Can Hormonal Therapy Help Treat Triple-Negative Breast Cancer?

Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org Senior Editor, Jamie DePolo. 

Jamie DePolo: Hello. As always, thanks for listening. Doctors and researchers have known for many years that the hormone estrogen makes hormone receptor-positive breast cancers grow by attaching to the estrogen receptors on the cancer cells.

Now, new research suggests that estrogen may play a role in allowing hormone receptor-negative breast cancers to grow. This is because estrogen limits the ability of the immune system to attack cancer cells and also makes immunotherapy medicines like Keytruda less effective. Keytruda is used to treat both early-stage and advanced-stage triple-negative breast cancer. Triple-negative breast cancer doesn’t have hormone receptors or HER2 receptors. 

Our guest is Dr. Donald McDonnell, professor of medicine, pharmacology, and cancer biology, and cell biology at the Duke University School of Medicine. He’s the senior author of the study and is going to help us understand what the results could mean for people with breast cancer. Dr. McDonnell, welcome to the podcast. 

Dr. Donald McDonnell: Jamie, thank you very much for giving me the opportunity to tell you about our new research. 

Jamie DePolo: So, your study is a little complicated, perhaps, for non-scientists, so I'm hoping we can sort of break it down into chunks.

You were looking at a type of white blood cell called an eosinophil. And my understanding is that eosinophils are immune system cells that help protect the body from bacteria, allergens, other things. So, how did you start studying those in connection with breast cancer? Because that’s…I know I hear a lot about eosinophils and asthma. So, I'm wondering how you made the connection with breast cancer. 

Dr. Donald McDonnell: That’s great. So, Jamie, let’s kind of go back just one step because you asked an important question and that is, how did we get into this? So, if you don’t mind, just let me tell you a little bit about our background…

Jamie DePolo: Sure.

Dr. Donald McDonnell: Because then it will become a little bit more apparent. So, for the past 30 years or so, my group has been involved in trying to develop new anti-estrogens for breast cancer.

You know, back when we started off, those people said, oh, aromatase inhibitors have kind of stolen the show, there’s no need for new endocrine therapies. I didn’t subscribe and my team didn’t subscribe to that idea. We started the whole field of oral SERDs or selective estrogen receptor degraders, and through our work we discovered elacestrant, which is now called Orserdu, and I'm happy to say that it’s approved by the FDA in patients with ER positive metastatic breast cancer. And also, we have a second drug called lasofoxifene, which is in development now. It’s a SERM, selective estrogen receptor modulator, maybe a different side effect profile than elacestrant, and it hopefully will be approved in the not-too-distant future. It’s in phase III. 

So, the reason I bring that up is really not to tell you what we did, per se, but to say that when we had finished that work, I was kind of at a crossroads in my research program. Do I continue to beat the estrogen receptor, developing better and better anti-estrogens to accomplish maybe incremental advances? Or, do I take a change in direction? And so, fueled by our desire to submit an application to the Department of Defense grant support program. We came up with the idea that maybe the efficacy – or how well these drugs work – is not just by how well they inhibit the estrogen receptor in the cancer cell, but actually has more holistic effects, in that estrogens affect the body in a way that actually makes the body better at fighting cancer. So, that’s how we started this. 

The first foray into that then was really a question, you know. We have been focusing since, boy oh boy, since the ‘50s, even before that, the ‘40s, on the estrogen receptor in the cancer cell. And that’s not going away. The estrogen receptor in the cancer cell is a really, really good target. What people had forgotten is that cells, we call immune cells…cells that basically help us to fight infections as you said…these cells also express the estrogen receptor. And it’s been long known in the field of immunology and reproductive biology that estrogens modulate the activity of these immune cells, but the two fields really never came together. 

Our field trying to hit the estrogen receptor in the cancer cell, and the other field saying that estrogens have activities outside the cancer cell. And so, we basically asked a very fundamental question: Is there any role for the estrogen receptor in modulating or regulating the biology of cancers other than estrogen receptor-positive breast cancers? Like triple-negative, HER2 positive, and in fact, other cancers outside of the realm of breast cancer. And the answer in every question we’ve asked that we’re going to discuss today is a tick mark. Estrogens are bad. Estrogens are bad. Okay? And a lot of the efficacy, a lot of the efficacy of existing and contemporary medicines also require their ability to inhibit estrogen signaling in the immune cell. 

