DR NEIL LOVE: Dr Burstein mentioned the dilemma that clinicians are now facing in incorporating the new data from the ATAC trial into the adjuvant therapy treatment decisions of postmenopausal patients. A few hours after Dr Michael Baum presented the compelling ATAC results in San Antonio, I met with Dr Jack Cuzick, a regular guest to the Breast Cancer Update series. Dr Cuzick had a fascinating role in the ATAC trial. And as I was to soon to find out, as the only independent statistician for the study, he alone kept the biggest secret in breast cancer research for more than six months.

DR JACK CUZICK: My role is the so-called independent statistician. This was a groundbreaking trial in terms of methodology and in terms of the partnership between industry and academia. Because it was a placebo-controlled trial that was going to be used for regulatory purposes, it made sense for the industry to do all of the monitoring, the data collection and the data management. But, they did that blind to what treatment any of the patients were on. So only I, as the independent statistician, was able to actually link that data with the treatment code to provide the monitoring results for the data-monitoring committee, and then ultimately to do the analysis which you have seen today.

DR. LOVE: So you were seeing the data yourself and then presenting that data to the data-monitoring committee?

DR CUZICK: That's right. My role as independent statistician was essentially a bridge between the steering committee, which ran the trial, and the data-monitoring committee, which kept an eye on the results as it was going along. So, the only person who actually saw the unblinded data was myself. The data-monitoring committee got the results as coded results A, B and C. They could have unblinded it if they wished to, but they chose not to.

DR. LOVE: So, you're the only person who has been watching this trial evolve in an unblinded fashion?

DR CUZICK: That's correct. So, it's been a difficult six months, because the results began to appear about 6 months ago, in a very early way. We've been monitoring on a monthly basis more recently.

DR. LOVE: So, what were your thoughts when you started to see this evolve over the last six months?

DR CUZICK: Of course it was great excitement because tamoxifen has been the standard treatment, endocrine treatment, for breast cancer for 30 or 40 years. To now see a new treatment that looks like it is going to be better, not only in terms of efficacy but also side effects, was very, very exciting. It was very difficult to keep quiet. But, I think we did manage to maintain the blindness. Actually, no one knew the results until they were announced today.

DR. LOVE: What was it like for you to sit in the auditorium today?

DR CUZICK: It was quite exciting actually, and a relief in a way. At least now, I can talk about the results. It has been a little difficult to know these results and not be able to speak to anyone about them. This, of course, is still early data; it is only two-and-a-half years out. But, we're seeing the same striking improvement that is very consistent in terms of being unaffected by subgroups. The fact that the contralateral disease seems to be even more affected then the recurrence data; it is all really very exciting.

DR. LOVE: Would you say that there were any qualitative surprises or things that we didn't expect?

DR CUZICK: Well, that's interesting because we asked people what they thought the results would be. In fact there was a steering committee meeting that met three weeks ago in which the results were presented. Before I announced the results, we had them all fill out a form indicating what they thought the results would be. They were all over the place. We had six people who said the combination was going to be the best, four that said anastrozole would be the best, and four that felt there wasn't going to be any difference at this early stage. So, there was a lot of uncertainty.
I guess the thing that is most striking is the clear evidences that the combination in no better than tamoxifen alone. We were beginning to see the evidence from the advanced disease trials that the aromatase inhibitors looked to be more affective than tamoxifen. So, although that is really gratifying to see in the adjuvant setting, that's not so unexpected. I think nobody had a clear view of what would happen in the combination arm, and the fact that the agonist properties of tamoxifen seem to be dominant in an estrogen-deprived situation; it is really very interesting.

DR. LOVE: I wonder what's going on there. Mike mentioned the concept that maybe, in a very, very low estrogen environment; tamoxifen has an agonist or stimulatory affect. On the other hand, if we lower estrogen levels by giving a patient a LHRH agonist, tamoxifen works just fine.

