This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lim, H.-S. Articles by Ro, J. Search for Related Content PubMed PubMed Citation Articles by Lim, H.-S. Articles by Ro, J. Related Articles Related Correspondence

Clinical Implications of CYP2D6 Genotypes Predictive of Tamoxifen Pharmacokinetics in Metastatic Breast Cancer

Hyeong-Seok Lim, Han Ju Lee, Keun Seok Lee, Eun Sook Lee, In-Jin Jang, Jungsil Ro

From the Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi; and Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea

Address reprint requests to Jungsil Ro, MD, Research Institute and Hospital, National Cancer Center, 809 Madu1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do, 411-769, Republic of Korea; e-mail: jungsro{at}ncc.re.kr

Purpose: The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer.

Patients and Methods: Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes.

Results: Patients carrying CYP2D6*10/*10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P < .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P < .0001), whereas no difference by PXR genotypes was found. CYP2D6*10/*10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D6*10/*10 than for others (5.0 v 21.8 months, P = .0032)

Conclusion: CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.

Supported by NCC Grants No. 0410590 and 0210150.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA, and the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Related Correspondence

• CYP2D6 and Ockham's Razor
  Francois Eisinger
  JCO 2008 26: 686-687 [Full Text]

This article has been cited by other articles:

				D. F. Hayes, V. Stearns, J. Rae, D. Flockhart, and on behalf of the Consortium on Breast Cancer Pharm A Model Citizen? Is Tamoxifen More Effective Than Aromatase Inhibitors if We Pick the Right Patients? J Natl Cancer Inst, May 7, 2008; 100(9): 610 - 613. [Full Text] [PDF]

				Z. Desta and D. A. Flockhart In Reply J. Clin. Oncol., April 1, 2008; 26(10): 1765 - 1766. [Full Text] [PDF]

				N. U. Lin and E. P. Winer Advances in Adjuvant Endocrine Therapy for Postmenopausal Women J. Clin. Oncol., February 10, 2008; 26(5): 798 - 805. [Abstract] [Full Text] [PDF]

				F. Eisinger CYP2D6 and Ockham's Razor J. Clin. Oncol., February 1, 2008; 26(4): 686 - 687. [Full Text] [PDF]

				Z. Desta and D. A. Flockhart Germline Pharmacogenetics of Tamoxifen Response: Have We Learned Enough? J. Clin. Oncol., November 20, 2007; 25(33): 5147 - 5149. [Full Text] [PDF]