DR TERRY MAMOUNAS SUPPLEMENT

DR LOVE: What do you think about the ATAC trial data? What it showed and what the implications are?

DR MAMOUNAS: Well, I think, certainly, that will make a significant impact. This is the first time we see an agent actually beating tamoxifen after many, many years of tamoxifen supremacy. Whether that will translate into survival is still unknown, but certainly the disease-free survival data are significant, about 20-percent reduction. And the contralateral breast cancer data are very significant.

So, I think that will lead to an adoption of anastrozole as adjuvant therapy, particularly in older patients where you try to avoid the thromboembolic adverse events of tamoxifen and the stroke, and the endometrial cancer, which appear to be much decreased with anastrozole. I think then, eventually, it will work its way to most postmenopausal patients.

DR LOVE: What was the reaction of the NSABP members involved with the STAR trial? I know you’re very involved with that. One of the thoughts I had was, is this going to discourage people from putting people in the STAR trial, because maybe the effects look so dramatic with anastrozole?

DR MAMOUNAS: I don’t think so. We haven’t really seen that. I think that people will be concerned with fractures, particularly in healthy patients. One of the advantages of tamoxifen in that population is – and raloxifene, for all that – is the increase in bone density. So, people have to weigh the pros and cons in this particular trial.

The other thing is that, although the STAR trial is for postmenopausal patients, because we don’t have a lot of data with raloxifene in premenopausal women, SERMs may still be very effective in the premenopausal patients. So, I don’t think tamoxifen is going to go away. But we haven’t seen a reduction. Certainly, that gives us a lot of hope for another prevention trial in the future, looking at aromatase inhibitors versus tamoxifen. This has already been done, or planned, in Europe, the IBIS trial. But maybe there will be a role of using another aromatase inhibitor, particularly, again, as I mentioned earlier, exemestane, which appears to have some differential effects on the bone, and perhaps on the lipids in the blood.

DR LOVE: Do you think that the ATAC trial results might affect accrual to studies, not so much where the endocrine therapy is an issue, but where ER-positive patients can come in. I’m specifically thinking about a trial like B-30, for example, where the patients can be ER-positive and they can receive endocrine therapy. Are you going to see an imbalance because just by play of chance some docs are using anastrozole and some are using tamoxifen?

DR MAMOUNAS: Right now, as it stands, we don’t allow anything but tamoxifen. But, certainly, we may have to change that, particularly when anastrozole gets approved when it goes to the FDA. Other groups are looking at allowing patients to be treated either with tamoxifen or an aromatase inhibitor, or their choice as well.

Those large trials typically will not result in imbalances. Because they’re so large eventually the distribution of patients getting tamoxifen or anastrozole will be equal between the arms of the study. We may not have a choice — in our new studies, already the NCI is commenting that we have to allow for aromatase inhibitors. So, starting with the Xeloda trial, we will allow and we may have to do that with the clodronate trial, as well, because we have a long time to go.

DR LOVE: I guess you can stratify.

DR MAMOUNAS: You can stratify, although, as I said, because these are large, randomized trials, even factors that you don’t stratify for are so much equally distributed at the end of the trial, that it doesn’t make much of a difference.

DR LOVE: Any other new trials that you’re thinking about implementing?

DR MAMOUNAS: We do have a trial, or we’ve been planning a trial, for quite some time now, looking at patients with ipsilateral breast tumor recurrence or local regional recurrence, and trying to find whether there’s value for chemotherapy in these patients. This is a group of patients that has not been studied prospectively often, if at all. The concept is to see if we can give an active chemotherapy regimen to these patients, and would we make a difference in their survival?

As you know, the patients that develop IBTR have close to about 50 to 60 percent risk for systemic relapse in the next five years. And patients that develop local regional recurrence have close to 80 to 90 percent yet there’s no proven benefit of chemotherapy for these patients.

Hormonal therapy is used, obviously, we change the hormonal therapy if that happens, but chemotherapy has not been proven. So, we’re designing a trial, actually looking at adjuvant capecitabine plus Taxotere for those patients at the time of IBTR or local regional recurrence. Either alone or with hormonal therapy, if they are ER-positive.

