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

Br J Clin Pharmacol. 2021 Mar;87(3):1243-1252. doi: 10.1111/bcp.14500. Epub 2020 Aug 9.


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.

Keywords: adjuvant treatment; breast cancer; personalized medicine; pharmacogenetics; phenotype; tamoxifen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Antineoplastic Agents, Hormonal / adverse effects
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Cytochrome P-450 CYP2D6* / genetics
  • Female
  • Genotype
  • Humans
  • Retrospective Studies
  • Tamoxifen / analogs & derivatives
  • Tamoxifen / therapeutic use


  • Antineoplastic Agents, Hormonal
  • Tamoxifen
  • 4-hydroxy-N-desmethyltamoxifen
  • Cytochrome P-450 CYP2D6