Breast Cancer Research and Treatment

, Volume 161, Issue 3, pp 567–574 | Cite as

An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome

  • A. H. M. de Vries SchultinkEmail author
  • X. Alexi
  • E. van Werkhoven
  • L. Madlensky
  • L. Natarajan
  • S. W. Flatt
  • W. Zwart
  • S. C. Linn
  • B. A. Parker
  • A. H. B. Wu
  • J. P. Pierce
  • A. D. R. Huitema
  • J. H. Beijnen



Endoxifen concentrations have been associated with breast cancer recurrence in tamoxifen-treated patients. However, tamoxifen itself and other metabolites also show antiestrogenic anti-tumor activity. Therefore, the aim of this study was to develop a comprehensive Antiestrogenic Activity Score (AAS), which accounts for concentration and antiestrogenic activity of tamoxifen and three metabolites. An association between the AAS and recurrence-free survival was investigated and compared to a previously published threshold for endoxifen concentrations of 5.97 ng/mL.

Patients and methods

The antiestrogenic activities of tamoxifen, (Z)-endoxifen, (Z)-4-hydroxytamoxifen, and N-desmethyltamoxifen were determined in a cell proliferation assay. The AAS was determined by calculating the sum of each metabolite concentration multiplied by an IC50 ratio, relative to tamoxifen. The AAS was calculated for 1370 patients with estrogen receptor alpha (ERα)-positive breast cancer. An association between AAS and recurrence was investigated using Cox regression and compared with the 5.97 ng/mL endoxifen threshold using concordance indices.


An AAS threshold of 1798 was associated with recurrence-free survival, hazard ratio (HR) 0.67 (95% confidence interval (CI) 0.47–0.96), bias corrected after bootstrap HR 0.69 (95% CI 0.48–0.99). The concordance indices for AAS and endoxifen did not significantly differ; however, using the AAS threshold instead of endoxifen led to different dose recommendations for 5.2% of the patients.


Endoxifen concentrations can serve as a proxy for the antiestrogenic effect of tamoxifen and metabolites. However, for the aggregate effect of tamoxifen and three metabolites, defined by an integrative algorithm, a trend towards improving treatment is seen and moreover, is significantly associated with breast cancer recurrence.


Tamoxifen Metabolites Algorithm Recurrence-free survival 



This work was supported by data from the WHEL study, which was initiated with the support of the Walton Family Foundation and was continued with funding from National Cancer Institute (CA69375). SC Linn received research funding from A Sister’s Hope. L Natarajan was partially supported by funding from the National Cancer Institute R01 (CA166293). BA Parker received (institutional) research funding from Genentech, Novartis, and GlaxoSmithKline.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10549_2016_4083_MOESM1_ESM.docx (88 kb)
Supplementary material 1 (DOCX 88 kb)
10549_2016_4083_MOESM2_ESM.docx (16 kb)
Supplementary material 2 (DOCX 15 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • A. H. M. de Vries Schultink
    • 1
    Email author
  • X. Alexi
    • 2
  • E. van Werkhoven
    • 3
  • L. Madlensky
    • 4
  • L. Natarajan
    • 4
  • S. W. Flatt
    • 4
  • W. Zwart
    • 2
  • S. C. Linn
    • 2
    • 5
  • B. A. Parker
    • 4
  • A. H. B. Wu
    • 6
  • J. P. Pierce
    • 4
  • A. D. R. Huitema
    • 1
    • 7
  • J. H. Beijnen
    • 1
    • 8
  1. 1.Department of Pharmacy and PharmacologyAntoni van Leeuwenhoek – The Netherlands Cancer Institute and MC SlotervaartAmsterdamThe Netherlands
  2. 2.Division of Molecular PathologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Department of BiometricsAntoni van Leeuwenhoek – The Netherlands Cancer InstituteAmsterdamThe Netherlands
  4. 4.Moores Cancer CenterUniversity of California San DiegoSan DiegoUSA
  5. 5.Department of PathologyUniversity Medical CenterUtrechtThe Netherlands
  6. 6.Laboratory MedicineUniversity of CaliforniaSan FranciscoUSA
  7. 7.Department of Clinical PharmacyUniversity Medical Center UtrechtUtrechtThe Netherlands
  8. 8.Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical PharmacologyUtrecht UniversityUtrechtThe Netherlands

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