Understanding Radiation Resistance and Barriers to Quality Care with Dr. Lori Pierce
By BCRF | March 1, 2021
By BCRF | March 1, 2021
For so many breast cancer patients, radiation therapy can bring extraordinary benefits—top among them improved survival rates and reduced recurrence. But there are also challenges and questions: Why do some people experience a recurrence after treatment? How can we reduce side effects? How can we ensure the right patients receive radiation therapy—and that the treatment works as well as possible?
These are among the many medical mysteries to which Dr. Lori Pierce has dedicated her career to answering. Dr. Pierce and her colleagues are currently trying to determine why, after surgery and radiation therapy, breast cancer can come back and whether blocking the androgen receptor can lead to increased radiation sensitizing.
Dr. Pierce is a radiation oncologist, professor, and vice provost for academic and faculty affairs at the University of Michigan. Among many other leadership roles, she also serves as president of the American Society of Clinical Oncology (ASCO). A national leader in breast cancer research, she has published more than 180 manuscripts and book chapters and has received numerous teaching and leadership awards. She has been a BCRF investigator since 2003 and is a member of the Foundation’s Scientific Advisory Board. Her current BCRF grant is supported by Ulta Beauty.
In this episode of our podcast, she talks about her work in the lab, the importance of BCRF, and, more recently, as ASCO president.
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Chris Riback: Dr. Pierce, thank you for joining.
Dr. Lori Pierce: Glad to be with you, Chris.
Chris Riback: If we could start at the highest level with radiation therapy, how important is its role in helping breast cancer patients after surgery?
Dr. Lori Pierce: Radiation is a very key component to the successful treatment of women with breast cancer. Lumpectomy and radiation is a standard treatment for patients with early-stage breast cancer and so radiation is given not only to reduce the risk of the cancer coming back in that breast. But we now have seen through a lot of trials that by doing that, you improve a patient's survival. So, radiation is very important in breast conservation, and it's also important in those patients whose tumor requires them to have a mastectomy, but there may be some patients who have a mastectomy, who need radiation as well, and that also has been shown to improve survival. So, radiation is a very important component of care in early-stage breast cancer.
Chris Riback: And you mentioned one of the key and really just very challenging areas, I'm sure. I mean, so many aspects of breast cancer are frightening and emotional, and frankly sad. And one area that you just mentioned and that you do work on, is around recurrence. A patient has surgery, has radiation therapy, hopes she or he has “beaten” cancer, and then it comes back. How devastating. How challenging is recurrence in the whole spectrum of breast cancer?
Dr. Lori Pierce: Yes, so we do everything we can to minimize the chance of recurrence. All of the trials that we do, they’re trials help to identify the latest advances in breast cancer to further reduce the risk of recurrence, while maintaining quality of life. So that's a very important concept. Having said that, despite the very best care, there are a few cancers, breast cancers, that will come back despite getting the appropriate care. And if you look at the trials that have been done that have included radiation, patients who've had radiation following breast conservation, roughly about 10 percent of patients will have a recurrence in the breast. And so, the vast majority of them do very, very well, but there's about 10 percent that have recurrence. And that's actually been the focus of a lot of the work that I've done, thanks to funding and support from BCRF.
Chris Riback: And so, let's talk about the work that you've done across your career and focus in on some of the recent work and recent research that you are focusing on. There are, of course, so many areas of radiation oncology that one could discuss with you, including some incredible work going on globally around not identifying who would benefit from radiation therapy, but rather gaining greater clarity around who wouldn't benefit and therefore, doesn't need radiation therapy.
So maybe we can talk about that in this conversation, as well. But I want to ask you first about what I believe is your current research, what is the androgen receptor, and what role might it play in resistance to radiation therapy?
Dr. Lori Pierce: So, great question. Let me give you a little bit of background. So, for those patients who have a recurrence in their breast, we think it's probably due to resistance to radiation, that that breast cancer cell has found a way to resist the effect of radiation. And so, we've tried to focus on strategies to be able to lessen that resistance and, at the same time, again thanks to BCRF, we're trying to come up with molecular markers that can predict those cancers that may be resistant to radiation. Because if you can pick out those cancers, you then can know which patients should receive some of these strategies that we're trying to come up with, that can decrease the resistance to radiation. So that's kind of a two-pronged approach.
