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You are here: Home: BCU 4|2002: Interviews: Dr. Kent Osbourne
DR OSBORNE SUPPLEMENT:
DR NEIL LOVE: Welcome to Breast Cancer Update, an audio review journal for medical oncologists. This is Dr Neil Love. This year's 19th annual Miami Breast Cancer Conference hosted almost 1000 physicians. Meeting director, Dr Dan Osman has always emphasized the daily practice application of emerging research information that characterizes, for example, the San Antonio Breast Cancer Symposium, which occurs a couple of months previously. This year, the Breast Cancer Update team, working with Dr Osman, conducted a "patterns of care" study on 200 oncologists and surgeons. These data on breast cancer management, along with many of the interactive case studies presented at the Miami meeting, are highlighted in a special print supplement to this issue and on BreastCancerUpdate.com. During the Miami meeting, I met with one of the speakers, Dr Kent Osborne, who is also a chairperson of the San Antonio Symposium. Reflecting back on the historic initial plenary session in San Antonio that he moderated, Dr Osborne began by commenting on the biologic and clinical implications of data presented from the massive ATAC adjuvant trial demonstrating an advantage to anastrozole compared to tamoxifen.
DR KENT OSBORNE: It establishes a new paradigm in the sense that it suggests that this form of blocking the estrogen-receptor pathway - that is, lowering the estrogen level to very, very low levels - is more anti-estrogenic for the tumor than giving tamoxifen, a drug that has some intrinsic agonist activity on its own. When you think of it in that way, the third arm - the combination arm - is going to be inferior. Because you're giving back a weak estrogen - tamoxifen, and combining it with something to lower the estrogen to very low levels, and that's just going to be counterproductive. You're going to get the result that you get with tamoxifen alone. So, I thought from that point of view, that is, it established this principle that aromatase inhibitors, to lower the estrogen level, were a more potent way to attack the receptor than tamoxifen, and probably other SERMs, as well.
On the other hand, when you think about applicability to patients, I think we have to keep in mind that the data are very early - two-and-a-half to three years of follow-up. I don't think they're likely to change much over time, because of the size of the study, but it is early. We don't yet know whether there will be a survival benefit overall. And, while anastrozole was better than tamoxifen with regard to some side effects, with regard to others, it wasn't. One of those, that's important for women, is osteoporosis and bone fractures. So, I suspect that many women who are on these aromatase inhibitors for long periods of time are going to have to be treated with bisphosphonates. That's going to increase the expense of the treatment.
Also, the absolute benefit is small in a certain subgroup - the relative reduction of recurrence was about 20 percent. About one out of every five women who would have recurred on, say tamoxifen would have been spared a recurrence if they had been randomized to anastrozole. When you get down to a low-risk population of women, like a node-negative woman with a two-centimeter tumor, who might have a 20-percent risk of recurrence without any adjuvant therapy, with tamoxifen it might reduce it down to 12. If you had given her anastrozole instead of tamoxifen it might lower from 12 to 10 or 11 probably 11. That's a fairly small gain for the possibility of having worsening bones and bone density deterioration and so forth.
On the other hand, in patients with high-risk of disease, that proportional reduction can be significant to them. First, I think that you can consider aromatase inhibitors in the adjuvant situation. I'd be more likely to do it in women with a higher risk of disease. I think we're going to have to keep a very close eye on serial bone densities to make sure that we're not causing a lot of osteoporosis.
DR LOVE: Do you have any concerns that with serial bone densities, even in spite of that, there might be a problem? Or do you think that you can be pretty comfortable by doing that the patient will be protected?
DR OSBORNE: I suspect that that will be sufficient. You can lose bone, as you know, very quickly. When women go through menopause, usually, 75-90 percent of the bone loss that occurs does so within the first five years. And probably much of that during the first two or three years. So, you can lose bone very quickly.
I think baseline bone densities are going to be indicated if patients already have a low bone density, and then those are going to be particularly of concern. But I think it's something that we're going to have to pay a little bit more attention to then we do when patients are on tamoxifen. When they're on tamoxifen, they're essentially on estrogen replacement therapy from the point of view of bone density. And so, I may not get a bone density.
DR LOVE: That first morning of the San Antonio meeting was classic. I don't ever remember seeing so much research data that was fascinating presented in a few hours. Another thing that happened during that morning was Trevor Powles' presentations with the clodronate study. And, of course, Mike Baum, when he presented the ATAC trial referred back to that. What were your thoughts about the study, clodronate and the potential synergy there?