DR CUZICK: Yes, but we're talking about a much lower level of reduction now. I think that has been a key biological observation that ideally should be more clearly demonstrated by specific studies. But it does indicate that if you get estrogen right down to the virtually 0 levels that aromatase inhibitors achieve in post menopausal women, then the dominant effects are just the agonist properties of tamoxifen. We know, in postmenopausal women, that tamoxifen completely saturates the receptor. I guess, in retrospect, you might say that estrogen levels were irrelevant to the tamoxifen effect in postmenopausal women because once the receptors are completely saturated there is no benefit by reducing estrogen levels down lower. That's another way to look at it. Once you saturated the receptors with tamoxifen, which you do in postmenopausal women, going on to then reduce estrogen levels lower has got no effect on the disease.

DR. LOVE: In terms of the benefits, a lot of people were expecting them, and the side effects are all things that have kind of been seen, but perhaps it was interesting to see them so early. There were people who thought there was going to be a benefit, but that we wouldn't see it this quickly.

DR CUZICK: Yes, I think it's a surprise too, that the benefit emerged so clearly and so strongly. We're talking about in receptor-positive women a 25% reduction in recurrence rates, which is really quite substantial.

DR. LOVE: 25% over tamoxifen.

DR CUZICK: Yes, which is almost - tamoxifen itself produces about a 40% reduction in recurrence rates and then to get another 25% on top of that is just an enormous step forward. And, to do so with a side effect profile that is generally more favorable. I think that we need to look at that more carefully, and that's one of the areas where we need to be cautious. This is early days for a very new drug with a profoundly different effect in terms of reducing estrogen levels to these very, very low levels. You begin to see effects on bones, which hopefully will be manageable, but they are pretty clearly real. There are more concerns about cognitive function and whether or not these very low levels will actually affect memory and cognition. Again, these are probably manageable problems, but there is still work to be done in that area.

DR. LOVE: Let's talk about those two things specifically, because in a way, it was a little hard to understand some of the numbers that were put up there. For example, there was a difference in fractures that was discussed, but at this point the actual number was very minimal. It was 2% or something. What does that really mean?

DR CUZICK: In fact, the fracture rate was increased by 60%. It went from roughly 5% in tamoxifen up to about 7% in anastrozole. So, the relative increase is, in fact, higher then that. The relative increase was over 50%. But, it's a small number to start with. Of course, we know that tamoxifen has a beneficial effect on fractures. But there is still the issue of what extent you are just seeing the beneficial effect of tamoxifen compared to the lack of a beneficial effect with anastrozole, or whether in fact, anastrozole is actually increasing the fracture rate.

DR. LOVE: So, in other words, we really don't know what the fracture rate or the difference would be in terms of bone density of anastrozole compared to just being postmenopausal?

DR CUZICK: There will be some more data coming out on the bone subprotocol in a few more months. But at this stage, all we can really say is that we've got an increase of over 50% in fractures. We know that about half of that could be attributed to the reduction there is in fracture rates associated with tamoxifen if we use the P-1 trial as evidence of how much reduction there is in fractures in women just taking tamoxifen. So probably, half of that effect is a tamoxifen benefit and the other half is an anastrozole deficit in bone.

DR. LOVE: The last time we talked, you talked about the issue of if that's going to happen, one option might be to use bisphosphonates and other strategies. Any thoughts about how difficult it might be to reverse that?

DR CUZICK: I think it's going to be reversible. In fact, it is now going to emerge as one of the key issues in breast cancer management. Particularly, if we are talking about giving aromatase inhibitors for a long time. This is just thirty months of treatment. The trial is scheduled to go on for five years, but there is discussion as to whether or not we should rerandomize it five years to go on for ten years. We're talking about really long-term issues. The issue of how to manage bone is going to become paramount. There will be discussions of how to do that within the ATAC trial. In the forth coming prevention trial, the IBIS II trial, we've got a very detailed bone protocol in which we want to look at 900 women very carefully not only to monitor the effects on bone upfront, but also to look at strategies for controlling that. So, in that subprotocol women will be randomized to get vitamin D and calcium supplements or placebo. Hopefully, that will control bone for the majority of women, but if that fails and they do become osteoporotic, then we need to look at the bisphosphonates. I think there will be a lot of effort in terms of determining how effective bisphosphonates will be in this circumstance.

