DR TONY HOWELL SUPPLEMENT

DR NEIL LOVE: Dr Sledge commented on one of the most discussed new data sets in breast cancer clinical research — the initial results of the ATAC adjuvant trial, comparing anastrozole to tamoxifen to the combination. I met with Dr Tony Howell, a faculty member of the recent Miami Breast Cancer Conference, and a key investigator in this historic study. Dr Howell has been a pioneer in endocrine therapy of breast cancer and later on in our conversation, he provided an update on fulvestrant, a fascinating new addition to the hormonal armamentarium. But he began our conversation by tracing the background to the development of the ATAC study.

DR ANTHONY HOWELL: Clearly the idea of anastrozole for adjuvant therapy came in because it was being successful for advanced disease. It actually came through extraordinarily quickly because there wasn’t any phase II study. It went straight through from phase I to phase III in second-line advanced disease. And, then clearly an adjuvant trial had to be designed. And it was actually designed by Michael Baum and, I think, Joan Houghton, on the back of an envelope. It was a three-arm study, obviously – anastrozole, tamoxifen and the combination.

A lot of people complained about the combination because there was no data on this at all, and no rationale really. But despite the complaints, the trial went ahead as a three-arm study. As far as the combination arm is concerned, to my mind, what we found was entirely predictable. In animal models, in the immature rat uterus assay, for example, if you have a low estrogen environment, tamoxifen stimulates uterine growth. If you have a high estrogen environment, tamoxifen acts as an anti-estrogen. So, why wouldn’t that happen in patients? And I guess my suggestion is that we’ve got tamoxifen working in a low-estrogen environment. Under those circumstances, it’s slightly more likely to be an agonist than an antagonist.

Another reason, which is quite possible, but we won’t know until we get the receptor data, is the fact that tamoxifen does not seem as active in low estrogen receptor conditions as anastrozole or letrozole, at least from the Matt Ellis data. If you look at the response rate according to the Allred score in his data, you see that tamoxifen only works with an Allred score above three. Whereas, in fact, letrozole works with an Allred score of 2, 3, and 4, as well as the higher scores. So, that may be another reason why tamoxifen is not as effective as anastrozole. Anastrozole may be working at low estrogen concentrations, and clearly, the data that will come out of the biological sub-study within ATAC are going to be extremely interesting.
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DR LOVE: But this thing about aromatase inhibitors working with low levels of estrogen better than tamoxifen, does that have anything to do with why the combination arm didn’t work as well?

DR HOWELL: I think that is the likely explanation. Let’s get it straight. The combination arm is very similar to tamoxifen. What we’re just talking about is a small reduction in activity compared with tamoxifen, which is definitely nowhere near significance. But you have to explain why it is slightly worse than tamoxifen, and of course, you have to explain why it is definitely worse than anastrozole. And so the slight worsening compared to tamoxifen, is to my mind, likely to be due to the fact that tamoxifen is more likely to be an agonist in a low estrogen environment. Whereas, then you have to explain why tamoxifen and the combination are not as good as anastrozole, and that may be because anastrozole seems to – or letrozole, at least – but the aromatase inhibitors seem to work, for example, in HER2-positive tumors, and they work in tumors with low levels of estrogen receptor from the Matt Ellis data. Although, clearly, we need to confirm those data that Matt produced, because they are extremely interesting and, if true, give us the explanation of why one set of drugs, the aromatase inhibitors, are better than another set of drugs, the SERMs.

DR LOVE: I assume you’re going to be looking at HER2 status in the ATAC trial?

DR HOWELL: Mitch Dowsett is heading up the biological sub-committee of the ATAC trial, and he will be looking at that.

DR LOVE: Will you be able to look at Allred scores in terms of ER?

DR HOWELL: We will look at ER, and Mitch will be doing that. I think he does the Allred score. I’m not totally convinced that the Allred score is the right way to look at it. We, in Europe, tend to look at the numbers of cells positive, rather than their intensity, although there are also groups in Europe who look at intensity particularly the Cardiff and the Edinburgh groups. So, there’s a variation in how receptor is looked at in Europe as there is a variation across the United States. I agree with Kent Osborne when he says that the variation is extraordinarily worrying.

DR LOVE: Yeah. Particularly as we get better and better hormonal therapy, it gets more and more worrying.

DR HOWELL: We are just analyzing our own data on 900 women who have had adjuvant tamoxifen or not. And we find that the low estrogen receptor, in terms of percentage of cells, naught to 20 percent, that we see responsiveness, an effect of tamoxifen in the adjuvant situation, in a low-receptor environment, as did Craig Allred. So, that’s a little bit against the Matt Ellis data. But clearly, we need to look at measuring low levels of estrogen receptor, because my gut feeling is that, if any receptor is there, it’s a positive. And clearly, you can miss a very low positive quite easily. Patients are not being put on adjuvant therapy, who should be being put on adjuvant therapy.