DR OSBORNE: Well, it looks like that the bisphosphonates may have more than one advantage in a breast cancer patient. That is, they will help to preserve bone density and reduce the chance of osteoporosis. And maybe they will also help as a breast cancer therapy in the sense that, what it looks like happens is, bisphosphonates make the bones less fertile soil for the breast cancer cells. You can actually show that, by shutting off osteoclast-induced resorption of the bone, reduced growth factors coming from the bone into the tumor environment and apoptosis of the tumor cells in experimental animals. So, this may actually turn out to be an indirect anti-tumor therapy. I think the data are beginning to accumulate that these may be a reasonable adjunctive treatment to use.
I wish we had a way of knowing which patients to use it in. Obviously, those that don't have bone metastasis maybe are not the right ones, but those that do have microscopic bone metastases, if we could pick them out ahead of time. The Germans use the bone marrow aspirate and biopsy to do that. Maybe that's the way to go. But it is beginning to look like this is going to be a useful therapy. It would be really interesting to see the results of some of the adjuvant trials that are ongoing right now, using more potent bisphosphonates - pamidronate or Zometa - which have just started or are ongoing, as well as the NSABP Clodronate trial, which is essentially trying to reproduce those data. So, I think there's still some inconsistency of the trial results, but it looks like with the better trials, bisphosphonates are going to be a useful agent to consider in women.
DR LOVE: Getting back to the ATAC trial, you mentioned the issue about bone, which there seems to be a way to deal with at least potentially. But the other thing was the decrease in thrombotic events, the decrease in the endometrial cancer, better tolerability in terms of vasomotor symptoms. Does that all jive together as being a more tolerable adjuvant therapy to you?
DR OSBORNE: Oh, I guess so. But those are not common and severe toxicities. They are severe, if you have them, but they are not common toxicities. And the difference in the hot flashes was pretty modest. So, while I've been using aromatase inhibitors in women already, who have a propensity for thrombophlebitis or previous pulmonary emboli, for instance, the advantage there, I would say, is modest. But it's another advantage, and it wouldn't take much to trigger the use of an aromatase inhibitor, rather than tamoxifen, in many patients.
DR LOVE: From a research implication, particularly in terms of what it might mean to future clinical trials, what were your thoughts about the second breast cancer data in the ATAC trial?
DR OSBORNE: Well, the second breast cancer data were even more provocative. They showed a very dramatic further reduction in contralateral breast cancer, suggesting that this may be a very potent prevention type agent. And I haven't done the calculations to figure out what the aromatase inhibitor would have been compared to placebo in the old tamoxifen trials, but it must be close to a 75-percent reduction.
DR LOVE: Actually, Tony Howell presented that yesterday, and the calculations were that they would have predicted 60 second breast cancers. The tamoxifen arm had 30 and the anastrozole arm had nine. So, that's about 80 some percent.
DR OSBORNE: Eighty-plus percent reduction. That's pretty dramatic. Of course, now, when you're treating relatively normal women for prevention, then these other side effects like bone loss become much, much more important. You could argue that there's a trade-off with less endometrial cancers. But, again, people are going to have to really keep a close eye on the bones.
The other thing is, of course, that we're not able to treat premenopausal women with these agents. I'm in the school that thinks that earlier treatment is better. Certainly, with tamoxifen, it's better tolerated in the younger person. But more than that, I think that cancers are likely to be already present in postmenopausal women, and maybe the main thing you're doing is suppressing a cancer that's already there, as opposed to preventing it. Where, in a younger woman, you'd have a better chance to actually prevent it. But no, I think the aromatase inhibitors are worth investigating, given that data, in a high-risk population.
DR LOVE: Let's talk a little bit about the application of the ATAC trial data to clinical practice. I'm curious, right now when you see a postmenopausal, receptor-positive woman that you are thinking about giving or going to recommend tamoxifen to, are you bringing up the issue of anastrozole?
DR OSBORNE: Yes, of course. They brought it up themselves for the first month or so after the data came out, but I bring it up. We like to put a lot of our patients on clinical trials, as many as we can. We participate in the NSABP studies. So I talk with them about it. I also talk with them about the potential availability of the NSABP trial that randomizes patients between an aromatase inhibitor after they've completed their tamoxifen. So, many women are satisfied to learn that. Or, if I talk to them and they're already on tamoxifen and they're doing well, they seem to be reluctant to switch.
