420

Endocrine therapy using aromatase inhibitors, selective estrogen receptor modifiers (SERMs) and other types of endocrine treatment options is playing a major role in the concept of breast cancer treatment and is currently standard treatment of hormone-sensitive (ER and/or PGR positive) breast cancer, both in the adjuvant and metastatic setting. Recently, the adipocytokine leptin has been shown to induce the functional activation of the estrogen receptor alpha (ER-α) in MCF-7 breast cancer cells and to stimulate aromatase activity by interference with the aromatase promoters II and I.3 in vitro. In addition, plasma leptin levels have been shown to be correlated to overall survival in postmenopausal breast cancer patients. Thus, we tested whether different drugs currently established for endocrine therapy of breast cancer may influence on plasma leptin levels. All patients (n = 89) were postmenopausal and treated for metastatic breast cancer at the Department of Medicine, Section of Oncology at the Haukeland University Hospital, Bergen, Norway. Patients treated with the non-steroidal aromatase inhibitors anastrozole (n = 22) and letrozole (n = 21), as well as the steroidal aromatase inactivators formestane (n = 16) and exemestane (n = 10) were available. These findings were compared to patients treated with tamoxifen (n = 7) or diethylstilbestrol (n = 13). Plasma levels of estrone (E1), estradiol (E2) and estrone sulfate (E1S) were measured with highly sensitive radioimmunoassays while plasma leptin levels as well as androstenedione levels were measured with commercial kits. Treatment with exemestane (25 mg daily) caused a significant decrease of plasma leptin levels by 27% (7% -42.7%, geom. mean with 95% inverals of the mean) following about 3 months of treatment (P = 0.022, Wilcoxon's matched pair signed rank test). In contrast, all other endocrine treatment modalities did not cause any significant change in plasma leptin levels during the first 3 months of treatment. One possible explanation for this distinct effect of exemestane on plasma leptin may be the weak androgen effects of exemestane and its major metabolite 17-hydro-exemestane. Androgens have been suggested to decrease plasma leptin levels while estrogens are believed to increase leptin levels through transcriptional activation of the LEP gene. Thus, our findings suggest a distinct influence of exemestane on the adipocytokine leptin, suggesting an additional mechanism of action to exemestane beside the well-documented potent effect on aromatization. Our preliminary, albeit significant, findings should be confirmed by a larger number of patients treated with exemestane with a longer follow-up.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]