Jamie DePolo: That’s so interesting. And it makes me ask a question that’s probably completely unrelated to your research, but I'm thinking about when I started writing about immunotherapy for breast cancer and I was always told breast cancers are very cold tumors. They don’t have a lot of immune cells in them. It’s going to be difficult to get an immunotherapy to work. And I'm wondering now, is it because of estrogen? Is that sort of playing a role in keeping the immune cells out of the tumor? Is that like a whole other area of research?

Dr. Donald McDonnell: You're absolutely right. Nothing is absolute, right? So, I mean, estrogens do contribute to the establishment of what’s called an immunosuppressive stage within the tumor. So, it basically blocks the trafficking of the cells we want to get into the tumor to fight the tumor, and also those cells that are actually in the tumor, it tells them to turn off the alarm signals and everything’s okay here and be quiet.

But there are a couple of misnomers out there. One misnomer is that breast tumors…and I'm talking about this globally now – all subtypes – are immunologically cold, okay, and there’s some truth to that. Okay? What is not true is that the breast tumors are immune cell deserts. They have plenty of immune cells in them, but the immune cells are put to sleep. One of the factors that puts them to sleep is estrogens. Now this makes perfect sense. 

So, think about what the main role of estrogens are. Estrogens are not there to promote tumor growth. I can positively tell you that.  It’s a reproductive hormone. And one of the functions of estrogens, which is quite clearly understood, is to suppress immunity against the fetus in the mother, okay? So, it’s a protect…it has lots of functions, but one of its functions is to prevent rejection of the fetus, okay? So, it reduces the efficacy of the macrophages, the various immune cells. And so, basically what has happened is…and this is kind of a generalized statement…is that the breast tumor has learned to do, if you want, what the uterus and the reproductive system already knows what to do. How to quiet this thing down. There’s a lot of complexity in this, but that’s pretty much what’s going on here. 

I think that’s why I wanted to get into this. Is because, oh, it’s kind of interesting. When I was an undergraduate, I wanted to be an immunologist. I just wasn’t smart enough. When I had the opportunity to come back to immunology, I jumped at it. And to be honest with you, getting this DOD, it was called a DOD Innovator Grant. Innovator because they wanted people who had already got established track records, but they wanted them to take a swing for the fences, not be ridiculous, but basically leveraging the base of their knowledge to take a new approach, and we did. And I really think this is going to work. And I'm hoping later in the podcast we can tell you about how we’re translating this research because there’s no point in doing this fundamental research if it can't be translated.

Jamie DePolo: Absolutely. As one of my old bosses used to say, knowledge without application is knowledge shorn of meaning. 

Dr. Donald McDonnell: Well, I, you know, if you were to walk through in my laboratory, and you talked to every one of my graduate students, and post-docs, and fellows, and you ask them about their project, I would be very disappointed if they don’t go, and this is how I want to translate this. 

Jamie DePolo: Yes. That’s…that’s wonderful. So, I want to go back to the eosinophils. So…

Dr. Donald McDonnell: Yeah.

Jamie DePolo: …how did you come to focus on that particular immune cell because there are so many of them. So, what made that one seem attractive?

Dr. Donald McDonnell: So, you mentioned Keytruda, you know, in breast cancer. And you know, Keytruda essentially is a drug that awakens a class of immune cells called T-cells within the tumor. Okay?

Jamie DePolo: Mm-hmm.

Dr. Donald McDonnell: And we decided that, you know, everybody and his mother is working on T-cells right now. We can't really contribute to that. And a clinical fellow and a post-doctoral fellow in my lab had a really, really good idea, and it was to do a chart review. Just a simple chart review. I mean, the advantage of being at Duke is we’ve had, you know, hundreds of thousands, and I mean that literally, of patients whose medical records we can, you know, obviously anonymously, we can profile. 

Jamie DePolo: Sure.