The new patient is the patient that perhaps is the most difficult. There, I go over the pluses and minuses. I go over their risk of recurrence and how much added benefit they would get from what we know so far on the aromatase inhibitors. Then, together, we make a decision about it.
DR LOVE: Has there been a consistent conclusion over the last couple of months in terms of who gets tamoxifen and who gets anastrozole?
DR OSBORNE: In my own practice, I would say that the lower-risk patients tend to still get tamoxifen, and the higher-risk patients get an aromatase inhibitor, primarily because of the bone issue. Maybe patients who had a hysterectomy also would be more likely to get tamoxifen because that particular benefit is no longer a problem. But you just have to individualize. Certainly, I think the aromatase inhibitors are going to be used more and more as we get more and more data.
DR LOVE: When you say an aromatase inhibitor, do you discuss all three or just anastrozole in these new adjuvant patients?
DR OSBORNE: Well, I think anastrozole is the one that people know about and the one for which we have the data. I tend to talk more about anastrozole because that's the one that people know about and bring up themselves, and that's the one we have data for.
DR LOVE: What about the determination of whether the patient, in fact, is postmenopausal? Specifically, the patient who is premenopausal at diagnosis, starts out on adjuvant chemotherapy, and ceases menstruating? Do you, at that point, view her as a postmenopausal woman in your decisions?
DR OSBORNE: Well, there are a couple of issues there. They might be postmenopausal, but the lack of a menstrual period doesn't guarantee that. So that patient, particularly a younger-age patient, needs to have an endocrine workup with FSH-LH and serum estradiol to be sure that they're postmenopausal. And, of course, even if they are, they may regain menstrual function. So, the 45-year-old or 42-year-old that loses menstrual function, that's a difficult case. Some of those women will regain it. Some of those are not postmenopausal even though they have amenorrhea. You have to really be careful there. It might be a better choice to use an ovarian ablation agent, rather than an aromatase inhibitor. But, if you're sure they are postmenopausal, I think an aromatase inhibitor is a reasonable choice.
DR LOVE: Another topic I wanted to ask you about is Faslodex. Can you start out by talking a little bit about the biology of Faslodex, how it works and what it is?
DR OSBORNE: Well, initially, Faslodex would have been grouped in along with other so-called anti-estrogens, like tamoxifen. But, in fact, if you look at the spectrum of drugs that interact with the estrogen receptor, there's estrogen on one end of the spectrum, and estrogen seems to stimulate most genes that are under its control after binding to the estrogen receptor. Then there are drugs like tamoxifen that stimulate some genes and inhibit others, depending on the tissue and gene. Then, at the far other end of the spectrum, there are drugs that seem to have a predominantly so-called pure anti-estrogenic profile. That means that on every gene that people look at, they're anti-estrogenic. They have none of these agonist qualities that tamoxifen does. One of these is Faslodex.
It's a different structure than the other SERMs, and I'd like to still think of it as a SERM that has pure antagonist qualities as opposed to some other new classification. But other people say they should be called pure anti-estrogens or pure antagonists.
DR LOVE: I've heard estrogen-receptor downregulator, too. That's another one?
DR OSBORNE: That's another one because it describes one of the differences in its mechanism of action. But it's a different structure. It's a steroid compound. It looks almost exactly like estradiol in structure except it has a side chain that seems to confer its anti-estrogenic qualities whereas the other SERMs - like tamoxifen, toremifene and the others - are non-steroidal compounds.
So, Faslodex has a different structure. In laboratory studies, there are two or three activation domains on the estrogen-receptor protein and these three different areas seem to be important in activating the transcription of genes. Tamoxifen only blocks one of those, probably the most important one, but it only blocks one of those. It leaves open - the other one is still active. Maybe that gives rise to some of the agonist qualities of tamoxifen, for instance. Faslodex, in contrast, blocks all of the activation domains on the receptor.
In addition, there's some less conclusive data that maybe Faslodex interferes with receptor dimerization. But then, there's the other observation that Faslodex-bound receptor is degraded so that somehow when Faslodex binds that receptor, it induces degradation pathways. What people find is that when you measure the estrogen receptor, over time, after treating an animal, a cell or a person with Faslodex, the amount of receptor in a cell declines. There have been studies showing that the receptor winds up in lysosomes and gets degraded.
