DR NEIL LOVE: Welcome to Breast Cancer Update. This is Dr Neil Love. It's always been interesting to observe the ebb and flow of new research information presented at major oncology meetings, and to compare notes with colleagues about, for example, whether this was a hot ASCO or a boring one. But I have yet to meet anyone who attended the recent San Antonio Breast Cancer Symposium who did not relish the seemingly endless eruption of fascinating new data, highlighted by the presentation of the first results of the massive ATAC trial. However, some of the most provocative information at San Antonio often comes via the hundreds of excellent posters, and I sat down with Dr Harold Burstein, the author of a couple of my favorite posters at this year's meeting to follow up on these interesting reports.

DR HAROLD BURSTEIN: There are two clinical trials posters that are being presented. The first is a neoadjuvant program of Herceptin in combination with Taxol followed by surgery for women with HER2-positive, Stage II or Stage III breast cancer. This is a study we concluded already with 40 women on study and have shown that there's a very high clinical response rate to the combination. Seventy-eight percent of the women responded to up-front therapy. The pathologic, complete response rate, that is, the disappearance of all tumor from the breast or lymph nodes was 18 percent. That is a pretty encouraging number compared to historic experience. The study is novel for a couple of reasons. First, it's actually the first trial of up-front Herceptin therapy, so there's a lot of interest in just defining the response rate. Secondly, we did cardiac analyses on our patients while they were getting Herceptin and Taxol, and then again while they were getting their AC chemotherapy, which was their post-surgery adjuvant treatment. Our results are very similar to those that George Sledge presented here at this meeting; namely, that there is a decline in the ejection fraction in a significant number of patients on the order of 10 to 20 percent. But fortunately, none of our patients had developed any symptoms of congestive heart failure, and those changes also seem to be reversible over time.

DR. LOVE: Now, when did that decrease occur? Was it right after the Taxol-Herceptin? Or did you see it at the very end after the AC? When did you measure it?

DR BURSTEIN: Three of the four patients who had a decline in their ejection fraction had it during the AC or at the end of the AC phase of therapy. So, people held their ejection fraction pretty well through the Taxol-Herceptin part. Then they went through the surgery, and then there were these subtle declines during the AC portion.

DR. LOVE: Any way to know whether you would have seen that with AC alone? Are there any prospective data like that?

DR BURSTEIN: There are older data looking at this. It's not something we've checked in a long time. Most of us feel that these kinds of changes are consistent with what you might see with AC alone. We don't know, because it's obviously not a randomized study, if adding the Herceptin changes that at all.

DR. LOVE: What exactly was the regimen in terms of the dose?

DR BURSTEIN: The treatment program was 12 weeks of induction chemotherapy with Taxol and Herceptin. We have Herceptin at 4 milligrams per kilogram, which is the usual loading dose and then 2 milligrams per kilogram weekly for 11 further weeks. Taxol was given as it was given in the original randomized study. So that was 175 per meter squared every three weeks. They got four, three-week cycles like that. Then they had their surgery, and then they received four cycles of standard AC chemotherapy out back, if you will, after their surgery. Then they went on to radiation and/or hormone therapy as was appropriate for their case.

DR. LOVE: What's the next step?

DR BURSTEIN: Well, there are a couple of things yet to be done. One very interesting question is what happens to the tumor with Herceptin exposure. And ours is actually the first study that has tissue samples before and after Herceptin therapy.

DR. LOVE: That's right. Cool.

DR BURSTEIN: We are in the process of analyzing those results right now, and I think it's going to be very interesting to see what dynamic changes there are in the tumors' HER2 status with exposure to Herceptin.

DR. LOVE: That is fascinating. You don't have any data yet?

DR BURSTEIN: We have some preliminary data. It looks like - the confounding factors are that some patients totally lost all tumor. So, you can't test them afterwards. And, of course, those would be the ones you might be most curious to know what was going on. We know that in patients who had residual disease, the majority of patients still had residual HER2 expression on the tumor. So, at a first-order analysis, loss of HER2 status is not the trivial explanation for resistance to Herceptin therapy.

DR. LOVE: Of course, these women really weren't resistant, though.

DR BURSTEIN: They may not be resistant. It's not known if we'd treated them further. Of course, most of them did respond at some level. It's just that they had residual disease.

DR. LOVE: Did any of them progress?

DR BURSTEIN: Not in our experience with the testing.

DR. LOVE: That's fascinating. Now, these women were all IHC, FISH, or both?

DR BURSTEIN: The eligibility included IHC-positive 2+ or 3+ because we began the study about two years ago. Of the 40 patients, 30 were 3+. We're actually in the process now, of going back and defining the FISH status for all the patients on the study.

DR. LOVE: That's fascinating, too. Another question, it may be a little bit esoteric, but I've heard people ask and I looked at the literature to try to find an answer, but what is the effect of having Herceptin on board at the time that you do a HER2 assay?

DR BURSTEIN: Right. Again, ours is the first data that we will be able to show, to address this. At a first-order analysis, it looks like it is technically feasible to test for HER2 status after they've been exposed to Herceptin, though we don't have data on the long-term comparable efficacy of that testing.

DR. LOVE: Yeah. I asked some pathologists what they thought it would show, and they thought it probably wouldn't affect it. But I guess you'll be the first study to actually look at it.

DR BURSTEIN: That's why we like the study very much. So, that's been very gratifying as a study, to do.

DR BURSTEIN: The other piece of this study that is being presented is serologic response with the extracellular domain of the HER2 protein and tracking that in these patients as they receive neoadjuvant therapy with Herceptin. We have shown that in patients who are responding, it looks like detection of the serum portion of the ECD, that extracellular domain, is a pretty good tumor marker in those patients. That is, the patients who respond tended to have declines in their serum marker.

DR. LOVE: Wow!

