Abstract
Objective: To review published data on the metabolism of toremifene and assess any implications for treatment decisions. Significance: The use of selective estrogen receptor modulators (SERMs) forms part of the treatment backbone of hormone receptor positive breast cancer. Studies have shown that tamoxifen and toremifene, the two SERMs approved in the treatment of hormone receptor positive breast cancer, have similar efficacy and safety profiles. Although tamoxifen metabolism has been extensively studied, there has been limited information regarding toremifene metabolism and any potential implications for practice. Purpose: To review recent data on the metabolism of toremifene as well as significant drug-drug interactions that may impact treatment decisions. Methods: A literature review was conducted using www.pubmed.com. Toremifene, metabolism, Fareston, cytochrome P450, and CYP2D6 were used as search terms. Results: Toremifene is thought to be active in its parent form, and is mainly metabolized in the liver by CYP3A4. In contrast, tamoxifen requires metabolism by CYP2D6 to be converted to its biologically active 4-hyroxyl metabolites. Data suggest that potent CYP2D6 inhibitors, such as certain selective serotonin reuptake inhibitors (SSRIs), can result in alterations in plasma concentrations of the 4-hydroxyl metabolites of tamoxifen. Although published studies on the use of SSRIs and outcome of adjuvant therapy with tamoxifen remain discordant, NCCN guidelines currently recommend against coadministration of strong inhibitors of CYP2D6 and tamoxifen. A series of recent studies directly compared the metabolic activity of toremifene and tamoxifen in human liver microsomes and showed that metabolism of toremifene was unaffected by the presence of potent CYP2D6 inhibitors or by CYP2D6 genetic status. However, metabolism of tamoxifen was significantly altered by CYP2D6 inhibitors and CYP2D6 genetic status.. Concentrations of the active form of toremifene were unaffected by SSRIs or potential variation in CYP2D6 genetic status. Discussion: Although variations in CYP2D6 metabolic activity cause differences in plasma concentrations of active tamoxifen metabolites, the debate regarding the clinical sequelae of the CYP2D6 alterations and outcomes in patients taking tamoxifen is ongoing. Potential drug-drug interactions with SSRIs may alter the efficacy of tamoxifen and thereby inform treatment choices. Toremifene is unaffected by coadministration with SSRIs and represents a well-studied SERM option for treating patients with estrogen-positive breast cancer where CYP2D6 inhibition may be of concern.