All of our endocrine therapies target the estrogen receptor. That's the whole thing, you want to block the estrogen-receptor function or you want to get rid of the ligand, so-called estrogen that activates the receptor - that's how oophorectomy and aromatase inhibitors work. If you really want to design the best therapy, it would be to get rid of the receptor. Then you'd have no effect of estrogen at all. That's what Faslodex does. It reduces the level of the receptor. In some cases, you can't measure it after exposure to Faslodex.
So for those reasons, those different mechanisms of action, one could hypothesize, first, that Faslodex would be a more potent anti-tumor drug. It doesn't have any of this agonist activity. It blocks all the transcription domains and gets rid of the receptor. It might be more active. Secondly, it might work even in tumors that are resistant to tamoxifen, particularly those tumors that the resistance is due to tamoxifen-stimulated growth.
So, with those hypotheses in mind, it was studied in experimental animals, human breast cancer cells, and then eventually in patients. What we found in the laboratory in experimental animals was, yes, it is a more potent anti-estrogen than either oophorectomy to reduce the estrogen level or tamoxifen. This benefit showed up mostly as a marked prolongation to the time to resistance to development. So that in our model, by 100 days, three or four months, many of the tumors in mice treated with tamoxifen are beginning to re-grow and become resistant at the start of tamoxifen-stimulated growth.
With Faslodex, the period of time it takes for some tumors to become resistant is over twice as long. Not all tumors do. We've had some tumors - maybe 15 or 20 percent of them never started to re-grow on Faslodex. Some of those we've biopsied the area where the tumor was and there's no viable tumor. We've never seen that with any other endocrine therapy. It suggests that maybe in this model, Faslodex can even cure some of the mice.
So, we found that it's a more potent anti-tumor inhibitor. And when we used it in tumors that were being stimulated by tamoxifen, it inhibited those. We hypothesized it would in tamoxifen-resistant patients. Then it was taken to trials in the UK. I think it was a 19-patient trial. Most of the patients had acquired tamoxifen resistance. There was a sizable response rate and impressive response duration in those patients of over two years, which is really pretty long when you think of second-line hormonal therapy in tamoxifen-resistant tumors.
DR LOVE: Where are we in terms of clinical trials of Faslodex?
DR OSBORNE: As a result of the UK19-patient Phase II trial, several Phase III trials were activated in metastatic disease. Two of them - one in Europe and one in the States - compared Faslodex versus Arimidex as second-line therapy. Another, which has finished accrual, compared Faslodex directly with tamoxifen in metastatic disease. The tamoxifen study is maturing.
The two Arimidex studies are important studies. Remember that there are studies now to suggest that the aromatase inhibitors themselves are a little bit better than tamoxifen in metastatic disease. The European trial and the American trial are a little bit different in their structure and in results. I think the American trial has a better design. It was a double-blind study. Patients assigned to Arimidex still got the injections, but they received a placebo injection. So, it's clearly blinded. Also, because the patients had to come to the clinic once a month to get their injection, even if they happened to be assigned to Arimidex, there is consistency with regard to the patient being seen.
In the European trial, it was not a double-blinded trial, and the patients on Arimidex were seen every three months. The patients on Faslodex, of course, were seen by someone - might have been a nurse - every month. It runs the potential to have some bias there in terms of identifying when the patient progresses. Since the Faslodex group in the European trial is being seen a little more often, conceivably you would be identifying progressor patients a little earlier than an Arimidex patient.
Having said that, the results in the American trial show that the response rates are about the same between the two drugs. But in the American trial the response duration is about twice as long compared to Arimidex. In the UK trial, it doesn't show that. It doesn't show that the response duration is longer. So, we have a dilemma. Both of these are large trials. Why is that? One hypothesis is that: It could be due to these differences in follow-up of the patients. I don't know if you identified patients a month or two earlier, whether statistically that would show up as a change in response duration that would explain this result. I don't know whether that's the case or not. But we have slightly different results.
You have to keep in mind, though; aromatase inhibitors are very good drugs in and of themselves. In one trial, it's at least as good as Arimidex. In the other trial, at least in one parameter that you might have predicted from our model, actually, it might take a longer time for resistance to develop in those tumors that have a response, we see an advantage.
DR LOVE: How about toxicity and side effects?
DR OSBORNE: This is really very well tolerated. The monthly injection seemed like it was going to be a problem, but patients don't complain about it. It doesn't cause much pain or discomfort. That was specifically asked for, as you might imagine, and it's just not turned out to be an issue. The other side effects between Arimidex and Faslodex are very similar, and both drugs are very well tolerated.
