The Influences of Adherence to Tamoxifen and CYP2D6 Pharmacogenetics on Plasma Concentrations of the Active Metabolite (Z)‐Endoxifen in Breast Cancer

Abstract

Tamoxifen efficacy in breast cancer is suspected to depend on adherence and intact drug metabolism. We evaluated the role of adherence behavior and pharmacogenetics on the formation rate of (Z)‐endoxifen. In 192 Brazilian patients, we assessed plasma levels of tamoxifen and its metabolites at 3, 6, and 12 months of treatment (liquid‐chromatography tandem mass spectrometry), adherence behavior (Morisky, Green, and Levine medication adherence scale), and cytochrome P450 2D6 (CYP2D6) and other pharmacogene polymorphisms (matrix‐assisted laser‐desorption‐ionization time of flight) mass spectrometry, real‐time polymerase chain reaction). Adherence explained 47% of the variability of tamoxifen plasma concentrations (P < 0.001). Although CYP2D6 alone explained 26.4%, the combination with adherence explained 40% of (Z)‐endoxifen variability at 12 months (P < 0.001). The influence of low adherence to not achieving relevant (Z)‐endoxifen levels was highest in patients with noncompromised CYP2D6 function (relative risk 3.65; 95% confidence interval 1.48–8.99). As a proof‐of‐concept, we demonstrated that (Z)‐endoxifen levels are influenced both by patient adherence to tamoxifen and CYP2D6, which is particularly relevant for patients with full CYP2D6 function.

Endocrine Therapy in Early Breast Cancer

“…Recently, a report from Swedish breast cancer cohort registries linked to the Swedish Prescribed Drug Registry evaluated more than 1,300 patients assigned to take adjuvant tamoxifen. They found that discontinuation rates, presumably because of toxicity, were 7.2, 7.6, 6.7, and 18.8% among poor, intermediate, normal, and ultra-rapid CYP2D6 metabolizers, respectively, confirming previously published reports [53-55]. In addition, they observed a breast cancer-specific mortality, with highest rates in the poor and ultra-rapid metabolizer groups, which is rather difficult to explain.…”

Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

“…Nardin et al [ 71 ] also confirmed in 2020 that tamoxifen metabolite levels were affected by the CYP2D6 genotype, with the strongest effect for endoxifen concentrations. PMs carrying two non-functional alleles had 4.5 to 5.5 times lower endoxifen concentrations than NMs carrying two functional alleles.…”

“…Reasons for quitting early are the development of side effects, suboptimal patient physician communication, or low perception of the tumor recurrence risk [71]. Multivariate analyses showed that about 47% of tamoxifen plasma concentration variability is explained by patient adherence behavior; in addition, the combination of CYP2D6 genotype and adherence behavior explained 40% of endoxifen plasma concentration variability at 12 months [71]. He et al [78] investigated the relationship between CYP2D6 metabolizer status and tamoxifen discontinuation in a prospective-retrospective study, showing that UMs had a discontinuation rate of 18.8% at 6 months after the start of tamoxifen treatment.…”

“…This study was conducted in 192 Brazilian breast cancer patients with endoxifen concentrations measured at 3, 6, and 12 months after the start tamoxifen treatment. Additionally, CYP2D6 phenotypes significantly predicted tamoxifen metabolite levels across all time points in multivariate analyses [ 71 ].…”

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies

“…Furthermore, around 20% [ 7 ] of patients are considered at risk for C SS , min ENDX below a proposed therapeutic threshold due to impaired CYP2D6 activity and additional high unexplained IIV. Of note, tamoxifen adherence could significantly increase the explained variability of endoxifen plasma concentrations in breast cancer patients [ 30 ]. An MIPD early dose finding framework has been proposed to increase the proportion of patients reaching target endoxifen concentrations and mitigate the high IIV observed in C SS , min ENDX [ 25 ].…”