DR BURSTEIN: So, there's a lot of new stuff that will actually be coming out of the study

DR. LOVE: That's cool.

DR BURSTEIN: For a single institution, 40-person study, I think we're going to learn a lot, actually.

DR. LOVE: Interesting. So, it actually functions as a marker.

DR BURSTEIN: It can in some instances.

DR. LOVE: Huh. What about histologic changes within the tumor when you compare pre and post? Any comments or any information on that yet?

DR BURSTEIN: We are still looking. I can tell you that grossly the tumors look like there's some treatment effect. It doesn't look particularly different from treatment effect that you might see with chemotherapy alone. Beyond that, we're still fleshing out the data.

DR. LOVE: Any other sophisticated testing of the tumor? Microarray or anything like that?

DR BURSTEIN: We have people at our institutions that are very interested in this, and we have a few patients for whom such fresh tissue will be available. But we're not going to have comprehensive data on that.

DR. LOVE: Where do you see this heading in terms of larger randomized studies?

DR BURSTEIN: Well, I think ultimately a neoadjuvant study of Herceptin-based therapy would be very interesting. There have been a lot of studies that have shown that neoadjuvant treatment is equivalent to adjuvant treatment, overall, for chemotherapy. However, one interpretation of the study in the metastatic setting of Herceptin-based treatment is that earlier Herceptin exposure is better than later Herceptin exposure. As you may know, chemotherapy plus Herceptin up front was superior to chemotherapy alone, even though two-thirds of the women who got chemotherapy in the metastatic setting without Herceptin subsequently did receive Herceptin therapy as part of their treatment. Despite that crossover of two-thirds of the patients, there was still a survival advantage for the up-front combination of Herceptin with chemotherapy. So, I actually think that whereas, in chemotherapy by itself, we've very convincingly shown it doesn't matter what the sequence of treatment is. I wonder if earlier exposure with Herceptin might be clinically valuable. Most of the ongoing adjuvant studies that are looking at Herceptin involve women getting sequential chemotherapy first and then chemotherapy with Herceptin added on afterwards as the control arm.

DR. LOVE: In the past a lot of times, we've taken a very step-wise approach to clinical trial design. First we want to prove one thing. Then we go to the next step. And, of course, we don't have any evidence right now in terms of Herceptin in the adjuvant setting. On the other hand, if you look at the ATAC trial, which they launched before there was even metastatic data, because they were trying to make an assumption, do you think that this is ready to be tested in a randomized trial? Do we need to see the adjuvant data first?

DR BURSTEIN: I think that before going to a large neoadjuvant randomized study, it's fair to start with the adjuvant trial data. There's a difference between treating women in the curative sense when you're using adjuvant treatments versus a palliative approach with metastatic disease. I think that you have to be much more cautious when introducing things into the adjuvant setting.

DR. LOVE: How large were the tumors in the women?

DR BURSTEIN: We actually had a large number of women who had inflammatory breast cancer, and most of the other women had very generous tumors. These were women referred to us because they really had inoperable breast cancer, usually.

DR. LOVE: Really?

DR BURSTEIN: Or at least large palpable tumors.

DR. LOVE: So, most of them, or all of them were T-3 or more?

DR BURSTEIN: No. It was split 50-50 between Stage II and Stage III. But there were a lot of women who had Stage II-B and III-A breast cancer.

DR. LOVE: Did you think about - I'm sure you thought about the issue of continuing Herceptin post-op?

DR BURSTEIN: We did think about it, but the only end points we thought we could address with that were really safety and feasibility, which is important, but for which there are other sites that are going to generate adequate data.

DR. LOVE: I know one of the key issues - I guess the key issue you were looking at was safety, toxicity, doability, so to speak?

DR BURSTEIN: It was safety. But we were also very interested in some of these pathological correlates, so the neoadjuvant setting was a nice way to approach that.

DR. LOVE: Any kind of gut feeling about the quality of the responses? How many of the 40 women actually had either partial or complete responses?

DR BURSTEIN: Nearly 80 percent of the women had nearly partial or complete clinical responses. So this is clearly an active regimen. Having said that, everybody finds 75 to 80 percent responses in the neoadjuvant setting. So, whether it's an advance yet remains to be seen.

DR. LOVE: Were you a little disappointed that the CR rate wasn't maybe higher?

DR BURSTEIN: Actually, I think that, given the patient population, women who had large tumors including inflammatory breast cancer -

DR. LOVE: That's true.

DR BURSTEIN: - and for HER2-positive tumors, which have historically been more refractory to therapy, I'm actually very encouraged. The NSABP cites for AC chemotherapy this common number of about nine or 10 percent complete pathologic response to induction chemotherapy with AC. But, of course, they also use some hormones at the same time. They use tamoxifen at the same time. So I think in comparison to that number, our data looks pretty good. We'll see what happens.

DR. LOVE: That's a great poster. What else are you presenting here?

DR BURSTEIN: This is a much more esoteric study. At Dana-Farber there has been a group of investigators very interested in the PPAR. That's the peroxisome proliferator-activated response genes, PPAR-gamma, which is an interesting intracellular signaling family. There is very interesting data that stimulating the PPAR-gamma chain can cause tumor cell differentiation in a variety of tumor cell lines including breast cancer. So, if you have breast cancer cell lines in the lab and you expose them to a PPAR-gamma agonist, the cell lines slow down their rate of growth. They well up and change shape, and they begin to accumulate fat within them. And there are other changes, such as a downregulation of the MUC-1 or CA 15-3 protein. So, it turns out that there are commercially available drugs that have this PPAR-gamma agonist activity. These are drugs like troglitazone and rosiglitazone that are used to treat diabetes.

DR. LOVE: Hmm.

