Edited comments by Francesco Boccardo, MD

Rationale for the use of aromatase inhibitors following adjuvant tamoxifen

The newer aromatase inhibitors are as effective as, if not better than, tamoxifen as first-line therapy for advanced disease; they do not affect the uterus or increase the risk of thromboembolic disease. On the other hand, aromatase inhibitors can lead to osteoporosis, and as reported in the ATAC trial, the aromatase inhibitors are associated with an increased incidence of fractures.

Approximately 10 to 12 years ago, we began exploring the role of adjuvant aromatase inhibitors following a course of adjuvant tamoxifen. Although adjuvant tamoxifen is very effective, it is not devoid of serious side effects. Attention to the possible mechanisms of tamoxifen resistance was also growing. One particular mechanism of resistance, an increase in aromatase activity in the breast tumors of women exposed to tamoxifen, provided strong biological support for this sequencing approach.

We believed a sequential approach could have potential advantages over a five-year course of adjuvant tamoxifen or even an adjuvant aromatase inhibitor. A sequential approach would allow women to receive a class of compounds that might help circumvent tamoxifen resistance, while limiting the exposure to aromatase inhibitors and costs of treatment.

Italian Tamoxifen Arimidex R (ITA) trial

In the ITA trial, 448 postmenopausal women with ER-positive, node-positive breast cancer were randomly assigned to continue tamoxifen or switch to anastrozole following treatment with two to three years of adjuvant tamoxifen. The treatment groups were balanced with respect to median age, tumor size and grade, number of involved nodes, type of primary treatment, and prior radiation therapy or chemotherapy. The median age for both groups was 63 years. The median duration of tamoxifen therapy prior to randomization was 28 months in each group.

After a median follow-up of three years, 17 recurrences occurred in the women who switched to anastrozole and 45 recurrences occurred in the women who continued on tamoxifen. The women who continued on tamoxifen had more second primary tumors (including five endometrial cancers), distant metastases and locoregional recurrences (including ipsilateral breast recurrences, locoregional node recurrences, or both). According to the Kaplan-Meier curves, the women who switched to anastrozole had a significantly longer event-free, progression-free and local relapse-free survival. They also had a longer, although not significant (p = 0.06), distant metastases-free survival. Overall survival (p = 0.1) was also longer for the women who switched to anastrozole, but there were few deaths since the data are immature.

The treatment discontinuation rates for both groups were similar (8.4 percent for tamoxifen and eight percent for anastrozole). Women who continued on tamoxifen exhibited significantly more gynecologic changes, many of which were serious and required hospitalization. More severe treatment-related adverse events were reported in the women who continued on tamoxifen (Figure 4.1).

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