Abstract 5682: Modeling the pharmacological importance of endoxifen for the treatment of ER-positive breast cancer in premenopausal patients

Abstract

Abstract Long term adjuvant tamoxifen therapy for five years is the antiestrogenic standard of care for ER-positive breast cancer in premenopausal patients. The metabolic activation of tamoxifen by CYP2D6 to endoxifen remains controversial to plan the treatment of patients with breast cancer. However, all retrospective studies focus entirely on postmenopausal patients and no studies have been undertaken in the relevant premenopausal treatment population. We have addressed the issue of the pharmacological importance of endoxifen to control the estrogen-stimulated growth of four ER-positive breast cancer cell lines (MCF-7, T47-D, BT-474 and ZR-75). We have modeled the actual estrogen environment in the laboratory (estradiol plus estrone) based on previous data from premenopausal patients taking tamoxifen (Jordan et al, JNCI 2001; 83:1488-91). Our strategy was to evaluate the anti-proliferative actions of actual concentrations of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen combined, based on the actual measurements reported for these metabolites in patients who were extensive metabolizers (EM), intermediate metabolizers (IM) or poor metabolizers (PM) (Mürdter et al, Clin Pharmacol Ther 2011; 89:708-17). These data were then compared with similar anti-proliferative experiments in the four cell lines, using endoxifen obtained from four sources (Mayo Clinic, University of Indiana, Institut für Klinische Pharmakologie (IKP) and the Fox Chase Cancer Center). Each cell line was evaluated with the clinically relevant circulating levels of estrogen, with and without the inclusion of the different endoxifens at the published concentrations from EM, IM and PM. It is important to note that all synthetic endoxifen currently available is an impure mixture of geometric isomers. Therefore, results obtained are only an estimate of the efficacy of endoxifen in the patient. To address this issue, we have specifically synthesized the appropriate isomer of endoxifen as a fixed ring compound that can no longer isomerize. We have previously used this strategy to discover the actual pharmacology of the two geometric isomers of 4-hydroxytamoxifen (Murphy et al, Mol Pharm 1990; 38:737-43). The results demonstrate the essential requirement with the appropriate concentration of endoxifen necessary to block estrogen-mediated cell replication. Acknowledgements: This work (VCJ) was supported the subcontract under the SU2C (AACR) Grant number SU2C-AACR-DT0409; the Susan G Komen For The Cure Foundation under Award number SAC100009. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5682. doi:1538-7445.AM2012-5682