How Breast Cancer Drugs Are Developed
July 18, 2014

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In this Breastcancer.org podcast, Suzanne Wardell, Ph.D., talks about how breast cancer drugs are developed and why some drugs never make it to market. Dr. Wardell is a research scientist at Duke University in North Carolina. Her research interests lie in understanding the processes by which breast cancers develop resistance to tamoxifen and aromatase inhibitors and in developing drugs that will target estrogen receptor activity in these resistant tumors. Listen to the podcast to hear Dr. Wardell talk about:

  • bazedoxifene (BZA), a SERM approved in Europe to treat osteoporosis that has been shown to stop the growth of hormone-receptor-positive breast cancer cells
  • the importance of clinical trials
  • new research she's conducting suggesting that women diagnosed with breast cancer who do some form of moderate exercise three times a week while in treatment have better outcomes than women who don’t exercise; this applies to women who didn't exercise before being diagnosed, as well as women who did

Running time: 28:09

Show Full Transcript

Jamie DePolo: Hello everyone. Welcome to this edition of the Breastcancer.org podcast. I'm Jamie DePolo. I'm the senior editor here at Breastcancer.org, and I'm pretty excited today. We have a very, very interesting guest. Her name is Dr. Suzanne Wardell, and she is a research scientist at Duke University in North Carolina.

Her research focuses on understanding the processes by which breast cancers develop resistance to tamoxifen and aromatase inhibitors, and also in developing drugs that target estrogen receptor activity in these resistance tumors. Some of you may recognize Dr. Wardell’s name. She posted a very interesting blog on our site talking about drug development, and she’s also been a commenter in one of our boards, the Stage IV and Metastatic Breast Cancer ONLY forum. And her comments were very much appreciated there, so we thought we’d have her on a podcast so maybe a few more people could learn about how breast cancer drugs are developed and why, perhaps, when you hear about a drug, say, one year, and then you don’t see it on the market for 10 years or maybe you don’t see it on the market ever. And she’s going to tell us how some of these things work.

So, Dr. Wardell, welcome. It’s very nice to have you here today.

Dr. Suzanne Wardell: Thank you, Jamie. It’s a privilege to be here.

Jamie DePolo: So, before we get into all the drug-development process, how did you get interested in this area of work?

Dr. Suzanne Wardell: That’s an interesting question. I'm actually…I wouldn’t say necessarily a card-carrying breast cancer biologist. It certainly has been the focus in the research that I do. I'm actually am more of an estrogen-receptor person, and we’re interested in estrogen-receptor activities and how it can be targeted for treatment of a number of different things. Postmenopausal osteoporosis, endometriosis, as well as breast cancer, of course, is one of the major areas in which we need to target this receptor. So I would say that’s why I ended up in breast cancer, mostly because we’re very interested in the estrogen receptor and how it’s working both in a normal situation as well as in a cancer situation.

Jamie DePolo: And how did you get interested in that field?

Dr. Suzanne Wardell: As a graduate student, some time ago, I was working on the progesterone receptor, and it became clear that, particularly for progesterone receptor, there seems to be a role in breast cancer, but we don’t even really understand its role in normal biology. And so that just made me very interested in, what are these receptors really doing? And then, as you progress into a cancer situation, how is their activity changing? How’s it going from a normal to an abnormal?

Jamie DePolo: Okay. That’s very interesting. So let’s talk about the drug development process. I know you’ve worked a lot with one specific drug, and I'm not going to pronounce it correctly…

Dr. Suzanne Wardell: Bazedoxifene.

Jamie DePolo: Bazedoxifene, thank you very much. We’re going to call it BZA for simplicity’s sake here, I think, because I will trip over it, I'm sure. And that particular drug is approved in Europe to treat osteoporosis, and I know some women here were interested in finding out why it’s not approved in the United States. And, anecdotally, we know that it can show some cancer-suppression activity, correct?

Dr. Suzanne Wardell: [Yes.]

Jamie DePolo: But the research specifically on cancer has not been done for that drug.

Dr. Suzanne Wardell: Yes. So, bazedoxifene has kind of an interesting clinical history in that it was identified by Wyeth at the time, and since been bought by Pfizer, as an estrogen-receptor ligand, so an activator, a molecule that will bind to the estrogen receptor and activate its activities, that had activity in the bone and that it mimics estrogen in the bone, but it blocks estrogen-receptor activity in the breast and the uterus.

