Clin Pharmacol Ther. 2014 Feb;95(2):216-27. doi: 10.1038/clpt.2013.186. Epub 2013 Sep 23.

CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.

Province MA¹, Goetz MP², Brauch H³, Flockhart DA⁴, Hebert JM⁵, Whaley R⁵, Suman VJ⁶, Schroth W³, Winter S³, Zembutsu H⁷, Mushiroda T⁸, Newman WG⁹, Lee MT¹⁰, Ambrosone CB¹¹, Beckmann MW¹², Choi JY¹³, Dieudonné AS¹⁴, Fasching PA¹⁵, Ferraldeschi R⁹, Gong L⁵, Haschke-Becher E¹⁶, Howell A¹⁷, Jordan LB¹⁸, Hamann U¹⁹, Kiyotani K⁸, Krippl P²⁰, Lambrechts D²¹, Latif A⁹, Langsenlehner U²⁰, Lorizio W²², Neven P²³, Nguyen AT⁴, Park BW²⁴, Purdie CA¹⁸, Quinlan P²⁵, Renner W²⁰, Schmidt M²⁶, Schwab M²⁷, Shin JG²⁸, Stingl JC²⁹, Wegman P³⁰, Wingren S³⁰, Wu AH³¹, Ziv E²², Zirpoli G¹¹, Thompson AM²⁵, Jordan VC³², Nakamura Y⁷, Altman RB³³, Ames MM³⁴, Weinshilboum RM³⁴, Eichelbaum M³, Ingle JN³⁵, Klein TE⁵; International Tamoxifen Pharmacogenomics Consortium.

Collaborators (80)

Hamann U, Boländer J, Ulmer HU, Brauch H, Schroth W, Schwab M, Winter S, Eichelbaum M, Fritz P, Simon W, Stingl JC, Flockhart DA, Nguyen AT, Shin JG, Choi JY, Goetz MP, Ingle JN, Suman VJ, Weinshilboum RM, Purdie CA, Jordan LB, Wegman P, Zembutsu H, Mushiroda T, Kiyotani K, Ambrosone CB, Fasching PA, Strick R, Beckmann MW, Neven P, Dieudonné AS, Fasching PA, Strick R, Beckmann MW, Neven P, Haschke-Becher E, Wu AH, Lorizio W, Ziv E, Quinlan P, Jordan LB, Purdie CA, Schmidt M, Koelbl H, Newman WG, Ferraldeschi R, Howell A, Latif A, Park BW, Suman VJ, Klein TE, Whaley R, Province MA, Klein TE, Whaley R, Hebert JM, Gong L, Altman RB, Klein TE, Ambrosone CA, Brauch H, Shin JG, Goetz MP, Newman WG, Neven P, Thompson AM, Wingren S, Zembutsu H, Ziv E, Altman RB, Brauch H, Eichelbaum M, Flockhart DA, Goetz MP, Ingle JN, Jordan VC, Klein TE, Osborne K, Nakamura Y, Weinshilboum RM.

Author information

1: Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
2: Department of Oncology and Pharmacology, Mayo Clinic, Rochester, Minnesota, USA.
3: Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University, Tuebingen, Germany.
4: Division of Clinical Pharmacology, School of Medicine, Indiana University, Bloomington, Indiana, USA.
5: Department of Genetics, School of Medicine, Stanford University, Stanford, California, USA.
6: Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
7: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
8: Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama, Japan.
9: Centre for Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
10: Laboratory for International Alliance, RIKEN Center for Genomic Medicine, Yokohama, Japan.
11: Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
12: Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
13: Department of Biomedical Science, Graduate School, Seoul National University, Seoul, Korea.
14: Department of Oncology, Catholic University Leuven, Leuven, Belgium.
15: 1] Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany [2] Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA.
16: University Institute of Medical and Chemical Laboratory Diagnostics, Paracelsus Private Medical University, Salzburg, Austria.
17: The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
18: Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK.
19: Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
20: Medical University Graz, Graz, Austria.
21: Vesalius Research Center, VIB and Laboratory of Translational Genetics, Department of Oncology, Catholic University Leuven, Leuven, Belgium.
22: Division of General Internal Medicine, Department of Medicine and Clinical Pharmacology and Experimental Therapeutics, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.
23: Department of Gynecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.
24: Department of Surgery, Yonsei University Health System, Seoul, Korea.
25: Dundee Cancer Centre, Dundee, UK.
26: 1] Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University, Tuebingen, Germany [2] Department of Gynecology and Obstetrics, University of Mainz, Mainz, Germany.
27: Department of Clinical Pharmacology and Toxicology, University Hospital Tuebingen, Tuebingen, Germany.
28: 1] Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Korea [2] Department of Clinical Pharmacology, Inje University Busan Paik Hospital, Busan, Korea.
29: Division of Research, Federal Institute for Drugs and Medical Devices, University of Bonn Medical Faculty, Bonn, Germany.
30: Department of Clinical Medicine, Ö rebro University, Örebro, Sweden.
31: Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
32: Department of Oncology, Georgetown University, Washington, DC, USA.
33: 1] Department of Genetics, School of Medicine, Stanford University, Stanford, California, USA [2] Department of Bioengineering, Stanford University, Stanford, California, USA.
34: Department of Pharmacology, Mayo Clinic, Rochester, Minnesota, USA.
35: Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.

Abstract

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.