DR CRAIG HENDERSON SUPPLEMENT

DR NEIL LOVE: 14 years of producing the Breast Cancer Update series has left me with countless fond memories of interviewing brilliant and creative people like George Sledge and Tony Howell. Our next speaker always provides an intriguing and usually unpredictable trip through the maze of breast cancer biology and clinical research. Craig Henderson seems to thrive on innovative ideas, and as usual, after meeting with him during the Miami Breast Cancer Conference, I came away scratching my head in deep thought. Dr Henderson began this sojourn by addressing what he considers the most important recent development in the field.

DR CRAIG HENDERSON: I think that the most exciting and challenging issue in this last year was the presentation in San Antonio of the ATAC trial. Now, I can’t really say that it’s affected my practice yet, except that I have to discuss that with every patient. I don’t mean that in a negative sense. Clearly, they are important data, but I don’t think we know quite what to do with it yet.

First of all, it’s dramatic, the advantage of Arimidex over tamoxifen. Secondly, the trial is so big that it’s very credible, and it’s hard not to believe that that’s correct. On the other hand, there clearly is not enough follow-up to say anything about survival. Frequently, the end points and the outcomes of studies are not what we think they’re going to be. Oftentimes we don’t understand the mechanisms quite as well as we think.

Let me give you an example. First of all early in my career in the ‘80s, I wrote, “tamoxifen is not a good adjuvant. After all, we had to kill all the cells.” That was the era in which we were beginning to do high-dose chemotherapy. The idea of something that just suppressed growth didn’t make sense. Of course, our thinking has changed a lot. Then we said, well, if it does work and we’re just suppressing the tumor, we obviously have to give it for a lifetime. But then we get five years versus ten years, and clearly, there’s not an advantage. In fact, it’s kind of weird that ten is worse than five years. Well, then, sometimes the science follows.

Now we have good data that we’ve heard from people like Kent Osborne and Craig Jordan and so on. We know that in some situations tamoxifen can actually stimulate tumor growth. And we know that tamoxifen does a lot of things other than just its effect on breast cancer. You can have all the overviews and everything in the world — it’s hard from clinical and laboratory data together to get the whole picture. So, all of a sudden, we have this explosion of interesting information, starting about a decade ago when we got the new generation of aromatase inhibitors. So it wasn’t too surprising that Arimidex was better than tamoxifen, but I have to say that I was betting that the two would be better than either one.

DR LOVE: I think a lot of people were.

DR HENDERSON: Yeah. I suspect that Kent Osborne wasn’t, and that he was betting the other way around. I wish we all had to put our money down before the answer or something where we were identifiable before we saw the results. That’s kind of fun, when you see the results. So, given all of that, I asked myself, should I wait until I have the survival data, or do I go for it now?

Then the other thing that’s clearly important is bone. So, I say, well, am I going to give a bisphosphonate at the same time? The data on suppression of bone metastases, or the delay of bone metastases, using bisphosphonates is pretty compelling.

Then the other thing that I found kind of fascinating – I’ve been thinking to myself, we don’t need three aromatase inhibitors. But one of the things that’s emerging is they may not all be the same. I guess it’s kind of like an extension now of what I said about the ATAC being exciting.
.
So, I tell my patients about the ATAC trial. I think you’re obligated to. The results are just too important. I tend to start out with tamoxifen, yet I am prepared to change at any time. I think maybe the other thing that’s important is that there are patients, for one reason or another, whom you can’t give tamoxifen to. I’m very comfortable switching in those patients, if I need to, and I wouldn’t have been as comfortable six months ago.

DR LOVE: So, you see a patient right now who’s 60 years old, who’s got five positive nodes, and she’s ER-positive. How would you shade your presentation of that? What exactly would you say to the woman?

DR HENDERSON: Well, first of all, 60-year-old woman with an estrogen receptor-positive tumor is always going to get hormone therapy. In fact, probably unlike a lot of people, I would certainly discuss chemotherapy with her, but I would give her hormone therapy. I would tell her the results of the ATAC trial and tell her that, at this point, because of the issues about survival – and for a 60-year-old woman, bone is very important. People sometimes forget that if you take all 60-year-old women, the most common cause of death is cardiovascular disease.

DR LOVE: But not in a woman with five positive nodes.

DR HENDERSON: No. But the point still is that for all women osteoporosis is second. I found that surprising when I learned that. I didn’t realize that the mortality from osteoporosis was quite that high. Then third is breast cancer. And five positive nodes – I never write off patients. I have too many five-positive-nodes that I’ve been seeing for 20 years. I still see patients that come to me from the years I was at the Farber.