DR BURSTEIN: So, they're very safe. There's a lot of tremendous safety experience in diabetics, and because of the pre-clinical rationale, we did a small Phase II study to see what it would do in women with advanced breast cancer. Our patient population was a very heavily pre-treated patient population with metastatic disease. These women were required to have failed at least two hormonal therapies if they were estrogen receptor-positive tumors or one chemotherapy if they were ER-negative. And, in fact, most of the women had had much more therapy than that.
So, we tried this drug in these women and, unfortunately, it didn't really seem to make very much clinical impact upon the course of their disease. But the impressive thing to us was that within seven or eight months, we were able to accrue 22 women to this trial to begin to address this question. I think it just highlights the fact that, if you have safe, innovative therapies, that you can find women who are interested in evaluating these with you as part of a clinical study. And we sort of need to take more opportunities to try various combinations and ideas like that.

DR. LOVE: That's really fascinating. Did you do any pre and post biopsies? Do you have any tissue to look at?

DR BURSTEIN: The protocol called for that to be done. But in clinical practice, it's very hard to get women to comply with that. So, we only had three or four women who were willing to do that and had accessible tumor where we could reliably get biopsies before and afterwards. So, I don't know that that information will help us further.

DR. LOVE: Have you seen that? Have you looked at those?

DR BURSTEIN: We have, and it's not informative.

DR. LOVE: You say you have or haven't?

DR BURSTEIN: We have looked, and it's not been informative.

DR. LOVE: It doesn't look like it really does anything.

DR BURSTEIN: Yeah.

DR. LOVE: Interesting.

DR BURSTEIN: There are other family members that may be worth considering, and it may be worth looking at this in a less heavily pretreated patient population. But this was an in-house study that was very much driven by our basic scientists wanting to make a contribution in the clinic. It was internally very gratifying because it was a nice collaboration for us. And again, I think it speaks to the fact that there is a wellspring of good faith in our patients, such that if we have innovative ideas for non-toxic treatments, they are willing to explore them with you.

DR. LOVE: Interesting. Sometimes I think about the fact that the way we try to evaluate agents in terms of seeing whether things shrink down, particularly, as you say in an advanced disease setting, maybe we need to rethink that. If we found something that just caused people - you're talking about differentiating or something.

DR BURSTEIN: Correct.

DR. LOVE: Maybe the tumor would just sort of stay the same?

DR BURSTEIN: It's a very interesting idea. These drugs are being used right now in liposarcoma. That's the one disease where there have been objective responses.

DR. LOVE: Really?

DR BURSTEIN: DR George Dimitri at Dana-Farber is leading a national study in liposarcoma on the utility of this class of drug. One of the things they are looking at in some select patients are PET scan changes, with the idea that as a differentiation agent, you might see changes in tumor metabolism without seeing overt clinical change. So, I think you're right that we need to be more open to innovative ways for evaluating newer drugs.

DR. LOVE: Well that's a good one. What else have you got?

DR BURSTEIN: Another study that one of our young staff members at Dana-Farber has done is a very interesting study on patient preferences for learning about the results of clinical trials in which these patients participated.

DR. LOVE: Wow!

DR BURSTEIN: As you may know, we usually do not share clinical results with patients who participated in the study in a systematic fashion. Patients certainly may find out the results, but there is not a very standardized way of sharing the results with patients or their family members, if they have participated. And no one has really ever analyzed whether or not patients would like to find out this information. You could imagine on the one hand that patients would be very excited to learn what the results were. On the other hand, you could imagine that patients might be somewhat worried, anxious or concerned about the results. Perhaps one treatment arm did better than another. Perhaps the treatment was less effective than they had imagined.
One of our young staff members named Ann Partridge wrote a survey to ask patients who were participating in a clinical trial whether or not they'd like to find out the results of the study. This is, to our knowledge, the first such analysis that's ever been done. The study itself was a multi-center study of Herceptin in combination with Navelbine, another chemotherapy drug, as first-line treatment for HER2-positive breast cancer. Our group has done as fair amount of work with Herceptin and Navelbine internally, and this was a 15-center site study that we just concluded accrual to. And during the first week of treatment with these two drugs, the patients were asked to complete a survey, asking them for their preference. And the fascinating thing is that 96 percent of the patients who responded to this survey indicated that they were very interested in knowing the results of the study and they very much wanted to be informed. In fact, 96 percent of the patients said yes to the question - or, rather, said yes, they agreed with the statement, "I feel I have a right to know the results of the clinical trial in which I am participating." So, that's a fascinating observation just to see how much interest there is.
There are some caveats to any study, there always are. But there are some important ones in this. The first is that about half the patients did say that their interest in finding out the results might be affected by how they personally did. So, it's easy to imagine that someone who did very well on the study would be more interested in finding out just how good this was then someone who may not have benefited from the clinical trial.

DR. LOVE: Now, you ask them, though, in the beginning of the treatment.

DR BURSTEIN: That's correct.

DR. LOVE: Were the patients also asked at the end?

DR BURSTEIN: They weren't. This was just a one-shot deal.

DR. LOVE: Huh.

DR BURSTEIN: Just to get a baseline measure of their interest. So, I think it's very provocative and really challenges the clinical research community to think about ways of communicating back to patients what has been learned in clinical trials. Obviously, this was not a randomized study where one arm was going to do differently from another arm, and these were straightforward treatments. Everybody got the same treatment and these are agents that are known to be effective. So, people's feelings may differ, than in a randomized study.
The other thing that you have to be concerned about is, there's this old business adage that says everybody asks for feedback, but what they want is praise. When you see that 100 percent, essentially, of patients want to know the results, you have to be a little concerned that there's some of that going on. That is, that people would like to be told that things went well for them and that this was the right decision for them based on the data that you might discover later on. So, having said all those things, I think it's actually a fascinating little study and the first data is being presented here at a poster session this week. And I think that Ann has really stumbled into something. Well, to say stumbled makes it sound more accidental, we knew that this was something interesting to look at. Ann has cleverly looked at something that may really change how we communicate with patients in the future.

