I met with Dr Pike to explore the implications of his work to the breast cancer survivor, but before that, let me allow you to listen to the section of his presentation that piqued my interest about HRT, and specifically the role of progestins in breast cancer risk.

DR. PIKE: One of the biggest risk factors for breast cancer at the moment is estrogen-progesterone replacement therapy. What I regard as the most preventable cause of breast cancer that's around today - estrogen-progesterone replacement therapy. There have been three large studies recently, all of them showing much greater increase in breast cancer risk from estrogen-progesterone replacement therapy than from estrogen replacement therapy alone. Maybe three or four times greater. Now, you can argue about whether this is real, but you would be foolish to argue whether this is real, because, in fact, while you're arguing, we're still prescribing this drug. And in fact, we don't have to prescribe it in this way. First of all, are the results reasonable? Of course they are. The group in Michigan at Michigan State - Dr. Hofseth and her colleagues - showed that breast cell mitotic rate on continuous combined estrogen-progesterone replacement therapy was more than double that of women on estrogen replacement therapy alone. So, here was the first bit of real non-epidemiological evidence that this was true. The second set of evidence came from a randomized trial - the PEPI trial - where Greendale and her colleagues showed that there was a much greater increase in mammographic densities of women on estrogen-progestin than on estrogen alone. So, there's really oodles of evidence, which says this is true. For us to argue about it is really foolish.

Now the question is, "Are mammographic densities a good biomarker? They're a fabulous biomarker. They're the biggest risk factor for breast cancer we know. So, the question that we ought to ask ourselves is, "How do we fix it?" Instead of arguing about whether it's three percent a year or six percent a year increase, we need to deal with it. To deal with it, you need to deal with the progestins, and the way to deal with the progestins is to give them less frequently. Both Bruce Ettinger in Oakland and Williams at UCLA showed that if you gave progestins for 12-14 days every three months - instead of every month - you got complete control of hyperplasia. We showed in an epidemiological study that this was extremely likely to be successful in preventing endometrial cancer. Remember, the problem is to prevent endometrial cancer. Now, why don't people do this? They don't do this because the Swedish study was published in the Lancet, which said giving progestins every three or four months would not work. Well, it doesn't work in Scandinavia because they don't use Premarin. There's nothing magic about Premarin. What's magic about Premarin is that it's a very low-dose estrogen. That 0.625 milligrams of Premarin is not the same as two milligrams of estradiol valerate, which is what is used in Scandinavia. So although we need to prove that this isn't true by other people doing the study, at the current time there is no reason why progestins can't be cut by at least two-thirds, simply by prescribing them every third month instead of every month. My colleagues and I in Los Angeles have prescribed this every four months with complete success.

Now, there's another system which I'm in favor of, but that's because I don't have to do it - the use of an intrauterine device. Quite a lot of female gynecologists are doing this. You use a Progestasert, which unfortunately you have to remove every 18 months. It contains a very low dose of progesterone that does not get into the circulation. Or you can use the new IUD containing progestins, levonorgestrel and Mirena, which should last for 10 years. Quite a lot of people are doing this. There seems to be no reason why a woman shouldn't be offered this alternative. There is no risk in a 55-year-old woman of pelvic inflammatory disease, and this is a completely successful way of turning estrogen-progesterone replacement therapy into estrogen replacement therapy.

Now, the final thing is if people don't want to try either of those, you can actually give progesterone by an intravaginal route. Now, the point about that is you can change the ratio of concentrations in the endometrium to the blood by a factor of 50 by taking, effectively, Prometrium, intravaginally, rather than by mouth. This needs to be done, and we are currently doing this study now.

So, here's the real question that we have to ask ourselves and which it's time we addressed to the FDA: Here are three hormone replacement therapy drugs that are on the market at the moment. Here's Prempro, which you all know about. There is Wyeth Ayerst, .625 milligrams of conjugated estrogen and 2.5 milligrams of midroxy progesterone acetate. We know what this does. This is not good for breast cancer. But here's another one that's just been okayed. One milligram estradiol and .09 milligrams or norgestimate, one of the new progestins, for three days every six. Well, if you read why they're doing this, they're doing this to keep ER and PR at the highest levels. This is potentially a disaster, and yet the FDA passed it because it controlled hot flashes. Anything will control hot flashes. There's no requirement of the FDA at the current time to show that new forms of estrogen-progesterone replacement therapy do not increase breast cancer risk, and we must insist on that, because this is a major cause of breast cancer in the United States at the moment. In postmenopausal women in the United States it is causing about 10 percent of all breast cancers.

DR. LOVE: For many years, Dr Pike has expounded on the estrogen-breast cancer risk connection, and his pioneering work on LH-RH agonists and add-back low dose estrogens is a fascinating model of chemoprevention with many implications to oncologic practice. During our interview, we explored the analogy of this endocrine model to what happens to breast cancer patients made prematurely menopausal with adjuvant chemotherapy and the dilemma when estrogen replacement is considered to ameliorate vasomotor symptoms.

