Research Papers:
Variations in plasma concentrations of tamoxifen metabolites and the effects of genetic polymorphisms on tamoxifen metabolism in Korean patients with breast cancer
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Abstract
Hye In Woo1,*, Se Kyung Lee2,*, Jiyoung Kim3, Seok Won Kim2, Jonghan Yu2, Soo Youn Bae4, Jeong Eon Lee2, Seok Jin Nam2,** and Soo-Youn Lee5,6,**
1Department of Laboratory Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
2Division of Breast Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
3Department of Surgery, Jeju National University School of Medicine, Jeju National University Hospital, Jeju, Korea
4Division of Breast and Endocrine Surgery, Department of Surgery, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
5Department of Clinical Pharmacology & Therapeutics, Samsung Medical Center, Seoul, Korea
6Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
*Co-primary authors
**These authors contributed equally to this work
Correspondence to:
Seok Jin Nam, email: [email protected]
Soo-Youn Lee, email: [email protected]
Keywords: tamoxifen; metabolite; drug monitoring; genotype; variation
Received: April 28, 2017 Accepted: October 12, 2017 Published: November 01, 2017
ABSTRACT
Inter-individual variation in tamoxifen metabolism in breast cancer patients is caused by various genetic and clinical factors. We measured the plasma concentrations of tamoxifen and its metabolites and investigated genetic polymorphisms influencing those concentrations. We measured the concentrations of tamoxifen, endoxifen, N-desmethyltamoxifen (NDM), and 4-hydroxytamoxifen (4-OH tamoxifen) in 550 plasma specimens from 281 breast cancer patients treated with tamoxifen. Duplicate or triplicate specimens were obtained from 179 patients at 3-month intervals. In 80 patients, genotyping for tamoxifen metabolizing enzymes was performed using the DMET Plus array and long-range PCR. Plasma concentrations of tamoxifen and its metabolites showed wide variations among patients. The following genetic polymorphisms were associated with the plasma concentrations when body mass index and tamoxifen concentrations were considered as co-variables: CYP1A2 -2467delT, CYP2B6 genotype, CYP2D6 activity score (AS), and FMO3 441C>T. CYP2D6 AS and three variants in the SULT1E1 gene showed correlation with ratios of tamoxifen metabolites. CYP2D6 AS was the only variable that showed associations with both metabolite concentration and ratio: endoxifen (P < 0.001), NDM (P < 0.001), endoxifen/NDM (P < 0.001), NDM/tamoxifen (P < 0.001), and 4-OH tamoxifen/tamoxifen (P = 0.005). Serial measurements of 448 plasma concentrations in 179 patients at 3-month intervals showed wide intra-individual variation. Our study showed that genetic polymorphisms can in part determine the baseline concentrations of tamoxifen and its metabolites. However, marked intra-individual variations during follow-up monitoring were observed, and this could not be explained by genotype. Therefore, serial measurements of tamoxifen and its metabolites would be helpful in monitoring in vivo tamoxifen metabolic status.
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