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

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

doi:10.1002/1878-0261.12865

Abstract

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≤3.26nm (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, >8.13nm) 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.

Highlights

Endocrine therapy is indicated for estrogen receptor (ER)-positive breast cancer (BC) patients to attenuate the cell supportive effect of estrogens and prevent growth of residual micro-metastatic disease after surgery
We aimed to provide further evidence on the association between impaired tamoxifen metabolism and BC outcome by confirming the predictive effect of our previously determined therapeutic concentration thresholds for Z-4OHtam (3.26 nM) and Z-endoxifen (9 nM) in an independent patient cohort
We selected the ‘tamoxifen-only’ patient group in order to study the tamoxifen metabolite effect on clinical outcome without potential influence from later change in endocrine treatment from tamoxifen to an aromatase inhibitor. This a priori determined subgroup had similar stage characteristics as the patients included in the learning set in which our thresholds were identified [17]

Summary

Introduction

Endocrine therapy is indicated for estrogen receptor (ER)-positive breast cancer (BC) patients to attenuate the cell supportive effect of estrogens and prevent growth of residual micro-metastatic disease after surgery. This can be achieved by mitigated production of estrogens by aromatase inhibitors in postmenopausal women or by inhibiting ER transcriptional activity by the use of selective ER modulators like tamoxifen in premenopausal women. Adjuvant treatment with tamoxifen for 5 years significantly improves outcomes for women with ER-positive BC [2], and extending the treatment time to 10 years adds additional outcome benefits [3]. Metabolic resistance may be an additional mechanism of resistance to tamoxifen

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