DR LOVE: So, it would be capecitabine-Taxotere versus –

DR MAMOUNAS: Nothing. Or capecitabine-Taxotere plus choice of hormonal therapy versus hormonal therapy alone.

DR LOVE: Hmm. And what caused you to choose the capecitabine-Taxotere?

DR MAMOUNAS: Well, again, the survival data that we saw. Initially, we were thinking about Taxotere as a non-cross resistant. Because most of these patients will have seen either anthracyclines or alkylating agents in the adjuvant setting, and we have good evidence of activity, but then with the data with capecitabine, we felt that we can take probably the maximum benefit. And a lot of those patients also have not seen 5FU, because they did it with AC. But even if they did it with CMF, I think there’s good data to support activity with the taxane in these patients.

DR LOVE: Would you require prior AC?

DR MAMOUNAS: No. In fact, the way it is written now — and that’s a process evolving, of course, and being reviewed — we allow any adjuvant therapy, including taxanes as adjuvant except Taxotere. Because, I mean, there’s evidence that there is activity with Taxotere in Taxol failures, particularly those that had the three-hour infusions. Most of the adjuvant patients who have Taxol will have a three-hour infusion. So, there’s some activity with the Taxotere in Taxol failures.

DR LOVE: That’s really a cool idea. Nobody’s looked at it. People keep saying, we’ll never have trial data on that.

DR MAMOUNAS: Right.

DR LOVE: But that’s a great idea.

DR MAMOUNAS: Yeah.

DR LOVE: Who was the lead person on that?

DR MAMOUNAS: I’m the co-investigator with Irene Wapnir from Stanford.

DR LOVE: Wow! That’s great.

DR MAMOUNAS: The problem with that trial will be accrual. We will see how successful it will be. It’s been tried before. There was a randomized trial looking at tamoxifen and chemotherapy that actually accrued only about 50 patients and was never reported. That is the only randomized trial, actually, that looked at chemotherapy in the setting of local recurrence.

DR LOVE: What about Stage IV NED, a patient who has a lesion somewhere else that’s removed?

DR MAMOUNAS: That’s almost another category of patients, very close to what we’re talking about. Because, in essence, we’re talking about close to Stage IV NED. Actually, we would require in our trial, to have a complete removal of the lesion, either in the breast, chest wall or supraclavicular area. And then local therapy is at the discretion of the investigator. But, we don’t operate, today, on Stage IV NED because it may actually attenuate the effect.

DR LOVE: Interesting. Have you been able to get numbers on how many women a year have local recurrence and what percent you think you could get?

DR MAMOUNAS: Well, those patients are there. Typically, you expect about a 10- to 20-percent local recurrence in patients with operable breast cancer. The key is to get them into the trial, and have them willing to be randomized because a lot of people may have biases. These patients are treated with everything from nothing to bone marrow transplantation in the older days. So, it’s hard to know. What we’ve done so far in our research is in the NSABP trials, those patients don’t get chemotherapy about 30-40 percent of the time. So, the oncologists are very divided in the treatment of these patients. So, hopefully, they’ll be willing to randomize them.

The other thing is that this is not a big trial. We can do it with about 800 patients because the event rate is so high. We don’t need thousands of patients for this trial.

DR LOVE: And, again, where is this? It’s been written up?

DR MAMOUNAS: We’ve already submitted the concept earlier to the NCI. We had some comments. They wanted us to justify the high rate of recurrence with the IBTR, and now we’re writing the concept, and it’s about to be submitted in the next couple of months.

DR LOVE: Was this just for patients who had breast conservation or also mastectomy?

DR MAMOUNAS: No. Actually, mastectomy, as well, because we expanded it to local regional recurrence, too. If you have a chest wall recurrence or regional recurrence of nodes, irrespective of your surgery, then we’ll include those patients. That will help us decrease the sample size because the event rate goes up.

So, whether that will work differentially in the IBTR patients versus the local recurrence patients remains to be seen. It would be nice to have enough events in patients in both groups to prove that it works both because it may be a different situation in IBTR versus local regional recurrence.

But following IBTR, we see about a 50- to 60-percent systemic relapse subsequently. That’s something people underestimate. A lot of times they think IBTR is a benign type of thing and we’ll take the breast off and we’ll be okay. But the patients recur systemically, substantially so.

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