There are theoretical reasons why Faslodex might not cause hot flashes because it seems like it doesn't cross the blood-brain barrier very well. After all, these are patients who have already been through menopause, usually, for quite some time, and they've probably adjusted to the hot flashes and they've gone away. In that setting, any endocrine therapy doesn't seem to bring on hot flashes very much. And both of them had a low level of hot flashes.
DR LOVE: Any other unexpected toxicities?
DR OSBORNE: Not really.
DR LOVE: At this point, do we know anything about bone or lipids?
DR OSBORNE: Very, very little. Not enough to say we have a conclusive answer. Obviously, these more pure anti-estrogens could theoretically be deleterious in bone and could be deleterious with cholesterol. That's not going to be important at all, obviously, for metastatic breast cancer. It becomes a little bit of a more important issue for adjuvant therapy. It becomes a big issue for prevention. So, I think additional studies are needed to sort those out. But if the drug is a lot better than some of our standard therapies, like tamoxifen for instance, in cancer patients, those other side effects are not as important. They can be dealt with, with other therapies. So, in patients who have low bone density, theoretically you could use bisphosphonates to counteract that. It's a potential negative, the healthier that the patient that you're studying is. But if it's a lot better cancer drug, in the end it will still be useful.
DR LOVE: What about combinations of Faslodex and other endocrine interventions? Any that intuitively makes sense?
DR OSBORNE: Well, I think a lot of them might. I think particularly intriguing would be an aromatase inhibitor plus Faslodex. There, you're doing two things. You're getting rid of the ligand, estradiol, or at least you're reducing it down to a very low level, and you're depleting the receptor. That might, theoretically, be a better way of treating patients. So, that would be an interesting combination.
DR LOVE: How do you think the intramuscular injection is going to be received by patients? Clinically, I can see a lot of different angles there. One, there may be reimbursement issues, but actually, I guess it could turn out to be an advantage in terms of reimbursement, to get an injectible. Obviously, there's the downside of receiving an injection, although there's probably a positive side, too, in terms of interfacing with nurses. How do you think that whole issue is going to play out in terms of the anti-tumor, non-biologic issues?
DR OSBORNE: Initially, we were a little bit concerned by the fact that it required a monthly IM injection. In fact, in the trial, it was not a problem, and most people I think would say that very few patients declined participation simply because they were going to get an IM injection. These are patients with metastatic breast cancer. If they think that there might be a better therapy or something that could work - I mean, after all, we give them high-dose chemotherapy and bone marrow transplantation. A monthly IM injection is a pretty modest annoyance, particularly since it doesn't cause very much, if any, real side effects.
Initially, the nurses were upset because they are routinely taught that you don't give more than a couple of ccs intramuscularly. In England, they were giving 5 ccs in one injection. Once the nurses got trained in the UK, it wasn't a problem. We thought it was going to be a problem in the States, and that's why we decided to give bilateral injections of 2 ccs in each dose. I think, from what I know now, if I had a patient, I'd give all of it in one dose in one buttock. That seems easier and it doesn't seem to be any more toxic or have any more side effects. If you think about it, would you rather have a little bit of soreness in one buttock or would you rather have a little bit in the other? In fact, most patients have none, so it's really a non-issue. I think it just requires education of the nurses and physicians, that giving a big dose is okay in this situation.
So, in the end, I think for metastatic disease it's not an issue. Maybe it will be a little bit more of a problem when you go to healthier and healthier patients. But I think if they knew that they had a drug that was more effective - and now I'm assuming - but let's just take the possibility that in the adjuvant setting, it's a little more effective. I don't think you'd have any trouble convincing a cancer patient who has a life-threatening disease to come over and have a nurse giving her an IM injection once a month.
The other issue that continues to bother some people and me is the dose of Faslodex. I'm concerned that, at least in some women, the dose is insufficient. Also, the serum levels don't reach steady state until after the second or third injection. I'm afraid that many patients are deemed to have progressive disease during that first month or two before they even have sufficient levels to downregulate the receptor. One way to get around that would be to give two injections during the first month to boost up the level more quickly. I think one of the trials that's going to be coming up - a large randomized trial that's likely to be done, comparing again, as I understand it, an aromatase inhibitor with Faslodex versus the combination - will do just that.
