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

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 on‐going 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 moderate‐to‐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.