And so, getting to the question that you asked, many years ago when I first started working in this area of radiation resistance, I did a trial with a chemotherapy agent, gemcitabine, with radiation, and I did it and I won't bore you with the details, but it was a trial that was done in patients who had had a mastectomy and had a recurrence after a mastectomy, and had really, really difficult disease to control. And the good news was that trial showed that all the tumors were controlled with gemcitabine and radiation. So that was a home run. What wasn't a home run, is that it caused a lot of side effects. There were a lot of skin problems in patients who had that treatment. And I must say the patients that we treated, they were fine with it. I wasn't fine with it because, there are probably ways that we can achieve the same outcome, but have it be more tolerable to patients.
And so, then we started working with another class of drugs, something called PARP inhibitors. And again, not to bore you with the details, but PARP inhibitors, they inhibit an enzyme called PARP, and PARP basically helps cells to repair DNA strand breaks. So, DNA, of course, is the control. It dictates what the cell is going to do, and it has all of the genetic material in the DNA. And, luckily, cancer cells have some difficulty in being able to repair damage to the DNA. And so if they need PARP and then you inhibit them from getting PARP, then they have even further difficulty repairing their DNA damage. And radiation causes DNA damage, so it's a marriage made in heaven, to have radiation and a PARP inhibitor.
So, long story short, we did a lot of studies early on to show that it was safe. We did it in the lab first, and then we did a phase one study, thanks to BCRF. So the phase one study was a clinical study, which multiple institutions participated, in which we tested that PARP inhibitors could be safely given for breast cancer, and we showed that. And now, again, thanks to the work that BCRF funded, there is now a national study that is looking at radiation with or without PARP inhibitors in patients who have inflammatory breast cancer, which is a very aggressive type of breast cancer. So, it just shows that when you have an idea and you have BCRF behind you, you can take a concept from the lab and do the appropriate clinical trials to be able to bring it into the clinical arena. So that's the full story with PARP.
And you mentioned the androgen receptors. So that's a receptor that is on the cell that is a hormone type receptor. And we know that about 50 percent of triple-negative breast cancers—cancers who don't have an estrogen receptor, don't have a progesterone receptor, and don't have a HER2/neu receptor—which means our therapies that fight ER, estrogen receptor, and progesterone receptor-positive tumors, and HER2/neu positive tumors won't work in triple negatives, because they don't have the ability to bind.
Chris Riback: Yes, they can't catch it when it comes in.
Dr. Lori Pierce: They can't catch it when it comes in, that's right. And they're also a very high rate of having androgen receptors on the cells of cancers that are estrogen receptor-positive. And that's very good too because even though we have incredibly effective hormonal therapies for estrogen and progesterone receptor-positive cancers, not all cancers will be controlled with them. Not all estrogen and progesterone receptor-positive cancers will be controlled. Sometimes cancers find a way to evade drugs that bind to these receptors. And so knowing that androgen receptors are also on these cells, gives us another way of being able to sense whether that can increase radiation sensitivity.
And sure enough, in our laboratory data, we've shown that for estrogen receptor-negative and triple-negative cancers that have the androgen receptor, that when you give radiation, if you have a drug that blocks that androgen receptor, and then you do radiation, that makes them more sensitive to radiation. So, you get more bang for the buck, if you will, and more sensitization with that androgen receptor. And so, we are now working toward trying to do a clinical trial. And the good news is that there are a lot of drugs out there that are used in prostate cancer that we know are safe and have been used for many, many years for prostate cancers, generally. Most of them have androgen receptors also, and we know these drugs are very safe, so we can bring them into the breast cancer arena and, actually, some of them are already used for breast cancer patients for those who have disease that has spread. And so, we know that they're safe drugs and we're looking at how to combine them safely with radiation.
Chris Riback: Can I tell you, in so many of these conversations among the many things that amazed me in several of them, is how often learnings, insights gained from one type of cancer, get translated into another type of cancer. And so, how did that actually work, the connection between the androgen receptors that are noted in prostate cancer to possibly addressing them in breast cancer? How was that connection? Were androgen receptors not previously recognized in breast cancer? I kind of assume they must have been, or was there some advance in prostate cancer and then people, like you said, "Well, wait a second. There's something that connects here." How was that connection made?
Dr. Lori Pierce: Great question. So, we have known for quite a while that androgen receptors were on breast cancer cells, but it's clear some of the significant advances that have been identified in prostate cancer, that made us all take a look at that. And then also, there are so many similarities between prostate and breast cancer. They're both hormonally driven cancers, to a large degree. And then some of our gene expression data from some of the trials that we did earlier in the lab, and some of the cell lines identified some of these androgen receptor compounds as being compounds that would be very active in some of these cell lines. So, it was kind of like the sun and the moon were aligned and also, it helps that earlier on, one of the investigators who were working with me, who was at Michigan at the time, who's now left to go to UCSF is a prostate cancer researcher. And so, so it was kind of just the right idea at the right time.