DR. LOVE: I would think in terms of a non-protocol situation, there's no reason that a clinician can't just monitor bone density?

DR CUZICK: Well, I think that's the answer. I mean DEXA scans are really quite straightforward to do, and now they're a small cost compared to the cost of these drugs. To monitor bone density and treat it as needed, I think, is going to be the answer.

DR. LOVE: That was one of the side effects, or the down sides that came out. The other one was the arthralgias. Anything that's mentioned in terms of that, and how much of a problem that was?

DR CUZICK: Difficult to say at this stage. This has certainly been observed in a number of different aromatase inhibitors, so it does seem to be a real effect. The result is overwhelming clear, here, in this trial. It didn't have a large effect in terms of dropouts, so women were able to manage that. We need to look it a lot more carefully in terms of the severity of that data and the duration of that data. To be honest we haven't fully explored that information.

DR. LOVE: Although the number that I saw was not that large, I think it was a 6% difference?

DR CUZICK: It was a 6% difference. A 6% increase, which is quite a big change. But, those numbers are for any severity, at any stage. We need to look rather carefully, as to whether this is a continuing problem and whether it is mild, moderate or severe as well.

DR. LOVE: I think the anecdotal observations that I hear people talking about are that these generally are tolerable and that women usually are able to continue treatment. Is that your take on it?

DR CUZICK: I think that's what we've seen. Certainly the dropout rates have been very, very low in this trial. The women have been more than happy to stay on the treatment.

DR. LOVE: There was another thing that I was absolutely stunned by. To me it was the most striking thing and I was amazed that it would be seen this early. In fact, the last time you and I talked, we discussed the IBIS trial. I remember we talked about second breast cancers and you said, "We're not going to see that that early." When those numbers went up, I was stunned.

DR CUZICK: I've been quietly stunned with that data for some time now. We've been watching it very, very carefully. It's very, very exciting. This is a very serious prospect for prevention now. We're talking about a 60% reduction of contralateral tumors from the rate that tamoxifen was achieving. Which itself is 50% reduction from no treatments at all. If that actually pans out, we're talking about a potential of 80% reduction in new cancers. If this were to be the case in the prevention setting that would just be fantastic.

DR. LOVE: The other thing about that is, as I've seen people react to the tamoxifen prevention data, and of course there is lots of debate about what that really means, and how it applies clinically. I think the big thing that has held people back in terms of tamoxifen has been the issue of endometrial cancer and thrombosis, and you're not seeing that here.

DR CUZICK: The endometrial cancer data is very striking. There are eleven cases in the tamoxifen arm vs. three in anastrozole. So, it is right down to the background rates in the general population. There is no evidence whatsoever for the endometrial cancer problems. The thromboembolic problems also aren't there. Those are the two key issues that really make tamoxifen a difficult issue in prevention, and why we're continuing with the IBIS I trial. We think the balance between those side effects and the benefits in breast cancer incidence are still not clear.

DR. LOVE: Any reason to wonder whether or not the anastrozole might actually reduce the incidence of endometrial cancer?

DR CUZICK: Well, we know endometrial cancer is associated with estrogen stimulus, and if you're going to reduce the estrogen stimulus, there's no reason to think that you aren't going to be reducing endometrial cancer. That is a real prospect, the numbers are too small at this stage to do more than speculate on that. Undoubtedly, we will have quite a lot of data emerging on that over time. It is a real prospect that you may have a drug here that's reducing endometrial cancer risk.