DR. LOVE: I wonder, too, when you have patients who participate in studies and then the patients die, for example in Phase I trials, whether or not the families would want to know about it.

DR BURSTEIN: You are a good interviewer. We asked that in the study, and you're good to anticipate that, because that was a real concern in treating patients with metastatic disease. The vast majority of patients indicated that they would want a friend or family member to be informed of the results of the study. So, there's a tremendous interest in this from the patients' part. I think that the challenges are to begin to understand this desire a little better, and then really to think cleverly and creatively about how most meaningfully to communicate results of studies to patients.

DR. LOVE: I think the idea of the patient talking about having the right to it, and also maybe our obligation to give back a little bit is interesting, too. A lot of times there's altruism involved in why people participate in trials, and I think for them to know - and, of course, not every trial is going to be positive - is important. For example, here we are at the San Antonio meeting. We have the ATAC trial. It's really a major development in breast cancer. Those 9,300, of course, they're going to be informed for practical reasons, but, patients are making a valuable contribution, and they should get something back.

DR BURSTEIN: Absolutely. Clinical research has advanced because of the tremendous generosity of the patients who participate in studies. We like to think that that generosity is linked to very good care and the art of having a good clinical trial is one where, even though you were in a study, you're getting the best care. So, we need to convey that message to patients and, in return, we have to share with them the results and how we learn things. That's a very complicated message to get across, particularly when it may be down the road that some patients do better than others, or one arm of a study doesn't look as good as another arm. That's what happens in research and sharing that information in a respectful and appropriate manner is going to be something that's hard to do, but worth learning how to do.

DR. LOVE: What are some of the things that have come out Dana-Farber in the last year or two in breast cancer, that you think are important contributions? You mentioned the Herceptin-Navelbine data and trial. What other key things have come out of the center?

DR BURSTEIN: Well, we've been interested in some studies of concurrent chemotherapy and radiation therapy. As you know, there's been a lot of interest in the past couple of years in adding taxane therapy to, say AC chemotherapy in the adjuvant setting. That prolongs the length of therapy by an additional three months and puts radiation therapy at the end of that, typically. So, our group was interested in seeing if we could give radiation therapy at the same time as taxol, and we designed a Phase I trial to answer that question, whether patients got AC chemotherapy followed by taxol with concurrent radiation. The retrospective literature has sort of been a mixed bag on this. Some centers think they can. Some centers think they can't. Nobody had really ever tested the question. We did taxol administration in two ways. We had a weekly program, four weekly doses of taxol, and then an every-three-week program, which is the way of course, it's been studied in most of the cooperative group studies to date. And we learned some very important things. The first thing we learned is that weekly taxol with radiation was too toxic. Taxol probably is a radiation-sensitizer, and the weekly administration meant that there was an unacceptably high risk of pulmonary complications, radiation-related pneumonitis. And the second thing we learned is that at the doses we used of radiation and of chemotherapy, it probably would be feasible to do every-three-week taxol with concurrent radiation therapy. So, that was a gratifying experience.
Now, that is not a huge change in the overall management of breast cancer from one single center. But, I think it's an example of what we've tried to do, which is to get our professional colleagues to work more closely together, so that a patient has a shorter duration of treatment and hopefully can move on with their life in a more expeditious fashion.

DR. LOVE: We're starting to see new trials coming out looking at the combination of Taxotere and capecitabine in the neoadjuvant and adjuvant setting. Capecitabine's kind of interesting in terms of potential interaction with radiation therapy. Has your group been discussing that at all?

DR BURSTEIN: We have been. Our group did a - with the leadership of Jay Harris in the Joint Center for Radiation Oncology in the early 1990s. They did a study of concurrent CMF chemotherapy with radiation. There is some concern over cutaneous toxicity because 5FU analogs do sensitize the skin to radiation therapy, though again, it looked like it would be feasible with the correct doses of radiation. The interesting thing about this when you step back one step is that in all the tumors where they've studied concurrent radiation therapy and chemotherapy versus sequential chemotherapy and radiation - things like rectal tumors and gastric tumors - the combination is better. Now, those tumors have a much higher local failure rate than most breast cancer does, so it's not clear that you can extrapolate to this. But it would be very exciting if we could find a way to shorten the whole duration of therapy, give the radiation therapy earlier and perhaps take advantage of some of those clinical interactions.

DR. LOVE: The thing I was thinking about is, I heard that radiation therapy upregulates TP, thymidine phosphorylase. And the question - so you have the 5FU issue, but the question of whether or not it would potentiate the effect within the tumor?

DR BURSTEIN: That's an interesting thought. I hadn't thought of that. I don't know the biochemistry well enough to say. But there may be reasons why it's worth trying these things together.

DR. LOVE: I seem to recall Craig Henderson talking about the ACT adjuvant study, and he looked at what the outcomes were. Have you reviewed that?

DR BURSTEIN: Well, there were - most of the patients got AC for three months or AC followed by Taxol for a total of six months, and then got the radiation at the end of their chemotherapy.

DR. LOVE: Right.

DR BURSTEIN: In the unpublished, but reported data from that experience, the local failure rates seem to be the same. That is, there does not seem to be an adverse effect of waiting an additional three months to administer the radiation therapy. So, it may be that the timing of the radiation is not critical in patients who are receiving ongoing chemotherapy. On the other hand, it would still be nice to finish everything up within that whole time frame and spare the patient an additional seven or eight weeks of treatment with radiation.