Chris Riback: Now why in the world would anyone want to leave Michigan, especially to go out to San Francisco? You'll have to do additional research on that problem.
Dr. Lori Pierce: You know, I agree with you, but I think it's worked out to be a very good move for him.
Chris Riback: I'm sure.
Dr. Lori Pierce: So, I don't begrudge him that, but he is Dr. Felix Feng. He is an amazing researcher and he's gone on to do great things.
Chris Riback: Especially talking with you in the middle of winter in Ann Arbor. I'm sure there are several reasons right outside your window, why going to San Francisco might make sense. So, to quickly finish up on this research that you're doing, I'm trying to just confirm, where are you in the research? Have you been able to start the clinical trial, or did you say earlier that you recognized as you're doing some lab work and now, you're getting ready to do the clinical trials on this?
Dr. Lori Pierce: We are getting ready to do it. We're actually writing a concept, even as we speak, and hopefully, you'll see something in the not-too-distant future.
Chris Riback: Excellent. We will keep our eyes out.
Dr. Lori Pierce: And I'll also add, I mentioned that we were doing preclinical work in the estrogen receptor-positive cell lines, and interestingly, although the receptor-negative cell lines if you have the androgen receptor inhibitor, and then you do radiation sensitization, we didn't see that in those that had the androgen receptor that were ER-positive. So, we're trying to figure out mechanistically what is the difference? But what's interesting, you study one question, and another question comes up, especially a question from years ago. We're looking at the sensitivity of radiation with your common estrogen receptor inhibitors like Tamoxifen, the aromatase inhibitors.
Many, many years ago, I wrote a paper in the Journal of Clinical Oncology. Long story short, it was about the timing of giving, let's say Tamoxifen and radiation. Should you give them at the same time? Should you do your radiation first and your Tamoxifen to follow? Because there were reasons, and I won't bore you with the details, that there were theoretical concerns that doing the two together would lessen the effectiveness of the radiation. So many places would do the radiation first and then start the hormonal therapy. Well, now that we're into this studying of androgen receptors, ER receptors, why do we see sensitization? Why don't we see sensitization?
We've started to run some lab tests, and we're actually seeing that you get sensitization just by having the hormonal therapy at the same time as radiation. And, actually, this is the subject of a couple of trials that are currently ongoing about the sequencing of hormonal therapy and radiation. But this is something that, coupled with the laboratory data and depending on how the clinical data comes out, will be something very fundamentally important, potentially, to cancer patients who have ER-positive cancer, who get radiation, and how best to sequence these therapies. So, it's just interesting. Again, the paper I wrote was in 2005, and so now we've come around from the clinical paper to the laboratory exercise and actually finding that there may be sensitization just from using our very widely utilized hormonal therapies with radiation.
Chris Riback: Yes, that is wonderful, and it is a terrific insight how questions can then lead to additional questions and to additional questions. And I am sure we could have a whole conversation on that, I'm sure, and I would imagine that's part of the fuel of what keeps people like you going with the energy and pace that you keep up every day. It's got to be that curiosity.
Dr. Lori Pierce: It is because these are basic clinical questions. These are questions that our patients need answers to. And those that are the most important incentive for what we do. It has to be relevant and it has to be something that will favorably alter a patient's course, for sure.
Chris Riback: Were you always curious, were you a curious kid?
Dr. Lori Pierce: Extremely. Extremely, always, always. I have a couple of broken bones when I was a kid to go for it. I was always getting into things.
Chris Riback: Yes. I'm getting that sense about you. Yes, so you found out your limits the hard way, but fortunately at least as a scientific researcher, medical professional, no limits yet that we know of. None that we'll talk about at least right now.
Before we move on, because I want to ask you a little bit about your work with ASCO (the American Society of Clinical Oncology), and you don't need me to tell you that you were the president there. But you kind of reacted earlier, when I mentioned the importance of some of the work going on globally, around gaining greater clarity of who wouldn't benefit and therefore doesn't need radiation therapy. What's the status of that work generally, and why does that excite you so much?
