title: An Antiestrogenic Activity Score for tamoxifen and its metabolites is associated with breast cancer outcome.
abstract: 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.
  
  
  
  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 IC50ratio, 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.
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek - The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. ah.d.vriesschultink@nki.nl.
authors.forename: A H M
authors.initials: AH
authors.lastname: de Vries Schultink
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: X
authors.initials: X
authors.lastname: Alexi
authors.affiliation: Department of Biometrics, Antoni van Leeuwenhoek - The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: van Werkhoven
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Madlensky
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Natarajan
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Flatt
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Zwart
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.|Department of Pathology, University Medical Center, Utrecht, The Netherlands.
authors.forename: S C
authors.initials: SC
authors.lastname: Linn
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Parker
authors.affiliation: Laboratory Medicine, University of California, San Francisco, CA, USA.
authors.forename: A H B
authors.initials: AH
authors.lastname: Wu
authors.affiliation: Moores Cancer Center, University of California San Diego, San Diego, CA, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Pierce
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek - The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.|Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: A D R
authors.initials: AD
authors.lastname: Huitema
authors.affiliation: Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek - The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.|Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism* / Q000401:mortality*; D004305:Dose-Response Relationship, Drug; D004965:Estrogen Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D053208:Kaplan-Meier Estimate; D011379:Prognosis; D016016:Proportional Hazards Models; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D013629:Tamoxifen
keywords: Algorithm; Metabolites; Recurrence-free survival; Tamoxifen