Dr. Donald McDonnell: What they did was, they tried to come up with a clinical scenario that might tell us a little bit about how estrogens affect immune cells. And the clinical scenario was women, pre-menopausal women now these are, pre-menopausal women who are undergoing an oophorectomy, okay, removal of the ovaries, for the treatment of breast cancer. Okay? So, these women will have a precipitous drop in estrogens at the time of oophorectomy. And so, what we were able to do, because, you know, we, meaning physicians, recommend complete blood cell counts all along the course of treatment. We now had in the records what the immune cell profile and the blood was of a woman prior to getting her ovaries removed, post getting her ovaries removed, and then at time points thereafter. Okay? 

So, that information was there. It took a lot of time to actually go through the records and you know, validate and things like that. But the bottom line was, what we found was, that in the blood, now this is not in tumors, this is in the blood so it’s just a signpost for what’s going on, we actually got a big surprise, and that is in these women there was a very substantial increase in the number of eosinophils. I’ll tell you about those cells in a second. It was substantial. And when we looked at long periods of time afterwards, that effect was sustained. 

Jamie DePolo: Oh, so they stayed high?

Dr. Donald McDonnell: They stayed high. It wasn’t just this stochastic, you know, point in time. And the other thing, which a very astute reviewer of our paper asked, you know, could this be just secondary to chemotherapy? You know, that they – the women, yes, they got a precipitous drop in their estrogens and the eosinophil numbers correlated with that, but most of these women also got chemotherapy. Okay? And could that be?  And so, what we were able to do because we have these massive data bases, we were able to explore regimens that had chemotherapy in it and no chemotherapy, and the effect was maintained independent of chemotherapy. 

And so, to be honest with you, I mean, of course, there may be other variables, but you know, you know the old story when it walks like a duck and talks like a duck, sometimes it’s a duck. Really, that’s what got us into it.

So, the reason that people really have skirted this cell or ignored it or give it the lack of respect, is that there’s not very many of them in the blood, okay? And in fact, when you go and you get your annual physical this year, go look at the CBC count, look at the blood counts, and you will notice that the number of cells is down, you know, less than 1 or 2 percent of all your white blood cells are eosinophils, and if it goes up above that you will get a flag saying that you probably have some sort of an infection or usually it’s something like a parasitic infection or something like that. So, it’s rare to see these things change.

Jamie DePolo: Okay.

Dr. Donald McDonnell: So, nobody’s looked at it before. So, we decided to do that, and I got to say, I'm going to give credit to the post-doc who drove this project, Sandeep Artham, because I don’t know, maybe I'm getting to be like an old curmudgeon. It took him a long time to convince me that these were the most important cells to study. And the reason was because we had other cells that we were looking at, macrophages, NK cells, dendritic cells. And there’s a limited amount of resources and I was trying to spend my money, my research money, the best. But you know in fair play to Sandeep, he basically, you know, kept bringing me that one more piece of data that kept me on the hook. That one more piece of data. And he came out with a phenomenal study. And so, what we had to do, you know, is after we got that clinical result, we had to go to animal studies. Okay?

Jamie DePolo: Mm-hmm.

Dr. Donald McDonnell: And so, he did what I would consider to be an exhaustive analysis. He manipulated eosinophil biology in every way that’s possible, and the conclusions of all of the studies in all of the experiments he did was, is that we want increased numbers and increased activity of eosinophils in a patient with breast cancer. Right? 

Jamie DePolo: Really?

Dr. Donald McDonnell: Yeah.

Jamie DePolo: And why? What do they do?

Dr. Donald McDonnell: So, natively, or naturally if you want, I suppose naturally. They’re a part of the immune system. It’s called the innate immune system, okay? And basically, they’re there to basically sit around and wait, as you said, for pathogens or for things that don’t look good and go, and they’re one of the first cells that charge into a wound or charge to a point of an infection and establish, you know, if you want, the front line. Okay? They get in there very quick. They’re short-lived cells. They’re produced quick. They die quick. They’re deadly. They’re only produced, as I said, in very small numbers. 

And so, what is being found in many different cancers and even in breast cancers, specifically in triple-negative breast cancer, there’s a correlation between high numbers of eosinophils in a tumor and overall outcome, independent of any treatment. So, that says something, right? And then, in other cancers…it’s not been established in breast cancer yet because it’s too early…but in other cancers, it’s been shown that high numbers of eosinophils, these little white blood cells, in a tumor, predicts a very good response to immunotherapy. 

