DR GEORGE SLEDGE SUPPLEMENT

DR LOVE: Getting back to Nancy’s presentation, any overall take-away that you have from this update?

DR SLEDGE: Well, if we look at this trial, which was designed in the late 1980s and randomized patients with node-positive, estrogen-receptor-positive, premenopausal breast cancer to receive either CAF, a standard chemotherapy at the time, CAF followed by Zoladex, or CAF followed by Zoladex and tamoxifen. This trial was designed at the time where many thought that tamoxifen would have no advantage in premenopausal patients. So, the obvious fourth arm, which was CAF-T, was not incorporated.

Allowing for that qualification, what these data suggest is that Zoladex probably has its greatest effect in the youngest group of women, who are, say, under the age of 40. That, looking at an unplanned retrospective subset analysis, which, of course, is always fraught with danger, the suggestion of that analysis would be that shutting off a women’s ovaries in the setting where chemotherapy has not already shut if off, for a young woman, is probably a good thing.

DR LOVE: Is that something you’ve been doing?

DR SLEDGE: Well, I’ve been privy to this data through ECOG for the last year. I will say that in my own practice, I have tended to offer more ovarian ablation to younger women, certainly, than I was doing three or four years ago.

DR LOVE: It’s easy to just pick out the younger women. But isn’t the real issue whether or not they’re still premenopausal endocrinologically regardless of their age? If you have a 38-year-old woman who stops having her period after chemotherapy then she’s postmenopausal. But is she’s 44 and is still having her periods, I mean, what’s the age really have to do with it other than a statistical thing?

DR SLEDGE: Well, it partly is statistical. Partly, presumably, is the fact that for many women – well, for a much higher proportion of women who are older and closer to their natural menopause, chemotherapy is much more likely to shut down their ovaries. Even for the women whose ovaries are not shut down immediately by chemotherapy, if they’re closer to their natural menopause, they’re probably more likely to become estrogen-deprived on the basis of natural progression through menopause in a short time. So, I think that’s what underlies the statistics. But I think your point is extremely well taken. If you are a premenopausal woman and if we’re asking the question – What’s most likely to benefit that woman? What’s most likely to prevent her cancer from coming back? The simple answer is that the best that we can do to deprive her tumor of estrogen, the more likely we are to see real benefit. And, again, we’re most likely to see the greatest benefit in that group of women who have the most estrogen for the longest period of time. That’s the younger women.

DR LOVE: Well, the other thing that was really a neat curve, and I don’t know maybe she’s showed that before, but I don’t remember ever seeing it was just the CAF treatment alone arm – those who became menopausal from CAF and those who didn’t. It was a major difference. Had you seen that before?

DR SLEDGE: I had not seen that before even though those data have been presented at the ECOG group meeting. There’s a couple of different possibilities to that. One is the obvious one, which is that estrogen deprivation is good for you and that being menopausal is a sign of that.

The other possibility is that this may be confounded by some other effect. For instance, if there are different circulating levels of Cytoxan, Adriamycin and Fluorouracil, different pharmacokinetics for those drugs in two different patients. So that one patient has relatively higher circulating dose levels of the agent inducing the menopause and the other patient has relatively lower dose levels, well, menopausal status may be a marker for the pharmacokinetics, rather than menopause causing the benefit itself. That’s a possibility. I would certainly prefer the one you mentioned to, in essence, what’s an intra-patient dose intensity argument.

DR LOVE: Let me give you a clinical question. You have a patient who’s got five or eight positive nodes; she’s strongly ER-positive. She’s 38. She’s gotten her ACT.

DR SLEDGE: Mm-hmm.

DR LOVE: Even though she’s ER-positive.

DR SLEDGE: Well, why don’t we say that she’s received some combination chemotherapy.

DR LOVE: She’s gotten her chemotherapy and she’s just having absolutely normal menstrual periods.

DR SLEDGE: Yes.

DR LOVE: So, now what do you do?

DR SLEDGE: I’m likely to recommend to that patient that she undergo some ovarian ablation procedure, be it surgical or medical.

DR LOVE: Okay. She says, fine. Then what? Anything else?

DR SLEDGE: Well, I don’t think it’s unreasonable to put that patient on tamoxifen, as well. Certainly, the group of patients who did the best overall in the overall trial analysis were the patients who received chemotherapy plus Zoladex plus tamoxifen. So, I would feel comfortable putting patients on all three.

