DR TONY HOWELL SUPPLEMENT

DR LOVE: Can you capsulize what we know right now about the estrogen-estrogen receptor interaction? What happens when you give a drug like tamoxifen and what happens when you give a drug like Faslodex?

DR HOWELL: Well, we know that the effects on the ER with Faslodex are different than tamoxifen. Tamoxifen causes dimerization of the receptor binding to the estrogen response element, and then activation of AF-1, but inactivation of AF-2, and partial estrogen-agonist activity and partial antagonist activity depending on the cell and the gene promoter context.

Faslodex is different, and there’s a lot of data to suggest that it’s different, in that, first of all, it probably causes some dimerization, but it increases the turnover of receptors. So some receptor goes out of the nucleus. And the turnover time of the receptor is greatly reduced. The second thing is that when it does bind and cause dimerization and the receptor gets to the estrogen response element it inactivates AF-1 and AF-2. So, it totally switches off the receptor.

So, on those two mechanisms, it has a different effect than tamoxifen. And this is seen in the preoperative studies where you give Faslodex and look over a period of two to three weeks, what happens to immunostaining for estrogen receptor. Whereas, with tamoxifen, after two weeks, you can stain almost as much receptor as you had in the pre-treatment sample. In the Faslodex sample there’s virtually no receptor there to be stained. So, that indicates that there’s a totally different mechanism of action.

DR LOVE: Any biologic reason to think that it might be a better drug than an aromatase inhibitor?

DR HOWELL: Yes, because you’re blocking the receptor continuously with Faslodex, and there’s no receptor there for any estradiol, which is around, to stimulate the tumor. Whereas, what Arimidex is doing, obviously, is lowering the serum estradiol, but there’s still estradiol around, which could potentially stimulate the tumor. We know from the work of Dick Santen, particularly, which is being reproduced by Mitch Dowsett, that, looking at MCF-7 cells, those cells sort of hunt the prevailing estrogen concentrations. If you take MCF-7 cells and put them in vitro and do a dose response curve to estrogen, you find that they are maximally stimulated by 10–9 molar estradiol. But then if you deprive those cells of estrogen for a month, you find that the dose response curve shifts to the left, dramatically. That then the cells are sensitive to 10–15 molar estradiol.

DR LOVE: Wow! So, they increase their sensitivity?

DR HOWELL: They increase their sensitivity quite dramatically. That’s a very, very important experiment that Dick has done. So, you’ve got a woman on Arimidex and you’ve lowered the estradiol to virtually undetectable levels, say from 50 picomolar to 5 or 2 picomolar. But if Dick’s data are transferable into humans – and I don’t see any reason why not – there is the potential for the tumor to adapt to the lower prevailing estradiol concentration, and so therefore, to circumvent the effect of Arimidex.

DR LOVE: Is this a genetic adaptation?

DR HOWELL: Nobody knows, to be quite honest, the mechanism of it. My own hypothesis is that there are clones of cells within the MCF-7 cell milieu, which actually have the ability to respond to such low levels of estradiol. But it may be some change within co-activators for example. Susan Fuqua has published a very, very interesting paper in Cancer Research where she showed that an estrogen receptor with a mutation at amino acid 303 in the hinge region, between the D part of the receptor and the E part of the receptor, the hormone binding part. If you have that mutation, the tumor is sensitive, and she’s shown this in pre-malignant lesions that the tumor is sensitive to exceedingly low concentrations of estradiol. It seems that the co-activators c-activate at a much lower concentration, in essence steroid receptor co-activator 1 causes stimulation at a much lower concentration of estradiol.

So, that’s information concerning the fact that that is now actually being shown in pre-malignant lesions in women. Dick Santen’s hypothesis, or data, if you like, may indicate that that’s what’s happening in tumors in women, and that may mean that there is an ability of tumors to get around the very low estradiol concentrations of Arimidex and for tumors to be stimulated by those low concentrations. Whereas, theoretically, ICI 182,780 should completely switch off receptors forever more. Actually, of course, we know that that doesn’t happen, because even in the phase II study, where we had fairly well selected patients, the median duration of response was only 24 months, and those tumors actually did become resistant.

The in vitro data would suggest that that resistance is not due to stimulation by ICI 182,780. And those tumors don’t become stimulated either by ICI 182,780 or low concentrations of estradiol, and nobody knows how tumors become resistant ICI 182,780. I think we have to see the data from the randomized trials.

The Santen and the Fuqua data are tremendously important for the way that we look at endocrine therapy in the future. Because what Santen then did was, in the estrogen deprived MCF-7 cells that were maximally stimulated by 10–15 molar estradiol, he then gave those cells 10–10 molar estradiol, and they apoptosed. They were completely eliminated. So that adding back – because 10–10 molar was a lot of estrogen for those particular cells that were maximally stimulated by 10–15. And so that is very, very important for the future of endocrine therapy because we may add back to women who are failing on Arimidex or we may add back even before that failing, some estrogen. We may cause tumor depression by adding back small doses of estrogen. We’ve done a study where we’ve added back more estradiol in women who’ve had four endocrine therapies. We’ve added back Stilbestrol in large doses.

DR LOVE: Like the old days?

DR HOWELL: Like the old days. But it sort of tests Santen’s hypothesis. Adding back estradiol in this group of 30 patients that we studied showed, after four endocrine therapies – they may have had oophorectomy, they may have had tamoxifen, they may have had a couple of aromatase inhibitors and then they have estradiol – and a third of those women responded for a median duration of one year. So, this thinking that you could re-challenge with estradiol, is important. We have not thought out endocrine therapy sufficiently, and that we may alternate with aromatase inhibitors, estrogens; there’s maybe a lot more mileage in endocrine therapy than we actually know.

There is also a preoperative trial being organized by the EORTC, in Europe, which is simply one injection of Faslodex after the diagnosis of breast cancer has been made versus an injection of placebo. And, of course, the Faslodex injection being present for over one month would cover the operative period in terms of anti-estrogenicity, with a potent anti-estrogen with estrogen receptor levels lowered. And if there is anything in the hypothesis from Bernie Fisher and others, that something happens around the peri-operative period this should be able to pick that up, because the aim is to put 3,000 women into that study. And then the patients can have any adjuvant therapy that they want, because that should all come out in the wash with 3,000 patients.

DR LOVE: I assume that the ER would be determined before the Faslodex?

DR HOWELL: No.

DR LOVE: Oh, really?

DR HOWELL: No, because you want to give the drug as soon as you’ve done that true-cut biopsy. And waiting around for ER estimations – which, in some centers, may take up to a week or two weeks – would mitigate the effect of giving the drug. So, no. The protocol is that you see the women, you do the true-cut biopsy, and as soon as you’ve got the result of the true-cut biopsy, then that is invasive cancer. Then you randomize her straight away.

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