And so, now you ask me, why? The main reason the why is, is because…we think, these cells have two activities. One is they are directly cytotoxic. In other words, they go in, they actually latch on to a cancer cell and they squirt toxins basically into the cancer cell and cause the cancer cells to burst. Okay? Well, that’s good because any time a cancer cell bursts, there’s damage, there’s more inflammation. Inflammation is a bad thing in everything except cancer. We want inflammation in the tumor. Okay? So, that’s one way. 

The second thing which they do, is that they send out signals, okay, to other cells, like T-cells, which are the major immune cell that we want to activate. And they send out signals to other cells like macrophages and NK cells. So, we think about them in a war, a battle. They’re the guys that are front, they’re at the front line. They’re on their walkie-talkies and they’re radioing back saying we need reinforcements, and we need infantry and we need military support from the air. That’s basically what the neutrophils do, or I beg your pardon, what the eosinophils do. So, I think that’s really the crux of why we did it. And now, you know, ask me more questions and I’ll tell you what this means to me.

Jamie DePolo: Sure. Well, now I…when I read the paper, I'm not going to pretend I understood everything, but there was a lot of discussion about tumor-associated tissue eosinophilia and I think that means that there are more eosinophils in the tumor. Is that right? And why…is that a good thing just for what you talked about? Because the more there are the more cancer cells are going to be destroyed?

Dr. Donald McDonnell: So, that’s a very good question. And so, the first thing I’ll start off by saying, is that everyone in our field loves acronyms. Some young post-doc someday sat down and said, tissue-associated tumor eosinophilia, I’ll call that TATE. And so, now everybody refers to it as TATE. So basically, what it is, TATE is as I just said. It’s a measure of the number of eosinophils that are in the tumor. And so, what people have done, not only in breast cancer, but outside of breast cancer, colon cancer, and melanoma, and lung cancer, and that they’ve shown that increased TATE, increased numbers of eosinophils, as I said a minute ago, track with a good prognosis, independent of treatment, and are a great predictor of response to immunotherapy. 

And so, I think that’s why we got excited because we have found out that estrogens increase in animal models of triple-negative breast cancer, and also in melanoma and colorectal cancer actually, we've shown that estrogens actually inhibit TATE. They inhibit the very process that we want to increase. Okay? And we’ve proven this every which way that we possibly could in multiple different animal models. It’s actually a phenomenally rigorous study and compliments to the team who did it.

Jamie DePolo: I have to ask one more question because I go to conferences and I see a lot of presentations about TILs, tumor-infiltrating lymphocytes, and how that…if there are more of those, that predicts a better response, better prognosis. So, it sounds like TATE is something similar, but I've not heard about TATE as much with breast cancer. So, is this a common thing to measure yet? Or is your lab really the only one doing it, or is it, you know, sort of just starting where…

Dr. Donald McDonnell: I think the latter. I think it’s just starting. I think that in some other fields it’s maybe a little bit more common to study it, but to be honest with you, I would say cancer writ large, there’s not very much study of eosinophils or all the eosinophils. And again, you know, if you look from the top, it’s T-cells, it’s B-cells, it’s dendritic cells, it’s NK cells, and you know, the poor sister is the eosinophils down at the bottom. 

And to be honest with you, some of that is because they’re very difficult to study because they are: A: Low numbers, okay? Low numbers, but extremely powerful. And B: Their half life is very short. They really don’t live very long. Whereas, you know, T-cells can live for days, months, and years, and eosinophils last for minutes, hours, maybe a day. But I think these are technical issues. As a scientist, I don’t think these are relatively hard things for us to solve if we get really interested in this. So, in fact, my group is…we’ve put our flagpole. We are going to stay and work in this field and in fact, we are just writing another paper on this right now. 

Jamie DePolo: And so, you did the mouse study. You found that estrogen decreased the number of eosinophils and TATE. So, I kind of have two questions.

One is how do we translate this to people? And then the other one is I'm wondering if you could sort of explain the mechanism. I mean, I think I understand, but if you have more TATE, more eosinophils in a cell, how does that make an immunotherapy medicine like Keytruda more effective? Is Keytruda activating those cells, or how does that work? So, two big questions. 

