INTERVIEW WITH DR. MICHAEL BAUM

DR. LOVE: One other thing I wanted to ask you in terms of the disease free survival advantage that I've heard a few people comment on was that there was a relatively small number of women in the trial who got chemotherapy, I think it was about 20%. The question of whether or not the advantage of Arimidex is going to be seen in that subset.

DR. BAUM: It's a question that we are asking of ourselves and of our database. It's not a straightforward question because they are confounders, in that these women are likely to be node-positive and likely to be among the ER-negative group. So, we've got to do a Cox regression analysis to sort that out. It will be done. I hope it will be within the paper that Aman Buzdar will deliver next May at ASCO.

DR. LOVE: What were the other side effects seen in the trial and particularly the ones on the other side of the line, so to speak.

DR. BAUM: To many people the most exciting part of this study is the safety profile of anastrozole. That's why the trial was powered out for equivalence. There is a highly significant reduction in hot flashes, highly significant reduction in the incidence of vaginal discharge and vaginal bleeding. And although in numerical terms, very small numbers, already a significant reduction in endometrial cancer. To me the risk of endomitral cancer has been exaggerated in tamoxifen, it's very rare, and it's curable. The problem with tamoxifen is the number of women who are referred to gynecologists to exclude endometrial cancer. So you get women with vaginal discharge, vaginal bleeding, they have transvaginal ultrasound, you see abnormal looking endometrium
you scare the woman, she undergoes hysteroscopy, and they find atrophic endometrium. So just to reduce that hazard is, I think a big plus for anastrozole. Now, perhaps even more important because we are now beginning to consider life-threatening events, there is a significant reduction in strokes, cerebrovascular accidents and a significant reduction in thromboembolic events. So the safety profile, apart from bone mineral density, strongly favors anastrozole. and as far as bone mineral density is concerned, I think that is something that we can handle, providing we anticipate it.

DR. LOVE: The hot flash thing was very interesting because the advance disease study suggests that they were about the same in anastrozole and actually the other aromatase inhibitors and tamoxifen. And yet clinicians would say, "I don't really associate hot flashes with the aromatase inhibitors." I always wondered whether it was something about the power of these advance disease studies.

DR. BAUM: I think it's the power because we are looking at a reduction of I think about 8% percent in the incidence. That's taking it down from 30% to 20%, to pick that up you need a very large number of patients. We're talking 9000 patients not 300 patients.

DR. LOVE: Is it the largest study ever done in cancer medicine?

DR. BAUM: It's the largest study ever done in the treatment of cancer, cancer therapy. The prevention studies are larger.

DR. LOVE: It was interesting comparing the size of ATAC to the size of the original tamoxifen your NATO study. How many women were in that?

DR. BAUM: 1200. The NATO trial started in 1977, they target was 1000 patients, at that time that was one of the biggest trials.

DR. LOVE: That's right. It was the biggest trial in the initial overview. Some of those original trials, even like the CMF and the original NSABP study, were I think a few hundred patients.

DR. BAUM: 800

DR. LOVE: Right, right. Getting back to the toxicity. Another thing that was very interesting, it seemed like there was less weight gain in the anastrozole arm.

DR. BAUM: That's an odd one, because that's the way I expressed it in the slide, but I don't believe there was weight gain with tamoxifen. This is anecdotal the placebo control charts do not show weight gain. Most women on tamoxifen blame their weight gain on tamoxifen, but I have to remind everyone in the days before we used tamoxifen the diagnosis and treatment of breast cancer was associated with weight gain. You can speculate why, but I would think a lot of women were comfort eating. A lot of women were precipitated into the menopause, and menopause is associated with weight gain. So it is an intriguing thought that there may in fact be weight loss with anastrozole rather than a reduction in weight gain.

DR. LOVE: Any pathopsychological reason to think why you would have weight loss?

DR. BAUM: Your guess is as good as mine.

DR. LOVE: When you look at the incidence of endometrial cancer, vaginal bleeding, the endometrial issues and then the thrombotic issues that was seen in the anastrozole arm is it your take that it's about baseline for postmenopausal women? Or do you think any of them were actually reduced?

DR. BAUM: I think its baseline. It's a very good question. We're asking that ourselves because there was no control group. But the .1% incidence of endometrial cancer in this population of 3300 is about baseline.

DR. LOVE: Now obviously one of the questions, or THE question is what does it mean? Or certainly one of the questions that comes out of this presentation is what does this mean in terms of patient care today? Of course, the other big question is what does it mean about the design of future clinical trials. So why don't we talk about those two issues. In terms of patient care today, without even trying to get into what people should do, because I know you, and no one else in research likes to do that. Right now, what does the risk benefit profile look like to you, for anastrozole vs. tamoxifen as adjuvant therapy?

DR. BAUM: I would say, even if there were equivalence, the profile of anastrozole looks better so far. But, this is only two and a half years of treatment, we cannot say what five years of treatment are going to do. There maybe a greater incidence of fractures, and the really serious life threatening fractures of the hip, if they're going to come, and they're coming much later there is a lot of cortical bone in the hip and most of the fractures we are seeing are in fact wrist fractures. All I can say is there is an average follow up of two and a half years. The safety profile of anastrozole looks better, the tolerability of anastrozole is undoubtedly better than that of tamoxifen. If the efficacy continues to diverge than you can start making therapeutic recommendations.
But, you asked me what would I say to women today. Well the first thing, if women are already on adjuvant tamoxifen, I think it would be hazardous, foolish, and irresponsible to switch to anastrozole. We haven't tested that combination, we have no idea what that might do, and listening to some of the theoretical stuff over the last two days, the endocrine system and it's relationship with breast cancer is hideously complicated. So, you would be embarking on a therapeutic regiment about which there is nothing known. So, I would urge against that, very, very strongly.
For a woman just diagnosed with breast cancer, I think she should be made aware of the data, in the same way I'm providing you with my insights. I trust my colleagues, my professional colleagues, to do this in a responsible way. I have sufficient respect for women with breast cancer, to know that most of them would make a rational decision. I think the rational decision would be to consider tamoxifen still the gold standard, at least until we produce an update of the results at ASCO next May. I feel very, very sorry for the women diagnose with breast cancer over the six months. You have to recognize that there will be periods of uncertainty in the evolution of medicine and the evolution of science. We're going to live through a period of uncertainty.
My primary concern is for the welfare of the volunteers the women in the trial. We're in the process of deciding how we are going to handle it and what the mechanisms will be for handling it. These discussions are confidential at the moment. The process has already been activated and one of the great limiting factors will be the IRBs in the USA and the MRECs in the UK, the ethical issues.

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