And this is kind of a long story in that it’s been known for about 50 years now, that women who are treated with tamoxifen actually have increased bone density. That was kind of a serendipitous observation, and so the idea at the time was, “Well, if we could dial out some of the activities of tamoxifen, specifically the activation of the endometrial tissue, then we would have a safe treatment for postmenopausal osteoporosis. Because that is actually a huge medical problem and it costs the United States government alone, a billion dollars every year because of all the fractures that go along with osteoporosis.” And so, in the development of this class of drugs, they were looking for drugs that would not cause the endometrial stimulation that tamoxifen does but would still retain that activity in the bone, so that they could safely target the bone without having the side effects of either increased risk of breast cancer or increased risk of uterine cancer.

So this story was entirely intended for women’s health, really. Not for use in cancer. Just anecdotally, at the same time that bazedoxifene was identified by Wyeth, another drug, pipendoxifene, which is very, very similar, was identified at the same time, and that one was earmarked for breast cancer.

So, pipendoxifene was actually taken forward and reached phase II trials in which women that were recruited to these trials had actually already progressed through both tamoxifen and aromatase inhibitors.

Jamie DePolo: And were having no response after that?

Dr. Suzanne Wardell: Clearly. Exactly. And so, these women then were treated with pipendoxifene, and the company, at the time, set themselves far too high of a response bar. They set themselves a 50% response bar, which I think most oncologists will tell you in a population that has already progressed through one or more treatments, that is not a realistic goal.

Jamie DePolo: Just to clarify, I want to make sure everybody understands, when you say a response bar, that means how many women or, actually, how many tumors were responding to the drug.

Dr. Suzanne Wardell: Exactly. And so, they set a 50% response bar; 30 is generally what is used in the field. And in this trial of pipendoxifene, they actually cleared 30 easily, but they didn’t quite make it to 50, weren’t sure what to do with those results because then that places a black mark against the drug, because it didn’t meet its trial goal. That then makes it that much more difficult to get through the FDA.

And so they shelved that drug. It made several oncologists unhappy, to say the least. So, that ended the interest at the time in targeting the estrogen receptor in a cancer situation with these drugs. However, bazedoxifene went forward into treatment trials for postmenopausal osteoporosis. Does fantastic; it’s got a similar effect as raloxifene except that it lacks hot flash. That’s one of the side effects that women particularly object to with raloxifene treatments is hot flash.

Jamie DePolo: And, I should say, raloxifene, also known as Evista.

Dr. Suzanne Wardell: Evista, yes. So, that is where, that originally was its intended path, and then, in the past year, bazedoxifene plus essentially Premarin has been approved for the treatment of osteoporosis, or women at risk for postmenopausal osteoporosis, but also for hot flash, because it provides a safe, relatively, as compared to other treatments, a safer option of hormone therapy in the postmenopausal setting. And the reason for that is that the bazedoxifene, opposing the estrogen signal, predominates throughout the body and the breasts and the uterus. It also predominates in the bone, so you still get bone protection, but there's just enough estrogen that leaks into the brain to block hot flash.

And so, that was really the clinical goal that Pfizer had for this drug. That means that all of the clinical trials that they have done with bazedoxifene, either as a single therapy or combined with Premarin, were not, what we say, powered to analyze breast cancer risk. So, when we are designing a clinical trial, we have to do a clinical trial in a population that is at risk for the condition that we want to treat. And so the patients selected into the trials were actually recruited based on their bone density, not on their breast cancer risk.

And so while, anecdotally, they can say that they saw no increased risk in breast cancer, they cannot say that they saw, necessarily, protection against breast cancer. That means even though we have terrific data to show that this compound is very active in all of our cell models, animal models, you name it, of both, actually, endometriosis as well as breast cancer, Pfizer would have to go back and redo all of those phase II trials looking at a population that is at risk for breast cancer.

Jamie DePolo: OK, and that costs millions of dollars, correct?

Dr. Suzanne Wardell: Many millions of dollars. And so, it’s something that they have to be very much convinced they are going to get benefit out of doing that, which is not to say that they are not interested in doing it. The work that we’ve been doing more recently with this compound is, actually, Pfizer said to us, “You know, we’re not sure that just bringing this forward as a monotherapy is going to be the most effective way to develop this for breast cancer. What if we look at this as a combination therapy?”