Dr. Donald McDonnell: Two big questions and let me work through them. So, the first one is, how do we fix this? Okay. Well, the good news is I've gone to great lengths to tell you that estrogens are bad for eosinophils, okay? And there might be a biological reason for that, you know, going back to reproduction and things like that. So, the good news is that we have a ton of clinically useful estrogen receptor inhibitors. Okay? Obviously, the one that everyone knows in your podcast is tamoxifen, which was developed by Craig Jordan back in the ‘70s and revolutionized the care of breast cancer. 

Subsequently, we got aromatase inhibitors, you know, popularized by the Brodies, and that actually was the second revolution, if you want. And now, we've come back and there are, you know, elacestrant, lasofoxifene, camizestrant. There’s a whole pile of new contemporary medicines that target the estrogen receptor. So, I think that’s covered. Okay?

We know, at least from animal studies, now, we’ve looked at several different contemporary ER modulators, and we have shown that we can block the negative effects of estrogens on eosinophils. We can increase the activity of eosinophils. We can increase the number of eosinophils, and we can increase the number of eosinophils that get to the tumor and do their job. So, it’s pretty interesting. 

And straightaway, let me just tell you, is that yes, and I cut off the question. This means that this intervention will now, I believe, be useful to more than just patients whose tumors are estrogen receptor-positive. Because remember, all these activities are extrinsic to the tumor. Okay? 

Jamie DePolo: Right.

Dr. Donald McDonnell: So, that’s the first part. I’ll tell you about how we’re going to translate that in a second after I get to the second.

The second question is, well, gosh, you got all these eosinophils in the tumor, why are they increasing the efficacy of, you know, Keytruda, for instance, okay, immunotherapies? What we really believe right now, the best guess, is that the chemicals that are produced by the eosinophil in the tumor are increasing the number of T-cells in the tumor. That’s the one thing we see, TILs. So, it’s increasing the number of TILs. 

And that was evident in our studies in the animal models. But I don’t think that’s the only thing, myself. And now what we’re exploring is, is that we think they also may be affecting the activity of the T-cells in the tumor as well. So, the weak link or the Achilles foot in our study, is that we know it’s good, we’re not absolutely sure why it’s good yet. But you don’t need to know the mechanism to take advantage of the pathways right now. So, that’s my next part. 

Jamie DePolo: Okay.

Dr. Donald McDonnell: Okay. So then, the next part of that buried in those two questions was how do you translate this? 

Jamie DePolo: Right. Right.

Dr. Donald McDonnell: So, currently we are developing a clinical trial whereby we’re first of all going to show in patients with breast cancer, that if we treat them with a contemporary SERD prospectively, not just looking at a chart review, that we actually do increase the number of eosinophils in the blood, which is obviously a great biomarker, but we also increase TATE. That’s the first thing that we need to do. And so, the sort of study…I'm doing this with a colleague, Alexandra Thomas, who is a medical oncologist here at Duke, phenomenal person, is open to discussing my wacky ideas and putting me in place when needs to be. But we’re actually designing the study whereby we’re going to do a window of opportunity study. 

So, these would be women who have…actually we’re going to go in triple-negative breast cancer, right? Because we want to separate out the effects in the cancer cell from outside the cancer cell. We believe that this really could impact patients with triple-negative. And remember, they’re really the only ones that get immunotherapy right now. And so, we want a proximal near-term effect on clinical care. Okay? 

So, let me back up and say, what we’re going to do is, you know, patients come in, they’re diagnosed with a tumor, they’ve got a whole blood work up to be done between the point of, yes, you know, Mrs. Jones, you have a tumor to the point of, you know, you have an operation or you have the beginning of the neoadjuvant protocol.

During that three weeks, okay, we are going to…three to four weeks…we will expose women to a clinically useful, clinically tested ER modulator. We will then, you know, take a biopsy of that tumor, okay, and also blood, and we’ll ask…we’ll test our hypothesis. 

The first thing is, will the treatment with this anti-estrogen increase TATE in the tumor, okay? That’s the first thing we do. And then the second thing, which is, you know, kind of…is like falling off a log, it’s so obvious, is now when we add this estrogen receptor modulator on top of standard of care, which is now chemotherapy and immunotherapy, do we increase the pathological complete response in these patients? I'm optimistic that we will, of course, but so is everyone when you start off. That’s why you got to do clinical trials. 