DR. PIKE: Oncologists have got a young woman, she's on chemotherapy or she's been oophorectomized, and she's having lots of hot flashes. What do you do about it? That's a real problem. I think the answer in these situations is that you give the minimum dose and you make sure you don't give progestins with it, because for the control of hot flashes, estrogens will do it. There's recent data which suggests that low-dose estrogen might do it better, in the sense that you don't need the high-dose estrogen. So, I would suggest that you try to control it with .3 milligrams of Premarin and then .45, and not start off at .625, and that you would taper this off as soon as you had controlled the symptoms.

Now, if the woman is on tamoxifen at the same time, does it matter? I think the answer is no, and I'll tell you why I believe this. In the premenopausal woman who's given tamoxifen she's got high levels of estrogen, because tamoxifen is acting as a stimulant to the ovary. And yet tamoxifen still works. In the P-1 study and in randomized trials tamoxifen is very effective in essentially preventing contralateral disease or, in the P-1 study, preventing the first cancer. So, I believe that if you are on an anti-estrogen at the same time, like tamoxifen, that a small dose of estrogen probably doesn't matter.

DR. LOVE: I have seen some data suggesting that low-dose estrogen actually can be effective in ameliorating hot flashes in a woman on tamoxifen. Do you subscribe to that?

DR. PIKE: I know that the group at Royal Marsden in England that's what they use, and I presume that, they find that low-dose works, right? So that I think, especially if used for a short time, it's very hard to argue that that's not okay.

DR. LOVE: I take it that, in general, your thought is that estrogen replacement without progesterone is - does it actually raise breast cancer risk? I hear you saying it's not as high. Does it even raise it?

DR. PIKE: Yes. Yes, I believe it does. I think the overview that was done a few years ago, which reported on all the epidemiological studies ever done, showed that it increased risk about 2% per year of use. Now, let me explain what that means. If you use it for five years, your risk is increased by 10%. There are arguments about whether that increased risk, how much longer will it last after you stop? In the studies I've done, I always find it lasts and lasts and lasts. But other people have not found this. I'm not really sure, I have ideas about why this might be, but I'm not really sure. So, you do get a small increased risk of breast cancer. But if, for example, you just use it for a few years to control hot flashes that would be a completely reasonable thing for a woman to want to do. Hot flashes are pretty awful.

DR. LOVE: Now, when I asked you about this issue, you immediately lighted on the big problem that oncologists deal with all the time, which is the younger woman who's becoming prematurely menopausal from chemotherapy. Now, let me draw this out for you a little bit. You have a 40-year-old woman, actively menstruating, gets breast cancer, and receives chemotherapy. Two scenarios:

Scenario 1: She receives an adjuvant chemotherapy that does not make her menopausal, and she continues to menstruate.

Scenario 2: She receives a chemotherapy that makes her totally menopausal and she receives, then, hormone replacement therapy.

Now, would I be correct in saying that, in fact, because HRT creates a much lower exposure of estrogen, than being premenopausal -- Do you see where I'm trying to go with this?

DR. PIKE: I know exactly where you're going.

DR. LOVE: By taking HRT she's not really increasing her risk any more than if she had continued to menstruate. Does that make any sense?

DR. PIKE: That makes complete sense. In fact, if you look at what the effect is on mammographic densities - which is some totality of what the effect is - what you find is that the mammographic densities are decreased about 10% or 11%, if you oophorectomize a woman or if she goes through menopause. If you put her on estrogen-progesterone replacement therapy, you abrogate about half that decrease. So, she's still going to be better off even though she's taking HRT. That's true, that she is better off than if she had continued to ovulate. However, you don't have to do that. What I said this morning is what I think people ought to do under such circumstances, you ought to give estrogen replacement therapy at the minimum dose to control hot flashes and so on, which is maybe, for her, .45, but even if it's .625, and give progestins much less frequently than we now currently do.

DR. LOVE: You also mentioned the possibility of intravaginal and intrauterine progestins.

DR. PIKE: Right. IUD's, intrauterine devices, the one that contains progesterone alone has been on the market for maybe close to 30 years. Its called Progestasert. It only lasts a year, maybe 18 months in an older woman, then has to be re-changed. But that device certainly would provide you very low-dose progesterone because that's been measured.

Now, for the new IUD that's just been licensed by the Food and Drug Administration, which contains levonorgestrel - not progesterone but a synthetic - because of its nature, this IUD will last five to ten years, possibly longer for a postmenopausal woman. We don't know whether, because that's not progesterone in the blood, it's levonorgestrel in the blood, whether that's a very low dose. What I think we ought to be doing at the moment is actually finding a small number of women and putting them on this levonorgestrel IUD postmenopausally, and prove that it doesn't change mammographic densities. I believe that the data that I've read says it's not going to change mammographic densities. That's then another possibility that a woman might like to do, because, although the insertion is possibly unpleasant it's just a one-off job and it lasts for a long, long time.