And so we have been looking at the activity of bazedoxifene, BZA, in our different models of breast cancer when it’s combined with kinase inhibitors of different pathways. And actually, we’re even more excited about this drug, so we’re hoping that Pfizer is just as excited about this drug, because it has very real potential.

Jamie DePolo: When you say a kinase inhibitor, are there drugs on the market now that you're combining them with?

Dr. Suzanne Wardell: One of the ones that is of interest is a compound called palbociclib, which is a CDK46 inhibitor, was recently shown in the PALOMA-I trial to, when combined with letrizole, an aromatase inhibitor, the palbo-letrizole treatment group, that those patients actually saw a greater than two-fold increase in their progression-free survival time. And that was in stage III patients, so women who already had advanced cancer, and that’s a pretty exciting result.

And so, then that says that targeting the estrogen receptor together with the CDK4/6 pathway has real treatment potential. And so that is leading them to consider branching out to other ways that we can target the estrogen receptor.

And one of the liabilities of the aromatase inhibitors is that they cause a loss of bone density because estrogen signaling is required to maintain bone density. If you use a compound like bazedoxifene, or any of a number of other different drugs of this class, you would actually be able to maintain bone density at the same time as targeting the estrogen receptor in tumors.

Jamie DePolo: Okay. And part of the reason, too, when you were talking about how Pfizer might not be interested, one is the cost, but then it also has to show, if I understand drug development properly, they would have to show that this new compound works just as well or even better than what's on the market right now.

Dr. Suzanne Wardell: And that’s exactly true.

Jamie DePolo: And that can be, if it works just as well, then some people would say, “Why should we probably pay more for this new drug if we have something on the market now that perhaps is already a generic and it costs much less.”

Dr. Suzanne Wardell: And that’s exactly right. That is probably why we will never see…I can't necessarily say never, but it is unlikely we will ever see anything unseat tamoxifen and the aromatase inhibitors in an initial treatment setting. Because those drugs are very effective for most women, and they're now generic, and they're cheap.

Jamie DePolo: Right. And part of that, the insurance companies play into a little bit, too, because they would say, “Well, if this is available for this much less, why should we pay for this brand new thing that costs so much more?”

Dr. Suzanne Wardell: Exactly. Let’s say that the benefit is only 10% greater, but it costs 80% more, they're not going to approve that treatment.

Jamie DePolo: Okay. Now, is BZA, if I'm understanding right, BZA is not approved in the United States to treat osteoporosis.

Dr. Suzanne Wardell: That is true. It is approved in Europe and in Japan, and now was recently approved in Mexico.

Jamie DePolo: Okay. Now, can you talk about why that is?

Dr. Suzanne Wardell: Yes. So, part of it is because they are marketing, instead, the formulation with Premarin plus bazedoxifene. It’s called Duavee. And there is very strong clinical data to show that not all estrogens are the same when it comes to hormone replacement therapy. So in the 10-year follow-up data after the cessation of the Women’s Health Initiative trial, looking at the patients that had already had a hysterectomy and so they were only treated with the Premarin only combination, as opposed to the Prempro that included also the progesterone analog, they actually see reduced rates of breast cancer in these patients. This is different from pretty much most formulations of estrogen that are on the market.

And so, all of the clinical trials that Pfizer has done combining bazedoxifene with an estrogen has been done with Premarin. Their concern is if bazedoxifene is available as a monotherapy, they do not want the liability of a doctor prescribing, “Well, I’ll just give you bazedoxifene and then an estrogen patch.” Because that combination has not been tested, and there's no way for them to be confident that you're not going to see an increased risk of breast cancer, because it’s not known.

Jamie DePolo: Okay. And that’s not a concern in Europe or Mexico, or other places that it’s approved?

Dr. Suzanne Wardell: That has not been launched, actually. They started with a launch in the United States, I believe they're also launching in Europe and Japan. But that kind of falls into the, “We’ve already approved. It’s already on the market.” I can understand how that can be confusing.

Jamie DePolo: Yes. I am very confused, actually.

Dr. Suzanne Wardell: A second reason I think that probably Pfizer has not chosen to go ahead and register -- they have a letter from the FDA that they can register bazedoxifene, they have chosen not to do so -- I think in part because of the fact that Evista will come off patent, I believe this year or next year. And so what that places them in a situation, actually a very losing situation for them, in that they could spend several million dollars launching bazedoxifene by itself in the United States, only to lose out to the generic raloxifene because that is what the insurance companies will be willing to pay for.

