Edited comments by I Craig Henderson, MD, FACP, FRCP

Role of the aromatase inhibitors in the adjuvant setting

The aromatase inhibitors are now clearly viewed as the most effective and important adjuvant endocrine therapy for postmenopausal women.

In the last three or four years we've seen an unexpected shift from tamoxifen, the "star" for 30 years, to the aromatase inhibitors. After the presentation of the initial ATAC trial results, ASCO did not recommend the aromatase inhibitors as adjuvant therapy because there were no survival data. Interestingly, the FDA approved adjuvant anastrozole as adjuvant therapy. It's also clear to me that community-based doctors are using adjuvant anastrozole to a greater extent than most academic physicians.

The dramatic results from the MA17 trial of letrozole after tamoxifen have thrown everyone into turmoil (Figure 2.1). The levels of significance are so great that neither physicians nor patients can ignore them. Again, we don't have survival data, and it will be difficult to evaluate survival at any point in the future. Additionally, we won't be able to replicate those results because it wouldn't be ethical to repeat that study. In fact, the NSABP trial evaluating exemestane in postmenopausal patients with receptor-positive breast cancer, which was identical in design, was closed to accrual immediately. I also don't think it's possible to ignore the ATAC trial results any longer.

Aromatase inhibitors following five years of adjuvant tamoxifen

It may be reasonable to offer an aromatase inhibitor to patients who completed a five-year course of adjuvant tamoxifen as long as five or 10 years previously. However, with every year that passes, the absolute risk of recurrence decreases; therefore, the risk-to-benefit ratio changes. Every year, the risks become more important relative to the benefit. As the risk of recurrence decreases, the toxicities of therapy become much more important.

Endocrine therapy following five years of adjuvant anastrozole

Kent Osborne proposed the possibility of studying the use of adjuvant tamoxifen in women who have already received five years of adjuvant anastrozole. Most physicians are concerned about this strategy because there are no data to support it. Another option would be 10 years of an adjuvant aromatase inhibitor. Most physicians seem to be more comfortable with that strategy.

Italian Tamoxifen Arimidex® (ITA) trial: Adjuvant anastrozole following two years of adjuvant tamoxifen

In the ITA trial, patients received a total of five years of therapy — either tamoxifen alone or tamoxifen for at least two years followed by anastrozole (Figure 2.2). Results from the ITA trial confirm the data from the MA17 trial in which patients received five years of adjuvant tamoxifen and then an aromatase inhibitor. It is unknown whether 10 years of an adjuvant aromatase inhibitor alone would be more effective than five years of adjuvant tamoxifen followed by five years of an adjuvant aromatase inhibitor. Although the ITA trial was a small study, I’m willing to accept it as being fundamentally correct because the results are consistent with those from the MA17 trial. In both trials, a clear advantage was demonstrated for the crossover to an aromatase inhibitor after tamoxifen.

Switching to adjuvant anastrozole while receiving adjuvant tamoxifen

In a postmenopausal woman who has received two to three years of adjuvant tamoxifen and is doing well, I wouldn’t recommend changing to adjuvant anastrozole. I would have the patient finish the five years of adjuvant tamoxifen and then change to an aromatase inhibitor. However, if the patient felt strongly about switching or was having some symptoms on tamoxifen, I’d be very comfortable switching therapy at two or three years.

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