You know, my position, Jamie, has always been, is that the reason for a lot of failures of drugs in the clinic is not necessarily because the disease is complex, which, you know, that’s indisputable. It’s because we don’t fully validate the target and the approach before we go into humans. I will state to you right now there is nothing more that I think that I can do to validate this without doing a clinical study. And that’s why Alex, Alexandra, Alex, is really working with me to get this in place. 

Jamie DePolo: Right. And I want to make sure I understand. If you're looking at pathologic complete response, this would be given before surgery. You're going to give these medicines before surgery, you do surgery, look at a piece of the tumor, and see if there are more eosinophils in there?

Dr. Donald McDonnell: Yeah. And the blood as well. 

Jamie DePolo: Okay.

Dr. Donald McDonnell: It would be great if we could actually see this in the blood, right? Because then we don’t have to biopsy, you know, in subsequent clinical trials. If there’s a correlation between blood eosinophils and tumor eosinophils. If one is a surrogate for the other, then we don’t have to go, and you know do these invasive biopsies all the time. So, that’s where we are right now. So, what are we doing? We’re making the decision right now as to which ER modulator to use, and to be honest with you in total…just to be upfront and declaring my conflict of interest, of course…

Jamie DePolo: Of course.

Dr. Donald McDonnell: We have a financial interest. We, being Duke, in lasofoxifene. We decided that it was good to use that drug. Now, I promised you that we picked this drug, not necessarily because it was one we had, but this is a drug that I was involved in the development over 30 years ago, but it was developed for osteoporosis. It’s not a degrader of the estrogen receptor, it’s a SERM [selective estrogen receptor modulator]. And the reason I picked this one was because there’s a tremendous number of toxicities associated with immunotherapy and there are toxicities associated with SERDs, selective estrogen receptor degraders. A lot of which we don’t really understand on a molecular basis. But lasofoxifene was actually in an 8,000-patient trial for osteoporosis and so the side effect profile…I'm very comfortable with the side effect profile and I don’t think it’s going to add to the toxicity of ICBs, that’s the reason I chose lasofoxifene. 

Jamie DePolo: Okay. I have to ask you one more question. At the beginning when we started talking, you mentioned that removal of the ovaries also caused a big increase in eosinophils. 

Dr. Donald McDonnell: Right.

Jamie DePolo: Is that something you're considering as a companion treatment to any of this, or how does that fit in anywhere?

Dr. Donald McDonnell: Well, of course, it does, right? Because it reduces…I mean I've already told you that the reason we got into this is because bilateral oophorectomy resulted in a dramatic increase in eosinophils that was long-lived in patients. Now we don’t have any outcomes on those patients because this was a chart review.

But the answer to your question is, yes. But I don’t want to stand here and say, that you know, a woman with breast cancer or other cancers where eosinophilia is important, you know, has to get a bilateral oophorectomy. We may consider gonadotrophin releasing hormone agonist, like Lupron, or you know, a GnRH agonist, I'm sorry. 

Jamie DePolo: Just to shut them down during treatment.

Dr. Donald McDonnell: Yeah. I mean that would be probably enough. I think that’s probably the best way to think about it now, is that shutting down a pituitary hypothalamic access like we do in patients with pre-menopausal estrogen receptor breast cancer would probably be the regimen that you would use for other cancers as well.

Now, one thing I will add, you brought it up to my attention, is that, you know, a lot of women who are on chemotherapy at least have a transient hypoestrogenic state, which that in of itself is probably helpful as well. 

Jamie DePolo: Meaning chemotherapy stops the ovaries from working?

Dr. Donald McDonnell: It does, yeah. And so, if you stop producing estrogens you're essentially accomplishing, I won’t say the same, but a similar activity to a GnRH agonist, because obviously you don’t get total shutdown of estrogen production with chemotherapy, at least not in all patients. 

Jamie DePolo: Right. Well then, let me ask you this. Do women who are post-menopausal, have you looked at this? Do they just in general have higher levels of eosinophils?