DR. LOVE: Absolutely. I want to talk a little bit about how some of these research advances have been implemented in practice, and particularly the one that I think about when I think about you and your group is Herceptin-Navelbine. I'm curious how you take that into your practice outside of a clinical trial. So, my first question to you is: Generally speaking, how do you approach the patient who's HER2-positive, let's just say ER-negative, who had prior AC chemotherapy and has relapsed relatively recently?

DR BURSTEIN: Well, I think for such a patient, the standard of care now would be Herceptin in combination with chemotherapy. There are a variety of chemotherapy regimens that have been studied with Herceptin, and these are all very reasonable choices. The most comprehensive data that's available includes Andy Seidman's study of Herceptin with weekly Taxol, our study of Herceptin with Navelbine. There have been studies with Herceptin-Taxotere and, as you know, the UCLA group has been championing this triplet combination of Taxotere with the platinums and Herceptin. All of these are clearly very effective regimens. All of them look like they are reasonably safe from a cardiotoxicity point of view. So for clinicians, I think, you are choosing between multiple sets of active regiments and basing the decision on side effect profiles, personal preference, and that there's really very little data to suggest that one regimen is superior to another.
I'm actually pleased to say that our group has led the development of a randomized study that we call the Traviota study - T-R-A-V-I-O-T-A - which stands for trastuzumab and vinorelbine or taxane. This is going to be the first randomized study to ask a question of whether Herceptin-Navelbine is different, superior or inferior to Herceptin in combination with the taxanes. Outside of a research study, I really base it on the side effect profiles. Some patients have neuropathies, so you want to be cautious about using drugs that can cause neuropathy. Some patients may or may not be willing to lose their hair. So, you want to pick regimens that have less likely alopecia. Some patients may be very concerned about steroid administration or things like that. So, we know a lot about the side effects of these drugs and, outside of a study, I think that's how you end up making a choice.

DR. LOVE: The trial that you just described, is that going to also be single-institution or multiple?

DR BURSTEIN: That is a 50-institution study that is now accruing at over 40 institutions already. The accrual goal is 250 patients.

DR. LOVE: Who's running it?

DR BURSTEIN: We are leading it.

DR. LOVE: Hmm. So, you want to make any prediction about what's going to be seen?

DR BURSTEIN: I think we're going to find that these are all very reasonable regimens and that we will have good news for patients which is that there'll be several choices to choose from.

DR. LOVE: Do you think they'll have equal efficacy in both arms?

DR BURSTEIN: I think it's possible that they won't, but we just won't know. The response rates that have been reported in the various Phase II studies of Herceptin with Navelbine, Herceptin with Taxol and Herceptin with Taxotere all would fall within an overlapping confidence interval. So, any one of them would be reasonable.

DR. LOVE: You would think so. I mean, with 200 patients, you'd have to have a pretty big difference in order to see a -

DR BURSTEIN: We do. And I think that what we really want to characterize objectively are some of the response rates and toxicity profiles.

DR. LOVE: Is it physician choice in terms of which taxane, or is that specified?

DR BURSTEIN: No. It's physician choice. So, you're randomized to either the Navelbine combination or to a taxane combination, and the physician can choose either weekly Taxol or weekly Taxotere.

DR. LOVE: What are the criteria for the trial in terms of HER2 testing?

DR BURSTEIN: Patients need to be HER2-positive, either 3+ by immunohistochemistry or FISH-positive. The additional criteria are measurable disease by the RESIST criteria, reasonably good performance status, no prior chemotherapy for metastatic disease and no active CNS disease.

DR. LOVE: In terms of getting back to your treatment off protocol, I'm sure most, if not all, of your patients are going on study, but in those situations with the patients not on study, are you using any single-agent Herceptin?

DR BURNSTEIN: Sometimes I am. Though, I confess it's relatively infrequently. More commonly, we're giving people Herceptin with chemotherapy and then, if they are fortunate and have a terrific response, then we will often pull back on the chemotherapy and continue with maintenance Herceptin as a single agent. I think a lot of people around the country are doing that.

DR. LOVE: Roughly how long on average are they receiving chemotherapy?

DR BURNSTEIN: I usually continue it for between four and six months, though it really depends on how brisk the patient's response has been and what kind of problems they've had with the chemotherapy.

DR. LOVE: I assume you continue the Herceptin until they progress?

DR BURNSTEIN: That's correct.

DR. LOVE: And then what?

DR BURNSTEIN: Well, they have a variety of choices. I think most people would probably reinstitute chemotherapy with Herceptin at that point, but in fact, we don't know if there is a role for ongoing Herceptin treatment in such a setting. MD Anderson is leading a randomized study to address that question. They are taking patients who have had Taxol or Taxotere with Herceptin, have had disease progression and are then randomized to either Navelbine alone or Navelbine with Herceptin. We're also embarking on an interesting Phase I-II study where we are looking at patients who have had disease progression on Herceptin and who then will be treated with a non-specific immunoadjuvant. A drug called a CpG class of drugs, which gooses the innate immunity in a patient, the natural killer cells and monocyte activity in a patient. Our goal of this study is to see if we can take advantage of some putative immune mechanisms for Herceptin therapy and try and get immune-based responses in patients receiving this antibody treatment.

DR. LOVE: Interesting. How long do you generally continue? Do you go through two or three subsequent treatments, or do you play it be ear?

DR BURNSTEIN: It's highly variable, and this is probably the most important question confronting us right now in the treatment of HER2-positive metastatic disease. That is, when do you stop the Herceptin because we really have no adequate data? As you know, last year Debu Tripathy from San Francisco presented the second-line Herceptin plus chemotherapy data at this meeting from the Genentech study. And the response rate to second-line Herceptin with any chemotherapy agent was very low, on the order of 10 to 15 percent. So, whether or not maintenance Herceptin therapy is clinically valuable is a huge question. In practice, we often roll patients over from one Herceptin-based-chemotherapy regimen to another; however, if they want to do a research study where they're not allowed to get Herceptin, we would stop the treatment. Similarly, if they've never had an anthracycline before, and we feel like we need to either start one or to reinitiate an anthracycline therapy, then we would stop the Herceptin and go ahead with anthracycline therapy for a while. So, there's tremendous heterogeneity in how we handle those patients.