Jamie DePolo: I see. Okay. So while it’s approved in those countries, it doesn’t necessarily mean that Pfizer has launched it.

Dr. Suzanne Wardell: It has been launched, actually. It is available in Mexico, and in Europe, and Japan. But it has also been…in Europe, it’s been available for quite some time. Years now. So, I think it’s a difference in timing, because they certainly cannot recoup the costs of registering, marketing, and then, you know, you spend several million dollars convincing doctors to try it, and so it becomes a losing situation for them.

Jamie DePolo: Okay. All right. So hopefully that helps everybody understand the whole process in why sometimes… because the trials also take many, many years to go through, like, a phase II trial, a phase III trial, so that’s why you may hear about something that sounds very promising, and then 10 years later, perhaps, it’s finally on the market. There's just that huge lag time in there.

Dr. Suzanne Wardell: That is exactly right, because there are…you have to do, essentially, a minimum of 3 years to look at…because you could say, “Well, we’re going to treat for a year.” Well, that’s great, but it’s going to take you 2 years to accrue enough patients to have a statistically relevant answer in your trial, because unfortunately 10 patients doesn’t do it. A hundred patients doesn’t do it. You have to get into thousands. And it takes quite a while to accrue all of those, even if you're working at multiple clinical sites.

Then you have to follow all of those patients for this prescribed 1 year, 2 year, sometimes 5 years, and so it can be at least a 3- to 7-year process to finish a clinical trial.

Jamie DePolo: Sure, and that kind of underscores, I think, the importance of clinical trials. We do have information about clinical trials on the Breastcancer.org site, and, I mean, me, personally, I would like to just give a big thanks to any woman who decides to enroll in a trial, because you are helping move drug development forward, and you don’t know if you're getting the drug that’s being studied or maybe you're getting a placebo, but in either case, you're helping move it forward, and while I understand a clinical trial is not right for everybody, it really does help the whole situation.

Dr. Suzanne Wardell: It does, and actually, I would say that I have found an incredible willingness in breast cancer patients to do exactly that. There's really… speaking to these women, there’s a feeling of sisterhood in that it may not help me but it’s going to help the next women, and I have to say, I'm really proud of them for that.

Jamie DePolo: That’s awesome. And I know, too, I think people were particularly interested in BZA because it seems like so much of the research focuses on early stage. And I know that women who have been diagnosed with metastatic disease sometimes feel like they’ve kind of been pushed in a corner. Like nobody wants to hear about them.

Dr. Suzanne Wardell: That’s exactly why our lab is particularly interested in finding drugs that are effective in that situation, because that’s a very underserved population. The two most underserved populations of breast cancer patients are those who are diagnosed with triple-negative disease, because there really is no key pathway that can obviously be targeted, and also those who have progressed after therapies targeting the estrogen receptor.

Jamie DePolo: And that number is growing each year. I mean, as treatments become better and better, you hear about more people… cancer is considered a chronic condition. They're living with cancer for 5 years, 10 years, 15 years.

Dr. Suzanne Wardell: And doing so with amazing courage. What also is particularly interesting to me is that as we’re becoming more and more adept at managing systemic disease and inhibiting the growth of the metastases, we’re finding that more and more, we need to come up with treatments that can reach the brain. Because brain metastases is a growing problem, because we are getting so good with the lapatinibs and the Herceptin and inhibiting the growth of the bone mets and the lung mets and the liver mets, that we have to be able to reach the brain.

Jamie DePolo: Okay. Is that, and I don’t know necessarily if there's a certain progression with breast cancer, is it usually like bone, liver, and then brain would be the final sort of metastases spot?

Dr. Suzanne Wardell: That is actually…that is the case in estrogen-receptor-positive disease. For the triple-negative patients, it is not uncommon for them to first present with metastases to the brain.

Jamie DePolo: Okay. So that would make sense. And that’s kind of a whole tricky situation, too, because you need to get across the blood/brain barrier but not harm the brain.

Dr. Suzanne Wardell: That’s exactly right. Yes.

Jamie DePolo: And is your lab working on that as well?

Dr. Suzanne Wardell: We are.

Jamie DePolo: Is there anything you can talk about, or no?

Dr. Suzanne Wardell: Not at this time.

Jamie DePolo: Okay. That’s fine. I understand that things are proprietary. I know you mentioned you were working on the combination of the targeted therapy and the BZA, are there any other treatments that you're working on that you can talk about?

