Impairment of endoxifen formation in tamoxifen‐treated premenopausal breast cancer patients carrying reduced‐function CYP2D6 alleles

Abstract

Aims: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects. Methods: In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with ongoing postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography-tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records. Results: In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6-5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced-function alleles, 2 null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null-alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderateto-severe side effects were reported in a concentration-dependent manner. Conclusion: Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null-alleles, but also in carriers of 2 reduced-function alleles. This finding may be highly relevant for future, genotype-based dose considerations.

Evaluation of the CYP2D6 Haplotype Activity Scores Based on Metabolic Ratios of 4,700 Patients Treated With Three Different CYP2D6 Substrates

“…Data from several in vitro and in vivo reports argue that the extent of metabolic activity decrease caused by the CYP2D6*10 9,10 and CYP2D6*41 7,11–13 alleles is > 50% and in compliance, the recent consensus guidelines decreased the metabolic activity score approximation for CYP2D6*10 from 50% to 25% 5 . The results here obtained, which are based on a very large number of patients, support these data and argue that the decrease in metabolic activity encoded by the CYP2D6Decr alleles is indeed lower than 50% compared with the one of CYP2D6Norm .…”

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

“…Taken together, these studies [70,71] confirmed that CYP2D6 metabolizer status is a strong determinant of endoxifen plasma concentration and that increasing CYP2D6 allele activity correlates with increasing plasma levels.…”

“…However, this threshold was questioned, because the study was not designed to determine this endoxifen threshold [68,69]. In 2020, in all homozygous carriers of CYP2D6 non-functional alleles, but also in carriers of two reduced function alleles, significantly reduced endoxifen levels were observed [70]. A total of 118 Swedish premenopausal breast cancer patients genotyped for nine different allelic variants using blood as a source of genomic DNA showed that the endoxifen concentration in 32% of patients did not reach this putative threshold.…”

“…Thus, both PMs and UMs have a worse prognosis for breast cancer compared to NMs after receiving a standard dose of tamoxifen. Other studies already provided evidence that PMs have a lower endoxifen level than NMs; therefore, worse prognosis is expected [70,71]. Unlike PMs, UMs are expected to have a higher endoxifen level as compared to NMs and therefore should have a tamoxifen response after standard tamoxifen dosage.…”

CYP2D6 Reduced Function Variants and Genotype/Phenotype Translations of CYP2D6 Intermediate Metabolizers: Implications for Personalized Drug Dosing in Psychiatry

“…These inconsistencies may have important clinical implications for genotype-based dose recommendations of many psychiatric drugs, as CYP2D6 generally plays a key role in the metabolism of such agents. However, the same concerns CYP2D6 drug substrates from other therapeutic classes, e.g., tamoxifen, where Thorén et al (2020) reported a significantly stronger impact of CYP2D6*41 than CYP2D6*10 on the CYP2D6-mediated bioactivation to endoxifen (Thorén et al, 2020), which mainly mediates the preventive effect on breast cancer recurrence.…”