New research supports switching from to exemestane after two to three years of tamoxifen therapy in women with primary breast cancer

DailyUpdates 23rd March 2004: One in 8 women in the United States (approximately 13.3 percent) will develop breast cancer during her lifetime. New data suggests that women with primary breast cancer may benefit from a switch to the aromatase inhibitor, exemestane after two to three years of tamoxifen therapy.

One in 8 women in the United States (approximately 13.3 percent) will develop breast cancer during her lifetime. Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse.

Tamoxifen is an anti-hormonal agent that competes with estrogen for binding sites in target tissues such as breast. Another approach to the treatment of breast cancer involves the inhibition of the metabolic pathways responsible for the production of estrogen. Aromatase is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women.

The anti-hormonals market is in a particularly dynamic period. Tamoxifen will soon be replaced by the leading aromatase agents that are more effective and produce fewer adverse events. The new generation of aromatase inhibitors, led by AstraZeneca’s Arimidex, will soon make tamoxifen obsolete. Pfizer's Exemestane (Aromasin) is another aromatase inhibitor.

Exemstane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation.

In the March edition of the New England Journal of Medicine, Coombes et al report on the data from a study investigating the efficacy of exemestane administered after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.

In their double-blind, randomized trial Coombes et al investigated whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival.

Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported. Of these 183 were in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68, representing a significant 32% reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7% at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group.

First approved in the United Kingdom in 1998, exemestane is now approved in 49 countries, including the US, where it is indicated for the treatment of advanced breast cancer in post-menopausal women whose disease has progressed following tamoxifen therapy. This study shows that exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment supporting a therapeutic switch.

(source DailyUpdates 23rd March; for a full abstract of the original paper see N Engl J Med. 2004 Mar 11;350(11):1081-92.)

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