DR TERRY MAMOUNAS SUPPLEMENT

DR MAMOUNAS: What do you think that trial’s going to show?

DR LOVE: Well, we hope that it will show that Herceptin is of value in patients with node-positive breast cancer. Certainly, the data from the metastatic trial are very exciting. Five months prolongation of median survival with concomitant AC-Herceptin or Taxol-Herceptin versus, in essence, delayed Herceptin, where they had recurrence of the chemotherapy, seems very promising. We don’t see that kind of prolongation of median survival that commonly in metastatic trials. So, we hope that it will show a benefit. But I think we have to be very careful of not adopting using Herceptin in the adjuvant setting before we get results from the randomized trials, because, certainly, there’s a big drawback here, and that’s cardiac toxicity.

DR LOVE: It’s interesting, when we present cases to physicians in the community — and you saw some of these here in this meeting — particularly, if you present a woman who has five or ten positive nodes or inflammatory breast cancer as HER2-positive, there are a lot of physicians who say they are using Herceptin off protocol in those kinds of situations. What are your thoughts on that?

DR MAMOUNAS: Well, certainly, somebody that has very bad disease, inflammatory breast cancer, that sort of goes over the type of patients that we put in our trial, and in those patients, I guess, you could theoretically justify it. Although, again, I would be very hesitant in using it without proven benefit, particularly in lieu of the side effects. But for patients with positive nodes, I would not use it today, knowing what I know. I just don’t feel comfortable. How can you justify putting the patient in congestive heart failure where you really have no proven benefit? A lot of things that work in the metastatic setting sometimes don’t work in the adjuvant setting. We’ve seen this time and again. So, I think that leap of faith, I cannot justify making right now.

DR LOVE: Do you think that the time’s going to come when IHC is not done for HER2 and everybody gets FISHed?

DR MAMOUNAS: I think so. I think the results with the FISH from the metastatic trial are so significant, why bother? I think it will be interesting to just do the FISH up front. If the FISH becomes less expensive, I think it will be very cost-effective doing FISH without the immunohistochemistry.

DR LOVE: What other trial ideas have you all talked about in terms of Herceptin, or trials that you see out there that you find interesting?

DR MAMOUNAS: Well, certainly, I think the approach that the BCIRG has taken of developing a non-anthracycline-containing regimen with Herceptin is interesting, and it may prove to be a good strategy because we might not be able to use Herceptin with anthracyclines. That remains to be seen. Certainly, there appears to be synergies between taxanes, Taxotere, in that particular study, cisplatin or carboplatin and Herceptin. And certainly, that’s a good approach. But again, that remains to be seen. I’m not quite sure that even that regimen will not show some cardiac toxicity, maybe something inherent to Herceptin. In fact, George Sledge presented some data in San Antonio, showing that when they started with Taxol-Herceptin, there was some real cardiac toxicity. Not very common, but still some drop in ejection fractions and one case of congestive heart failure. So, even the Taxol-Herceptin combination — or at least the taxane and Herceptin combination, which, probably due to the Herceptin, has some inherent risk of cardiac toxicity. It’s not only the anthracyclines that causes that to happen.

In terms of other trials that we are currently doing, we have a very important trial, and that’s an oral clodronate trial, an oral bisphosphonate trial in patients with both node-negative and node-positive breast cancer. We have been significantly impressed with the data from both Germany and now, the Canadian and the U.K. trial, showing that clodronate reduces bone metastases and in one trial non-bone metastases, and now in two trials, improves survival. At the San Antonio meeting, there were updated the results from the Canadian trial, showing a significant prolongation in survival. So, we’re doing a large study of 3,000 patients looking at three years of oral clodronate versus three years of placebo leaving the adjuvant therapy otherwise at the discretion of the investigator. We chose three years because it appears that clodronate is almost like tamoxifen, that you have to give it for longer periods of time to get the benefit

In the U.K.-Canadian trial, actually, they use it for two years. The reduction was significant during therapy, but it became non-significant afterwards. So, we would like to see whether we get more mileage out of using clodronate for longer periods of time.

DR LOVE: That’s a really cool trial, particularly now in view of the ATAC trial coming out, showing improvement in disease-free survival, but problems in terms of bone. And Mike Baum talked about the synergy that might be involved there. But, you know, one thing that’s kind of strange about that study is that it’s studying a drug that’s not available in the United States, and sounds like maybe it isn’t going to be available. So, if the trial’s positive, then what are we going to do?

DR MAMOUNAS: Well, hopefully, if the trial is positive, the drug will become available. I mean, they’ll take it to the FDA. I don’t know if they have plans of doing that based on the Canadian trial that now shows survival benefit. They might. But certainly clodronate is available in Europe and Canada, and it’s a very well tolerated bisphosphonate, and does not have a lot of the side effects of Fosamax, for example, which is an amino-bisphosphonate, because clodronate is not. So, certainly, it’s an easy drug to take and hopefully it will be approved and be available. But I agree with you, that in lieu of the ATAC trial results, it may be a reasonable strategy in the future to use an aromatase inhibitor with a bisphosphonate as adjuvant therapy.