Dr. Lori Pierce: So, for any type of therapy for breast cancer or any type of cancers, there are potentially positives, [and] there are also negatives. You don't want to offer treatment to a patient who really doesn't need it. And so, it's important to be able to discern those characteristics about a specific cancer that tell you whether that patient needs treatment now. It's the ultimate individualizing treatment, to know which patients don't need treatment. But the other side of the coin, is you have to do this very carefully, because there have been many advances [in] the use of radiation. And just like I said, we know that radiation not only reduces the risk of a recurrence, but also improves survival, so it has to be very, very carefully studied.
Similar to medical oncology—having the Oncotype DX test, being able, through a series of trials, be able to discern those patients who would do well in the absence of chemotherapy—we're doing the same kinds of things with radiation, and there are currently trials. So, the short answer to your question, is the trials are currently ongoing. Looking at selected patients or patients who have specific aspects of their cancers that are, and I'm doing air quotes here, "that are favorable," so those that are certainly estrogen receptor-positive, those who have small tumors, patients who may be older, as opposed to 35-year-old patients with cancer, and trying to then see within that selected group, whether they would do equally well without radiation. So, the trials are currently ongoing, very important studies. And hopefully, in the next two to four years, we'll start to have some meaningful data from those trials.
Chris Riback: Excellent. Look forward to that. I want to talk to you about all the free time that you clearly have because with not enough on your plate, you decided, "Well, why don't I add a little role like ASCO president," with all the extra time that you have? Was that your thinking in taking that on?
Dr. Lori Pierce: Yes, that on that summarized it pretty well.
Chris Riback: It seems like it. So in that role, what does the theme, "Equity: Every patient. Every day. Everywhere" mean?
Dr. Lori Pierce: So yes, I have the honor to be ASCO president, and when you're voted to be president, the first year you're actually president-elect, and during that year, you get to select the theme that you want to focus on during your year as presidency, and you just name the theme. "Equity: Every patient. Every day. Everywhere." This is so important to me. It's important to all of us as clinicians. I am African-American and for just about every endpoint, oh gosh, almost every endpoint that you can look at, people of color do less well and cancer is no exception. And the reasons there are so complicated. If this were a slide show I have a word cloud where I have all of these terms that have to be considered when you think about equity, and it's such a simple word, but it seems to be so complicated to achieve.
And certainly ASCO, by nature of what ASCO does, ever since ASCO was created, it has focused on equity of care. It's what it's all about. And so, there were a lot of initiatives that ASCO already were doing full force, in terms of equity. And some of them included some of the young investigator awards, career development awards, focusing on health disparities, in which BCRF has provided funding for multiple of these grants. So, this has been something that ASCO has been doing. But, for my year, I added additional initiatives to ASCO's portfolio because this is so important. I mean, care has to be given equitably to all. It shouldn't make a difference of their financial situation. Shouldn't make a difference of their age. Shouldn't make a difference of if they're in a rural community or inner city. Shouldn't make a difference what color they are. Everyone is entitled to high quality care. And so, there are many initiatives that ASCO has and new initiatives to focus on equity of care.
Chris Riback: And as I read some of what you've written and said about this, it's also about directly impacting outcomes, isn't it?
Dr. Lori Pierce: Oh, for sure. And, yes, the short answer to that question is absolutely yes. And you can look at it from so many different perspectives. How do you directly affect outcomes? You affect outcomes by the therapies you give. You affect outcomes by the workup, to be able to adequately stage patients. You affect outcomes by some of the social determinants of health that really impact people on every level. You affect outcomes by survivorship issues, prevention issues, modifiable risk factors. All of those components affect the outcomes of our patients.
Chris Riback: Yes. I don't know exactly where I read this, that you said, but it gets to exactly what you were saying, that some of the disparities are due to social determinants of health, which you just mentioned. I'm quoting you here, "like where people live, their level of education, where they work, their financial resources," and it's hard for us to directly impact those, but we can impact how we give care and that it is equitable. And that struck me because it has such an awareness, obviously, about the entire range of social determinants of health. Obviously, you would love to solve all of those, and maybe in due time, you will. But you make very clear what you and your role, what doctors, researchers, scientists, clinicians, caregivers, can directly impact right now, and that's the care.
Dr. Lori Pierce: The care, that's correct. You can also advocate for your patients, with local members of legislatures and state and national. We need to be able to understand cancer through the lens of our patients and what are the barriers that they see. We have all of these incredible therapies, but if there are barriers that prevent a patient from receiving it, then all those therapies are for not. So, it's important that, as caregivers, we actually spend some time asking questions to understand what are the barriers to a patient receiving the care that we recommend. So, one of the initiatives that we have this year is to create a social determinants of health set of podcasts and videos. And it will educate. It's really geared primarily for our fellows and early career oncologists—because they're our leaders for tomorrow—to really understand what the social determines of health are.