Dr. Donald McDonnell: It turns out that we want to do that. It turns out that’s a little bit more difficult to do. But it’s okay. But the reason it’s more difficult to do is because we would need a pre- and post-. You know, each patient has to be their own control. 

Jamie DePolo: Ah. Okay.

Dr. Donald McDonnell: Right. And so, you know, when we look at pre-menopausal women, the delta was so large that was easy to see, but now if you're talking about post-menopausal women the delta is going to be much lower.

If I was to think of cancer obviously that I'm most interested in doing my trials in first, it’s triple-negative breast cancer. It’s a cancer of younger women, they’re usually cycling, estrogens are pretty high. Okay. So, I have the best chance of success. I don’t want to say it like I want to be successful. The best chance of making an impact in those patients. 

So, we had a study that we did with, I think it was 48 women, a third were pre-menopausal and two thirds were post-menopausal patients. And what we did was, we actually asked women to enroll as they had been diagnosed with breast cancer. We took a sample of their blood and then they went through their, you know, their chemotherapy and their radiation where it was indicated. And then, they went on endocrine therapy. And we followed them then for six months post-endocrine therapy, taking three additional blood draws. And then we basically analyzed the blood. Okay? And what we found was, there were changes in immune cells, particularly in B-cells, which is another immune cell. 

And so, the first thing I said was, let’s rush back and look at the eosinophils. Well, darn it, but using the methodology we used to actually take the blood, we can't study the eosinophils. And I was so devastated. 

Jamie DePolo: Oh, wow.

Dr. Donald McDonnell: Yeah. They’re so rare that we had to use a different methodology, but you know, it’s like hindsight is 20/20, we didn’t know about eosinophils when we started the study. If I was starting that study today, the first cell I'd be looking at is eosinophils and I'd have a much more definitive answer for the question you just asked me.

Jamie DePolo: Okay. Okay. That’s very interesting. So, it sounds like…I mean, I'm going to ask you about your next steps…but it sounds like anti-estrogen therapy or hormonal therapy, whatever we want to call it, could be potentially prescribed to somebody diagnosed with triple-negative breast cancer that would help make the immunotherapy more effective. That’s what your study is looking at?

Dr. Donald McDonnell: That’s exactly what we’re proposing. That’s exactly what we’re proposing. And let me just tell you, we focused…just because if this paper caught your attention on eosinophils…but we have another paper we published in the Journal of Clinical Investigation about 18 months ago showing that anti-estrogens also have a beneficial effect in macrophages, which is another immune cell. Tumors are not natural. Why is all this complexity there? And it turns out that it’s the old story. Tumors have usurped normal biological processes. 

So, think about when you puncture yourself with a needle or, you know, you cut yourself in the garden, you know, you get an infection, right? The very first thing that happens is that eosinophils and the neutrophils come in here. Neutrophils are another cell we didn’t talk about. We don’t study them much because they’re just very, very hard to study in animals. But anyway, then the next thing that comes in is the T-cells, the next thing that comes in the B-cells. And it’s like having all the team of first responders there, right? And so, that’s good. But then what happens is, is that, you know, naturally in the skin, they say okay, we have enough first responders here. What we need now is that we need the builders to come back and rebuild the place, okay? It’s called wound repair response. But if you actually look what estrogens do to the tumor, they induce the wound repair response. 

Jamie DePolo: Oh, interesting. 

Dr. Donald McDonnell: It’s not that suddenly estrogens are bad, they’re doing exactly what they’re supposed to be doing. 

Jamie DePolo: Right.

Dr. Donald McDonnell: The tumor has basically said, hey, I'm a wound. 

Jamie DePolo: Right.

Dr. Donald McDonnell: And it’s not, right? But it’s basically figured it out. That by basically looking like a wounded piece of tissue, that you get the repair process going on, and the repair process unfortunately is immunosuppressive by definition. And so, with respect to immunity, okay, I don’t see a downside of endocrine therapy in any cancer. 

Jamie DePolo: Okay. Well, except for the side effects. I mean that’s…well, that would be the only downside. 

Dr. Donald McDonnell: With respect to therapeutic efficacy.

Jamie DePolo: Oh, I see.

