Tamoxifen Pharmacogenetics and Metabolism: Results From the Prospective CYPTAM Study

J Clin Oncol. 2019 Mar 10;37(8):636-646. doi: 10.1200/JCO.18.00307. Epub 2019 Jan 24.


Purpose: Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM (The Netherlands National Trial Register: NTR1509) study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome in patients with early-stage breast cancer receiving tamoxifen.

Patients and methods: From February 2008 to December 2010, patients with breast cancer treated with adjuvant tamoxifen were included. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation. Blood samples were retrieved for CYP2D6 genotyping and endoxifen measurements by Amplichip (Roche Diagnostics, Indianapolis, IN) and high-performance liquid chromatography-tandem mass spectrometry, respectively. Endoxifen concentrations were analyzed as a continuous variable, classifying patients into quartiles and using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were associated with relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt) by Cox regression analysis.

Results: A total of 667 pre- and postmenopausal patients were enrolled and had received tamoxifen for a median time of 0.37 years (range, 0.23 to 0.6 years) before study entry. No association was found between endoxifen concentrations and RFSt (adjusted hazard ratio, 0.991; 95% CI, 0.946 to 1.038; P = .691). Also, neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results. In addition, no association was found between CYP2D6 genotype and RFSt (adjusted hazard ratio, 0.929; 95% CI, 0.525 to 1.642; P = .799).

Conclusion: This prospective clinical study shows no association between endoxifen concentrations or CYP2D6 genotypes and clinical outcome in patients with early-stage breast cancer receiving adjuvant tamoxifen.

Publication types

  • Clinical Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents, Hormonal / administration & dosage
  • Antineoplastic Agents, Hormonal / blood*
  • Antineoplastic Agents, Hormonal / pharmacokinetics
  • Belgium
  • Breast Neoplasms / blood
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Chemotherapy, Adjuvant
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism*
  • Disease Progression
  • Female
  • Humans
  • Middle Aged
  • Neoplasm Metastasis
  • Neoplasm Recurrence, Local
  • Neoplasm Staging
  • Netherlands
  • Pharmacogenetics
  • Pharmacogenomic Variants*
  • Progression-Free Survival
  • Prospective Studies
  • Tamoxifen / administration & dosage
  • Tamoxifen / analogs & derivatives*
  • Tamoxifen / blood*
  • Tamoxifen / pharmacokinetics


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

Associated data

  • NTR/NTR1509