DR. LOVE: What about in the adjuvant setting? You can bet - and of course, at this meeting in one of the case sessions, one of the first things people brought up was the young woman, HER2-positive, 15 positive nodes. Are there any situations where you're using adjuvant Herceptin outside of a trial?

DR BURSTEIN: No. Those patients really should go on a clinical study. I think this is a great instance where treatment as part of a clinical trial is better treatment than treatment outside of a research study. There are trials available at most large cancer centers in the adjuvant setting. This is a very promising drug. It's obviously generated tremendous enthusiasm. But there are concerns about long-term side effects including cardiac damage, and people are being committed to a year of Herceptin in the adjuvant studies. We really have no idea if that's an appropriate length of time. So, while all of us hope to bring the advances to our patients as soon as possible, we have tried very hard to limit use of adjuvant Herceptin to patients on study.

DR. LOVE: Getting back again to the non-protocol setting, what about the HER2-positive, ER-positive patient?

DR BURSTEIN: Those patients need hormone therapy. There's a lot of data including data presented at this meeting this week which has suggested that HER2-positive and hormone-receptor-positive patients may get less benefit from hormone-based therapy than do HER2-negative, ER-positive patients. However, that doesn't mean they don't get benefit. That means they get less benefit. Some patients may get fabulous responses to tamoxifen or to aromatase inhibitors in this setting. So our clinical practice has been to use hormonal therapy as long as that's appropriate. And when the patient is now in need of chemotherapy, to introduce chemotherapy with Herceptin. I think there actually are two pieces of data that support that. The first is that in the Genentech study - again, the pivotal study of Herceptin with chemotherapy - they looked at response rate as a function of ER status. The drug and chemotherapy combination were equally effective in ER-positive and ER-negative patients. The other thing they looked at was, they specifically looked at response rate as a function of prior hormone therapy in the ER-positive groups. And prior hormone therapy did not, in any way, impact on the response to Herceptin with chemotherapy in that group of patients. So, I look at that as data supporting the idea that, let's use hormones for as long as possible, maximize our utilization of those drugs, spare the patient the time in the infusion chair and the possible side effects of therapy, and then, typically, when it's time for chemotherapy start that with Herceptin, if they're HER2-positive. Now, having said that, I don't know if that's the best way to do it. We don't really have data to the point. Certainly Herceptin is active as a single agent, and the women who don't really want to get chemotherapy and who aren't candidates anymore for hormone treatment, I know that around the country would start on single-agent Herceptin, and that is not an unreasonable option, either.

DR. LOVE: Do you ever use endocrine therapy plus Herceptin?

DR BURSTEIN: Well, we have had a study going on where we used an aromatase inhibitor and Herceptin as a straightforward Phase II study. The problem is that outside of a randomized study, you don't have data that this is superior. And, of course, it commits the patient to a weekly treatment that nobody really wants to do. The beauty of hormone therapy, aside from its effectiveness, is just the sheer convenience of it.

DR. LOVE: Just to trace out your algorithm, I can see your thinking. You're so imbued with all the clinical trials that are ongoing like a lot of people in clinical research, it affects your whole approach to therapy. So, I'm curious. For example, what about in the metastatic setting, the ER-negative, HER2-negative patient?

DR BURSTEIN: ER-negative, HER2-negative patient, well, those patients are still out there, and one of the ironies of life in the era of targeted therapy is what happens when you don't have a target? We have a lot of exciting opportunities right now for studies with women whose tumors are hormone receptor-positive or HER2-positive, and this group has really kind of fallen through the cracks. The good news is we still expect them to get benefit from more traditional chemotherapy, and you have a tremendous number of choices before you. The really interesting thing is, when you step back from the whole literature of chemotherapy for metastatic breast cancer, it probably doesn't make very much difference what you start with. The studies show that any number of agents can be effective. If the drug doesn't work after several cycles you obviously switch to another drug. We still practice principally single-agent sequential therapy for our patients. There are very many studies that have shown that combination therapy does not affect long-term survival compared to single-agent sequential therapy. So that's our norm for treating patients outside of a research study.

DR. LOVE: Just to track that out a little bit, what would be the most typical regimen that you would use in a patient who's relapsed shortly after AC, for example?

DR BURSTEIN: If they were refractory to the anthracycline then you probably would offer them a taxane or something like capecitabine or Navelbine outside of a research study.

DR. LOVE: What about the growing number of patients that we're seeing who are relapsing after ACT?

DR BURSTEIN: You just move further along the line.

DR. LOVE: Any preference in terms of which one?

DR BURSTEIN: I think that there may be individual preferences based, again, on side effect profile. Some patients like the convenience of an oral chemotherapy agent, so it's nice to start them with that. Other patients might prefer different drugs. But there's no compelling data in my mind that you have to choose one drug or another in that setting.

DR. LOVE: Of course, I have to ask you the question I've been asking everybody this week. What do you think about the ATAC trial?

