DR CRAIG HENDERSON SUPPLEMENT

DR HENDERSON: So, I’ve been puzzling for years because all I’ve been talking about now in these last few minutes is the effect on the ovary. But somehow we have his idea, at least I had it, rather naïvely, that once a woman stops menstruating the ovary somehow flops over and dies. It’s a simplistic notion, but I don’t think I’m alone in dismissing the ovary.

When you hear discussions, for example, on aromatase inhibitors, they routinely start about something about the fact that androstenedione is produced by the adrenal gland, and then that goes to various fat tissues and then the breast tissues themselves and is converted with aromatase to estrogens. That’s the usual lecture. Nobody mentions anything about the ovary there.

So, a couple of things now, I’ve been pondering this last year. And I talked about some of this at ASCO last year, and I’ve given further lectures since on it. But first thing I did is I went back to the literature on postmenopausal ovarian function. I looked up all the papers that I could find.

The first thing you see is that in fact, when a woman has her last menstrual period, her ovaries don’t stop functioning. We knew this, in a way, before I looked up these papers, because we know that women frequently will have, during the perimenopausal period, short menses. They’ll go for three or four months without one, and then maybe have another one, and then they’ll go maybe six months. But it’s interesting how that goes on for quite a while. But when you actually look at the formal studies, you find that, in fact, there is quite a bit of estrogen production and that it tails off. In fact, one of the best studies indicated that the average time that the ovary continues to produce estrogen is four years, with outliers as far as 10 years.

Now, the other thing, of course, is that you also have testosterone and androstenedione being produced. In fact, as women age, if anything, there is more and more production, rather than less.

DR LOVE: From the ovary.

DR HENDERSON: From the ovary. And so, when those aromatases are working, they’re not working just on – in fact, probably half of the androgens in a postmenopausal woman come from the ovary, and the other half from the adrenal gland. It was interesting, when I started my career, we always did adrenalectomies, and the surgeons always took the ovaries at the same time. Of course, these were postmenopausal women. But I thought that was stupid. Why should they go down, it’s a bigger operation? A Little extra fee? I was kind of cynical about it. Now I look at it from this point of view, and I have to say, by the way, that some of the best responses I’ve had in my entire career were those older adrenalectomy patients. I had patients that were in remission for 10 years or more after adrenalectomy.

DR LOVE: Hmm.

DR HENDERSON: It was a funny time, and we forget. The other group that have had the longest remissions of my career — these are, now, metastatic disease patients — are patients who had ovarian ablation. Anybody that’s been practicing for a long time has always been aware of that. Okay. So, the ovary is not unimportant in the postmenopausal woman.

Then I look to see, well, are there any papers that have measured the effects of chemotherapy on androgens, for example, or estrogens in postmenopausal women? In fact, there are some data, very, very few, but they do suggest that chemotherapy reduces both estrogens and androgens even in postmenopausal women. As I said, this is very, very skimpy data, because it doesn’t fit with anybody’s hypothesis.

There’s another little pearl that people have forgotten. The first person to teach me was Nissen-Meyer. Remember Nissen-Meyer, the 6-day cyclophosphamide? He’s still alive, by the way. He’s about 90. Wonderful guy.

DR LOVE: I remember reading his papers.

DR HENDERSON: Well, he’s a very, very thoughtful scholar of the biology of breast disease. He did one of the earliest ovarian ablation trials — oophorectomy trials — in Norway back in actually, I think, his trial was in the early ‘50s. This was before he did chemotherapy. But they did an ovarian ablation trial. And they included postmenopausal women. In fact, most of those early trials had both pre- and postmenopausal women. After all, there wasn’t anything else to do, but, remember, the first adjuvant trials were all either surgical or radiation removal of the ovaries.

I’ve always thought that was kind of silly to include postmenopausal women. And almost everybody else says that that was silly. When you look at the effects, you don’t see any effects. So, I asked him one day, “Why did youe include postmenopausal women because it doesn’t make sense”? He said, “Oh, postmenopausal women will respond to oophorectomy.” They will? That was strange. But he said, “There’s one caveat. The only ones that respond are those who are in their sixties. The ones who are just a few years after the menopause don’t respond.”

Well, two comments on that, that are kind of interesting. The first is that a group of surgeons at the University of Oregon did an ovarian ablation, or oophorectomy series in the mid ‘80s, and they found exactly the same thing that Nissen-Meyer had told me years before. That is, ovarian ablation does work in postmenopausal women, but it’s only in the older postmenopausal women in which you get an effect. That was strange.

