DR GEORGE SLEDGE SUPPLEMENT

DR NEIL LOVE: Welcome to Breast Cancer Update. This is Dr Neil Love. The last San Antonio Breast Cancer Symposium contained a wealth of new clinical research information that is of immediate practical relevance to oncologic practice. One of the first presentations, by Dr George Sledge, addressed the crucial but poorly understood cardiac dysfunction that has been observed in breast cancer patients receiving trastuzumab. I met with Dr Sledge to discuss this and other emerging data sets in breast cancer, and he began by discussing the background to ECOG protocol 2198, a pilot adjuvant trial in node-positive, HER2-positive patients.

DR GEORGE SLEDGE: If you look at patients who are receiving Herceptin, there are certain things that we know about Herceptin-related cardiotoxicity. First, we have an enormous amount of data that suggests if you give Herceptin along with an anthracycline that significantly increases the rate of congestive cardiomyopathy. But, in the initial Genentech pivotal trial, there was also a group of patients who got Taxol plus Herceptin typically after they had received a prior anthracycline-based chemotherapy. Those patients suffered a smaller, but still real, incidence of cardiac events including occasional cases of congestive heart failure.

So, a reasonable question, moving Herceptin from the metastatic setting into the adjuvant setting is – How can we do that safely? How can we do that, particularly in a group of patients who we frequently give anthracyclines to? The common sense is that anthracyclines may, in fact, work better in HER2-positive patients.

So, ECOG 2198, when it was developed in 1998, was developed to address these concerns. The way the trial was set up was that patients who had lymph node-positive breast cancer and who were HER2-positive by immunohistochemistry received Adriamycin and Cytoxan following Taxol and Herceptin, rather than before Taxol and Herceptin. The idea at the time was a simple one. If the patient got all of her Herceptin prior to receiving Adriamycin and Cytoxan, then the concern of the interaction of Herceptin and Adriamycin would not exist and, therefore we’d see a lower rate of congestive cardiomyopathy.

As it turns out, like many hypotheses in medicine, this one was absolutely wrong. It was absolutely wrong for a fairly straightforward reason. What we’ve learned about Herceptin, basically in the last year as a result of the work of Dr Brian Leyland-Jones and his colleagues, is that Herceptin has a considerably longer half-life than we originally thought. So while we had designed the trial so that patients would be off Herceptin for three weeks before receiving their anthracycline, in fact, what we now know is that three weeks is not a sufficient clearance period to get rid of all the Herceptin from a patient’s serum.

DR LOVE: This study was randomized, correct?

DR SLEDGE: Yes. It was randomized, but only in a sense that all of the patients in the trial received Taxol and Herceptin up front. But the randomization was either to receive or not receive Herceptin after the Adriamycin and the Cytoxan.

But in terms of what I’m talking about, and that’s to say the overlap of Herceptin and Adriamycin, everyone on the study started receiving Adriamycin three weeks after their last dose of Herceptin. Based on what we know about the PK of this agent, it is likely that those patients still had circulating Herceptin when they received an anthracycline.

DR LOVE: But the other thing in terms of that study was, since both arms got Herceptin it seems like it might have been more helpful to have an arm that didn’t get Herceptin in order to compare cardiac toxicity.

DR SLEDGE: Well, perhaps. I don’t think that would be unreasonable, though of course, when we designed the trial in 1998, we didn’t know about the current PK data. Having said that, I find the results of the trial fairly reassuring and comforting. That’s to say, if we look overall at all of the patients who received Taxol and Herceptin followed by four cycles of Adriamycin and Cytoxan, there was a relatively low incidence of congestive heart failure.

DR LOVE: But I guess my question was, I couldn’t decipher whether or not the incidence that you saw was actually a baseline that maybe had nothing to do with the Herceptin.

DR SLEDGE: Yes. Our statistical assumption in designing this trial was that the baseline rate of congestive heart failure was somewhere around one percent, or perhaps ever so slightly less than one percent because that’s been trial data over the years. We saw a 1.7 percent rate of congestive heart failure for all of the patients entered into the trial. And, two of the four patients who had congestive heart failure had it in the context of a myocardial infarction, which presumably is not due to Herceptin. That left us with two patients out of more than 200 patients entered into the trial who had bona fide congestive heart failure, which presumably was related to their therapy. That’s, in essence, a one-percent incidence of congestive heart failure that’s probably appropriately attributable to the drugs.

DR LOVE: So, what would be your overall take on this in terms of what it means to a clinician in practice?

DR SLEDGE: Well, I think first off, this is, in fact, the first and, as far as I know, the only data where we’ve actually looked specifically at what Taxol and Herceptin in the absence of Adriamycin does to cardiac function. The answer is, it probably does a little. There are a few patients who had drops in their left ventricular ejection fraction. But it doesn’t do very much. These patients who had drops in left ventricular ejection fraction had their LVEFs bounce back by and large, despite the fact that they went onto Adriamycin and Cytoxan. So, I think that’s pretty reassuring for the practicing physician.

