Edited excerpts from the discussion:

DR WEINER: This 38-year-old woman presented in January 2004 with a 1.5-centimeter, poorly differentiated, ER-positive, PR-negative, HER2-negative, intraductal breast cancer. Vascular invasion was noted, and four lymph nodes were positive.

She was initially treated with dose-dense AC followed by paclitaxel and radiation therapy to the left breast and axilla. She was prescribed tamoxifen, 20 milligrams daily. Her last menstrual period was at the onset of chemotherapy.

DR LOVE: Kevin, this patient’s last menstrual period was less than a year ago and she’s on tamoxifen. Would it be appropriate to switch her to an aromatase inhibitor?

DR FOX: I think it would be appropriate to switch a patient from tamoxifen to an aromatase inhibitor after two years of therapy. However, that requires that the patient be in true menopause, which brings up a very important issue in this case: When can you be assured that this patient is truly in menopause? I think it’s safe to say that, for the first time this year, we were given some information that gives us a clue as to the natural history of chemotherapy-induced amenorrhea and its permanence, or lack of permanence, in women. I had never seen much on this issue before.

The late Dr Jeanne Petrek from Memorial was one of the organizers of a multi-institutional study, wherein newly diagnosed patients were recruited during or shortly after they completed adjuvant therapy. All that the study required was menstrual histories from these patients, essentially on a daily basis, for a three-year period. The data presented at ASCO (Petrek 2005) gave us an idea about how often women became amenorrheic and how often their menstrual periods resumed. Without belaboring the details, the most compelling observation was that if you looked at the percentage of patients after chemotherapy who were in a state of amenorrhea, the data were convincing that no reversibility remained after the second year.

On the other hand, quite a bit of reversibility was evident after the first year, especially in women under the age of 40. The point being that the premature prescription of an aromatase inhibitor might result in a therapeutic failure if the patient still has ovarian function.

What we’ve done, as an unofficial policy, is that if we need to confirm the patient’s menstrual status, we check their estradiol and FSH levels, for all its faults. We haven’t been burned thus far.

DR LOVE: Eric, this is a 38-year-old woman with four positive nodes. We know that in the postmenopausal woman, aromatase inhibitors reduce recurrence risk more than tamoxifen. What are your thoughts on how best to treat this perimenopausal patient?

DR WINER: The truth is, in a woman who is premenopausal at diagnosis, we don’t know that any aromatase inhibitor used in the first five years is better than tamoxifen. No such patients were included in the trials, other than the MA17 trial, which involved treatment after five years of tamoxifen. If you think about it, a premenopausal woman experiences ovarian suppression from chemotherapy, and if she is on tamoxifen she has received essentially two hormonal therapies, one of which is substantially lowering her estrogen levels.

It’s an important and unanswered question as to whether, in a premenopausal woman, ovarian suppression and an aromatase inhibitor are better than ovarian suppression with tamoxifen. That is the question being asked in the TEXT and SOFT trials, and I could imagine the results going either way — showing the aromatase inhibitor combination to be superior or inferior to the tamoxifen combination (4.1).

DR LOVE: Do you think that ovarian ablation and tamoxifen will be better than tamoxifen?

DR WINER: I suspect that it may be, but that wouldn’t keep me from enrolling someone in the study, because I’m not sufficiently convinced. The decision to add ovarian suppression and tamoxifen to treat a woman who’s still premenopausal after chemotherapy is a tough decision outside of a trial.

I do it occasionally, and sufficient data exist to make me comfortable with that, but at the same time, I wouldn’t say it’s the standard. However, I would be worried that this woman might start cycling again if you switch her too soon, and we don’t know that switching at any point in time will improve her outcome.

DR LOVE: If she came to see you in another couple of years and had now not menstruated for three years, would you switch her then?

DR WINER: I’m still a little nervous in a 38-year-old woman. If she were 48, had received AC followed by T and had not menstruated for three years, I’d be pretty comfortable. Although I realize those patients weren’t included in IES or the ABCSG ARNO study, I tend to switch those patients (Coombes 2004; Jakesz 2005). On the other hand, if this 38-year-old patient were menopausal at the four- to five-year point, I would switch to an AI then or perhaps sooner if we have additional data before then.

DR LOVE: Eric, our Patterns of Care study has shown us that the most common chemotherapy right now in the United States for a patient like this is dose-dense AC followed by T, exactly what she received. What are reasonable alternatives for a patient like this?

DR WINER: I think any of the so-called third-generation regimens are reasonable. I can’t tell you that one is better than the other, because they haven’t been compared to each other. The two main regimens are AC followed by paclitaxel given in a dosedense fashion, based on the results of the CALGB Intergroup study (Citron 2003), or TAC (Martin 2005). I think whatever you’re most comfortable using as a third-generation regimen is the regimen that you should use (4.2).

DR LOVE: What about AC followed by docetaxel? Our Patterns of Care studies show that is the second most common regimen used in a case like this.

DR WINER: Why give something that hasn’t been shown to be effective, although there’s every reason to think that it will be? Why not give the regimen as it was given in a trial? Now, if you have a patient who’s getting AC followed by paclitaxel and she’s having severe neuropathy, it’s reasonable to use docetaxel if you want to continue the taxane and you think it may be better tolerated from a neuropathy standpoint.

DR LOVE: Kevin, what regimen would you use in a patient like this?

DR FOX: We participated in the CALGB-9741 trial and became somewhat familiar with the dose-dense concept. When that trial was reported as a positive study, we began asking, “Why not give dose-dense therapy?” Gaining more experience with dose density after the sstudy, we saw no unique toxicities.

It was virtually always assured that patients could stay on schedule, which trimmed eight weeks off their course of therapy. Cost issues of growth factors notwithstanding, I still haven’t come up with a good reason not to do it, so it has been our standard approach outside of a clinical trial.

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