Tamoxifen Metabolite Concentrations, CYP2D6 Genotype, and Breast Cancer Outcomes

Abstract

We explored whether breast cancer outcomes are associated with endoxifen and other metabolites of tamoxifen, and to examine potential correlates of endoxifen concentrations including CYP2D6 metabolizer phenotype and body mass index (BMI). Tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen concentrations were measured from 1370 estrogen receptor positive breast cancer patients participating in the Women's Healthy Eating and Living (WHEL) Study, and tested for associations with breast cancer outcomes. Breast cancer outcomes were not associated with tamoxifen, 4-hydroxytamoxifen or N-desmethyltamoxifen concentrations. For endoxifen, a threshold was identified suggesting that women in the upper four quintiles of endoxifen had a 26% lower recurrence rate than women in the bottom quintile. (HR=0.74; 95% CI, [0.55, 1.00]). Predictors of membership in this higher risk bottom quintile were poor/ intermediate metabolizer genotype, higher BMI, and low tamoxifen concentrations. This study suggests a minimal threshold at which endoxifen is effective against breast cancer recurrence, which 80% of tamoxifen-takers achieve.

Tamoxifen — no longer a golden standard for adjuvant therapy in the treatment of premenopausal patients with hormone-sensitive breast cancer

“…On the other hand, however, in premenopausal patients, the potential benefit from prolonged use of TAM should be interpreted with caution, as this group of patients made up only 13% of the total number of patients treated within the studies comparing varied periods of using TAM [15][16][17]. Irrespective of individual differences in the pharmacokinetics of TAM, about 20% of patients treated with this medication did not reach the treatment threshold of endoxifen -its main active metabolite [18][19][20].…”

Pharmacogenetic testing of allelic variants of the CYP2D6 gene in hormone positive breast cancer

“…Было показано, что у IMs и PMs концентрация эндоксифена была ниже на 60 и 74 %, чем у EMs. Ген-дозазависимый эффект также проде-монстрирован для тамоксифена и соотношения мета-болитов N-дисметилтамоксифен / эндоксифен [35][36][37].…”

Role and pharmacologic significance of cytochrome P‐450 2D6 in oxidative metabolism of toremifene and tamoxifen

“…CYP2D6 activity is highly associated with TAM metabolism and may affect clinical activity. 11,12 Coincubation of TAM with potent, specific CYP2D6 chemical inhibitors such as quinidine and the antidepressant paroxetine confirmed that the inhibition of CYP2D6 activity prevents the formation of the important metabolite endoxifen. However, because TOR is less subject to CYP2D6-mediated hydroxylation, these inhibitors had little effect on the metabolism of TOR in our assays.…”

“…1). [10][11][12] These metabolites bind to the ER with up to 30-fold greater affinity than TAM, and this increased potency for binding translates into enhanced antiestrogen activity. …”

“…1). [10][11][12] These metabolites bind to the ER with up to 30-fold greater affinity than TAM, and this increased potency for binding translates into enhanced antiestrogen activity. [13][14][15][16] Whether these metabolites are responsible for TAM's variable clinical efficacy is a topic of considerable controversy.…”