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Annals of Oncology Advance Access originally published online on October 18, 2007
Annals of Oncology 2008 19(1):56-61; doi:10.1093/annonc/mdm434
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© 2007 European Society for Medical Oncology. For Permissions, please email: journals.permissions@oxfordjournals.org

breast cancer

Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism

J. Gjerde1,2, M. Hauglid2, H. Breilid3,4, S. Lundgren5,6, J. E. Varhaug7, E. R. Kisanga2, G. Mellgren1,2, V. M. Steen3,4 and E. A. Lien1,2,*

1 The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen
2 Section for Endocrinology, Institute of Medicine, University of Bergen, N-5021 Bergen
3 Dr E. Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, N-5021 Bergen
4 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen
5 Cancer Clinic, St Olavs University Hospital, N-7006 Trondheim
6 Department of Cancer Research and Molecular Medicine, Trondheim University Hospital, Norwegian University of Science and Technology, N-7006 Trondheim
7 Department of Surgery, Haukeland University Hospital, N-5021 Bergen, Norway

* Correspondence to: Dr E. A. Lien, Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway. Tel: +47-55-97-43-71; Fax: +47-55-97-58-14; E-mail: ernst.lien{at}med.uib.no

Background: Tamoxifen is hydroxylated by cytochrome P450 (CYP) 2D6 to the potent metabolites 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam), which are both conjugated by sulphotransferase (SULT)1A1. Clinical studies indicate that CYP2D6 and SULT1A1 genotypes are predictors for treatment response to tamoxifen. Therefore, we examined the relationship between CYP2D6 genotype, SULT1A1 genotype, SULT1A1 copy number and the pharmacokinetics of tamoxifen.

Patients and methods: The serum levels of tamoxifen and metabolites of 151 breast cancer patients were measured by high-pressure liquid chromatography–tandem mass spectrometry. The CYP2D6 and SULT1A1 polymorphisms and SULT1A1 copy number were determined by long PCR, PCR-based restriction fragment length polymorphism, DNA sequencing and fluorescence-based PCR.

Results: The levels of 4OHtam, 4OHNDtam and N-demethyltamoxifen were associated with CYP2D6 predicted enzymatic activity (P < 0.05). The SULT1A1 genotype or copy number did not influence the levels of tamoxifen and its metabolites. However, the ratios of N-demethyltamoxifen/tamoxifen and N-dedimethyltamoxifen/N-demethyltamoxifen were related to SULT1A1 genotype.

Conclusion: CYP2D6 and SULT1A1 genotypes may partly explain the wide inter-individual variations in the serum levels of tamoxifen and its metabolites. We propose that therapeutic drug monitoring should be included in studies linking CYP2D6 and SULT1A1 genotypes to clinical outcome.

Key words: breast cancer, CYP2D6, endoxifen, 4-OH-N-demethyltamoxifen, SULT1A1, tamoxifen

Received for publication July 5, 2007. Accepted for publication July 26, 2007.


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