DR LOVE: I’m not saying write it off. I’m just saying her health risk is breast cancer.

DR HENDERSON: I wouldn’t disagree with that at all. There’s no question that her biggest risk factor is her positive nodes. But I think you have to treat the whole patient, and I think you do have to be concerned about bone in a 60-year-old woman, and I think medical oncologists have to be.

DR LOVE: Incidentally, are you saying you wouldn’t give that woman chemotherapy?

DR HENDERSON: No. I probably wouldn’t. I would talk with her about what we know about chemotherapy, but I think that for a 60-year-old woman – now, let’s just say that her ER was pretty weak. I honestly believe that the importance of having accurate ERs is related to whether you give chemotherapy or not, rather than whether you give tamoxifen or not. There’s a lot of talk here at this conference about the bottom end. I personally think and I can’t prove this so, we’re getting into the area of opinion, but I think there’s a lot of inferential data that would suggest that as the estrogen receptor level increases, it should reflect a higher and higher percentage of the cells that are hormone-sensitive. Now, I don’t know that we know that for sure. I’d be interested in, for example, somebody like Craig Allred’s opinion on that. But I think he would probably say that that’s probably true.

We know, as we were discussing yesterday, that patients with even relatively small amounts of estrogen receptor will have a surprisingly large response. In other words, that there will be clear benefit even with small receptor values. What I’m saying is that with decisions about chemotherapy, I still feel that although chemotherapy will kill a receptor-positive cell, it makes sense to me, intuitively, that if the receptor-positive cell has been treated, or affected by hormone therapy, then you don’t need to kill it twice. So, that means that the reason that you’re adding chemotherapy is because you have cells that are not responsive to the hormone therapy. If you’ve got a tumor that is predominantly hormone-sensitive, then the added benefit of chemotherapy is going to be very small.

Now, we know, also – not just following that argument, but adding one other factor – that the older the woman is, the smaller the benefit from chemotherapy and then the smaller the added benefit from chemotherapy. The effects of chemotherapy correlate better with age than they do with menopausal status.

DR LOVE: I wanted to pick up on 10 things that you said, but let me just try to think of a couple of them. One of the things I hadn’t thought about, if you think about Craig Allred’s data that he presented again at this meeting, where he showed it was almost like there was this effect that, if you have any ER, you see an effect of adjuvant tamoxifen, and it really doesn’t change very much. It’s sort of like you go over the hump, and then you just see this effect.

And Peter Ravdin brought up the question of, “if breast cancer’s a clonal disease, why is it that you would have some ER-positive cells, the rest would not be? Why are you responding?” And you brought up the thought of maybe there was some interaction between the ER-positive cells and the other cells. Any thoughts about that whole discussion?

DR HENDERSON: Well, I have a couple of thoughts about the discussion yesterday. One is that I think Craig Allred is on the right track in the sense that I do believe that we need to have reproducible, accurate measures that quantify the amount of ER that’s there. The point that he was making yesterday is that we do not have those measures. They’re not in place with any of the immunohistochemical assays that are available. We did have that 20 years ago, but we don’t now.

The second point is if you want to make a correlation between the effect of therapy and the quantitative amount of a marker, you have to have two things. First you have to have an accurate assessment of the marker and second you have to have a sensitive end point. Now, what is the most sensitive end point when you’re studying breast cancer?

It is not response, and it’s not response duration. It’s not even survival in patients with metastatic breast cancer. The most sensitive end point is disease-free survival in women with early breast cancer. Anything you do in metastatic breast cancer is a crude kind of thing, because it’s just so complicated. So many things happen. The patients are so variable. It’s so hard to measure the disease. There are so many things that affect survival. So, the most sensitive marker we have for response is disease-free survival.

So, you ask yourself, do we have any evidence, any data, any data set, in which we have 1,000 to 3,000 patients where we can say these are reliable estimates of the size of the ER and also have reliable information on disease-free survival? We do have the latter. We have lots of trials, tens of thousands of patients, where the disease-free survival has been very, very carefully measured. We have small series, where we have probably very accurate estimates using the ligand-binding assays, but we don’t have both of those together. So, the question is one that we can only raise in theory.

The evidence does not exist because we don’t meet those two criteria – a sensitive end point in the clinic and a reproducible, accurate estimate of the size of the marker, in this case estrogen receptor in the laboratory. Those don’t exist.

Continue
Page 1 of 3

Home · Search