I think the clinician, as always, needs to practice the art of medicine. There are probably patients who one would want to avoid four cycles of AC and four cycles of Taxol and Herceptin regardless of what order. Certainly, if you look at the patients who ran into trouble on our trial, virtually all of them had some significant predisposition for cardiac disease.

DR LOVE: But right now, in terms of treating patients off protocol, the last time I talked to you, you were recommending strongly against using Herceptin.

DR SLEDGE: That’s absolutely correct. I still am strongly against using it in the adjuvant setting.

DR LOVE: What about considering Herceptin in the metastatic disease setting? Are there any situations where, because of prior cardiac disease, etc. that the clinician should not be using Herceptin?

DR SLEDGE: Well, I think the metastatic setting is quite a different setting, and we’re literally talking about a life-or-death setting for patients with HER2-positive metastatic breast cancer. The natural history of a HER2-positive, metastatic breast cancer, both in the ECOG data set and in the Genentech pivotal trial, is that with standard chemotherapy, these patients live, on average, about 17 months. That is just a miserable survival.

Herceptin clearly improves survival. It clearly improves survival even for the patients in the pivotal trial who received an anthracycline plus Herceptin. Even in a group of patients where a quarter of them developed a cardiac event, there was still a significant improvement in survival. This argues to me that, allowing for appropriate safety concerns, I think that for the vast majority of patients it’s reasonable to treat them with Herceptin if they have HER2-positive breast cancer.

DR LOVE: In terms a clinical algorithm that you use, do you routinely use Herceptin as part of your first-line therapy in HER2-positive patients?

DR SLEDGE: Routinely. Yes.

DR LOVE: Because one of the things I’ve heard people talk about is, well, I’m going to use Herceptin. The question is whether I use it by itself or with chemotherapy. Is that, again, the kind of algorithm you’ve used?

DR SLEDGE: Well, I think that’s a separate question, which is – Do we give Herceptin alone or do we give Herceptin in combination with chemotherapy? There are definitely patients who I will treat with Herceptin alone. There are definitely patients I’ll use Herceptin plus chemotherapy. Certainly, in the patient who has impaired performance status or where there are concerns about co-morbidities related to the chemotherapy, it’s certainly reasonable and appropriate to give that patient Herceptin. The patient who has what appears to be relatively indolent, small-volume disease, it certainly seems rational to give that patient single-agent Herceptin. I don’t think one’s lost a whole lot.

DR LOVE: Any take on what happens in the community in that regard in terms of managing HER2-positive patients? Do you think that most oncologists in practice are using Herceptin, either alone or with chemotherapy, for first-line therapy?

DR SLEDGE: My sense is that the majority are using Herceptin in combination with chemotherapy for first-line therapy, though I certainly run into physicians and see patients who are receiving single-agent Herceptin. Over the last couple of years, certainly there has been a general trend towards using Herceptin more and more up front in the metastatic setting, rather than later on.

DR LOVE: What about defining HER2 status? What’s your algorithm for that?

DR SLEDGE: Well, typically, the patient, of course, already comes to me with HER2 testing. If we look at the data that’s been generated from the trials available to us, to my mind it looks as if patients who are 2+ by immunohistochemistry frequently are HER2-negative when they’re tested by FISH. Both in the ECOG data set related to the trial I presented this morning, as well as several other data sets, if you’re 2+, probably only about a quarter of those patients are positive by FISH. So, certainly, for those patients, I pretty much routinely do FISH testing.

If the patient is a 3+ by immunohistochemistry and it’s from a lab where I trust the pathologist, I think the data is suggestive that being 3+ by immunohistochemistry and being FISH-positive probably give one fairly similar results in terms of clinical outcome and likelihood of response. So, I’m comfortable with either a 3+ by immunohistochemistry or FISH positivity in that setting.

DR LOVE: What about the patient who’s zero or 1+ by IHC. We know that some of those patients are going to be FISH-positive. Do you test any of those patients?

DR SLEDGE: I do, not regularly, but certainly in some cases. I view HER2-positive breast cancer as a breast cancer that has a fairly specific phenotype, and that’s to say it’s more likely to be a steroid receptor-negative disease. It’s somewhat more likely to occur in younger women, yet somewhat more likely to be associated with early relapse after initial diagnosis. So, if I have a patient who fits that phenotype, and yet has, say, a two- or three-year-old immunohistochemistry test, saying that the patient was negative, I’m quite happy re-testing that patient, and typically I’m going to re-test that patient with FISH.

DR LOVE: And if they’re positive by FISH?

DR SLEDGE: Then I’m going to treat them. Now, I would hasten to add that we really don’t have any clinical data on that group of patients, the patients who are immunohistochemistry-negative, but FISH-positive. But I think what we know about the biology is fairly straightforward. If you look at frozen sections where there are no questions about fixation artifacts that we have to deal with for paraffin-embedded sections, it is astonishingly rare to have cell-surface overexpression of the HER2 receptor without having amplification at the nuclear level for HER2. So it, to my mind, only makes sense that the FISH-positive patients are going to be the patients who are going to have ample amounts of receptor on their surface that we’ll be attacking with the antibody.

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