• Right modified radical mastectomy and radiation therapy
• Received doxorubicin/cyclophosphamide
• Entered a clinical trial of myeloablative therapy with stem cell and bone marrow transplant
• Underwent STAMP-V therapy with failure to engraft and severe refractory pancytopenia, multiple infections and severe thrombocytopenia
• Completed five years of tamoxifen in 2002
• Patient has osteoporosis
• Patient recently refused letrozole and zoledronic acid

Key discussion points:
	Aromatase inhibitors in patients at high risk completing five years of adjuvant tamoxifen

DR FREEDMAN: This patient is currently 54 years old, but she presented in December of 1996 at age 47 with an ER-positive, PR-negative infiltrating ductal carcinoma. She underwent a right modified radical mastectomy, and six of 18 lymph nodes were positive. At that time, we were collaborating with a local institution performing clinical trials with myeloablative therapy and stem cell and bone marrow transplant. She was entered into that study and was randomly assigned to four cycles of AC followed by STAMP-V myeloablative therapy and autologous bone marrow transplant. Subsequently she was going to receive tamoxifen following transplant.

She did very well with the adjuvant AC. Her marrow was harvested in September 1997 and evaluation of the bone marrow showed microscopic tumor but no evidence of metastatic disease by conventional scanning. She underwent STAMP-V therapy but, unfortunately, had a failure to engraft. She was left with severe refractory pancytopenia, which was complicated by multiple infections and severe thrombocytopenia, requiring platelet transfusions for several months. However, she did not have a relapse with her cancer.

She was started on tamoxifen and underwent a number of bone marrow biopsies during follow-up, which showed less than 10 percent cellularity. Her platelet counts were between 10,000 and 20,000.

DR LOVE: What was her menopausal status when she presented and when she began tamoxifen?

DR FREEDMAN: She was postmenopausal. In 2002, she was re-evaluated and had evidence of osteoporosis. She had finished five years of tamoxifen and I did not recommend continuing it, but I was very concerned about her future.

I offered her letrozole and zoledronic acid knowing that would be the only systemic therapy available to her if she were to relapse.

She had been traumatized by her prior therapy. In my practice, she's the only patient I've ever had who's had a failure to engraft with any bone marrow transplant that we've ever been part of, and she would not consent to more therapy.

DR LOVE: What about your discussions after the MA17 data came out in November 2003?

DR FREEDMAN: I was even more strongly in favor of her going on letrozole. I told her she was at risk for a skeletal event but I was hoping that by using zoledronic acid we would be able to reduce her risk. I thought that risk was less than the chance she might die from breast cancer.

DR LOCKER: I think what you recommended is absolutely appropriate, and data support what you are doing, both in terms of the letrozole after five years of tamoxifen and that zoledronic acid would eliminate or lessen the risk of osteoporosis in this woman.

DR LOVE: Peter, what are your thoughts about the relative risks and benefits of an aromatase inhibitor at this point, one year after having stopped tamoxifen?

DR RAVDIN: I think that for a node-positive woman, particularly one who is estrogen receptor-positive, a fair amount of residual risk is present even beyond five years. Although there's a gap in her therapy, nobody has any idea whether or not that affects things. I think it probably doesn't.

DR LOVE: Regarding this issue of patients who've already stopped tamoxifen a year ago or five years ago, obviously we don't have definite information on that.

The most common response I've heard from the research community is to apply the relative risk reduction concept and assume that whatever the risk is at that point in time, you're going to reduce it. Peter, do you think that is a rational extrapolation at this point?

DR RAVDIN: I think the further out patients get, the lower the risk gets. I don't have any enthusiasm for broaching the topic of whether patients who stopped tamoxifen five years ago should start an aromatase inhibitor. I usually mention that information is available, but I don't recommend such treatment. It is much more of an issue for women who stopped their tamoxifen within the last couple of years, and I think it's reasonable to consider starting an aromatase inhibitor in those patients.

DR LOVE: Gershon, in general, when you see a woman who's been on tamoxifen for two to three years, how do you approach the issue of considering a switch to an aromatase inhibitor?