Giving progesterone intravaginally, we don't yet know quite how to do it. The experience with intravaginal progesterone comes completely from in vitro fertilization clinics, where, here's a woman going to have an embryo implant, and they have to get the uterus ready for this implant artificially. The way they do that is by large doses of progesterone. If you give large doses of progesterone by mouth, the metabolites of progesterone tend to put you to sleep, so that doesn't work very well. You can give progesterone by depot injection, but the vaginal route seems to work wonderfully. You get high levels in the endometrium with very low levels in the blood, and that's a real possibility, which you could prescribe now. And that's called Crinone. But, again, the level in the blood is about two to three nanograms per milligram, which is low, but it's not vanishingly low. It's nowhere near as low as with the Progestasert.

DR. LOVE: I am thinking about how to visualize the premenopausal breast cancer patient. Because I think it's a matter of perception. Oncologists see a woman with breast cancer who's 40 years old and get very concerned about increasing her risk by giving her HRT. What I'm thinking is, in a sense, your whole concept of breast cancer prevention in the premenopausal woman, you give them an LH-RH agonist and substitute back estrogen. No?

DR. PIKE: Absolutely.

DR. LOVE: And in a sense, you could view giving chemotherapy - certainly it's not the best way to do an ovarian suppression - but they need to get the chemotherapy, as the exact same model. So, in a way, it's a positive thing, not a negative thing.

DR. PIKE: Yes.

DR. LOVE: But I don't think we see it that way.

DR. PIKE: No. But I think we will in time. I think what really happened here was that - you remember the history of this, right? In the early '70s estrogen was only good. It was a natural product, you made it yourself. Couldn't possibly hurt you. Then in the mid 1970s we discovered that estrogen actually was the cause of endometrial cancer, and estrogen replacement therapy was awful. It suddenly became awful before we realized that, of course estrogen can give you endometrial cancer, but it's wonderful for your bones, good for all sorts of other things. We need a balance here. But what happened was because of the concentration on the endometrium. The gynecologists felt they had to control the endometrium, so then progesterone became the magic. It's only now that I think everybody accepts that progesterone is a bad idea for the breast. We need to reduce its dose. I think this would be very interesting if, medical oncologists would say, "Well, this is what I'm going to do for premenopausal patients who are not ovulating anymore. I'm going to give them very low-dose estrogen and no progesterone, because I'm going to persuade them that they should be using an intrauterine device with very low progestins in it." That would be a very, very viable alternative to me.

DR. LOVE: Which people don't really think about. So, what you're really doing is, you're suppressing their ovaries, you're replacing them with low-dose estrogen in a safe way to give progesterone to protect their uterus. So, in fact, that whole strategy, taken together, is actually a breast cancer risk lowering intervention?

DR. PIKE: Yes, it is. There's no question that in a 30-year-old woman you need to give her some estrogen, because of everything we know about bone and possibilities related to cognitive function and so on. We need to work this out, urgently.

DR. LOVE: I've always been so fascinated by that whole strategy that you've been talking about for years in the premenopausal woman that we've been talking about. But one thing that I haven't heard you talk about - and I've always wanted to ask you about - is a similar kind of a strategy in postmenopausal women. And by that, I'm talking about aromatase inhibitors. Now we are starting to hear people talk about - and I think even now - I believe there's actually going to be a trial launched in high-risk women, looking at Arimidex, the third-generation aromatase inhibitor. Any thoughts about what you might postulate the effect would be on breast cancer risk by giving a high-risk postmenopausal woman an aromatase inhibitor?

DR. PIKE: Yes. It will reduce her breast cancer risk. But, you can't just block all this estrogen. I mean, the woman needs estrogen. Her bones need estrogen. Her brain needs estrogen. So, we're going to have to have the same approach that we do with SERMs, you have to look at everything. There's no real question that if you block all estrogen, you'll get a tremendous effect. Will you get as big an effect as tamoxifen? I don't know, because the effect of tamoxifen is really quite astounding. To get a 50% reduction in risk, effectively, instantaneously, that's really quite staggering. Now, you might get that with an aromatase inhibitor. I don't know. But let me tell you that you do get such an effect even in normal women, and that's something, which we've forgotten. There is a very famous Danish epidemiologist, and he pointed out that breast cancer rates increase sharply in premenopausal women and much less after menopause. But between pre-menopause and post-menopause over the perimenopausal period, breast cancer rates actually drop temporarily. That somehow must be because the cells were living in this estrogen-progesterone environment, and now they're changing to a low-level estrogen environment, and they must stop for a while. This drop is what has actually happened with tamoxifen. Right? So, the tamoxifen causes this sharp drop. But, if you look in premenopausal women, the drop in breast cancer rates with an oophorectomy is as sharp as with tamoxifen. So, any real drastic change in hormones will do this.