I'm also concerned that the serum level, even after steady state, may be a little bit low in some women. We get a hint of that because when you do biopsies in some women after they've been on the drug, the estrogen receptor is still detectable or it hasn't been downregulated as much as you'd like. So, I think that we need to do more studies, and I think the company feels that way and is going to be exploring some doses. Now, it's a hard drug to increase the dose because it's an intramuscular preparation. You can't give much more than five ml's in an injection, but you could give an injection on either side, for instance. People don't tend to mind these intramuscular injections. You could give two of them and double the dose. That might be another strategy to look at. But I think this dose issue is important to follow up on.
DR LOVE: What about in premenopausal women?
DR OSBORNE: We just don't know. If the dose is insufficient in some postmenopausal women, then I'm sure it's going to be insufficient in many premenopausal women. But we need to do the studies, and we need to see if there is activity in younger women. I'm very concerned that there won't be.
DR LOVE: What about adjuvant trials? Where does that stand?
DR OSBORNE: They're in the planning stage. But I'm sure that as more data on this dose issue and more data for metastatic disease become available, and if the data continue to look attractive, then I think it will be moved forward into the adjuvant situation.
DR LOVE: When you first presented these data at last year's San Antonio meeting, one of the points that you were making was perhaps we might see an even greater effect in the adjuvant setting. You used the analogy of tamoxifen, which was so-so in the metastatic setting, but had a great effect in the adjuvant. Is that still your thinking?
DR OSBORNE: That's been the case for almost every treatment that we can think of, endocrine therapy or chemotherapy, and I think we see the same thing with anastrozole now. It doesn't cure anybody with metastatic disease. The remissions are not that frequent, even in ER-positive patients. But when you put it into the adjuvant situation, where you have micro metastatic disease, then the effects are much, much greater. So, yes, I think the same thing would happen with Faslodex. The effects that we see in the adjuvant situation are likely to be much greater than the benefits in the metastatic setting.
DR LOVE: You mentioned the idea of combining Faslodex and anastrozole. Do you think that the fact that the ATAC trial combination arm was disappointing is going to push people away from looking at combination endocrine therapy?
DR OSBORNE: It might. But I think if they understand and you explain to them the biology behind it and how these drugs work, then they'll be less reluctant to do that. As I mentioned, when tamoxifen binds to the receptor versus Faslodex binding to the receptor, you get two different things. With Faslodex combined with an aromatase inhibitor, based on the biology, you wouldn't predict a worse outcome, like you do with tamoxifen that has this intrinsic partial estrogen agonist activity. Faslodex doesn't. And Faslodex tends to downregulate and get rid of the receptor, which might be the best form of therapy. So, I think when you understand the differences in how these drugs work at the molecular level, then it makes sense.
DR LOVE: In terms of combinations, I heard you talk yesterday about combining tyrosine kinase inhibitors. I am hearing more people talk about, for example, trastuzumab and endocrine therapy. You were talking about Iressa and tamoxifen. Can you talk a little bit biologically, in terms of what's happening in the cell and what the rationale is for these kinds of strategies?
DR OSBORNE: Well, it turns out that the estrogen pathway, through the estrogen receptor, is not as simple as we once thought it was. And that an important component to estrogen's growth-stimulating effects on the tumor involve growth-factor pathways. With some tumors, the growth-factor pathways probably don't add much. But in other tumors, particularly those for instance that have amplification of the HER2 oncogene, they do. What the growth factors essentially do, to make a long story short, is that they can phosphorylate and activate the estrogen receptor and activate one of the important estrogen-receptor co-activators, called SRC-3 or AIB-1. It goes by a variety of different names.
When you activate the receptor and activate AIB-1, SERMs like tamoxifen are converted into potent estrogens. In the laboratory, you can show that tamoxifen as a potent estrogen has very little antagonist activity. In experimental animals, you can show that. We just submitted a publication looking at the levels of HER2 and AIB-1 in human tumors, and showed that those tumors that have high levels of this AIB-1 co-activator, high levels of estrogen receptor and high levels of HER2 don't seem to benefit at all from tamoxifen.
DR LOVE: This was a clinical thing?
DR OSBORNE: It's a clinical study.
DR LOVE: Wow!
DR OSBORNE: So, now this clinical data from tumors supporting what we've been finding in the laboratory just adds more rationale to inhibiting those pathways. When you take a receptor tyrosine kinase inhibitor and treat a human breast cancer growing as a xenograft in an athymic mouse, if that xenograft does not have overactivity of the HER2-pathway, nothing happens. Iressa doesn't do anything. Herceptin doesn't do anything.
