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J Clin Oncol. 2019 Mar 10;37(8):636-646. doi: 10.1200/JCO.18.00307. Epub 2019 Jan 24.

Tamoxifen Pharmacogenetics and Metabolism: Results From the Prospective CYPTAM Study.

Author information

1
1 Leiden University Medical Center, Leiden, the Netherlands.
2
2 Netherlands Cancer Institute/Antoni van Leeuwenhoek, Amsterdam, the Netherlands.
3
3 Alrijne Leiden, Leiden, the Netherlands.
4
4 Reinier de Graaf Gasthuis, Delft, the Netherlands.
5
5 Medical Center Alkmaar, Alkmaar, the Netherlands.
6
6 Zaans Medisch Centrum, Zaandam, the Netherlands.
7
7 Alrijne Leiderdorp, Leiderdorp, the Netherlands.
8
8 Katholieke Universiteit Leuven, Leuven, Belgium.
9
9 St Antonius Ziekenhuis, Nieuwegein, the Netherlands.
10
10 University Hospitals Leuven, Leuven, Belgium.

Abstract

PURPOSE:

Tamoxifen is widely prescribed as adjuvant therapy in patients with early-stage breast cancer. It has been postulated that concentrations of endoxifen, the active metabolite of tamoxifen, are a better predictor of tamoxifen efficacy than CYP2D6 genotypes. Although in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy was described, confirmation based on prospective studies is lacking. The objective of the prospective CYPTAM (The Netherlands National Trial Register: NTR1509) study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome in patients with early-stage breast cancer receiving tamoxifen.

PATIENTS AND METHODS:

From February 2008 to December 2010, patients with breast cancer treated with adjuvant tamoxifen were included. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation. Blood samples were retrieved for CYP2D6 genotyping and endoxifen measurements by Amplichip (Roche Diagnostics, Indianapolis, IN) and high-performance liquid chromatography-tandem mass spectrometry, respectively. Endoxifen concentrations were analyzed as a continuous variable, classifying patients into quartiles and using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were associated with relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt) by Cox regression analysis.

RESULTS:

A total of 667 pre- and postmenopausal patients were enrolled and had received tamoxifen for a median time of 0.37 years (range, 0.23 to 0.6 years) before study entry. No association was found between endoxifen concentrations and RFSt (adjusted hazard ratio, 0.991; 95% CI, 0.946 to 1.038; P = .691). Also, neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results. In addition, no association was found between CYP2D6 genotype and RFSt (adjusted hazard ratio, 0.929; 95% CI, 0.525 to 1.642; P = .799).

CONCLUSION:

This prospective clinical study shows no association between endoxifen concentrations or CYP2D6 genotypes and clinical outcome in patients with early-stage breast cancer receiving adjuvant tamoxifen.

PMID:
30676859
DOI:
10.1200/JCO.18.00307

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