So, with Arimidex, it will depend on how big the shock change is. In a postmenopausal woman, she's got 20 PQ grams per mil of estradiol, and now she's going to have nothing. Well, you're going to have to look after her bones. You're going to have to do lots of other things. That's what's going to be the problem. It's going to be the same real problem with SERMs. You're going to have to prove that all these other things are okay, not that you're reducing breast cancer, because I'm sure you will.

DR. LOVE: I want to ask you about the bones, but before that, we know it certainly has an anti-tumor effect that's very significant. As a matter of fact, it looks like it may be greater than tamoxifen.

DR. PIKE: Correct.

DR. LOVE: So, clearly - and maybe it's because the breast cancers that develop in the postmenopausal women are sensitive to these changes…

DR. PIKE: Right.

DR. LOVE: So, clearly, the third-generation aromatase inhibitors, at least in terms of breast cancer have an anti-tumor effect.

DR. PIKE: Yes.

DR. LOVE: So, it wouldn't be a shock if it decreased the incidence, although, of course, we don't know at this point.

DR. PIKE: Yes, we do, because, in fact, common sense is usually right. We haven't proof, but the idea that this would happen - I mean whatever studies we're setting up should be set up with the notion that the answer is going to be, yes it does.

DR. LOVE: We have the ATAC trial coming out, which is an adjuvant trial. And, of course, one of their end points - and we might not see that right now, but certainly over the next few years, five or ten years, we're going to see second breast cancers coming out of that study.

DR. PIKE: Right.

DR. LOVE: So, that'll be a clue.

DR. LOVE: The ATAC trial certainly is looking at bone density, bone end points, lipid, cardiovascular, etcetera. Now, certainly we know that when a woman goes from having premenopausal levels of estrogen to postmenopausal levels, you see a big effect on bone. But do we know that going from a postmenopausal level of estrogens to an aromatase inhibitor postmenopausal level is going to further have a damaging effect bone?

DR. PIKE: Well, this depends on where you think the dose response curve is. Right? I mean, the big change occurs when you've got already premenopausal levels and suddenly you've got a fraction of them. There may be a fifth or a sixth or a seventh of the levels of hormones. Now you're going from 20 PQ grams per mil to 10 or something like that, or five. Is it a dose-response level? Is there a dose response curve at that level? I don't know any data that there is, but I do know data which says that if - you know, the most recent data which comes out, which says that for at least a proportion of women taking .3 milligrams of conjugated estrogen will look after their bone. Now, .3 is very much like the order of magnitude of going from 20 to 10. It's going from 20 to 30. So, I would guess, yes.
Now, if I might say something else about this low-dose estrogen, I think there's a real story to be discovered in there. The most recent studies of estrogen replacement therapy and bone related with women, who are not taking any progestins - of course, they're hysterectomized. They have found that much lower doses than normal will preserve bone. Now, I don't actually believe that. What I believe is this, if you put 100 women on a trial to control their hot flashes, and the hot flashes are controlled in 40 women, in those 40 women, the low dose they had might be enough to protect their bone, because of their metabolism of estrogen. Remember, everybody's metabolizing estrogen differently. They're absorbing it differently. So, for some women, a really low level will be sufficient; whereas, other women will need higher. It's to do, probably, with absorption of estrogens. And we need more work in the hormone replacement therapy set-up. We need more work on how do you titrate the dose for this woman. At the moment the titration is done on hot flashes. That's probably not good enough. Bone mineral density markers in the blood and in the urine, of course, are not good enough either. But this would be a way of even getting the estrogen level dose down overall, because for some women, .65 is actually too high.

DR. LOVE: But let me just clarify. You're saying that you are expecting aromatase inhibitors to have a deleterious effect on bone?

DR. PIKE: I would, yes. But, I mean, that's going to be easy to find out. Right?

DR. LOVE: Okay.

DR. PIKE: That's very easy to find out.

DR. LOVE: Do we know, for example, an experiment - because we don't have any data in a clinical setting that I know of.

DR. PIKE: No.

DR. LOVE: Okay. So, do we know from any laboratory work, to suggest that that further lowering is going to have a critical effect on bone?

DR. PIKE: No, not that I know.

DR. LOVE: So, I guess my question to you is, "If a trial like ATAC comes out and shows in 9,000 women that there's no difference in bone mineral density or fractures, would that be a shock to you, or you wouldn't be too surprised?"

DR. PIKE: I would be very surprised and delighted. It would be wonderful to know that, at that level, it didn't make any difference.

References

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