But, when you use the same therapy in the same tumor that's now been engineered to overexpress the HER2 oncogene, tamoxifen no longer works. It acts as an estrogen. When you use combined therapy with blockers of the growth factor receptor, Iressa or trastuzumab, either one, has a dramatic effect. It restores and prevents the tamoxifen-stimulated growth. So, it's restoring tamoxifen's antagonistic activity and getting rid of its agonist activity, which is mediated largely from the growth factor pathway.
We also find in the laboratory - and I'm sure it's going to happen in people, as well - that the normal tumors without overexpression of HER2, initially, are unaffected by Herceptin or Iressa. But while they're being treated with an endocrine agent, the cell upregulates signaling through the EGF-receptor HER2 pathway not by increasing the numbers of HER2 receptors. It may do it by increasing the numbers of EGF-receptors, but the signaling through that pathway is increased.
Furthermore, the signaling through what's called the stress kinase pathway is increased, and this has been shown in people, as well by Mitch Dowsett's group. You see increased levels of an enzyme called jun kinase, which is in the stress pathway. We've also shown increased levels of the p38 kinase. These can do the same thing. These get upregulated in the tumor over time, maybe as a protective mechanism. So this acquired resistance can be explained, maybe, by these growth factor pathways. And thus, maybe using the receptor tyrosine kinase inhibitors in combination with the drugs initially won't have an effect. But maybe it would delay the onset of acquired resistance.
DR LOVE: Any reason to think that there'd be greater synergy with a drug like Iressa than, for example, trastuzumab?
DR OSBORNE: There might be. These drugs, as it turns out, do slightly different things. It seems, from some data that was actually presented here, yesterday, by Lance Liotta's group, by Emanuel Petricoin, that maybe the major effect of blockade with trastuzumab is to inhibit the cell survival pathway by blocking PI3 kinase and down-regulating AKT. In some studies, you can't see a reduction in cell proliferation, for instance, with Herceptin. Iressa, on the other hand, in studies in nude mice and with human breast cancers transplanted into mice, the predominant effect may be a cell proliferation inhibition. These growth factor pathways can stimulate the cell survival pathway or the cell proliferation pathway or even the stress pathway. And these inhibitors may have variable effects on these different pathways. There's some evidence, at least, that maybe Iressa and trastuzumab may work slightly differently and, therefore, they might have different effects in different situations in the patient.
DR LOVE: Of course, this ties into something clinically that we've known, which is that women who are HER2-positive and ER-positive don't seem to have quite as much benefit from endocrine therapy, as those who are HER2- negative.
DR OSBORNE: That's right. I think that people point out that the studies are not dramatic and that they're inconsistent. That's all true, but I think that one of the reasons for that is the difficulty and non-standardization of the way we measure for HER2, number one. And number two is that we're only measuring one component. What we are showing now, in this clinical study that I referred to that we submitted for publication, is that it's only the tumors that have high levels of AIB-1 and HER2 that show lack of response to tamoxifen. If you have high HER2 levels but low AIB-1, or high AIB-1 but low HER2, patients benefit from tamoxifen very well. It's only those tumors that have high both, which makes sense. So, if you're just measuring HER2 by itself in a bunch of tumors, maybe you'll see a little bit of an effect, but not a big one, which is exactly what we see. But when you measure both, it's a dramatic effect.
DR LOVE: Do we know what percent of HER2-positive patients are also AIB-1- positive?
DR OSBORNE: It's interesting. They have a direct correlation with each other. So, it's more than half. It's about 60 percent of those that overexpress HER2, also overexpress AIB-1. So, that's going to mean that maybe 10 to 15 percent of tumors will express both. It's a small subset, but it's worthwhile to know about those, because then we would feel good about giving those other HER2-positive patients an endocrine therapy, like a SERM or tamoxifen.
DR LOVE: How do you usually approach the patient - for example, with first metastatic disease who is ER-positive, HER2-positive in terms of clinical decision-making?
DR OSBORNE: I still give them endocrine therapy, all other things being equal. In the past, I gave them tamoxifen, knowing that maybe there were some patients that wouldn't benefit. But some do. Now I tend to use more aromatase inhibitors in that situation based on data from my own laboratory showing that these HER2-overexpressing tumors respond very well to estrogen deprivation, whereas they don't respond at all to tamoxifen. The clinical data from Matt Ellis' neoadjuvant trial, which I find very interesting and hypothesis-generating, showed a dramatic difference between treatment with letrozole and treatment with tamoxifen in the HER2 overexpressing subset. Now, people argue it's a small number of patients and so forth, but the results were dramatic, and they follow what I think are biologic principles. So, I'm inclined to believe that they're true. We need more studies of that. But, for the moment, until we have more studies, I think using an aromatase inhibitor in that situation before tamoxifen makes a lot of sense.