Dr. Donald McDonnell: Okay. No, don’t worry. I'm very cautious and I hope that came through when I was telling you why I selected lasofoxifene. Is that quality of life and avoiding side effects, you know, it’s got to come right up in front of, you know, the desirable qualities of a drug or a drug treatment regimen now. So, but I do believe that, you know, what I'm proposing will be useful outside of breast cancer as well and particularly in triple-negative breast cancer. 

You know it’s interesting because I remember when I proposed this idea, okay? One of the pieces of data that I used to support it was the original registration trial for tamoxifen back in the ‘70s and ‘80s. And in that trial, they were looking at response to tamoxifen as a function of estrogen receptor status in the tumor, okay?

So, in other words, they wanted to know, did patients who had the estrogen receptor respond better or not at all to tamoxifen? And clearly the patients who had high levels of estrogen receptor…in the patients who had ER-positive tumors, but high levels of the receptor, responded better. 

But, you know, people forgot when you looked at the tumors that were classified as estrogen receptor-negative, okay? They responded as well. Not as well, but they responded. And I was standing up in a meeting recently and I just put that piece of data up…but I don’t need to justify that anymore because we’ve already shown it works. But I put it up and the first response was the response I predicted, and that was we just…they really were estrogen receptor-positive, we just weren’t good at measuring the estrogen receptor. And I was expecting that hand wave answer because that’s the easy answer, right? 

Jamie DePolo: Right.

Dr. Donald McDonnell: And what I would put it to you is there may be some truth in that, but it’s also evidence to suggest that tamoxifen, which is an anti-estrogen, was having some benefit in these patients who are classically estrogen receptor-negative. And then the last piece of data that I will kind of throw out there, is that as you probably know the definition of estrogen receptor-positive breast cancer keeps changing. 

Jamie DePolo: Yes.

Dr. Donald McDonnell: First it was N cells that were, you know, positive, the estrogen receptor by immuno staining. Now it’s N minus this, N minus this, now we’re down to a few percent. And so, maybe it’s time to think about, maybe not all the efficacy is coming through the estrogen receptor in the cancer cell, but it’s the estrogen receptor outside the cancer cell is important as well. And again, I want to reiterate, I am not saying that the estrogen receptor in the cancer cell is not an important target. It absolutely is. 

Jamie DePolo: Right.

Dr. Donald McDonnell: But what I'm saying is, we need to open our eyes to look at what the estrogen receptor modulators are doing to tumor immunity. And in our studies, it’s all positive.

Jamie DePolo: That is great. So, I guess we talked a little bit about it, but I wanted to sort of summarize and finish up. If you could just talk about your next steps and where you see this going. Like if this study that you’re doing…it sounds like it’s maybe a smaller study with women, pre-menopausal women with triple-negative disease. When you see that kind of finishing up and where does this lead us?

Dr. Donald McDonnell: Well, I mean, I think the better question is when do I see this starting?

Jamie DePolo: Okay. I thought…I apologize. I thought it was started. 

Dr. Donald McDonnell: We’re in the late design stage. So, it turns out, I mean, there’s some complexities with respect to timing, you know, when we do it and things like that. But I'm actually trying to make sure we…well, we are probably going to use lasofoxifene. I think we’ve already decided that one between Alexandra and I. And now it’s basically, how do we design the trial to make sure that we can recruit and actually get this done in a shorter period of time? I think we can. I think, you know, these studies are, you know, generally breast cancer patients are very motivated to participate in these types of studies because they can only be beneficial, the results. And so, I think we recruit fast.

So, I don’t want to make a guess as to how long it’s going to take me because that’s a little bit outside of my wheelhouse. I'm not a physician. I'm a molecular pharmacologist. But I will say that I'm hoping that, you know, podcasts like yours, and papers, you know, our paper that was published and read, will encourage other people to do similar studies. I'm not the only person who can do these, right? I can provide the rationale for other people who are also interested in trying to increase tumor immunity to look at this. And we are…we’re definitely going to be participants in this, but not at the exclusion of other colleagues getting involved as well. 

Jamie DePolo: That’s great. This is so very exciting. Dr. McDonnell, thank you so much. I appreciate your time and thank you for explaining this so well so we can all understand. 

Dr. Donald McDonnell: Thank you very much, Jamie.

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