My conversation today is with Dr. Nancy Davidson, simply one of the leading breast cancer researchers we have. Dr. Davidson characterizes herself as a physician scientist. She directly connects the human aspect of what she does, working with patients, with her research that has delivered key discoveries that are now common practice in breast cancer care. Dr. Davidson’s current research dives into one of the most challenging areas of breast cancer or any cancer, really, recurrence. Dr. Davidson is looking at how and why cancer recurs, and importantly, how might that recurrence be prevented in the first place.
This is the most recent of a lifetime of highly consequential research, care, and discovery that’s defined Dr. Davidson’s career. Some highlights: Dr. Davidson is senior vice president of the clinical research division at the Fred Hutchinson Cancer Research Center in Seattle. She is president and executive director of the Seattle Cancer Care Alliance as well as the head of the Department of Medicine in the Division of Medical Oncology at the University of Washington. She is the immediate past president of the American Association of Cancer Research and a past president of the American Society of Clinical Oncology. Dr. Davidson is a member of the BCRF scientific advisory board and has been a BCRF grantee since 1998.
We discussed all of that as well as one question from her father years ago that may have denied society a modern day Indiana Jones but instead gave us one of the leading physician scientists focused on cancer and breast cancer that we have. Here’s our conversation.
Chris Riback: I appreciate it. I saw a quote of yours or a I saw a video of yours and you said … The line really struck me. “Cancer is a challenge and an opportunity,” you said, “And something we will be able to overcome.” Tell me about that. Tell me about the challenge, tell me about the opportunity, and I’m sure everyone would like to share the optimism so tell me about it being something that we will overcome.
Dr. Davidson: Absolutely. I passionately believe in all three of those parts. First, it is an opportunity in the sense that we understand so much more now about cancers, because there’s so many different types, than we did some years ago. We’re on the cusp of being able to take that knowledge, to bring it forward. That’s where opportunities lie. I think we’re going to be able to overcome it in the sense that I believe that we will continue to take cancers to a point where some large number of them will be curable. I hope an even larger number of them will be preventable and there will also be a subset which will be what we would call controllable. Something where the patient and the cancer can hopefully live harmoniously, perhaps with therapy, until a point when some other health problem intervenes and may threaten their lives.
Complicated series of diseases where we’ve unlocked so much of the mysteries. Where we’re able to begin to take them forward in an opportunistic way, and with the goal of being able to overcome cancer in one of those ways.
Chris Riback: Let’s talk a little bit more about unlocking those mysteries. One of the ways you do it, and you mentioned this in that same video, is by your being a physician scientist, is how you characterize it. How do you connect the hands-on work that you do with patients with the work that you do in the research lab? Obviously it was clear that that connection was very meaningful to you. It really felt like it was meaningful on a couple of levels but why don’t you tell me about that? What does it mean to be a physician scientist?
Dr. Davidson: It’s the best job in the world. It gives you the opportunity to be able to care for patients who are in need and to have an impact on their lives. To make observations about what’s going on with them and their cancer, and to think about how you can take those observations back to a research setting and try to tackle those questions and then bring that information back to the clinic again, so that going back and forth between the lab and the clinic is so powerful to allow us to connect those great insights that were making in the lab with the lives of people.
For me, as an example Chris, the relative beginning of my career I was very interested in the challenge of hormone therapy. Many women with breast cancer have tumors that are susceptible to endocrine therapies, but some women don’t and they don’t because their tumors don’t make the estrogen receptor protein or the progesterone receptor protein. I got interested in why was that? Because these women were not able to take some of our classic therapies. That led me back to the lab and down this long path of looking at something called epigenetic gene regulation. A kind of way that the estrogen receptor expression might be regulated in breast cancer cells and whether there was a way that we could modify so that we could make it more approachable again as a target.
This was an example of a problem in the clinic, we can’t use our hormone therapies in women with estrogen receptor negative breast cancer, then going back to the lab to try to tease out why some of these tumors lack the estrogen receptor.
Chris Riback: When you think about your current work, that approach and understanding, you indicated it was at the beginning. It was at the relative beginning of your career and we all know how the things we learn at the beginning of a career can really shape an approach or a philosophy. Did what you just described and the discoveries that you made through that process, was that really meaningful, I guess, in terms of shaping your approach and the subsequent discoveries that you’ve made?
