Effects of Exemestane and Tamoxifen in a Postmenopausal Breast Cancer Model

Abstract

Purpose: To optimize treatment strategies for postmenopausal breast cancer patients, we investigated the efficacy of the steroidal aromatase inhibitor exemestane alone or in combination with the antiestrogen tamoxifen in a xenograft model of postmenopausal breast cancer. We also determined the effects of these agents in sequential secondline therapy and the effect of the nonsteroidal aromatase inhibitor letrozole on tumors that progressed on the above treatments.Experimental: Aromatase-transfected human estrogen receptor-positive breast cancer cells (MCF-7Ca) were grown as tumors in ovariectomized athymic mice. Animals received subcutaneous injection with vehicle, tamoxifen, exemestane, tamoxifen plus exemestane, and letrozole. Tumor volumes were measured weekly.Results: All treatments were effective initially in suppressing tumor growth as first-line therapy compared with vehicle treatment. Exemestane suppressed tumor growth to a greater extent than tamoxifen. However, the combination of tamoxifen plus exemestane was more effective than either drug alone. After tumor volumes doubled on initial treatment, the mice were crossed over to receive exemestane or tamoxifen. Tumor growth slowed briefly in mice treated with tamoxifen and crossed over to exemestane, but tumor growth continued unabated in those changed from exemestane to tamoxifen. However, letrozole was effective in both groups as third-line therapy for a limited period. Letrozole as initial single agent was the best overall treatment in terms of the degree of tumor suppression and the length of effectiveness of treatment.Conclusion: Exemestane was more effective in controlling tumor growth than tamoxifen. In addition, the combination of exemestane plus tamoxifen was clearly more effective than sequential use of these agents in the tumor model. However, the nonsteroidal aromatase inhibitor letrozole as first-line therapy was overall the most effective treatment in controlling tumor growth.

Activation of Mitogen-Activated Protein Kinase in Xenografts and Cells during Prolonged Treatment with Aromatase Inhibitor Letrozole

“…However, overall tumor growth rate may vary between experiments. In this study, the tumors had initially regressed during treatment with letrozole (30) but grew back more slowly than in other reported investigations (32,36) and had doubled after 32 weeks of treatment. Several mice were sacrificed during the course of the treatment for tumor analysis on weeks 4, 28, and 56.…”

“…For this purpose, we have used a model system in which human breast cancer cells expressing the ER and stably transfected with the aromatase gene are grown as tumors in ovariectomized, immunosuppressed mice (30). These tumors are sensitive to the effects of estrogen, antiestrogens, and aromatase inhibitors (30,32,33,(36)(37)(38)(39). However, overall tumor growth rate may vary between experiments.…”

Effect of Exemestane on Tamoxifen Pharmacokinetics in Postmenopausal Women Treated for Breast Cancer

“…This is analogous to the two-drug androgen blockade regimens commonly used in advanced prostatic neoplasms (17,18). Murine mammary tumor models suggest that the combination of tamoxifen and exemestane has greater activity than does either drug alone (19). In contrast, the addition of the type I aromatase inhibitors letrozole or anastrazole did not add to the benefit of tamoxifen in this 7,12-dimethylbenanthraceneinduced tumor model.…”

The discovery and mechanism of action of letrozole

“…Tumors that progressed during treatment with tamoxifen remained sensitive to second-line letrozole therapy, whereas tumors that progressed on letrozole did not respond to second-line treatment with tamoxifen or fulvestrant. In another series of experiments conducted by the same group using the MCF7Ca model, letrozole was even effective as third-line therapy for a limited period when administered after treatment with tamoxifen and exemestane [102]. The studies showed that although exemestane was more effective than tamoxifen in controlling tumor growth, letrozole as first-line therapy was the most effective treatment overall, both in terms of the degree of tumor suppression and the length of effectiveness of treatment [102].…”