DR BURSTEIN: You have to give tremendous credit to the organizers of the study. It's the largest single study, randomized trial, ever mounted in breast cancer medicine. Today, George Sledge reminded me that in the mid-1980s the FDA approved tamoxifen for ER-positive patients based on disease-free survival from two studies. The cumulative number of patients was fewer than 1,000. Now we have a randomized study from 9,000 patients.
There are several caveats about the ATAC study that you have to acknowledge. The first is that there was no survival difference. There were very few deaths on the study related to breast cancer - five women out of 9,000. If that's an accurate statistic, it is quite astonishing. So, these women had a very good prognosis. Obviously, the second point is that there is only very limited follow-up of two-and-a-half years. Having said that, I think that the time for the aromatase inhibitors in the early-stage setting is rapidly arising. There are compelling studies from the metastatic setting, comparing aromatase inhibitors to tamoxifen. They've all shown that aromatase inhibitors are at least as good as tamoxifen. There are neoadjuvant trials of nearly 1,000 patients comparing tamoxifen and aromatase inhibitors. They've shown that aromatase inhibitors are at least as good as tamoxifen. And now, hard on the heels of that data, we have this tremendously scaled 9,000-person study showing that an aromatase inhibitor may be even better than tamoxifen. So, I think the availability of this new drug is something we have to discuss with patients in the near future.
It must be said that tamoxifen has something of a bad reputation in the breast cancer public imagination. It's a remarkably safe drug, but there are these rare side effects that people have focused on. It seems in the preliminary look at the data from the ATAC trial that there are fewer menopausal symptoms, fewer cases of endometrial cancer, fewer strokes and other blood clot problems, and those are all things that patients are going to think about. The other interesting thing to note in the ATAC trial was there was somewhat greater osteoporotic events from the aromatase inhibitor arm. It's not clear if that's because this just represents the background level of osteoporotic fractures that you might see, and the tamoxifen actually boosts the bone mineral density a little bit. That's something we're going to want some long-term data on.
So, everyone's been trying to reach some kind of consensus. I don't know that the self-appointed experts have achieved that kind of consensus yet. I can tell you that I think, for a woman who's already on tamoxifen, I would leave her on tamoxifen. I think it's a very safe and effective drug with decades of proven experience. For women who are on tamoxifen and who are finishing their course of therapy, it's very interesting now to test some questions about sequencing treatment for tamoxifen followed by an aromatase inhibitor. I would encourage people to think about those studies that are ongoing at multiple sites already. For women who are newly diagnosed, I think that this is data they may wish to be very familiar with, and I think that it is likely that we'll see a lot of use of aromatase inhibitors in the first-line setting very soon.

DR. LOVE: What are you guessing that you're going to be doing with the next 10 or 20 patients that you see who are ER-positive or just finished their chemotherapy?

DR BURSTEIN: Well, for postmenopausal women, I think that this is an interesting option. We've already been doing this a little bit for women who had personal histories of uterine cancer or had family histories of uterine cancer or blood clot problems or they'd already had a DVT. And I think this is something that's going to be shared with more and more women now.

DR. LOVE: What do you think the bottom line will be? I mean, when I see you at ASCO and I say, "What's going on since the San Antonio meeting? What have you been doing?" What do you think you'll be saying?

DR BURSTEIN: While you don't want to jump on a bandwagon too quickly because there are a lot of unknowns and this is one presentation from one study, having said that, I think we'll be using a lot of aromatase inhibitors in the years to come for early-stage breast cancer.

DR. LOVE: Another interesting question would be: What about the woman who's premenopausal when she's diagnosed, maybe five positive nodes, high risk, ER-positive, she's finished her chemotherapy, and she's stopped menstruating?

DR BURSTEIN: Nancy Davidson gave a lovely talk yesterday on the role of hormonal therapy for premenopausal women and, in particular, ovarian ablation. And in the adjuvant studies, I think this is a compelling and important question for us to ask. There are very extensive, retrospective studies suggesting that women who go through menopause with chemotherapy do better in the long term. I think the data from the ATAC study force reanalysis of the question because the whole issue of whether you should suppress ovaries and then add an aromatase inhibitor is now a crucial one. Even before this, if you go back to the consensus conference in November 2000 at NIH, they identified the role of ovarian function in premenopausal women as one of the seminal questions in the breast cancer research program right now. So, I hope that all this attention on hormone therapy will reinvigorate this question. I know that the Intergroup is going to cooperate with the Europeans in a very large, very important randomized trial for premenopausal women who have ovarian function, either because they never received chemotherapy or because they continued to menstruate after chemotherapy. This study is going to be tamoxifen alone, which is still the only hormone therapy proven in premenopausal women, aside from ovarian ablation itself, versus ovarian ablation plus tamoxifen versus ovarian ablation plus an aromatase inhibitor. That study is going to be a global study, which really, I think, asks a very important question for women who are premenopausal.

DR. LOVE: Wow that's a great one! Is it up and running?

DR BURSTEIN: No. That one has been in development for the better part of the past year. There have been a lot of iterations of this study, but the important thing, I think, which has just coalesced is that there is going to be work shared with the Europeans and the Americans on this, so it's going to be a very large, global study. As you may know, there aren't that many women who will meet the criteria for this trial, in that a lot of women in the States will get chemotherapy and go through menopause with the chemotherapy. So, I think it's great that it's going to be such a global effort, and I think it's a very important trial.

DR. LOVE: And the lead person or the lead group?

DR BURSTEIN: The CALGB has been involved on the American side, and the IBCSG, Aron Goldhirsh's group out of Milan, has been the leader in the European discussions.

DR. LOVE: Certainly the issue of whether you induce ovarian ablation and add an aromatase inhibitor is very experimental. No question about this point?

DR BURSTEIN: Yes.

DR. LOVE: But then the question becomes, what is a postmenopausal woman, and if a woman has stopped menstruating and she endocrinologically has a postmenopausal profile, do you look at her and evaluate her the same way as a woman who walks in from the beginning as being postmenopausal?

DR BURSTEIN: That's a great question. One of the interesting things in the latest version of this protocol, which I hope will come to fruition, is that it will be open to women who have never had chemotherapy and to women who have had chemotherapy. Hopefully there'll be enough patients in each group that we can compare those experiences and see if chemotherapy, which may push people a little bit more towards menopause, will alter the natural history of the disease in addition to ovarian suppression.