Dr. Davidson: I think so. I think that this opportunity to learn from our patients and try to bring back to our patients is so very important to me. I wouldn’t pretend to say that the laboratory work that we started at that time ended up where we thought it would. Not surprisingly, cancer is a complicated set of diseases. The underlying biology is very, very complex and so where we started was not necessarily where we ended up. But I think that we did make insights that helped us to understand hormone resistance, the ways that breast cancers might not respond to hormone therapy. This allowed me to take that back and be able to participate in trials that look at hormone therapy and how best to give it. To look at ways that we might be able to reverse hormone resistance and some have been successful, some not quite so successful. But maybe what we would call productive failures. A good idea that didn’t turn out right where you learn something and you know to go in a different direction.
That back and forth between the lab and the clinic is so important in biomedical research generally these days. It’s incredibly important in cancer research and breast cancer is really, I think, it’s been at the forefront of that for so many years. That’s one reason why I went into breast cancer, was that even early in my career I could see how the biology we were learning about in the clinic was going to have profound impact on the women and men who were suffering from breast cancer.
Chris Riback: That’s such a fascinating topic. You just raised this idea of productive failures and as I’ve had the privilege to talk with researchers, physician scientists like yourself, I hear that frequently. You go down a road and sometimes it goes where one thinks it’s going to go and that terrific, assuming the hypothesis is proven out. Other times it doesn’t and sometimes I hear the challenge that can come from that but also connecting back to your idea of there are challenges and opportunities. These productive failures do end up occurring and new discoveries get made. It’s a really interesting concept that I kind of keep coming across in these conversations.
Let me ask about, then, your current research. First, make sure for me, please, that I’m understanding it correctly and you will feel free to correct me on anything that I have wrong. A person has breast cancer, maybe it’s another … or maybe another type of cancer and they have surgery or treatment and everything appears to be fine and thank goodness, etc. Then at some point later hormone positive breast cancer recurs. You hope to understand why that happens and how it possibly can be stopped. Is that right? Is that a fair characterization of your current work or how would you characterize it?
Dr. Davidson: Yeah. I think that’s quite reasonable. I would broaden it slightly to say that you have outlined a potential scenario for a person with newly-diagnosed breast cancer. They have early breast cancer, which is the norm in this country thanks to early detection. They have surgery or radio-therapy and likely some sorts of drug therapies. For the majority of women, of course, that will be the end of the story. Right? They will continue in life cancer-free and go on with all their normal activities. But a minority of women with either the hormone-receptor positive or the hormone-receptor negative breast cancers can have it come back. My particular niche, as you point out, has been the women who had the hormone-receptor positive breast cancer to begin with and did all the right things, took all those hormone therapies and everything, and nonetheless, they had the disease come back.
We’ve been focused on, first of all, how can we minimize the likelihood of recurrence, and second, if the patient does have the bad luck of having recurrence, are there ways we can mitigate that resistance? Can we overcome the resistance and maybe reintroduce hormone therapies with partner drugs or something like that?
Chris Riback: Where are you on this research? What stage is it at? How will the research work and what’s your hypothesis?
Dr. Davidson: Yeah. Our personal hypothesis was that maybe the use of what we call epigenetic modifiers, and these are agents that help to change gene expression in cancer cells in a reversible way. So changes that have taken place in the cancer cells that make them more malignant but which are reversible changes. I think you know that cancer has as its characteristics that there can be changes in the cell in the genetic material, in the DNA, the so-called genetic changes.
But sometimes there can be changes that are related to how the genetic material is used, called epigenetic changes and the beauty of those is they are potentially reversible. Our focus has been on these epigenetic changes, whether or not they might contribute to resistance to hormone therapies, and if they do, which we think that they certainly do in the laboratory, are there ways that we can translate that into clinical practice?
We’ve actually pursued this all the way through from cell models to preclinical models and ultimately we did do some clinical trials, early phase clinical trials looking at this potential approach, which were not the home run that we would have hoped for. Not surprisingly, perhaps, but gave us some insights which we’re now taking back into the lab to see whether we can refine our approach or not.
The second area that we’ve looked at is that one of the great discoveries by others in the last couple of years has been that there are actually mutations in the estrogen receptor gene itself in metastatic breast cancer that may confer resistance to hormone therapies. These changes in the sequence of the DNA may lead to the production of a hormone receptor that doesn’t act right. It doesn’t act in the normal fashion. That’s the second area that many, including us, are pursuing. How often do we see these changes, and if we see them, what do they mean functionally? How do they make the breast cancer behave differently?
