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Werner Schroth, DPhil; Matthew P. Goetz, MD; Ute Hamann, DPhil; Peter A. Fasching, MD; Marcus Schmidt, MD; Stefan Winter, MS; Peter Fritz, MD; Wolfgang Simon, MD; Vera J. Suman, DPhil; Matthew M. Ames, DPhil; Stephanie L. Safgren, BS, MS; Mary J. Kuffel, BS; Hans Ulrich Ulmer, MD; Julia Boländer, MD; Reiner Strick, DPhil; Matthias W. Beckmann, MD; Heinz Koelbl, MD; Richard M. Weinshilboum, MD; James N. Ingle, MD; Michel Eichelbaum, MD; Matthias Schwab, MD; Hiltrud Brauch, DPhil

JAMA. 2009;302(13):1429-1436.

Context  The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor–positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme.

Objective  To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen.

Design, Setting, and Patients  Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n=609), heterozygous extensive/intermediate (n=637), or poor (n=79) CYP2D6 metabolism.

Main Outcome Measures  Time to recurrence, event-free survival, disease-free survival, and overall survival.

Results  Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and 29.0% for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04-1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10-3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06-1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03-1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88-1.51).

Conclusion  Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.

Author Affiliations: Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology (Drs Schroth, Fritz, Eichelbaum, Schwab, and Brauch and Mr Winter) and Robert Bosch Hospital (Dr Simon), Stuttgart, Germany; University of Tübingen (Drs Schroth, Fritz, Eichelbaum, Schwab, and Brauch and Mr Winter) and Department of Clinical Pharmacology, University Hospital Tübingen (Dr Schwab), Tübingen, Germany; Departments of Oncology (Drs Goetz and Ingle), Molecular Pharmacology and Experimental Pharmaceutics (Dr Goetz, Ames, and Weinshilboum and Mss Safgren and Kuffel), and Biostatistics (Dr Suman), Mayo Clinic, Rochester, Minnesota; Deutsches Krebsforschungszentrum, Heidelberg, Germany (Dr Hamann); University Breast Center Franconia, University Hospital Erlangen, Erlangen, Germany (Drs Fasching, Strick, and Beckmann); Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles (Dr Fasching); Department of Gynecology and Obstetrics, University of Mainz, Mainz, Germany (Drs Schmidt and Koelbl); and Frauenklinik, Städtisches Klinikum, Karlsruhe, Germany (Drs Ulmer and Boländer).

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CYP2D6 Polymorphisms and Response to Tamoxifen
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