Molecular Oncology (Apr 2021)

Low Z‐4OHtam concentrations are associated with adverse clinical outcome among early stage premenopausal breast cancer patients treated with adjuvant tamoxifen

  • Thomas Helland,
  • Bjørn Naume,
  • Steinar Hustad,
  • Ersilia Bifulco,
  • Jan Terje Kvaløy,
  • Anna Barbro Sætersdal,
  • Marit Synnestvedt,
  • Tone Hoel Lende,
  • Bjørnar Gilje,
  • Ingvil Mjaaland,
  • Kjetil Weyde,
  • Egil Støre Blix,
  • Gro Wiedswang,
  • Elin Borgen,
  • Daniel Louis Hertz,
  • Emiel Adrianus Maria Janssen,
  • Gunnar Mellgren,
  • Håvard Søiland

DOI
https://doi.org/10.1002/1878-0261.12865
Journal volume & issue
Vol. 15, no. 4
pp. 957 – 967

Abstract

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Low steady‐state levels of active tamoxifen metabolites have been associated with inferior treatment outcomes. In this retrospective analysis of 406 estrogen receptor‐positive breast cancer (BC) patients receiving adjuvant tamoxifen as initial treatment, we have associated our previously reported thresholds for the two active metabolites, Z‐endoxifen and Z‐4‐hydroxy‐tamoxifen (Z‐4OHtam), with treatment outcomes in an independent cohort of BC patients. Among all patients, metabolite levels did not affect survival. However, in the premenopausal subgroup receiving tamoxifen alone (n = 191) we confirmed an inferior BC ‐specific survival in patients with the previously described serum concentration threshold of Z‐4OHtam ≤ 3.26 nm (HR = 2.37, 95% CI = 1.02–5.48, P = 0.039). The ‘dose–response’ survival trend in patients categorized to ordinal concentration cut‐points of Z‐4OHtamoxifen (≤ 3.26, 3.27–8.13, > 8.13 nm) was also replicated (P‐trend log‐rank = 0.048). Z‐endoxifen was not associated with outcome. This is the first study to confirm the association between a published active tamoxifen metabolite threshold and BC outcome in an independent patient cohort. Premenopausal patients receiving 5‐year of tamoxifen alone may benefit from therapeutic drug monitoring to ensure tamoxifen effectiveness.

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