Then the last area we’ve been pursuing is actually a subset of breast cancer. One called lobular cancer, which is about 15% of breast cancers that are diagnosed. Most are what we call ductal cancers. They start in the ducts of the breast. But some start I what we call the lobules, which is the part of the breast where the milk is actually manufactured. These lobular cancers may have a slightly different response to hormone therapy than the ductal cancers. That’s the third area that we’ve pursued over the last couple of years. General theme of hormone resistance, but the recognition that there are probably a lot of different ways that cancer cells get there and trying to tease out certain of those possibly roads and the trying to think about how we might identify them, characterize them, and then use them to intervene
Chris Riback: What a puzzle to unwind. When you look at the recurrence cases and the science that you’re doing around that, as you mentioned some of those are epigenetic which changes, I guess, non-DNA, non-genetic based changes based on, perhaps, environment or some other characteristic. Then others, as you just characterized, are DNA-based. How does that break down? Is it more common to see recurrence one direction or the other and how does that drive your research?
Dr. Davidson: Yeah. I think that’s an area that’s very much under investigation right now. I don’t think we have a good answer for your question. The recognition of these estrogen receptor mutations, believe or not, is pretty new. It’s only a couple years old. I think we’re coming to realize that they might take place in 10, 20, maybe 30% of hormone receptor positive breast cancers that have been previously treated with certain of the hormone therapies.
The epigenetic changes are a lot tougher for us to measure. We don’t have an easy test for that. So that’s an area that it’s hard for me to quantify the impact for you, although I would imagine that it probably contributes in some fashion to a number of patients who have hormone resistance. It’s just that it might do it in a number of different ways, in the way that it affects gene expression, and it’s hard for us to therefore know how to identify it and calculate that percentage.
Then we also know that the actual loss of the estrogen receptor that you and I just talked about, that’s seen in probably about 15 or 20% of all of the breast cancers as a form of hormone resistance. There are certain mechanisms that we can put a number around. There are other mechanisms where our ability to quantitate it is a little softer.
Chris Riback: Tell me, I mean all cancer research, I assume, all physician work, really probably all physician work just period, carries an emotional component as well. You’re dealing with human lives and as you described earlier, it’s that connection with the human that helps inspire and focus you on the research side, too. This particular area that you’re working in, just as I was trying to think about it and internalize it, you’re dealing with patients and people who believed, believe, that cancer was behind them and then recurrence occurs. Is that as difficult as it seems it might be? Does that in some way inspire you? Is it then maybe … I also try to think about it and I was thinking, well maybe it’s powerful to be able to talk with those patients and say, “Yes, this has occurred in your life and I’m working on it.”
Dr. Davidson: I think that patients are really what keeps us going, right? When you have some downtime in the lab and things aren’t going well, you remember where you’re trying to get to. You have only to go to see the patients whose lives you might potentially effect. Patients are also inspirational for me in the sense that we see our successes. You and I are focusing on hormone resistance, which has been one of my major personal interests, but there’s a whole field of breast cancer that involves breast cancers that are reliant on the protein called HER2, and that’s about 20% of breast cancers.
During my career, HER2 positive breast cancer some years ago, they were extremely difficult breast cancers. When they recurred they were pretty fast paced and generally quite lethal. Yet thanks to benched bedside kind of investigations like you and I are talking about, by other people, things like the drug Herceptin were developed. I can see how Herceptin has had an impact on women that I have cared for with HER2 positive breast cancer over the course of my career.
I remember women I took care of with HER2 positive breast cancer before we knew about this drug and I look at the women I take care of now and I can see how that laboratory research, by others, had an impact on those women. In my own world, we know I’m very interested in hormone therapy as you and I just talked about, and I can see how during the course of my career, when we started, Chris, we didn’t believe in hormone therapy for young women. We felt that in pre-menopausal women it wasn’t a useful strategy.
But with improved understanding of the biology of breast cancer we came to realize that it wasn’t the age of the patient, it was the biology of the tumor that was the driving force there. You know, the biology was the destiny. Once we knew that we could start to take those hormone approaches into our younger women and again, I’m still hearing from patients who were on the pivotal trial that I did on that topic, which started in … Oh golly. 1988. Some of those patients are still alive and in touch with me.
Chris Riback: Wow.