Dr. Suzanne Wardell: I think that none of the treatments are at a time that I can talk about. What we can talk about is we have been very interested in what are lifestyle changes that can be made that would reduce breast cancer risk and breast cancer progression. And this past year we have published an interesting study in which we have identified a metabolite of cholesterol that is…it’s what we say is stoichiometric. So that means that as you increase cholesterol, you increase this metabolite called 27-hydroxy cholesterol. I’ll just call it 27HC for ease. And as you increase 27HC, you increase the growth of breast cancer. And that is because it can actually bind to and activate the estrogen receptor.

Jamie DePolo: So this would be hormone-receptor-positive breast cancer?

Dr. Suzanne Wardell: Yes. And we’ll get to the negative, the hormone-receptor-negative, in just a second, because it actually has a role in that as well.

So, what we’re particularly concerned about is that that means that patients that are treated with an aromatase inhibitor intended to lower their estrogen levels to the basement, as low as you can get them, that’s wonderful. But if they have high cholesterol, and therefore high 27-hydroxy cholesterol, there's another ligand the estrogen receptor can use. And we’ve been able to show that in animal models of that situation, you actually do increase the growth of these tumors. And it’s not just cholesterol itself, it’s this particular metabolite.

And so that then has led us to begin studies evaluating whether statin therapies to lower cholesterol would be effective in reducing the growth of breast cancer tumors. But that’s an easily modified health factor that patients can do for themselves.

Jamie DePolo: Sure, and it lends, or it underscores the idea that maintaining a healthy weight, eating a healthy diet, keeping your cholesterol levels at a healthy level, all of that sort of helps reduce your risk overall.

Dr. Suzanne Wardell: It does, indeed. And secondarily, we also have been able to show that exercise really inhibits tumor growth. And that is -- we initially showed this in animal models. The exciting part of that though, the really exciting part, is that when we take a group of animals, we establish cancer in these animals, and then we allow them to exercise -- so in this case that is the animal model of the couch potato who is diagnosed with breast cancer and says, “All right, I'm going to get healthy,” and starts just even just an easy brisk walk, 20 minutes, 3 times a day, or sorry, 3 times a week -- these animals did so much better.

And it doesn’t matter – I mean, if you're a marathon runner, good for you. But you don’t have to become a marathon runner to get the benefits of the exercise, and you don’t have to do the exercise prior to being diagnosed. There's a benefit to exercise, no matter when you start.

Jamie DePolo: Oh, that’s very, very interesting. And you were able to show, or maybe you're working on this, that this was kind of independent of any treatments. This was just the exercise.

Dr. Suzanne Wardell: We haven’t been able to advance it to the treatments, but there is clinical data to show that adding exercise to a treatment regimen, whether it’s a targeted therapy or whether it’s chemotherapy -- and those are patients that I have ultimate respect for. When you're taking chemotherapy and you still make it in and you walk on the treadmill, that’s amazing to me. So, those patients are experiencing quite a bit of benefits for just getting exercise.

Jamie DePolo: Wow. I think, okay, if anyone takes anything away from this podcast, for me, that would be one of the most important things, and while, certainly, as you said, I understand it can be very, very difficult to get yourself motivated to get out and walk when you're on chemotherapy or when you're taking targeted therapy, but you're going to do that much better for yourself, if you can do that.

And I think, it sounds like you're talking about just like 15 minutes, 20 minutes, 3 times a week. Just a nice easy walk.

Dr. Suzanne Wardell: Yes. Brisk walk for yeah, 20 minutes, just get your heart rate going.

Jamie DePolo: Wow. Well, I'm going to be looking forward to more research coming out of your lab on that. That sounds very interesting.

Well, it looks like we’re almost out of time. I want to thank you so much for joining us today, Dr. Suzanne Wardell, from Duke University in North Carolina. Her research focuses on estrogen receptors in various cells, and that’s led her into studying treatments for breast cancer, and we are thrilled that you shared some of your knowledge with us today. Thank you so much.

Dr. Suzanne Wardell: Thank you very much.

Editor’s Note: On Feb. 3, 2015, the U.S. Food and Drug Administration granted accelerated approval for using the targeted therapy Ibrance (chemical name: palbociclib) in combination with Femara (chemical name: letrozole) to treat advanced-stage, estrogen-receptor-positive, HER2-negative breast cancer that hadn’t been treated with hormonal therapy before in postmenopausal women.

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