And there's one episode that is being taped this month about how to take a social determinants of health history. It's so important to find out if Mrs. Jones doesn't have transportation, can't come in for radiation, she can't come in for chemotherapy. Mrs. Jones has to work and can't get time off. So, they're just things that we're all taught in medical school. How to do an H and P [history and physical examination], but we need to kind of also how to solicit in our history, taking those barriers. And that knowledge will help us, in some cases. We can't do it all, but in some cases will help us to be able to help our patients better. Does that make sense?
Chris Riback: That makes a ton of sense. That's terrific. I would look forward to getting to learn more about that. I know you've mentioned it a couple of times, but broadly speaking, what role has BCRF played in your research?
Dr. Lori Pierce: So, BCRF, it's just a special organization. You know, it brings together breast cancer researchers who are doing incredible work to be able to cure breast cancer. And it has meetings, it has ways that we can interact with one another, and we learn from one another, and we collaborate. BCRF establishes this amazing collaboration of researchers. You know, some of the cell lines that we used for some of the work as I talked about earlier, were from other BCRF investigators. And then a few years back, some of the work I was doing then, which is different than what we talked about, was looking at radiation in women who have a BRCA1 or two mutation. And it involved bringing together a collaboration network of investigators, in order to have enough numbers of patients, to be able to make some clinically relevant observations.
And I was able to connect with other BCRF researchers to be able to establish these collaborations. And this work, even though it was a few years ago, is still being quoted. I just helped to co-lead the ASCO, ASTRO [American Society for Radiation Oncology], SSO [Society of Surgical Oncology] guidelines on hereditary breast cancer, and a lot of the work for the radiation part was from the work that I had done with this collaboration. So, BCRF essentially creates a family of breast cancer researchers. And it's just an honor to be able to be in that family and to be able to learn from others and to collaborate.
Chris Riback: And if I could, mindful of time, close out this conversation with my own question on history. How did you get into this? I mean, going back, for you was it always science? Was it always research? Did you ever think, perhaps you'd be a fiction novelist or world-class skier? I will confess, I have read about a Doc Weaver in Ahoskie, and I don't know if I'm pronouncing the –
Dr. Lori Pierce: Ahoskie! You've done your homework, oh, my gosh!
Chris Riback: North Carolina. So, what was Doc Weaver about?
Dr. Lori Pierce: Yes, so I'll just summarize it. And I have a lot of family in a small town called Ahoskie, and so in the summers, I would spend quite a bit of time there. And, in the sixties, you'd come to Ahoskie and the care was segregated. I mean, most of the people of color received their care from a physician of color, and his name was Dr. Weaver and he was wonderful. He was absolutely wonderful. And I noticed that. I noticed how he had the answers, how he was the doctor for everyone. Everyone looked up to him. Everyone realized just how special he was and certain things, when you're a kid, stick with you and that stuck with me. And that certainly was one of the seeds that led me to where I am today.
Chris Riback: And so, had you decided. I mean, was it pretty clear? Were you science-minded?
Dr. Lori Pierce: I was always science- and math-minded. I was always very inquisitive, which you stumbled upon earlier. And, as I mentioned earlier, yes because I was so inquisitive and I was pretty thin, I broke a couple of bones along the way. So, I ended up needing to get X-rays and all, and I was fascinated by X-rays. Absolutely fascinated by X-rays, to the point that I asked so many questions to the X-ray techs, that they would go get the radiologist to answer my questions. The radiologist went over the films with me, and I just thought that was just the coolest thing. And I decided then I wanted to be a radiologist, and that didn't change until I got to medical school.
And I won't bore you with the details, but while in medical school, I realized just how much I love working with patients and radiologists are wonderful, but they don't have that close of an interaction with the patients that they take films of. And I found radiation oncology, so that gave me the X-rays, it gave me the chance to work with patients, it gave me the chance to do clinical research, and it's just been a wonderful career.
Chris Riback: I sure hope you don't take this the wrong way, but the rest of us are so glad that you broke bones. That's excellent for the rest of us. Thank you.
Dr. Lori Pierce: That's how it all happened.
Chris Riback: That's how it all happened. Dr. Pierce, thank you so much for your time and, obviously, for the work that you do every day for patients.
Dr. Lori Pierce: It's so good to talk to you, Chris. Good to be able to talk about the work that we're doing, and hopefully it will resonate with some of the patients who hear this.
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