DR GEORGE SLEDGE SUPPLEMENT

DR LOVE: Any thoughts about some of the data that’s come out in the last year in terms of quality control both IHC, coming from the NSABP and Intergroup suggesting that some patients out there who are labeled as 3+ really aren’t? And then, also, more recently I heard from Edith Perez, a few patients are labeled as FISH-positive, who aren't. Any thoughts on that?

DR SLEDGE: Well, we clearly lack quality control for both FISH and immunohistochemistry. Clearly, there are laboratories that have done it for a long time, have done it well, and that you can trust. Clearly, there are laboratories that you probably can’t. I think this is highly analogous to the situation with estrogen receptor, which I’m sure, since you come from an era similar to mine, remember a period during the mid to late ‘70s, where one simply couldn’t trust estrogen receptor values in many cases. And I suspect that HER2 testing in the year 2001 is very similar to estrogen receptor testing, say in the year 1975 or 1976. We desperately need improvements in quality control.

DR LOVE: That’s a great analogy because when I think about it, again, one of the similarities is the relatively benign toxicity profile of Herceptin, as you see with hormonal therapy. I get concerned about people not being treated who maybe really are HER2-positive. It’s a shame to see somebody treated who shouldn’t be treated, but it was the same kind of thinking in terms of ER assays. And there were a lot of women over the years that truly had ER-positive tumors and didn’t get treated.

DR SLEDGE: That, of course, turns out to be astonishingly important in the adjuvant setting. One wonders how many patients around the world have died as a result of bad estrogen receptor testing and, if adjuvant Herceptin ends up having a similar benefit to adjuvant tamoxifen, we will run into exactly the same problem. I think it’s a real concern.

DR LOVE: When I saw you downstairs at the San Antonio symposium, you told me that you were really excited, and this is one of the best ones you’ve seen in years, or the most exciting information?

DR SLEDGE: Yes. This was an absolutely fascinating morning for the San Antonio Breast Cancer Conference and I think it would match up with any morning that I’ve seen in recent years in any breast cancer group of presentations.

We had Trevor Powles giving us the adjuvant clodronate trial, a multi-national trial involving some 1,000 patients who were randomized to receive or not receive the bisphosphonate, clodronate. That trial is showing a survival benefit for patients receiving adjuvant clodronate, albeit a marginal survival benefit.

We had a much larger and very impressive trial, the ATAC trial, in the adjuvant setting, that suggested for the first time that adjuvant aromatase therapy might prove superior to adjuvant hormonal therapy with tamoxifen, albeit with very early follow-up. And fascinatingly, that the combination of the two was no better than adjuvant tamoxifen. There’s some fascinating biology there that I think remains to be teased out over the next few years.

The ATAC trial was fascinating from a number of other standpoints. First, there was a marked reduction in the development of contralateral breast cancers for patients receiving Arimidex compared to tamoxifen — not an entirely expected finding, but a fascinating one.

DR LOVE: Particularly compared to tamoxifen.

DR SLEDGE: Yes, particularly compared to tamoxifen, which we already know reduces the incidence of contralateral breast cancers by up to half in some trials. This was a significant additional benefit on top of tamoxifen.

And, indeed, I think, in looking at those results, one has to wonder, long-term, what the results of the STAR trial will mean to us when they become available in the next few years.

DR LOVE: I was thinking about that, too. As a matter of fact, I asked a couple of the people involved in the STAR trial what they thought about that, and I think they’re kind of processing it. But you mean the question of whether or not comparing tamoxifen and raloxifene is going to maybe be a moot point someday?

DR SLEDGE: If we compare two SERMs – and I think the expectation of many of us looking at that trial, is that the differences in that trial will relate more to toxicity than efficacy. If that totally unwarranted prediction turns out to be the case – and we now have evidence that aromatase inhibitors are superior to tamoxifen – then, to a certain extent, the results of the STAR trial may be less relevant in the long run than I think many of us had hoped when the trial was initiated.

DR LOVE: Of course, it’s a long way from seeing some contralateral data to a prevention trial, probably five years, at least.

DR SLEDGE: Indeed. Though I would hasten to add that the justification for doing the breast cancer prevention trial in the first place was the data in terms of contralateral breast cancers, and that the relative risk reduction seen in the adjuvant trials for contralateral breast cancers have been pretty much identical to the benefits seen in the prevention setting. My suspicion is that one is translatable to the other, though, again, we don’t have data, as you point out.

DR LOVE: Yes. That contralateral data was absolutely shocking, particularly when you see the shape of the curves.

DR SLEDGE: It was striking and immediate, and huge in terms of the difference.

DR LOVE: Even if it had the same effect, later proved, five years, to have the same effect. The other issue that we saw with tamoxifen is people just don’t want to use it, I think some of it’s even psychological, because of endometrial cancer and thrombosis. That just doesn’t fit into the mindset of prevention. Of course, we’re not seeing that, at least at this point with anastrozole.

DR SLEDGE: In the ATAC trial there appeared to be a lower rate of deep venous thromboses and there appeared to be a lower rate of endometrial cancer. There appeared to be a lower rate of some quality-of-life things, such as hot flashes. I think, from a toxicity standpoint, the aromatase inhibitors may prove to be better than tamoxifen.