DR. LOVE: You're now talking about taking this into the prevention setting, and again, the last time we talked you were talking about the IBIS II trial that is going to look at anastrozole vs. tamoxifen vs. placebo. Where is that?

DR CUZICK: That study now has ethical approval, and it is all ready to go in the UK. We've been to the regulators and some of the funders and they basically felt that, given that the ATAC data were about to come out, they wanted to see those, particularly on the safety profile, before they actually made their decision. It's a very big day for the prevention trial. But now that this data is available, I'm fairly confident that we will be able to proceed rather rapidly with getting off with that trial.

DR. LOVE: Obviously, there is a huge difference in perspective about chemoprevention on each side of the Atlantic and you've been in the middle of that discussion. But I was wondering how the NSABP people were viewing these data, particularly in terms of the STAR trial looking at that question of two different SERMs in the face of these new data coming out?

DR CUZICK: I think both questions are still valid. The raloxifene data that we have to date also suggests a substantial benefit above and beyond tamoxifen in terms of breast cancer incidence reduction. A 70% type reduction as opposed to 50% reduction. In a sense, the two approaches are kind of at the same level now. We've got very clear early data from this one trial - the big effect on contralateral tumors. We've got similar kind of data although it is in the prevention setting from the MORE trial indicating similar levels of reduction with raloxifene. I think both approaches are still valid. I think this certainly stimulates the approach for using aromatase inhibitors. In the end, if they're both equally efficacious then the side effect profiles are going to dominate which one is going to be adopted. I think for that reason both trials are really quite valid still.

DR. LOVE: Another thing that came out today was the issue of hot flashes, which wasn't a huge surprise. On the other hand, I think in the metastatic setting it wasn't that clear. I think the clinicians had the feeling that anastrozole had less toxicity in terms of vasomotor symptoms, but the actual numbers in the metastatic trial didn't really show it. This seemed to show it pretty clearly.

DR CUZICK: That's right. The advanced disease studies were actually very similar. There was no clear evidence in terms of what was recorded, although I've gotten that impression from a number of clinicians as well. The results were surprising in my mind. I think it was another surprise that the effect was so large. It was about a 6% percent reduction from 34% down to 28% reporting it at any stage. With such big numbers, that's highly significant. We need to look at that a little more closely. There is a quality of life study within ATAC that is looking at 1000 women in more detail in terms of the specific symptoms, the whole range of symptoms, that they've had. This is just the toxicity data recorded in routine physician visits, without a checklist. It is simply a recording of any symptoms reported at follow-up visits. Still, I think it is quite valuable. Because the trial is placebo controlled it is probably unbiased.

DR. LOVE: When you say placebo controlled, what do you mean?

DR CUZICK: Sorry, in fact it's a double placebo. This is a complicated disease. It is a double-dummy trial. To be more precise, every patient takes two tablets. One is potentially placebo and one is active. So, they are either taking anastrozole and a tamoxifen placebo or tamoxifen and an anastrozole placebo, or both are active. But they don't know which is which. So, although we don't have an untreated arm, it is effectively a completely double-blind trial.

DR. LOVE: The conclusion is, there are less hot flashes with anastrozole?

DR CUZICK: Yes, and that seems to be quite clear from this data.

DR. LOVE: But, we don't know, for example, whether or not anastrozole increases hot flashes over a control.

DR CUZICK: That's correct. There is no control data here at all, but they are reduced compared to tamoxifen or the combination.

DR. LOVE: The other thing that was kind of surprising was there was less weight gain, if I saw those numbers correctly.

DR CUZICK: That data again, I think we want to look at more carefully because this was just looking at women who had a 10% weight gain or more over the first two years of the trial. Just according to recorded weights, in fact there were fewer such patients on the anastrozole arm than on the tamoxifen arm.

DR. LOVE: A lot of people ascribe weight gain to tamoxifen, and yet the placebo control trials haven't shown that.