The other thing – and, again, these are old data, long before we had ER and so on. People have forgotten this, because, remember, there was a time when we had to figure out, who we are going to treat with hormone therapies, and we didn’t have estrogen receptors or progesterone receptors to help us, so we had to use the clinical characteristics. I published this in the New England Journal in, I think, ’81, so it’s in the literature, where I looked at all of these trials and added all this stuff up. And, in fact, you will find that using all the various hormone therapies that are appropriate and using the right ones, estrogens, high-dose estrogens, in postmenopausal women — this also included tamoxifen data, and using ovarian ablation in younger women. But, you look at all of these patterns — we used a lot of androgens in those days — it turns out that you got the best responders, where those people who were premenopausal and very postmenopausal. There was a blip in there in the perimenopausal years where no kind of endocrine therapy worked very well. And so that sort of was just another little piece of the puzzle that seems to fit in.

So, where is all this going? I have a hunch — in fact, it’s more than a hunch — a hypothesis that I think we have to begin to test now, that, in fact, what we’re seeing in both pre- and postmenopausal women when we give chemotherapy, if they are receptor-positive, is an effect that is mediated through the ovary.

Now, I don’t want to oversimplify this because let’s say that you’ve got a breast cancer that has lots of ER-negative and lots of ER-positive. I imagine that there’s some additive effect. And so the way I practice, at least at this point, is that, if a woman has a wild and wooly tumor, which you can tell by looking in the microscope. It’s high grade. She has, let’s say, a very weak ER — and I always try to get what I can with the ER. I look at the tumor under the microscope with the pathologist. Everything makes me think that this woman is just marginally receptor-positive, and she were 60 with five positive nodes, I would consider giving both hormone therapy and chemotherapy.

On the other hand, if she’s strongly ER-positive, has a well-differentiated tumor, and let’s say she’s both ER- and PR-positive even with five positive nodes, I think the added benefit of the chemotherapy is going to be so small. She needs to be told that this may prolong your life by a few additional months, but probably is not going to prolong your life by years, the way the hormone therapy will.

DR LOVE: So, what you’re saying then is that when you look again, for example, at the CA-Taxol study in the ER-positive, postmenopausal woman, the reason you’re not seeing any benefit of adding the taxane is you’ve already given them tamoxifen. So, you’re just adding another hormonal intervention by giving them the chemotherapy?

DR HENDERSON: Well, what I’m saying is that I think in the case of that study – remember, we had patients with 15 positive nodes and patients who were ER-weakly-positive as well as strongly positive. But I was suggesting that the CA times four and the Taxol — we don’t know for sure, well with the CA times four, we do know. It doesn’t cause a lot of amenorrhea. My guess is that if we get at the data, which we probably will one of these days — but we did not collect it, by the way, in CALGB-9344 in the Intergroup study. But if we can get at that data, I think we will find that probably the taxanes do not give as much ovarian suppression as, let’s say 14 days of cyclophosphamide do.

Now, that’s a hypothesis, but my hypothesis is that neither CA times four nor Taxol times four represent optimal treatment if you want to get ovarian suppression. And what I’ve been saying is that I think ovarian suppression is important in receptor-positive patients whether they’re premenopausal or postmenopausal.

DR LOVE: How do you explain what’s going on in the 50- to 60-year-olds?

DR HENDERSON: As opposed to the 60- to 70-year-olds? Oh, I think that applies to women of all ages. In other words, what’s happening is, during the period from 50 to 60, a woman’s ovary is changing. In fact, it’s changing probably from the age of 40 to 60. A woman’s ovary is constantly changing, and the mix of estrogen and androgen is changing throughout that period of time She’s gradually getting decreases in estrogen, increases in androgen, and that in any given woman, it’s not a smooth process. Again, reflected by these funny perimenopausal patterns. It’s actually been documented in estrogen levels. And there’s also a lot of variation from woman to woman, which makes it very difficult to interpret data.

DR LOVE: So, for example, you mentioned the fact that the trials of ovarian ablation don’t show an effect in that age group, and they do in the older and younger. Why do you think that is?

DR HENDERSON: I’m not certain why that is. I just can’t answer that question. I link it to this earlier observation that in the perimenopausal women, endocrine therapy doesn’t work very well. But, nonetheless, I can’t explain why it doesn’t work in that perimenopausal group. That’s an old observation.

Over the years, I’ve always been trying to understand why higher doses of estrogen seem to be suppressive. Most of the animal models don’t really answer that question. I have to say this meeting is the first time where I’ve seen really elegant data — presented by Kent Osborne and Tony Howell yesterday — to understand the dose response curve, and the most elegant data to convince me that there really is a dose response curve to estrogen.

One of the things, of course, as you saw yesterday, was that we saw several different dose response curves. If you were to lump all those settings together, you would have a harder time seeing the dose response, simply because, depending on what your prior estrogen status is, you have a different dose response. In other words, if you’ve been estrogen deprived, it takes less estrogen to stimulate the tumor. And then you get a fall off with higher doses and tumor suppression at many different doses than if you haven’t been estrogen deprived. So, maybe those observations yesterday — I haven’t had enough time to kind of think about it more — but maybe they somehow relate in part to the question you’ve raised. I can’t give you a neat hypothesis at this point. But I found those very compelling and interesting data yesterday.

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