Dr. Davidson: And I like to think that it’s the engagement in that trial and the opportunity to participate, and in some cases to get what was then the experimental therapy and is now the standard therapy, made such a difference to them. This is so powerful for me as an investigator, and I hope it’s powerful for patients that they realize that their individual sorrow and, in some cases, tragedy, that we’re very focused on trying to minimize the chances that anybody would have to face that in the future.
Chris Riback: Yeah. That is very powerful and I would expect it is inspiring bi-directionally, I guess. Both in your direction and in theirs.
Dr. Davidson: I think it’s probably more inspiring to me. I expect if you’re a cancer patient you got a lot on your mind.
Chris Riback: Yeah, yeah.
Dr. Davidson: Being inspired by me is not part of it.
Chris Riback: Right.
Dr. Davidson: I guess it’s a tough place for people to be, I think. But, you know, one of the things that’s powerful for us is that so many patients are willing to be partners in the research process.
Chris Riback: Yeah. Very, very fair point. How did you get into this? I mean, going back. When I thought about this question originally my view of it changed just a little bit when I was watching that video. In this video, it’s on your … I think your Fred Hutch page, and you talk about the history of team science and you may or may not know, but the video goes to kind of an old … It’s like a black and white photo. It must be of the … I don’t know if it’s of the early days of Fred Hutch but certainly the previous days of Fred Hutch, and there they are. Five scientists, researchers, and they are five very nice looking, white men.
Dr. Davidson: Yeah.
Chris Riback: It’s your voice over that talking about the history and it certainly struck me. You’re a pioneer. You will not, surely, I assume, brag about your career but we can and we know the impact that you’ve made in your field, which is extraordinary. Was it always science for you? Was it always research when you were growing up? Did you ever think perhaps you’d be a fiction novelist instead? Tell me about you.
Dr. Davidson: Yeah. Well, I wanted to be an archeologist. I was very passionate about that, but my dad, a practical man. I’m the daughter of two geologists so I was in a scientific family, although a different kind of science. But my dad said, “Well, that’s fine, Nancy, but how are you going to make a living?” He kind of dispelled that archeology fantasy.
When I went off to college I did get interested in biology. I actually, because of a social connection, I decided I wanted to work in a lab and so the guy I was dating, his fraternity brother identified a lab that he was working in and where there was an opening. I ended up being an undergraduate research assistant in that lab, which turned out to be a lab focused on liver cancer. That got me interested in the field of cancer and as a consequence of that exposure and my college experience, I did go the medical school. I decided that it would give me the most possible options in terms of a career that I would want to follow.
After my first year in medical school I went home to live with my parents because, of course, medical school is extremely expensive and I needed to reduce my expenses. My parents lived near the National Institutes of Health in Bethesda, Maryland. I applied for a summer job there, which I got, and it was a paying job so I accepted it and it turned out it was in a breast cancer lab.
That is how I went into breast cancer, and it’s because of the excitement of that summer and because of the influence of two other individuals who are also supported by the Breast Cancer Research Foundation, Marc Lippman and Kent Osborne, two pioneers in the breast cancer field, who were at the early phases of their career and have also contributed so much in these areas of hormone response and have been inspiration for younger scientists like me.
Chris Riback: Wow. Well, we all certainly benefit from having you in this field, though it occurs to me that your father may have prevented us from having Indiana Jane before Indiana Jones.
Dr. Davidson: I know. I wish. I now do it … I’m a pretty big traveler so what I try to do is make sure I’m visiting those archeological areas where I would have loved to have been able to work.
Chris Riback: Very cool. Well, second career.
Dr. Davidson: Yeah, it is cool.
Chris Riback: There’s still time.
Dr. Davidson: You might be right. Yeah. You could be right. Sometimes when I see those sites, though, they’re pretty Spartan, and so I may be better off not in those tents in 120 degree sun.
Chris Riback: It sounds better. We all benefit from the choice that you made. Tell me quickly about BCRF. You mentioned the other leaders and people who have inspired you that are also BCRF sponsored. What role have they played for you? I know that you get support from a range of groups and organizations and we’re all grateful for that. Tell me about that support that you get from organizations and the role it plays in the research that you do.
Dr. Davidson: I’m going to focus that particularly on Breast Cancer Research Foundation if you don’t mind.
Chris Riback: I don’t.