DR CUZICK: All of the evidence that is reliable indicates that there is no weight gain associated with tamoxifen, and that weight gain is just as much on placebo as it is on tamoxifen. So, the conclusions you would draw here, and again it should be looked at much more carefully, is that potentially there is a bit of weight loss associated with anastrozole. I think it is too early to look at that data. We have only had the data in final form for three weeks, so we just touched the surface of really exploring a lot of these somewhat surprising new side effects.

DR. LOVE: By the fact that you are seeing all these data as they come out, are you aware of things that weren't even presented today?

DR CUZICK: I'm aware of some things. The full side effect profile, we actually didn't have in good form until three weeks ago. In terms of the event data, we were monitoring that and some of the major side effects throughout the trial. Some of the things like weight gain were not fully on the database because it was not a priority issue. We only had that data for a very short time.

DR. LOVE: I know you can't talk about specifics, but are there any other qualitative things that we're going to find out about, that you're aware of now? Or do we know the major qualitative things?

DR CUZICK: I think we know the major qualitative things. The thing that we did see today, that we haven't talked about is the reduction of strokes. This is a fairly elderly population. The age distribution is quite old, with a lot of women in their 70's and 80's in this trial. Over that first 30 months of treatment there was 2.1% strokes on tamoxifen, and only 1% on anastrozole. So, the stroke rate has been reduced by more than 50%. That is highly significant and potentially very important in terms of the prevention setting.

DR. LOVE: Also, there was a decrease in other thrombotic events.

DR CUZICK: Yes, which again, is less surprising because of the estrogen stimulus. There are other data around, but I think there is nothing major that I'm aware of that we'll see. There are some of the other endometrial symptoms and so forth, which hasn't been shown yet, for which there will be data available quite soon.

DR. LOVE: Vaginal bleeding was another thing that there was a big difference in.

DR CUZICK: That was an enormous effect. Again vaginal bleeding is increased by tamoxifen, and we saw an 80% reduction when you go onto anastrozole.

DR. LOVE: All these things, it seems like what is happening is: an absence of toxicity with anastrozole, an absence of the increase in thrombotic events, an absence of the increase of endometrial cancer and vaginal bleeding. Is that your take on this, or do you think they are actually being reduced?

DR CUZICK: It's too early to be really certain about reductions. At this stage, I think all we can be moderately confidant about is, that there is no increase for many of these things. Certainly issues like endometrial cancer and even thromboembolic events. There are theoretical reasons to believe they may be reduced because we know they're estrogen-related, so it is conceivable that they will be reduced below background rates. But it is too early to make those assumptions. It will be very difficult to do that without a control arm in the study.

DR. LOVE: You mentioned stroke, which you seemed a little bit perplexed about. We saw an increase rate of stroke in the prevention trial.

DR CUZICK: We saw that in the P-1 trial, and I think people were still a little skeptical as to whether that was real or not. It was observed as a hypothesis-generating observation almost. I think people were waiting to see whether or not that will be confirmed in some of the other prevention trials. This is kind of an indirect confirmation in a way that it is higher in tamoxifen than it is in anastrozole and that this may be a side effect of tamoxifen.

DR. LOVE: Obviously, there is going to be a huge amount of discussion amongst clinicians in terms of what this means. I'm sure you have already been exposed to lots of discussions. What about what it means to the trial itself? The patients in the trial or still on the trial, most of them are kind of in the middle of their treatment, I would guess.

DR CUZICK: Yes, most of the patients are in there third or fourth year of treatments, although there are about 20% of them who have less than three years of treatment at this stage. It is a very important issue. I think we will evolve in the way it is being dealt with. The one thing that is clear is that the women in the study will all be informed of these results, and they will be reconsented to join the trial. The other belief is that the combination arm will be discontinued.

DR. LOVE: What will happen to the women on the combination arm?

