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. 2017 Nov 28;19(1):125.
doi: 10.1186/s13058-017-0916-4.

Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients

Thomas Helland  1   2 , Nina Henne  2   3 , Ersilia Bifulco  2   3 , Bjørn Naume  4   5 , Elin Borgen  6 , Vessela N Kristensen  7 , Jan T Kvaløy  8   9 , Timothy L Lash  10 , Grethe I G Alnæs  7 , Ron H van Schaik  11 , Emiel A M Janssen  8   12 , Steinar Hustad  2   3 , Ernst A Lien  1   2 , Gunnar Mellgren  1   2 , Håvard Søiland  13   14
Affiliations

Serum concentrations of active tamoxifen metabolites predict long-term survival in adjuvantly treated breast cancer patients

Thomas Helland et al. Breast Cancer Res. .

Abstract

Background: Controversies exist as to whether the genetic polymorphisms of the enzymes responsible for the metabolism of tamoxifen can predict breast cancer outcome in patients using adjuvant tamoxifen. Direct measurement of concentrations of active tamoxifen metabolites in serum may be a more biological plausible and robust approach. We have investigated the association between CYP2D6 genotypes, serum concentrations of active tamoxifen metabolites, and long-term outcome in tamoxifen treated breast cancer patients.

Methods: From an original observational study comprising 817 breast cancer patients, 99 women with operable breast cancer were retrospectively included in the present study. This cohort of patients were adjuvantly treated with tamoxifen, had provided serum samples suitable for measuring tamoxifen metabolites, and were relapse-free at 3 years after the primary treatment commenced. The median follow-up time from this entry point to breast cancer death was 13.9 years. Patients were CYP2D6 genotyped and grouped into four CYP2D6 phenotype groups (Ultra rapid, extensive, intermediate, and poor metabolizers). Tamoxifen and nine metabolites were quantified in serum (n = 86) and compared with CYP2D6 phenotype groups and outcome.

Results: Breast cancer patients with low concentrations of Z-4-hydroxy-tamoxifen (Z-4OHtam; ≤ 3.26 nM) had a breast cancer-specific survival (BCSS) of 60% compared to 84% in patients with Z-4OHtam concentrations > 3.26 nM (p = 0.020, log-rank hazard ratio (HR) = 3.56, 95% confidence interval (CI) = 1.14-11.07). For patients with Z-4-hydroxy-N-desmethyl-tamoxifen (Z-endoxifen) levels ≤ 9.00 nM BCSS was 57% compared to 84% for patients with concentrations > 9.00 nM (p = 0.029, HR = 3.73, 95% CI = 1.05-13.22). Low concentrations of Z-4OHtam and Z-endoxifen were associated with poorer survival also after adjusting for clinically relevant variables (HR = 4.27, 95% CI = 1.35-13.58, and HR = 3.70, 95% CI = 1.03-13.25, respectively). Overall survival analysis showed similar survival differences for both active metabolites. The Antiestrogen Activity Score showed comparable effects, but did not improve the prognostic information.

Conclusions: Patients with Z-4OHtam and Z-endoxifen concentrations lower than 3.26 nM or 9.00 nM, respectively, showed an adverse outcome. Our results suggest that direct measurement of active tamoxifen metabolite concentrations could be of clinical value. Validation in larger study cohorts is warranted.

Keywords: 4OHtam; Adjuvant; Breast cancer; CYP2D6; Endoxifen; Metabolism; Prognosis; Survival; Tamoxifen.

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Conflict of interest statement

Ethics approval and consent to participate

All participants have given written consent and the original OSLO1 study was approved by the Norwegian Regional Ethical Committee (2015/1216).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
MRM transitions of tamoxifen and its metabolites. The chromatograms are obtained by analyzing the second point of the calibration curve. The chromatographic separation of isomers of 4OHtam and endoxifen are shown in the lowest and second lowest panels, respectively. APPI atmospheric pressure photoionization, MRM multiple reaction monitoring
Fig. 2
Fig. 2
Z4OHtam and Z-endoxifen concentrations compared by CYP2D6 phenotype groups. Impaired CYP2D6 function correlates with lower levels of Z-4OHtam and Z-endoxifen (p = 0.05 and p <0.001, respectively; Kruskal-Wallis). Cut-off values representing patients with high levels (green line) and low levels (red line) of active metabolites are shown. EM extensive metabolizer, IM intermediate metabolizer, PM poor metabolizer, UM ultra-rapid metabolizer
Fig. 3
Fig. 3
Kaplan-Meier plot of BCSS for CYP2D6 phenotypes. Patients are grouped according to CYP2D6 phenotype group as indicated by the colored lines. Time starting at 3 years after surgery. EM extensive metabolizer, IM intermediate metabolizer, PM poor metabolizer, UM ultra-rapid metabolizer
Fig. 4
Fig. 4
Kaplan-Meier plots of BCSS and overall survival for concentrations of active tamoxifen metabolites. Patients are grouped according to concentrations of active metabolites as indicated by colored lines. Time starting at 3 years after surgery. a,b BCSS for Z-4OHtam and Z-endoxifen at concentrations above and below 3.26 nM and 9.00 nM, respectively. c,d BCSS for Z-4OHtam and Z-endoxifen at three serum concentrations: low, intermediate, and high levels, as shown in the figure. e,f Overall survival for Z-4OHtam and Z-endoxifen at the same three concentrations as shown in c and d. HR hazard ratio
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