Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer

Abstract

Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R2: 53%, P<10−77). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14 nM) compared with high (>35 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS.

Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring—The TADE Study

“…In vitro and xenograft models have shown that breast cancer cell proliferation is endoxifen concentration dependent (16,17,20). Two large retrospective studies have shown a correlation between endoxifen level and disease-free survival in patients with early breast cancer treated with tamoxifen (18,19). Using quintile group analyses, both studies showed that endoxifen trough levels below approximately 15 nmol/L had worse outcome compared with those with higher levels in the adjuvant setting.…”

“…There is now increasing evidence that systemic exposure to endoxifen is important for anticancer effect (16)(17)(18)(19)(20). In vitro and xenograft models have shown that breast cancer cell proliferation is endoxifen concentration dependent (16,17,20).…”

Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity

“…Therefore, endoxifen concentration may play a key role in modulating tamoxifen's clinical effectiveness (14). Lower concentrations of endoxifen have been associated with an increased risk of recurrent or new primary breast cancer (14,15). However, one prospective study found the opposite, suggesting that higher endoxifen concentrations promote recurrence (16).…”

Perspectives of pharmacogenetics approach to personalized tamoxifen therapy

“…определили, что кон-центрация эндоксифена ниже 5,97 нг/мл коррелирует с увеличением рецидивов болезни [25], а P. Saladores и соавт. в своем исследовании установили, что уровень эндоксифена ниже 5,30 нг/мл влечет увеличение риска появления отсроченных рецидивов и смерти [34]. Одна-ко дальнейшее изучение необходимо.…”

“…были получены противоположные результаты: у носителей CYP2D6*4 наблюдалось снижение риска реци-дива болезни на фоне приема тамоксифена (relative risk = 0,28, 95% confi dence interval = 0,11-0,74, P=0,0089) и досто-верное увеличение DFS у гомозигот по CYP2D6*4 [29,30]. Также еще шесть исследований показывают достоверную связь между генотипом CYP2D6 и различными исходами лечения [17,[31][32][33][34][35][36] (табл. 1).…”