Now, the major qualifier here with the ATAC trial, of course, is that we have very brief follow-up, a median, as I recall, of somewhere around 29 months. So, we’re going to need a lot longer follow-up to make any definitive recommendations based on it. But, certainly, it represents a fascinating new avenue in terms of our therapy, not only in the adjuvant setting, but also in the chemoprevention setting.

I suppose one possible synthesis of this morning’s meeting is that down the road, we’re going to be giving patients aromatase inhibitors and then having to give them bisphosphonates in addition, not only for their potential benefit in terms of reducing recurrence, but also perhaps to prevent the fractures they get with the aromatase inhibitor.

DR LOVE: Anything else happening at this meeting or papers being presented, data that’s coming out, or even anything in the last few months, in terms of breast cancer, that’s got you excited?

DR SLEDGE: Well, I think there are several other interesting presentations at this meeting. Perhaps the most interesting one was a presentation by the NSABP that looked at the breast cancer prevention trial. Follow-up of that trial.

DR LOVE: That was interesting.

DR SLEDGE: The data that had been presented to us in the past regarding the P-1 trial was data that primarily looked at invasive cancers and non-invasive cancers. The NSABP has now gone back and looked at pre-malignant changes in the breast, some of which are quite benign, such as cystic disease and some of which are clearly on the road to breast cancer, such as hyperplasias both typical and atypical, and fibroadenomas.

What is seen in this analysis of the P-1 trial is that there appears to be a fairly generalized reduction in pre-malignant changes of the breast for women receiving tamoxifen as a chemopreventative agent. What was particularly striking to me, however, was the age-relatedness of this reduction. And, again, this represents a fascinating piece of biology. There was a huge reduction in terms of these pre-malignant events and, indeed, perhaps non-malignant or non-pre-malignant events in the younger women and little or no reduction in many of the categories for the older women. I find this an absolutely wonderful finding.

If we look from a toxicity standpoint at tamoxifen as a chemopreventative agent, it’s fairly clear that the greatest degree of toxicity occurs in older women. Problems such as deep venous thrombosis, thromboembolic events in general and endometrial cancer primarily represent problems for older women. So, using a chemopreventative agent such as tamoxifen in a younger woman, combining both the toxicity data plus the data that we heard this morning, now becomes a much more appealing thing.

DR LOVE: That was an amazing presentation. Any thoughts about why there was such a difference between the age groups?

DR SLEDGE: Well, to a certain extent, it represents the fact, I suspect, that younger women’s breasts are in constant motion compared to an older woman’s breasts. We certainly see higher frequencies, for instance, of fibrocystic changes, of cysts shrinking and swelling related to periods in younger women. And certainly, problems such as cyclic mastalgia are virtually entirely problems of younger women as opposed to older women. So, perhaps not surprisingly, those younger women are the women who get more breast biopsies for symptomatic problems. But there’s something probably a little bit deeper going on here, as well. Something that may reflect much more basic underlying biologic changes where something of major importance occurs when a woman goes through menopause.

DR LOVE: To me, there were two aspects of the presentation. One was that the benign breast disease changes, like cysts and even things that we don’t even associate with increasing the risk of breast cancer, were decreased again, mainly in younger women.

DR SLEDGE: Indeed.

DR LOVE: The other was these pre-malignant, even atypical hyperplasia being decreased again by tamoxifen. It also made me think a little bit about the debate that went on when the P-1 study first came out about is this “true prevention” or just treating early disease? Now we’re seeing less atypical hyperplasia, less pre-malignant change. I would assume, biologically, the implication is that maybe this is true prevention.

DR SLEDGE: Absolutely. I think that is the only read of this data. It’s probably also worth pointing out that, while we think we have some handle now on pre-malignant changes, we pretty clearly don’t have a very good handle on it. And while we have thought of breast cancer as, in essence, typical hyperplasia followed by atypical hyperplasia followed by DCIS followed by invasive cancer. In fact, that fairly straight route which we’ve mapped out in our minds may not be quite so straight, and that there may be a number of tributaries coming into the main stream. It may be that the more of these tributaries you shut down, the less a flood heads in the direction of breast cancer. That may well be one implication of what we heard this morning.

DR LOVE: The other thing that happened this morning that was interesting was when Nancy Davidson updated her trial, the Intergroup trial, of adjuvant ovarian ablation-tamoxifen. Maybe you’ve seen that update before, but I found that some of the newer data was kind of interesting. I think the whole thing kind of begins to start to integrate together.

DR SLEDGE: Yeah. It begins to tell a pretty good story all the way around. Part of the story it tells us is the continuing importance of hormonal manipulations in breast cancer for American oncologists, in particular. I think our European colleagues have always had a different view of this. But American oncologists, for a long time, I think, felt that hormonal therapy was of secondary importance in the treatment of breast cancer, and that what was really important was getting in good chemotherapy drugs in good, tough, strong doses. It’s absolutely clear from today, as it’s been clear to many of us for several years, that the kinder, gentler approach aimed at the biology of the tumor is very important. And that the better we get at shutting off the estrogen-receptor pathway, the better the advantage our patients have in terms of disease-free and overall survival.

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