DR LOVE: When those patients progress and you have decided that you no longer want to use hormonal therapy, how do you sort out your systemic options at that point in those patients?
DR OSBORNE: In the HER2-overexpressing patient, it depends on the situation. If the patient has relatively indolent disease and you can spare time to try them on a receptor tyrosine kinase inhibitor like trastuzumab by itself, then I would be inclined to do that. Then I would add chemotherapy if they don't respond or later at the time of progression. It's just a way to keep the quality of life pretty good. On the other hand, if the patient has a lot of visceral disease and so forth, then depending on what they might have had chemotherapy-wise in the adjuvant and how long they recurred after stopping adjuvant therapy, I might employ a taxane, for instance. Or I might use one of the other drugs that looks like may have an additive or synergistic effect when you combine them with trastuzumab.
DR LOVE: How long do you generally continue the Herceptin in those situations when they progress, whether they're on single-agent or with chemotherapy? Do you stop the Herceptin? Some people have been continuing it and adding another chemotherapeutic agent.
DR OSBORNE: That's what I tend to do, but I have no idea whether it's the right thing to do. It may be, and I think we need to have more study about the indefinite. So, I tend to continue it as long as we've elected to treat the patient with chemotherapy. It's expensive, and that bothers me. It's also impractical for some patients to have to come in every week, although there's a three-week preparation now. That makes it a little bit easier. But you could make some biologic arguments that Herceptin by itself is not what's inhibiting the tumor, but it is helping the chemotherapy drug work better. So, let's keep it there, priming the chemotherapy drug to work better. There is some data to suggest that that may be how it works. So, for the moment, I've been in the school that continues it.
DR LOVE: What about the HER2-negative patient let's say ER-negative, in general? How do you sort through systemic treatment options, first in the metastatic setting, for those patients?
DR OSBORNE: Well, most of the time, they're going to wind up getting chemotherapy initially, although there is a subset that maybe I don't believe the receptor assay. I'll repeat it. Or, if the tissue's not available, maybe I'll give the person a trial of endocrine therapy, if they have really indolent disease. There are some patients that behave more like ER-positive patients even though the receptor data say that they're negative. So sometimes there, I will go ahead and give an endocrine therapy. I realize there's only a five to ten-percent chance that there are really receptors there that might respond. But, you haven't lost anything, in my opinion, in those patients. So, in some cases, I'll give a trial of an endocrine therapy.
Most of the time I'll go to chemotherapy. What chemotherapy I use is based initially on what they had as an adjuvant therapy and how long they recurred after stopping their adjuvant therapy and so forth. When I first started taking care of breast cancer patients, I used to get really hung up on what was the right strategy for taking care of metastatic disease and which regimen should I use first, and which one should I use second. But now I'm really convinced that it doesn't make a difference at all. I think we're barely scratching the surface, and barely prolonging survival and improving quality of life with any of these therapies. In the CALGB study published several years ago they did a randomized series of trials of a Phase II agent with no track record in breast cancer comparing it with CAF chemotherapy. They then gave CAF when the patient progressed on the Phase II agent. There was no difference in overall survival. So, I think it probably doesn't make a bit of difference what sequence you use, what drugs you use.
I'm much less concerned about that than I was before. I'm also much more inclined to use experimental drugs earlier in the course than I was before because I can always go to the more established drugs if those don't work. We have not made much headway in metastatic breast cancer. We're still using, with the exception of the taxanes and some of the other newer agents and you could argue how much they really add, the same basic drugs that we did 20 years ago. We haven't made a lot of headway, and we haven't made a lot of progress in improving survival of those patients. So, we have a lot of room for improvement in the metastatic situation.
DR LOVE: Again that also leads into the issue of combination therapy. What are your thoughts on that?
DR OSBORNE: I tend to use combination therapy initially, again, depending on what the patient had before. If they haven't had an Adriamycin-containing regimen, I'd probably use a combination of Adriamycin. If they haven't had a taxane, I might use taxane plus Xeloda. But I can't argue with those who point out that the study showing a survival advantage did not have a crossover sequential arm, and my guess is, if you did, it would probably be the same. So, I think either a single agent or a combination. After that initial therapy, though, I tend to use single agents. I'm not a real strong believer that combinations offer anything other then more toxicity.
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