DR. LOVE: You don't like me asking about non-protocol therapy. I can tell.

DR BURSTEIN: There are very few answers from non-protocol therapy. I thought the NIH consensus conference in November of last year was very well done. But the summaries that they drew were polychemotherapy is valuable. You need two or three regimens for three or six months. It was very hard to identify one regimen as being superior to another. Maybe anthracycline regimens were a little bit better than non-anthracycline regimens. Too early to tell if taxanes were valuable. Too early to tell if HER2 testing was valuable in the adjuvant setting. So, there are a lot of questions. I think the most important thing is that women who are high risk for recurrence, who justify chemotherapy, get some chemotherapy. Once you get beyond that, it's been very hard to convince yourself that a particular way of giving chemotherapy is vastly superior to a different way of giving chemotherapy.

DR. LOVE: I just find that people in practice are very curious about how research leaders, particularly those like you who are totally imbued in breast cancer 24 hours a day, actually take care of their patients. Understanding that just like you, they are constantly making decisions without the kind of information you'd like to have, and how you shade those kinds of things. I think that question I just asked you is a perfect example because obviously we don't have a pure answer to the question of the 42-year-old woman who's menopausal because of chemotherapy. Is that the same as the 56-year-old woman who was in the ATAC trial?

DR BURSTEIN: Right.

DR. LOVE: But the truth of the matter is, you're going to go back to your clinic and somebody like that's going to walk in.

DR BURSTEIN: Yes.

DR. LOVE: You're going to do something, and that's what I'm curious about.

DR BURSTEIN: But part of this is talking to patients. The most important thing that doctors do is taking care of people. And, one of the fun things about being a doctor is spending time with the patient, listening to them, finding out what makes them tick, what kinds of things are important to them, and then working with them to come up with a treatment program that makes sense to them. I think the idea that there's one treatment that is the right way to give everybody, simply isn't the case.

DR. LOVE: I agree with you, and I understand that. But I think there are certain boundaries. I can tell just by talking to you for example, when I brought up adjuvant Herceptin, it was like boom, "No. We do not do that. That's not on the plate." I assume you probably don't discuss that as an option with your patients.

DR BURSTEIN: No, I don't consider - many patients have read about that and they're very interested. What I tell them is that we don't know the answers. I feel most comfortable doing that. Different clinicians may make different decisions.

DR. LOVE: I think that's the kind of thing that people really want to know. Which is okay? What are the things that absolutely, people just don't think are appropriate? What are the gray areas where we really don't have a good answer and there are a bunch of options, like you said the consensus conference? And then what is it that everybody can agree upon, combination chemotherapy for a premenopausal woman? Those three areas are the things that are tough to define, I think.

DR BURSTEIN: Well, and once you get into the flavors of combination chemotherapy, you've got 3,000 doctors and nurses here. I'm not sure two would agree on.

DR. LOVE: Another thing that's very fascinating to me, that I've been seeing more and more of, and it's something that you talked about earlier. There's a very fascinating dichotomy between the use of combination versus sequential single-agent chemotherapy in metastatic breast cancer.

DR BURSTEIN: It's an interesting topic. We all want to do the right things for patients and there are instances, you can imagine, when you feel like you have to get a response right now. And you pull out all the stops to accomplish that. But for most of our patients, I think that single-agent therapy in that setting remains the norm. It has the virtue of allowing you to really figure out which drug is working, so you're not giving unnecessary drugs to people, and it also is associated with less toxicity in most of the studies that have been done looking at combination versus single-agent therapy.

DR. LOVE: Anything else you want to add to any of the things that you've said?

DR BURSTEIN: I think that there is a sense that very exciting things are happening. An analogy I've used a couple of times this week to mixed success is: I think this is what the Venetians sensed when Marco Polo came back from China. You know, there's this whole cartload of exotic fruits and spices and different clothes and funny animals that no one's ever seen before, and books in different languages. And you have this tremendous sense of your horizons expanding before you as you look at all the biological drugs that are coming along, new hormone-based therapies, new opportunities for chemotherapy, how do we sequence these things, what's going to play out, what isn't. Everybody in Venice is running around just absolutely enthralled by all the different novel choices you have. And they are now sending out their own voyages of discovery and seeing what's going to come back. I think that's really where we are at with Herceptin and some of the newer biological treatments and some of the newer hormone agents. This is a taste of what people have been talking about for decades in the way of new treatments and targeted therapies. Which one's going to work, which angiogenesis inhibitor is going to play out clinically, who's going to have the better one of this, I have no idea. But there are fascinating things to evaluate and test in clinical science right now, and it really is going to be a golden age for clinical research. I think that patients should understand that there are going to be a remarkable number of opportunities available to them, and they should seek out opportunities for participating in these studies, because there really are some great new things coming along.

DR. LOVE: Yeah. I think, too, for clinicians who are out in practice, who are not seeing some of the things that are happening in clinical and basic research, who maybe get kind of jaded over the years because things -

DR BURSTEIN: Nothing ever changes. We all want to change the natural history of the disease. There's a lot of stuff going on right now which looks like it might be able to do that. It's a great time to be learning about clinical trials and to be participating in them as both an investigator and, hopefully, for our patients, as well. This sense of the decades of investment and basic science and molecular biology and pharmacology, we're getting to the point of some payoff, and that's very exciting.

DR. LOVE: So, Harold, do you feel optimistic?

DR BURSTEIN: I'm actually very optimistic. I think that you can get carried away. The only thing worse than hope is false hope. I'm sorry. That's not right. We don't want to give false hope to people. What we want to give them is genuine hope, and I think that you begin to get a sense in the breast cancer community that stuff is really happening, and that is very exciting. So, more to come. But I think a message for clinicians and for patients is that it's time to think very broadly about treatment choices and options. There are lots more choices than there ever have been.

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