Dr. Davidson: BCRF. Okay. You’re right that research is expensive and one of the things we’re constantly doing is trying to garner the resources to support our research, so I’m very grateful, of course, to the National Institutes of Health and the Department of Defense and American Cancer Society. Pretty major organizations that fund all sorts of cancer research in this country, but I do have a soft spot in my heart for the Breast Cancer Research Foundation.
In 1998, I remember it well. I still have the email. I got an email from Dr. Norton, who has been such a luminary in the Breast Cancer Research Foundation, asking me to apply for a grant from this organization. Lo and behold, I got it. So I’ve been very fortunate to receive support from to organization since that time, almost 20 years. It has allowed me to do so much. It really allowed me to take a flyer in that epigenetics area that you and I were just talking about. It was kind of not in the mainstream at the time. It allowed me to start some of my studies that then were eligible for things like NIH funding.
I was also able to use it to support other NIH things like the SPORE grants that we got. The Specialized Programs of Research Excellence. Big NIH grant. I’ve also been able to use it to help other people’s careers. It was a way to support young trainees as they came interesting other lab.
Chris Riback: Yeah.
Dr. Davidson: To allow them to get on their feet and to catch fire and to be able to go off. I’m grateful to the BCRF because they do invest in the individual in some cases. In my particular case, I started with their support at Johns Hopkins. They were willing to transfer the support for me to the University of Pittsburgh when I worked there and tried to establish a new breast cancer program. Most recently they followed me to Seattle to the Fred Hutchinson Cancer Center and to the University of Washington and the Seattle Cancer Care Alliance. They’re helping me to start up new collaborations with my colleagues here, who are very focused on metastasis.
That kind of unconditional support year after year has been so important. I also want to put in a plug that thanks to the BCRF, in the mid-2000s we in the breast cancer field had this kind of wild and crazy idea that we wanted to put together a consortium. Something that came to be called the Translational Breast Cancer Research Consortium. This is a group of now, I think, 17 academic cancer centers around the country that wanted to band together to be able to perform clinical trials. Biologically-based, kind of first in human, bio-specimen rich, innovative clinical trials for breast cancer. BCRF was the first funder that came in the door. They said, “Well that sounds like a good idea.” They allowed us to really take this to an organization that now involves 17 different academic cancer centers across the country.
Its administrative headquarters is at Johns Hopkins, where I was at the time. You know, that group … We’re, I think, coming up on performing our 50th clinical trial.
Dr. Davidson: An example of the BCRF having the vision to make an investment in what was kind of a wild and crazy idea at the time and following it through and supporting us into a very, very influential clinical trials group. I think they’ve been fantastic in supporting individual investigators like me, and then also having the vision to support these unusual team science opportunities. I just can’t say enough in the way of praise for the organization.
As a disclaimer, I’ve had the chance to be on the Scientific Advisory Board for a number of years.
And to help shape the scientific thinking, but I think that the nimble way that the Foundation thinks about funding, and the rigor. I mean, they definitely think pretty hard about the nature of the science and what’s going to be making a difference for patients, but just an impressive track record of success and no end in sight. I think the only reason why the organization is going to go out of business is when it achieves its mission.
Right, which is to basically prevent or cure breast cancer.
Chris Riback: I am sure they would be thrilled for the opportunity to go out of business in the way that you just described. Yeah. The scientists, researchers that I’ve had the privilege to speak with, what you’ve just described and the nimbleness combined with the rigor, I certainly feel it. I will say you may though have created a great, new marketing tagline for them, however. BCRF: The Wild and Crazy Research Organization. It’s a whole new-
Dr. Davidson: I think it was a wild and crazy idea.
Chris Riback: Ideas, yes. It’s a whole-
Dr. Davidson: Yeah. I think the organization is nimble and forward thinking.
Dr. Davidson: And not a wild and crazy organization but one that’s willing to take a look at wild and crazy ideas.
Chris Riback: Yeah. Which if you’re going to get to a cure on this, listen, they … Wild and crazy ideas, maybe that’ll be the way. Thank you. Thank you for your time.
Dr. Davidson: All right.
Chris Riback: Not only your wild and crazy approach but your rigorous approach on everything that you’ve done and thank you. Thank you so much for the conversation.
Dr. Davidson: Thank for the opportunity to talk with you. It’s been a great pleasure.
Chris Riback: That was my conversation with Dr. Nancy Davidson. What an incredible impact she continues to make. Sorry about that, archeology. My thanks to Dr. Davidson for joining and you for listening.
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