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Another point to be made is that for young women, induced menopause is not without its own immediate quality-of-life consequences. In the absence of evidence that these approaches are superior, one is potentially harming a woman’s quality of life in the short term.

Another problem is defining menopause in these patients because a patient can be without menses for years on tamoxifen yet still have functioning ovaries. Hal Burstein and colleagues, including myself, have reported in one series and I believe Dan Hayes in another that patients who experience amenorrhea on tamoxifen and are switched to an aromatase inhibitor may not be truly menopausal.

Some of these patients menstruate months or years after they’re switched. I’m less concerned about the woman if she already received tamoxifen because that’s the standard therapy. If a patient stops menstruating after tamoxifen, has a low estradiol level, and begins an aromatase inhibitor and then her estradiol rises, she hasn’t lost much because she received tamoxifen and “the rest is gravy.”

If a patient comes to me for a second opinion and another clinician has recommended ovarian suppression and an aromatase inhibitor off protocol, I try to be humble. I don’t know the answer, which means it’s not necessarily wrong. I describe why reasonable people might come to that recommendation, but typically I strongly highlight all of the places where the evidence is lacking and the reason I would not make that recommendation myself. Then I leave it at that.

Postmenopausal, Node-Negative

DR HUDIS: In Figure 6, it’s interesting that for up-front endocrine therapy, 25 percent of clinical investigators indicated they would give tamoxifen for two to three years and then switch to an aromatase inhibitor, whereas only seven percent of practicing oncologists indicated they would do so. I believe the clinical investigators are simply displaying less certainty on the early advantage of an aromatase inhibitor.

The investigators may have a deeper understanding of or may be weighing two issues differently than the practicing clinician. First, we probably know everything we will ever know about tamoxifen, so some may feel, “Tamoxifen is the devil that I know and I’m comfortable with it because I know what it will do.”

The second issue is that some investigators have examined the separation of the curves for tamoxifen and anastrozole and have decided there’s not much of an efficacy difference in those first couple of years, yet there might be medical advantages to being on the SERM for a while, such as improved bone health.

Initially I was more conservative in this setting, but now I would use an aromatase inhibitor up front. When discussing adjuvant therapy with patients, for better or worse, the conversation is about preventing recurrence and death from breast cancer.

In my experience, that’s the focal point for most patients, especially in the early days of their diagnosis and treatment. When that’s the case, in a narrow sense, the AI most steeply reduces the risk of recurrence. It may not be the overall best answer with regard to health in general, but overall health is not the dominant issue for most newly diagnosed patients.

For the occasional patient who wants tamoxifen because a friend took an aromatase inhibitor and did not tolerate it well, however, the data and the science give me some leeway. It’s not crazy to choose tamoxifen.

As for the respondents who selected five years of tamoxifen, I don’t interpret the available data as supporting that point of view. At the fifth year, patients who received aromatase inhibitors have a lower risk of recurrence and, now we know, a lower risk of death than people who have been on tamoxifen for five years.

However, we don’t have a way of directly comparing the results of the MA17 trial with 10 years of therapy against the five years of therapy the other strategies use. Five years of tamoxifen might be reasonable, especially for postmenopausal patients with ER-positive breast cancer who are at lower risk.

Breast Cancer Update 2007 (4)

DR KATHLEEN I PRITCHARD: It’s clear now that in the adjuvant endocrine setting, every postmenopausal woman should receive an aromatase inhibitor at some point. I tend to start most of my patients on an aromatase inhibitor up front. It’s clear that adding an aromatase inhibitor at the end of five years or after two to three years of tamoxifen is additionally beneficial. In the last few years it’s come down the pipeline that every one of the three different aromatase inhibitors seems to be useful in each setting.

Breast Cancer Update 2006 (3)

DR KEVIN R FOX: At the moment, you have to evaluate the adjuvant endocrine therapy data based on where the patient is in her course of treatment.

The ATAC trial addresses one scenario, which is treatment of the newly diagnosed postmenopausal patient with estrogen receptor-positive breast cancer, and this trial provides irrefutable evidence that anastrozole is superior to tamoxifen with respect to reducing the risk of recurrence. The available data suggest that five years of an aromatase inhibitor is the best therapy for the newly diagnosed patient.

The second scenario is that in which the patient is in the middle of a course of therapy. The International Exemestane Study and the trials of anastrozole, which were similarly constructed, were designed to enroll patients at the midpoint of a course of tamoxifen therapy and measure outcomes from the point of changing treatment.

Patients were randomly assigned to continue on tamoxifen or to switch to an aromatase inhibitor for the balance of the five-year period.

For the patient in the middle of a course of tamoxifen therapy or the premenopausal woman who has become amenorrheic from chemotherapy and has been on tamoxifen and amenorrheic for two years, it is appropriate to switch to an aromatase inhibitor.

A third situation is that in which the patient has completed five years of tamoxifen. One trial addressing this is MA17, which demonstrates that letrozole produces a small but measurable reduction in the risk of recurrence and an indication of a survival benefit in women with node-positive disease.

Breast Cancer Update 2006 (3)

DR JOHN F R ROBERTSON: Until now, we regarded five years of tamoxifen as the gold standard for postmenopausal patients with ER-positive disease. Now we have data comparing five years of an aromatase inhibitor to tamoxifen. Two studies indicate that the aromatase inhibitors are clearly more effective and have different side-effect profiles.

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