have this fairly strong desire to contribute to something that might make things a lot better for their daughters. It's the explanation that I have out of my experience, let's say.

Chris Riback: Yeah. Well, I do hear about it quite often. You see it and you see it in the women who participate, and it's remarkable. Dr. Piccart, to close this conversation, in listening to you, I'm struck by what feels to me to be a paradox within you but maybe there's a reason or maybe you'll explain it. On the one hand, you do not seem to be a very patient person. You discussed your frustration, you want action, everyone wants action, you want action and you are frustrated. In fact, I came across, I have to find it here but there was a quote I found of yours from 2015. You said the same thing I heard as a 2015 video of you. Where you said you were disappointed in much of the research output because very few biomarkers have been validated for their predictive value.

It struck me when I heard it there. It's striking me when I'm hearing it now. At the same time, you are running a project and working on a project, AURORA, that requires incredible patience. You are watching a disease within hundreds, maybe thousands of people over a period of years in order to work your way backwards to the origins of the disease. How do you reconcile those two sides of you that I'm hearing, the frustration? The fact that on some level, you perhaps and we're all grateful for this, are not very patient. On the other hand, you're running and working on a project that requires incredible patience.

Dr. Martine Piccart: Ah, that's another interesting question. Well, what I can tell you about AURORA and what gives me a lot of excitement and probably also helps me to be a little bit more patient is that of course, we are not going to wait until we have accumulated all the data on these 1000+ women. We are analyzing the material and the clinical data in badges. Already with the first analysis we did, I learned things that I didn't know, and that is what excites me. For example, we found that one in four metastatic breast cancer is displaying alterations in genes that are very important to repair DNA damage. That indicates that probably we are not using, at least for these women; one, four, we are not using the best possible cytotoxic agents that we have to treat them initially. If you look a little bit at guidelines for the treatment of metastatic breast cancer, you will see that the preferred regimen you should start with is a toxin.

Okay, so a general statement, which of course cannot be true because it cannot be the drug that fits the shoes of all the patients, it's impossible. I'm starting to realize that if we get some better knowledge of what's really going on in the cancer cells, we might become a lot better at choosing the best drugs. The best drugs if you have alterations in DNA with their genes, could be, for example, all drugs that are not too much excited about anymore, like Cytoxan. Cytoxan is a very good drug if you have these kinds of alteration. Cisplatin is another good drug. Usually, they are no longer part of the first, even not the second line choice of physicians. The way we practice medicine is okay, but I still have the feeling that we could do a lot better. This program will help us become better doctors.

Chris Riback: Well, I'm sure that it will. I'm not sure that ... You are a great doctor to begin with and luckily for the rest of us, and impatient one. We appreciate your lack of patience and your drive in your work, thank you. Thank you for the work that you're doing, thank you for taking the time to talk with me today.

Dr. Martine Piccart: Thank you.

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