How is tamoxifen metabolized?

Updated: Dec 07, 2018
  • Author: Maurie Markman, MD, MS; Chief Editor: Keith K Vaux, MD  more...
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Systemic tamoxifen has been the standard approach for reducing risk of recurrence in women with estrogen receptor (ER)–positive early-stage breast cancer for more than 40 years. Long-term data have demonstrated that the use of tamoxifen reduces recurrence and mortality by more than 30% in both premenopausal and postmenopausal women, regardless of the use of systemic chemotherapy. [1] Aromatase inhibitors (AIs), such as anastrozole (Arimidex) and exemestane (Aromasin), have been proven to be as effective as, or superior to, tamoxifen. AIs have been utilized as initial adjuvant therapy, as sequential therapy followed by 2-3 years of tamoxifen, or as an extended therapy following 4.5-6 years of tamoxifen. [2]

Tamoxifen is metabolized via CYP2D6 into endoxifen (4-OH-N-desmethyl-tamoxifen), its primary active metabolite. Multiple investigations have identified genetic variants of CYP2D6 that can affect its activity, which in turn affects the metabolism of tamoxifen. The proficiency with which CYP2D6 metabolizes tamoxifen was assumed to be associated with the specific variant of the gene that an individual possesses, on the basis of studies that were conducted in breast cancer patients taking selective serotonin reuptake inhibitors (SSRIs) to relieve hot flashes. [3, 4, 5]

Specifically, because SSRIs inhibit CYP2D6, significantly lower endoxifen concentrations were also found in the studies’ patients. Further analysis identified 3 different groups of patients on the basis of genetic variants of CYP2D6: patients with 2 wild-type (wt), or normal, alleles; those with 1 non-wt allele; and those with 2 non-wt alleles. In a direct dose-gene effect, patients with 2 non-wt alleles had lower concentrations of endoxifen than did those with 1 non-wt allele, and patients with 2 wt alleles had endoxifen levels similar to those of poor metabolizers of tamoxifen who were not taking SSRIs. [4, 5]  Follow-up studies identified the *4 variant (1846G>A) as the most common allele associated with poor metabolism of tamoxifen. [6, 7]

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