DR LOVE: I’ve heard it estimated that there may be 20 percent of breast cancer patients being diagnosed as having, in one way or another, a false-negative ER. That’s pretty scary.

DR HOWELL: I think that’s pretty high. But in the U.K., we have a quality control system, which is pretty rigorous. We have 200 laboratories in a quality control system, but there are laboratories that are not in the system, and they can just do what they like. In any small breast unit in the country, the pathologist with no experience can give an answer to an ER assay, which may be correct or may be incorrect. It’s a big, big worry.

DR LOVE: I guess from my take as a clinician, as I look at this debate about ER, I see two things. First is the actual performance of the test. There’s a lot of data out there, and you were just talking about some of it, questioning whether or not the test is getting done correctly. Secondly is the interpretation of the test. Even here at this meeting, when we polled the audience, we also did a survey of oncologists and surgeons before the meeting and asked – How do you define ER-positivity? The most common answer was if it was above a level set by the lab. We’ve looked around and labs will set a level anywhere from 10-20 percent of cells. Yet a lot of other people – and I don’t know what your take is – will consider adjuvant hormonal therapy if there’s any ER. Is that the way you approach it?

DR HOWELL: Yes. I think that was quite an interesting answer that most of your people coming to the conference would take the level that was decided by the lab. Then you have to ask – How does the lab come by a level? I guess they might look at Allred’s paper or they might look at other papers. There aren’t very many out there. There really aren’t many out there on which to gauge a level.

So if they take the lab level, they’re taking something, very often, out of the air. And I think it will come down to, if you’re certain about it, any ER-positive is positive. This was said years ago by an investigator in London, Charles Coombes, who published showing that any positive was indicative of response in advanced breast cancer. So, that then makes it very difficult, because one cell positive, is it positive or is it a false-positive? Is it a bit of dirt? Clearly, we need to know the answer to that question, and we actually don’t at the moment.

We need – and we will get – much more investigation. For example, the ATAC trial. We’ll have receptor measurements in that, and it is, as you well know, in vogue to have biological information about every trial that we do, and clearly we will be able to answer the question in the future. But, at the moment, there’s a high degree of uncertainty.

DR LOVE: There still are women in the ATAC trial, who are either ER-unknown or ER-negative. Is that correct?

DR HOWELL: That’s extremely embarrassing. There are women in the ATAC trial, who are ER-negative, about eight percent. And there are women in the ATAC trial who are still ER-unknown. In fact, we know the ER status is positive, ER+ and/or PR+ in over 80 percent of the women in the ATAC trial. So that is reassuring. If it were lower than that, one would be worried about the veracity of the results in the ATAC trial.

In fact, the positivity rate in the ATAC trial was lower than that, particularly because when the trial was started there were many centers in the U.K. that actually did not measure receptors on the patients going into the trial, because the protocol allowed receptor unknown. Clearly, that was a mistake. What happened was that AstraZeneca went back to all these labs and got the blocks from most of the patients and measured estrogen receptor, so that over 80 percent positive is reasonably reassuring.

DR LOVE: The interesting thing was that, even if you include the negatives and the unknown, there was still a statistical benefit in terms of disease-free survival.

DR HOWELL: Yes. That’s right. There is a benefit in the intention-to-treat analysis of all patients, which is about 18-percent reduction by anastrozole compared to tamoxifen. But, of course, that goes up to a 23-percent reduction as the hazard rate when you just take the ER-positive population. It’s interesting in the contralateral breast, you can predict how many contralateral breast cancers there would be in 3,000 women in one arm. There would be 60, if you didn’t treat the women. You can see how many you get with tamoxifen, which is 30, which is halved, and that’s what we expect with contralateral tumors. In the anastrozole arm there are only nine, so that’s about an 80-percent reduction in tumors in the anastrozole arm, which is really, really exciting. If that is translated into preventative therapy that augurs well for the prevention of breast cancer in the future.

DR LOVE: In fact, that’s about to go into trial as I understand with the IBIS II study?

DR HOWELL: The IBIS II trial is, at the moment, a three-arm preventive study to follow on from IBIS – so-called IBIS I. IBIS stands for International Breast Cancer Intervention Study, and the IBIS I study has 7,000 patients. The IBIS I study is like the other three tamoxifen trials – a comparison between placebo and tamoxifen. We have 7,000 women in the study. It closed to accrual over a year ago, and it’s analyzed at the moment.

The IBIS II study will be in postmenopausal patients because it’s anastrozole versus something. When we get the feel from our own investigators and from what opinion leaders think, we will then design the final IBIS II protocol. Now, it may be a three-arm study, which is anastrozole versus tamoxifen versus placebo, or it may be anastrozole versus placebo, or anastrozole versus tamoxifen. We, at the moment, are in some doubt. But we have geared up the study to start in September-October, and clearly there’s enormous enthusiasm for this study because we’ve had investigators around the world who want to buy in, including some of the people who are already in the American cooperative groups.

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