DR LOCKER: First you have to look at the risk. If a woman has multiple positive nodes, I discuss the two studies with two different aromatase inhibitors — exemestane and anastrozole — which demonstrate a benefit to switching at two to three years. I recommend it to women with node-positive disease.

The question is how this applies to patients with node-negative disease. In the Boccardo trial, which was the anastrozole switchover trial, all the women were node-positive. In the exemestane trial, about half of the patients were node-positive. Both of these studies were weighted towards women at higher risk. In women at lower risk, I present the data and say, "If you are comfortable on tamoxifen and you've had no positive nodes, fine." If they've had any issues at all with tamoxifen, they switch over to an aromatase inhibitor.

DR LOVE: Dr Favis?

DR FAVIS: We have all seen patients who perhaps had metastatic bone disease and did well on tamoxifen for over five years. I don't know what to do with those patients. I've been reluctant to discontinue it, and most of the patients have been reluctant to stop, too. I would have wondered, in your particular patient — when she refused to take an aromatase inhibitor — whether I would have just left her on the tamoxifen. There may not be much difference between your patient and somebody with known metastatic bone disease, except for maybe one log of tumor cells.

DR LOVE: That's a great point, particularly in view of the positive bone marrow.

DR FREEDMAN: I agonized over this and I felt that she was in an intermediate-risk group. We would all agree that she is a etastatic disease, yet technically, this is an adjuvant situation. I think if I had been enthusiastic about continuing tamoxifen, she would have continued it, but I had a hard time generating much enthusiasm for it.

DR RAVDIN: Is she already on a bisphosphonate?

DR FREEDMAN: No. She wouldn't take zoledronic acid, so I offerred her some of the other agents and she has decided not to take those either.

DR LOVE: You could also make the argument that she might potentially get a little tumor protection from a bisphosphonate. Peter, we have some randomized trials evaluating that question. What are your thoughts?

DR RAVDIN: The European data, at least from the largest trial, suggest that perhaps bisphosphonates will have an adjuvant effect. I think this is a fascinating area. It would be nice if bisphosphonates had an adjuvant effect, because that would strengthen the argument for the use of aromatase inhibitors. Right now, I'm not recommending bisphosphonates to my patients for their adjuvant effects, but I think there's going to be a lot more information of interest in this area.

DR LOVE: Another issue is which aromatase inhibitor should be used in which situation.

Gershon, the most common answer I'm hearing from research leaders is whichever one had the supporting data: anastrozole up front, anastrozole or exemestane after two or three years, or letrozole after five years. Is that your approach?

DR LOCKER: That is my approach. One question I ask is, "In patients you start on letrozole after five years of tamoxifen, for how long should they receive it?" The data was presented with a median of a little more than two years of follow-up, so do you treat them for five years? Do you treat them for two years? Do you treat them for three years? I don't have the foggiest idea.

DR RAVDIN: In all three of the large trials of aromatase inhibitors in early disease, the aromatase inhibitor clearly added benefit. I think all of these agents are going to be better than tamoxifen.

My guess is that the strategies we use will be based on the differential safety of these agents. They will possibly have different effects on bone density and other organs. In metastatic disease, there isn't a lot of difference between the efficacy of different hormonal therapies. We pick our therapy based on tolerability and safety. It'll be interesting to see the mature data from these studies, but I think they are all valuable agents and are actually improving hormonal care.

DR LOVE: Gershon, there was a lot of discussion based on laboratory data that maybe exemestane was going to have a bone-sparing effect. What are your thoughts on that since the Coombes study came out?

DR LOCKER: I was disappointed, because in the metastatic setting one of the criteria for using exemestane was that it was better for bone. In the Coombes study, women who were switched to exemestane — and this was after having tamoxifen, so, theoretically, their bones were pretty well built-up — still had a trend toward osteoporosis and fractures. I'm concerned about that.

There are two explanations. One is that they were off of tamoxifen and it was the natural loss of bone in somebody who's not on a bone-protective agent. Given that this was seen within two years, I'm concerned that it's more than just natural bone loss because if you follow women over two years, you really shouldn't see that much bone loss.

The other argument is that it was borderline statistically significant. I'm disappointed because when you decrease estrogen levels in the body by whatever means, it isn't good for bone.

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