DR TONY HOWELL SUPPLEMENT

DR LOVE: Has there been any talk about possibly having an arm with anastrozole and a bisphosphonate?

DR HOWELL: That’s a very important question. The real worry, as far as anastrozole is concerned, is twofold. One, is its effect on bone, and you’ll know from the ATAC trial, there was an increase in fracture rate. It was probably not as big an increase as it looks because in the control arm they were given tamoxifen, and tamoxifen prevented some fractures. But we estimate that half of the fracture rate in the ATAC trial is due to the negative effects of anastrozole. So, clearly, we need to have a bisphosphonate in IBIS II, and that also is under discussion at the moment, because there are some who wish to give everybody a bisphosphonate, and there are others who say, well, that’s over-treatment of a large part of the population.

DR LOVE: Why can’t you just do bone density measurements?

DR HOWELL: There is, at the moment, a bone sub-protocol, which has it in the first 1,000 patients have sequential bone density measurements. Then, the remainder of the patients should have bone density at the start, to know whether they are low and, if they are low at the start, at the moment the thinking is that they should go in the study, but they should be on bisphosphonates, as well. And we think that we need to work out the bisphosphonate issue and, in the end, I think it will come down to the fact that most patients will need serial bone density measurements.

DR LOVE: I’ve heard some people say, looking at the side effects and toxicity profile in ATAC, that if the efficacy had been exactly the same as tamoxifen, it still might be worth using anastrozole.

DR HOWELL: I haven’t heard that said, and that is extremely interesting, and I would agree with you. The thromboembolic complications are much lower. Endometrial cancer is much lower, and so that would make it an attractive drug from that point of view. The real problem is how to deal with the bone problems. But you could even say that that is a positive because these are postmenopausal women who might develop bone problems even if they haven’t developed breast cancer. So, this nicely focuses on bone, which is a problem for a large proportion of postmenopausal women. So, it’s almost like you could see the bone “problem” as an advantage.

DR LOVE: Also, in terms of anastrozole for adjuvant therapy, another unexpected benefit of having to focus on bone is, if the women do end up getting bisphosphonates, you might end up with a benefit in terms of metastatic disease. Trevor just presented his information, which is now the third clodronate study. What did you think about those data showing fewer bone mets and actually better survival in women who got clodronate?

DR HOWELL: That is very interesting. The clodronate data are also difficult, but to hear those data from Trevor at the San Antonio meeting presented in exactly the same session as the ATAC results makes it really interesting. In the same session, you have the very good result from ATAC and also you have a solution to the problem of bone in the anastrozole arm of the ATAC trial.

DR LOVE: Is there any reason to think that other bisphosphonates would be different than clodronate?

DR HOWELL: No. It’s only a matter of degree. The bisphosphonate that can be given weekly may be useful. But I spoke to Ingo Diel last night, and his view is that we have the most information about clodronate for women with breast problems, therefore, clodronate may be the drug to go with even though it’s an old drug and even though it’s been superceded by alendronate, for example. Because we have so much data on clodronate and it has a pretty low side-effect profile, it may be appropriate to use that bisphosphonate for the IBIS II trial.

I guess my feeling is, given the Ingo Diel data and Trevor Powles’ data, plus the ATAC data, we might treat all elderly women with ER-positive breast cancer with a combination of clodronate and anastrozole. That would make the treatment pretty safe, I guess, and then we may have an additional effect of clodronate on survival as those two trials have shown.

DR LOVE: Of course, clodronate’s not available commercially in the United States. So, would you substitute another bisphosphonate?

DR HOWELL: My feeling is, and I’ve spoken to the osteoporosis people on this and they don’t think there’s any qualitative difference between the bisphosphonates; that it is a quantitative problem. The real problem with bisphosphonates is obviously the toxicity, particularly GI toxicity, and we need to find the best bisphosphonate to have low GI toxicity. That’s my view.

DR LOVE: Can you talk a little bit about where things are right now with Faslodex as we move into the endocrine era?

DR HOWELL: Faslodex is going to be shortly accepted by the FDA. And all additional treatments for advanced breast cancer are useful. As you well know, we give sequential endocrine agents, and here you have another one that is a highly potent, estrogen receptor downregulator. In second-line therapy, it is equivalent to aromatase inhibitors. It is equivalent to our best drug. So, we have another best drug.

DR LOVE: With the current information we have right now, where do you see the place of Faslodex?

DR HOWELL: I think the first-line treatment for advanced disease in postmenopausal women is an aromatase inhibitor, if they haven’t already had one. Then I see Faslodex coming in after that, at the moment. I guess it probably doesn’t matter which order you give them in, but we have more data on aromatase inhibitors, and you have to treat patients on the basis of data. So, I’ve given an aromatase inhibitor followed by Faslodex.

DR LOVE: How much of a problem is the injection?

DR HOWELL: I think it’s a non-problem. In fact, it could be seen as an advantage that women don’t have to take pills every day. As you know, there haven’t been huge problems in terms of injection site reactions at all. Even the Japanese don’t have problems and they have smaller buttocks. So, I see that as possibly an advantage to the patient compared to taking pills. I guess it might be an advantage to the doctor in the United States because you get paid for giving injections, I understand. But that doesn’t happen in the rest of the world. But no, it’s just a non-problem. And women say they don’t mind having an injection if they’re getting an active compound. On the whole, it doesn’t concern most of them.

DR LOVE: Do you generally think that giving one 5-cc injection is better than two 2.5-cc injections?

DR HOWELL: I don’t see why you should give two. There is no difference in the pain, or there’s very little pain anyway. Why give two compared to one? In Europe, every woman’s just had one injection. In fact, in the two trials, the one done in the rest of the world and the one done in the U.S., there were more complaints of injection site reactions in American women compared with the rest of the world. Now, that may be of greater sensitivity or greater reporting in American women, but it may be due to the fact that they had two injections.

DR LOVE: I’ve heard people say that an aromatase inhibitor and Faslodex are going to be equivalent options, and maybe other issues, like whether an injection or pill would be better for that individual woman – is that your approach?

DR HOWELL: That’s great, isn’t it? You have a choice. Those treatments are clearly, pretty equivalent, and the woman can make the choice. If cost is not an issue, I guess both of these drugs are going to be more costly than tamoxifen.

DR LOVE: Now, when you say, in terms of first-line therapy, do you make a difference whether or not the woman’s had prior tamoxifen? For example, in the adjuvant setting.

DR HOWELL: No. It doesn’t seem to matter. We know that those drugs are equally active in women whether they have had previous adjuvant tamoxifen or previous tamoxifen for advanced disease. So, that’s not an issue. I guess if a woman hasn’t had adjuvant tamoxifen and gets relapse, she’s ER-positive, you’re not going to use tamoxifen in that situation. You’re going to use an aromatase inhibitor as first-line treatment. If expense is no option, you might well use Faslodex as a second-line treatment, and maybe you’ll keep tamoxifen right towards the end, with high-dose estrogens, which are making a comeback.

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