DR CUZICK: Again, there is discussion as to what will finally happen. But, it is very likely that they'll have a free choice of choosing one arm or the other. Or there is a possibility that they may actually be randomized between the two other arms until we get clear evidence of the difference between anastrozole and tamoxifen in terms of overall clinical benefits.

DR. LOVE: If the patient is informed of the results of the study and wants to know what they are receiving, will they be able to find out?

DR CUZICK: Of course, patients have that right at any stage.

DR. LOVE: So, they will be told what they are receiving and then they'd be out of the trial? Or could they continue?

DR CUZICK: If they break the code, they basically will be out of the trial.

DR. LOVE: Do you expect that to happen to any great extent?

DR CUZICK: It's really difficult to predict that at this stage. My feeling is that it is a little bit early to be declaring absolute victory and going home here. We're talking about 30 months of treatment; we've got an effect on overall disease free recurrence rates. We still don't have an effect even on distant recurrence, let alone breast cancer mortality. We do have some worries about the bone issue. I think there is a belief that it can be managed, but we don't have any evidence that it can be and we don't know how difficult it will be. My feeling is, personally, it probably makes sense to maintain those two arms, the tamoxifen alone arm and the anastrozole alone arm.

DR. LOVE: I guess the two populations that are out there in a non-protocol setting that there are going to be a lot of questions about are, obviously, the women presenting today with primary ER-positive breast cancer today, and the ER-positive women who are currently on adjuvant tamoxifen. I can see clinicians in the audience already scratching their heads about what they are going to do when they get back to the office.

DR CUZICK: I think there is going to be a very, very active period of head scratching and soul searching as to what the correct approach is on this. Especially for women who are already on tamoxifen and apparently doing well on it. In fact, these data provide no direct evidence at all for swapping treatment at some intermediate level. It is my hope that this trial will have a rerandomization at some stage to look at either stopping at five years or whatever stage women choose to stop. It is protocol that they will go to five years. They would either then stop treatment, or to go on anastrozole for another five years. That's an issue that we are discussing now, and we need to discuss those issues. I think the duration issue is going to emerge as a very key issue, you know, how long should you be on anastrozole.

DR. LOVE: Do you have any gut feeling about that?

DR CUZICK: My gut feeling is that probably longer is going to be substantially better than shorter. That five years may just be the beginning. It may be that ten years is best. The issues there will be the bone problems, and if there is an effect on cognition. Long-term treatment may require really learning how to manage these other symptoms.

DR. LOVE: You said that for the woman that is on adjuvant tamoxifen, we have no data, in terms of switching, for example if she is a couple years out. Any thoughts about what the risk/benefit would be? Do you have any guess on that, or do you just have no clue?

DR CUZICK: I don't think it is helpful to speculate. The quickest way to actually learn that information, would be for the women who are on the combined arm, which by and large looks to be essentially the same as the tamoxifen arm in terms of the side effect profile, in terms of the recurrence profile. If these women were rerandomized to tamoxifen or anastrozole, it would provide some indirect evidence about what happens if you carry on with tamoxifen. If you treat the two to three years that they have been on the combination as essentially being on tamoxifen, and if we randomize them, that would then be like five years of tamoxifen vs. say two years of tamoxifen vs. three years of anastrozole. I think we could learn a lot from that, if we actually do go forward with that. But, it is not clear that that would be possible.

DR. LOVE: Also, it might be interesting biologically, but by the time you have the answer it might be a moot point clinically, if the standard therapy switches. So, you will not have people starting out on tamoxifen if that, in fact, is what happens in practice.

DR CUZICK: That's always a possibility, yes.

DR. LOVE: Do you think that's what is going to happen? Do you think that as clinicians look at these data at this point, they are going to start using anastrozole?

DR CUZICK: I think it is dangerous to look too far into the future. Undoubtedly, there will be a move among some clinicians to adopt this as initial treatment. I would urge a bit of caution until we've actually got a little more long-term data. There could be some things that we don't know about that show up after even five years of treatment. Five years of follow-up could begin to change results. We saw for example, some of the early results on Taxol and so forth, and saw early changes which didn't even hold up for five years. I think it is always cautious with these early results, to not overreact.