DR LOVE: The problem is do we know that another bisphosphonate is going to be the same as clodronate? I guess we could say we do, but do we really?

DR MAMOUNAS: No. And I think there are some very promising bisphosphonates out there, including pamidronate and, more importantly, zoledronate. I think our plans, along with some other groups, is to compare them, eventually. Our approach was to start with the oral, mainly because this was the only bisphosphonate that we had some data in the adjuvant setting. It was easy to give, easy to take for the patients, and it’s a concept that we’d like to prove. It’s the first proof-of-concept trial. Once that is proven, I think that will open the horizon to do more trials and find the best bisphosphonate, although I’m a little hesitant with the intravenous bisphosphonates. It’s kind of hard to tell the patient to come for three years to get an intravenous dose. Even once a month, sitting in the chair and getting an intravenous infusion, I think that’s something that people will get easily very disinterested with.

DR LOVE: What other studies are you doing?

DR MAMOUNAS: We also are doing a study looking at another aromatase inhibitor, exemestane, sequentially to five years of tamoxifen therapy. So, the randomization after five years of tamoxifen for patients that are disease-free is between two years of placebo and two years of exemestane.

Exemestane, as you know, is a steroidal aromatase inhibitor and may have some advantages over the non-steroidal aromatase inhibitors particularly in the bone. There was some very interesting data in San Antonio; they were pre-clinical data that suggests that perhaps exemestane has actually a good effect on the bone. One of the metabolizers of exemestane actually maybe has androgenic activity, and that may actually increase bone density. So, we’d certainly like to see what will happen in patients after five years of tamoxifen, whether they will benefit from the addition of an aromatase inhibitor.

DR LOVE: When do you think you’re going to have results from that study?

DR MAMOUNAS: Probably not for a while. We started accruing about nine months ago in May of 2001, and we are looking for 3,000 patients. Accrual, it’s about 40-50 patients a month now. So, it’s going to be a while. Probably not for about five-six years.

DR LOVE: Do you think that maybe and I’ve heard Kathy Prichard say, “Well, maybe by the time we get results from trials like that, it’s going to be irrelevant, because people are not going to be on five years of tamoxifen. They'll have gotten an aromatase inhibitor.”

DR MAMOUNAS: Certainly, we’ll open a whole new set of questions. And if this approach is better than tamoxifen alone, then the natural comparison would be to compare this approach, perhaps, to an aromatase inhibitor upfront either followed by tamoxifen or an aromatase inhibitor alone. Those will be hard trials to do, because you’re going to have to have patients that take five years of tamoxifen. As this pool decreases, it will be hard to compare them. But, this certainly opens a whole new set of questions.

DR LOVE: Right now, though, you don’t really have an adjuvant trial looking at an endocrine question in ER-positive patients?

DR MAMOUNAS: No.

DR LOVE: Are you talking about doing that?

DR MAMOUNAS: We were looking at Faslodex, actually, or fulvestrant, as a potential adjuvant hormonal therapy. We’re still waiting, though, for the results of the comparison of tamoxifen to fulvestrant, and if these are favorable, certainly our enthusiasm will increase in moving this as adjuvant therapy. If, for some reason, though, that doesn’t show as much benefit as tamoxifen, certainly it will be hard to justify using it in the adjuvant setting. Fulvestrant is a pure anti-estrogen. It’s a good drug with a good toxicity profile, and certainly will find its way in the metastatic setting. The question is will it find its way in the adjuvant setting? But, so far, we’re waiting for the results before we can move on with that concept, which we actually had developed.

DR LOVE: What about DCIS? What are you doing in that right now?

DR MAMOUNAS: We actually are close to initiating a study in patients with DCIS, to do lumpectomy or radiation, comparing Arimidex, or anastrozole, to tamoxifen. In essence, replicating the results of the ATAC trial in this particular group of patients. Those are low-risk patients, and it’s not necessarily assumable that they will do better with anastrozole than tamoxifen. I think the question has to be proven, whether the risk-versus-benefit ratio as it relates to fractures and other end points will actually justify the use of an aromatase inhibitor in this group of patients.

We’re certainly very impressed with the data with opposite breast cancer reduction in the ATAC trial. Certainly, it makes it all the more justifiable to do this study, to prove that this is true for DCIS patients.

DR LOVE: I guess when you think about it, when you do a trial in DCIS of a systemic agent, a big part of your rationale is the second breast cancer.

DR MAMOUNAS: It’s contralateral breast cancer. Right.

DR LOVE: Those numbers on second breast cancer in the ATAC trial were very interesting.

DR MAMOUNAS: It’s about a 50-percent reduction over and above the reduction with tamoxifen, if you add the DCISs with the invasive cancers. And, if you take that, it would be 60 versus 15, so it’s almost a 75-percent reduction, which is very significant.

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