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CYP2D6 Genotypes, Endoxifen Levels, and Clinical Outcome in Early-Stage Breast Cancer Treated With Adjuvant Tamoxifen

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Key Points

  • Endoxifen concentrations were not associated with relapse-free survival during tamoxifen treatment.
  • No association of outcome with CYP2D6 genotype was observed.

In a Dutch-Belgian study (CYPTAM) reported in the Journal of Clinical Oncology, Sanchez-Spitman et al found no associations between CYP2D6 genotypes or levels of endoxifen (active metabolite of tamoxifen) and clinical outcomes in patients receiving adjuvant tamoxifen for early-stage breast cancer. CYP2D6 is considered the rate-limiting enzyme of the conversion of N-desmethyl-tamoxifen into endoxifen. Some evidence has suggested that concentrations of endoxifen are a better predictor of tamoxifen efficacy than CYP2D6 genotypes.

Study Details

The prospective study enrolled 667 pre- and postmenopausal women who were receiving adjuvant tamoxifen at sites in the Netherlands and Belgium between February 2008 and December 2010. Patients could be enrolled up to a maximum of 12 months after tamoxifen initiation.

Blood samples were obtained for CYP2D6 genotyping and endoxifen measurements. Endoxifen concentrations were analyzed as a continuous variable, with patients classified into quartiles, and by using an endoxifen threshold of 5.9 ng/mL. Endoxifen concentrations and CYP2D6 genotypes were analyzed for associated relapse-free survival (censored at the time of tamoxifen discontinuation; RFSt). CYP2D6 genotypes were classified as ultrarapid metabolizer (UM), extensive metabolizer (EM), heterozygous extensive metabolizer (hetEM), intermediate metabolizer (IM), and poor metabolizer (PM).

Associations With Relapse-Free Survival

Patients had received tamoxifen for a median of 0.37 years prior to study entry. Median follow-up was 6.4 years, and median duration of tamoxifen therapy was 2.5 years. On multivariate analysis, no significant association was found between RFSt and endoxifen concentrations as a continuous variable (adjusted hazard ratio [HR] = 0.991, P = .691), when a threshold level of 5.9 ng/mL was used (adjusted HR = 1.538, P = .267), or when levels were analyzed by quartile (overall P = .271). On multivariate analysis, no significant association was observed in RFSt for CYP2D6 genotypes of UM/EM vs hetEM/IM/PM (adjusted HR = 0.929, P = .799).

The investigators concluded, “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.”

Henk-Jan Guchelaar, PharmD, PhD, of the Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by ZOLEON (Stichting Oncologie HollandWest). The study authors' full disclosures can be found at jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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