Now, the related issues that, of course, come up, is that, if one goes out of one’s way to induce a premature menopause in that patient, then I think one has responsibilities to that patient in terms of trying to maintain the patient’s general health, such as looking at the patient’s serum lipids and trying to do things to improve the patient’s bone mineral density status. So, I think, if one is going to offer the patient this approach, one needs to offer the entire package.

DR LOVE: If, though, after you process the ATAC trial for more than four hours and are now starting to use anastrozole as adjuvant therapy, do you now look at this woman and say, well, she’s postmenopausal?

DR SLEDGE: Well, I’m uncomfortable doing that. The ATAC trial was a trial in postmenopausal women. I think, again, along the lines of paying one’s dues, one needs to re-investigate the same hypothesis in premenopausal women. I think it’s a hypothesis well worth investigating. I think if we were to look at the question – Does an LHRH agonist need to have an aromatase inhibitor added to it to get maximum benefit? Framing the question that way, I think it’s a very reasonable and testable hypothesis, and certainly one that we need to test.

DR LOVE: Anything else happen at this meeting? Any new things in the last couple of months, or new trials that are starting that are getting you excited?

DR SLEDGE: Well, in the Eastern Cooperative Oncology Group, in the very near future, we’ll be starting a trial that I think points us in a different direction. My colleague, Dr Kathy Miller at Indiana University will be chairing this trial through ECOG. The trial will be taking patients who have front-line, metastatic breast cancer, and randomizing them to either receive weekly Taxol, which is, of course, a commonly used therapy, or to receive weekly Taxol plus a recombinant humanized monoclonal antibody to vascular endothelial growth factor. This is the first large trial in the setting of breast cancer that will be looking at an anti-angiogenic agent in a front-line regimen. Hopefully, this will give us a fairly good idea in the near future as to whether or not these anti-angiogenic agents are going to offer something significant.

Now, I’ll also mention that in refractory disease, the recent completion of a trial of capecitabine plus or minus the anti-VEGF monoclonal antibody. So, in the very next few years, we’re going to be, in addition to hormonal therapy and in addition to HER2-directed therapy, we’re going to be able to see whether or not another molecularly-targeted biologic therapy – that’s to say, anti-angiogenic therapy – will add something significant. That, I think, is another very exciting direction for us.

DR LOVE: What’s the name of the anti-VEGF?

DR SLEDGE: The trade name is Avastin.

DR LOVE: You would think since the protocols have finished accrual, that the results will be available fairly soon?

DR SLEDGE: Well, this was a trial in anthracycline- and taxane-refractory patients receiving capecitabine. So, certainly one would expect, no later than a year or so from now, relatively mature data on a relatively large number of patients.

DR LOVE: What was the rationale to then go look at Taxol in addition to that?

DR SLEDGE: Well, the rationale for Taxol, aside from moving from a refractory setting to a front-line setting, is based on something that we’ve learned about the taxanes in recent years. That’s to say that in a number of preclinical models, taxanes are, in fact, pretty good anti-angiogenic agents themselves. They are fairly good at killing vascular endothelial cells in vitro. They affect capillary tubule formation. They affect capillary migration in preclinical models. In a number of preclinical models, when one treats a human tumor with a taxane, one sees decreased micro-vessel density. So, in fact, to a certain extent, we may have been using anti-angiogenic therapy for some time by giving patients our standard chemotherapy agents, such as the taxanes.

The hope is that by combining an agent that has both anti-cancer and anti-endothelial cell activity with another anti-angiogenic agent, one would get an additive or synergistic effect. Indeed, in some preclinical model systems, there have been synergistic effects against endothelial cells when one combines a taxane with anti-VEGF antibodies.

DR LOVE: How about with capecitabine? I know at one point you had raised the question whether capecitabine is somehow tied into anti-angiogenesis?

DR SLEDGE: Capecitabine represents a similar issue. Thymidine phosphorylase, which is the enzyme that metabolizes capecitabine to fluorouracil intra-tumorally, is also a pro-angiogenic agent. There is some intriguing preclinical data that suggests that capecitabine may itself have some anti-angiogenic activity. So, again, certainly the potential there exists that by combining a chemotherapeutic agent with an anti-angiogenic agent, to a certain extent, we’re combining two anti-angiogenic agents.

DR LOVE: I’ve seen some of the data that Kathy presented in terms of – I guess it’s a phase II study. There actually have been real partial responses with this agent.

DR SLEDGE: Yes, not only partial responses, but we’ve also seen, in fact, a complete response.

DR LOVE: Really?

DR SLEDGE: To anti-VEGF monoclonal antibody.

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