Additive Antitumor Effect of Aromatase Inhibitor Letrozole and Antiestrogen Fulvestrant in a Postmenopausal Breast Cancer Model

Abstract

Blocking estrogen receptors with antiestrogens and blocking estrogen synthesis with aromatase inhibitors are two strategies currently being used for reducing the effect of estrogen in postmenopausal estrogen receptor-positive breast cancer patients. To optimize these treatment strategies, we have investigated whether tumor progression can be delayed by combining the pure antiestrogen fulvestrant with the nonsteroidal aromatase inhibitor letrozole. These studies were done in ovariectomized, athymic mice bearing tumors of estrogen receptor-positive human breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). Groups of mice with equivalent tumor volumes were injected s.c. daily with vehicle (control; n = 6), fulvestrant (1 mg/d; n = 7), letrozole (10 Mg/d; n = 18), or letrozole (10 Mg/d) plus fulvestrant (1 mg/d; n = 5). All treatments were effective in suppressing tumor growth compared with controls (P < 0.001). Tumor volumes of the fulvestrant-treated group had doubled in 10 weeks. After 19 weeks of letrozole (10 Mg/d) treatment when tumors had nearly doubled in volume, mice (n = 18) were assigned to second-line therapy with letrozole (100 Mg/d; n = 6), tamoxifen (100 Mg/d; n = 6), or remained on letrozole treatment (10 Mg/d; n = 6). However, tumors continued to increase in volume in these groups. Tumors of animals treated with the combination of letrozole plus Faslodex regressed over 29 weeks of treatment by 45%. Thus, the combination of letrozole plus fulvestrant was more effective in suppressing tumor growth than either letrozole or fulvestrant alone or sequential therapies with tamoxifen or a higher dose of letrozole (100 Mg/d). (Cancer Res 2005; 65(12): 5439-44)

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.…”

“…The mixed-effect model is a powerful and flexible way to analyze unbalanced longitudinal data (31). Linear models that incorporate fixed effects (entire population) and random effects (individuals drawn at random from a population) are mixed effects models (31) and were used for our previously published studies (32,33). This approach allows an exponential variable controlling the rate of growth to be estimated for each of these treatment groups, with the random effects being estimated for each subject in a group (31).…”

“…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.…”

Novel retinoic acid metabolism blocking agents have potent inhibitory activities on human breast cancer cells and tumour growth

“…In addition, VN14-1 was efficacious in preventing the formation of MCF-7Ca tumours (Figure 10). We also observed that VN/14-1 treatment caused significant reduction in uterine wet weight (data not shown), which indicates that VN/14-1 can effectively block the uterotropic activity of oestrogens produced by peripheral aromatisation of androstenedione (Goss et al, 2000;Jelovac et al, 2005).…”

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

“…To investigate the mechanisms of resistance to aromatase inhibitors, one approach is to use the xenograft model with tumors of human breast cancer MCF-7Ca cells stably transfected with aromatase [142,143] (Figure 7). Mice were treated with letrozole until tumors eventually began to grow.…”