DR. LOVE: Although I think perhaps even if the efficacy were the same, the side effect profile itself might be enough, clinically, to cause people to switch.

DR CUZICK: I think that is a possibility. Again, the bone issue is the only issue in my mind that would raise concerns there. If that turns out to be manageable with DEXA scans and bisphosphonates, as needed, then I think you are probably right.

DR. LOVE: What about the other aromatase inhibitors that are available right now - the two that I'm aware of are letrozole and exemestane - in terms of using those or applying these data to those?

DR CUZICK: I think there will be a lot of discussion as to whether or not these results are going to be generic or not. Certainly we've seen in the advance- disease setting, both in second-line compared to Megace, the results are pretty similar. Then even in the first-line of trials, comparing them to tamoxifen in the advanced-disease setting, it looks like both letrozole and anastrozole show benefits over tamoxifen. So, it is hard in my mind to believe that there is going to be a substantial difference between letrozole and anastrozole in this setting.

DR. LOVE: On the other hand, there may be subtle differences in terms of side effects and pharmacokinetics. When you deal in the adjuvant situation it is a little different the metastatic disease.

DR CUZICK: It will be a difficult question. I think it will be a hard one to sort out. There is evidence that you get more complete suppression of estradiol with letrozole than you do with anastrozole. Whether or not that is important is an uncertain question both in terms of the side effect profile and in terms of the efficacy.

DR. LOVE: We don't know if that is going to lead to great efficacy and we also don't know whether, you mentioned bones, that might actually cause more problems.

DR CUZICK: Those are key questions. Ideally one would, now, like to think about head-to-head trials of aromatase inhibitors, one against the other, just to look at these questions. That's a big challenge, whether one company will choose to do a trial comparing their aromatase inhibitor to their competitors or not.

DR. LOVE: Do you know where adjuvant trials are right now? I'm not aware that there is anything comparable to ATAC out there for those other two drugs.

DR CUZICK: There are a number of other trials that are similar. I think all of the trials that are actually ongoing, are actually looking at tamoxifen followed by an aromatase inhibitor. There are no other trials that are actually started although there are some in planning that would look at aromatase inhibitors first vs. tamoxifen. There are a number of trials planned, but none of them have been started to my knowledge.

DR. LOVE: Any other trials that you are thinking about? What about a new adjuvant trial? Last time we talked, you were talking about maybe a pre-op by post-op? Where is the group? It's the ATAC trial group, or what is the group itself?

DR CUZICK: I think the ATAC trial group is looking for a new question now. There has been a lot of discussion about that. There are a number of interesting options. One that is really attractive is to look at the pure anti-estrogen. If we believe what we think we are seeing from the ATAC trial, it's the agonist properties of tamoxifen that are actually limiting it effectiveness. But there are drugs like Faslodex, which appear to be pure anti-estrogens, and whether or not they have something to offer against aromatase inhibitors that is a good question.
The other area where I think there is a need for trials - we've seen aromatase inhibitors being better than tamoxifen in postmenopausal women, but of course 1/3 of breast cancer is in premenopausal women where the LHRH agonists are an option for ER-positive women. The LHRH agonists, of course, make a woman postmenopausal at which stage you may ask whether or not you should add anastrozole or an aromatase inhibitor. I think that is an interesting question. Should we be talking about LHRH agonists plus anastrozole as the more complete method of depriving tumors from estrogen?

DR. LOVE: You can already make an argument for LHRH agonist to start with.

DR CUZICK: The evidence is clear that they're about as effective as chemotherapy in ER-positive women by themselves. If you are going to add an aromatase inhibitor to them, then they may, in fact, be more affective then chemotherapy.

DR. LOVE: If the patient is going to get chemotherapy, another strategy is to see what happens after the woman has chemotherapy and whether she is menopausal or not. If she is not, at that point think of an LHRH agonist again, even besides the issue of an aromatase inhibitor.

DR CUZICK: There is pretty clear evidence that chemotherapy actually works best when it renders women postmenopausal. That is another interesting question: In women not rendered postmenopausal with chemotherapy should you follow that with LHRH agonist?

DR. LOVE: Is there any reason to think that a woman that starts out as a premenopausal endocrine profile and becomes postmenopausal endocrine profile either by chemotherapy or LHRH agonist, would not have the same benefit as the patients in this trial? Where there any patients like that in this trial?

DR CUZICK: There were not.

DR. LOVE: So they had to be postmenopausal from the beginning because I know they could have had chemotherapy and then be randomized?

DR CUZICK: They had to be postmenopausal from the beginning. Although we did have a number of rectomized women, and if you believe that chemical castration is the same as hysterectomy, then there is no reason to believe that the aromatase inhibitors are not going to have the same affect. My guess would be that it should work just as well following an LHRH agonist. Of course, there is no data on that. No women have been given both treatments to my knowledge. So, there are questions of drug interactions that have to be looked at, and so forth.

DR. LOVE: At least there was one series that looked at women who were on tamoxifen and goserelin, and if they progressed, they stopped tamoxifen and started anastrozole. It was 20 patients. They had good responses. I think it was ASCO 2000.

DR CUZICK: You're asking where the next trials might be going. We are still talking about dealing with ER-positive disease in all of these aspects. There are the new EGF-receptor agonists or antagonists that are coming along, and Iressa is the one that is getting a lot of play now in terms of lung cancer, and so forth. I think we might be getting close to wanting to look at that in breast cancer as well.

DR. LOVE: As treatment or prevention?

DR CUZICK: As treatment initially I think, but if in fact we are only able to prevent ER-positive cancer with hormonal manipulations, we've been looking at this stage. Things that go after EGF-receptor may actually be able to prevent ER-negative cancers as well. That is something that we need to be thinking about although we have a ways to go before we are able to think about that in the preventative setting.

DR. LOVE: You talked about IBIS II in terms of postmenopausal women. Is there anything going on right now in terms of premenopausal women?

DR CUZICK: Nothing at all actually. I think that is a real issue. We are doing some very small studies in premenopausal women, just looking at lifestyle changes to see if we can understand how they work. There is increasing epidemiological evidence that exercise has a beneficial effect on cancer. Possibly some of the diet changes such as soy products may have an effect on breast cancer. This data is very week and whether or not we would ever be in a position to do a trial on these things, is a real challenge. The other issue that I think one can't ignore, is the whole business of alcohol in breast cancer. Consistent data is coming from studies that women who drink more alcohol - actually two drinks a day increases your risk by about 30%. Whether that is causal or not, is very difficult to know. If we could understand the mechanisms for that it might indicate approaches for dealing with premenopausal breast cancer, which we haven't thought about yet.

DR. LOVE: Do you think that once you all start talking about these data, perhaps there will be an interest in looking at LHRH agonist plus anastrozole for prevention of premenopausal women?

DR CUZICK: There already is an interest in looking at LHRH agonists with some sort of add back. At the moment we are doing some pilot studies looking at that plus raloxifene to protect bone. We've got to find an add back that's going to control symptoms. There are lots of exciting possibilities. LHRH agonist plus anastrozole plus some sort of bisphosphonate, plus maybe a little dosage of testosterone may be safer to add back than estrogen. Or, something like tibolone which is an androgenic type drug. These are all possibilities, but unfortunately they are complicated. We need to find a way to hone in on what the right formulation is going to be before we set off in any large prevention trial.

DR. LOVE: Is the group interested in looking at a LHRH agonist plus anastrozole as adjuvant therapy in premenopausal women?

DR CUZICK: They're certainly interested in looking at that.

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