Meta-Analysis

. 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

M A Province¹, M P Goetz², H Brauch³, D A Flockhart⁴, J M Hebert⁵, R Whaley⁵, V J Suman⁶, W Schroth³, S Winter³, H Zembutsu⁷, T Mushiroda⁸, W G Newman⁹, M-T M Lee¹⁰, C B Ambrosone¹¹, M W Beckmann¹², J-Y Choi¹³, A-S Dieudonné¹⁴, P A Fasching¹⁵, R Ferraldeschi⁹, L Gong⁵, E Haschke-Becher¹⁶, A Howell¹⁷, L B Jordan¹⁸, U Hamann¹⁹, K Kiyotani⁸, P Krippl²⁰, D Lambrechts²¹, A Latif⁹, U Langsenlehner²⁰, W Lorizio²², P Neven²³, A T Nguyen⁴, B-W Park²⁴, C A Purdie¹⁸, P Quinlan²⁵, W Renner²⁰, M Schmidt²⁶, M Schwab²⁷, J-G Shin²⁸, J C Stingl²⁹, P Wegman³⁰, S Wingren³⁰, A H B Wu³¹, E Ziv²², G Zirpoli¹¹, A M Thompson²⁵, V C Jordan³², Y Nakamura⁷, R B Altman³³, M M Ames³⁴, R M Weinshilboum³⁴, M Eichelbaum³, J N Ingle³⁵, T E Klein⁵; International Tamoxifen Pharmacogenomics Consortium

Collaborators, Affiliations

Collaborators

International Tamoxifen Pharmacogenomics Consortium:
Ute Hamann, Julia Boländer, Hans-Ulrich Ulmer, Hiltrud Brauch, Werner Schroth, Matthias Schwab, Stefan Winter, Michel Eichelbaum, Peter Fritz, Wolfgang Simon, Julia C Stingl, David A Flockhart, Anne T Nguyen, Jae-Gook Shin, Ji-Yeob Choi, Matthew P Goetz, James N Ingle, Vera J Suman, Richard M Weinshilboum, Colin A Purdie, Lee B Jordan, Pia Wegman, Hitoshi Zembutsu, Taisei Mushiroda, Kazuma Kiyotani, Christine B Ambrosone, Peter A Fasching, Reiner Strick, Matthias W Beckmann, Patrick Neven, Anne-Sophie Dieudonné, Peter A Fasching, Reiner Strick, Matthias W Beckmann, Patrick Neven, Elisabeth Haschke-Becher, Alan H B Wu, Wendy Lorizio, Elad Ziv, Philip Quinlan, Lee B Jordan, Colin A Purdie, Marcus Schmidt, Heinz Koelbl, William G Newman, Roberta Ferraldeschi, Anthony Howell, Ayse Latif, Byeong-Woo Park, Vera J Suman, Teri E Klein, Ryan Whaley, Michael A Province, Teri E Klein, Ryan Whaley, Joan M Hebert, Li Gong, Russ B Altman, Teri E Klein, Christine A Ambrosone, Hiltrud Brauch, Jae-Gook Shin, Matthew P Goetz, William G Newman, Patrick Neven, Alastair M Thompson, Sten Wingren, Hitoshi Zembutsu, Elad Ziv, Russ B Altman, Hiltrud Brauch, Michel Eichelbaum, David A Flockhart, Matthew P Goetz, James N Ingle, V Craig Jordan, Teri E Klein, Kent Osborne, Yusuke Nakamura, Richard M Weinshilboum

Affiliations

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.

PMID: 24060820
PMCID: PMC3904554
DOI: 10.1038/clpt.2013.186

Meta-Analysis

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

M A Province et al. Clin Pharmacol Ther. 2014 Feb.

. 2014 Feb;95(2):216-27.

doi: 10.1038/clpt.2013.186. Epub 2013 Sep 23.

Authors

Collaborators

International Tamoxifen Pharmacogenomics Consortium:
Ute Hamann, Julia Boländer, Hans-Ulrich Ulmer, Hiltrud Brauch, Werner Schroth, Matthias Schwab, Stefan Winter, Michel Eichelbaum, Peter Fritz, Wolfgang Simon, Julia C Stingl, David A Flockhart, Anne T Nguyen, Jae-Gook Shin, Ji-Yeob Choi, Matthew P Goetz, James N Ingle, Vera J Suman, Richard M Weinshilboum, Colin A Purdie, Lee B Jordan, Pia Wegman, Hitoshi Zembutsu, Taisei Mushiroda, Kazuma Kiyotani, Christine B Ambrosone, Peter A Fasching, Reiner Strick, Matthias W Beckmann, Patrick Neven, Anne-Sophie Dieudonné, Peter A Fasching, Reiner Strick, Matthias W Beckmann, Patrick Neven, Elisabeth Haschke-Becher, Alan H B Wu, Wendy Lorizio, Elad Ziv, Philip Quinlan, Lee B Jordan, Colin A Purdie, Marcus Schmidt, Heinz Koelbl, William G Newman, Roberta Ferraldeschi, Anthony Howell, Ayse Latif, Byeong-Woo Park, Vera J Suman, Teri E Klein, Ryan Whaley, Michael A Province, Teri E Klein, Ryan Whaley, Joan M Hebert, Li Gong, Russ B Altman, Teri E Klein, Christine A Ambrosone, Hiltrud Brauch, Jae-Gook Shin, Matthew P Goetz, William G Newman, Patrick Neven, Alastair M Thompson, Sten Wingren, Hitoshi Zembutsu, Elad Ziv, Russ B Altman, Hiltrud Brauch, Michel Eichelbaum, David A Flockhart, Matthew P Goetz, James N Ingle, V Craig Jordan, Teri E Klein, Kent Osborne, Yusuke Nakamura, Richard M Weinshilboum

Affiliations

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.

PMID: 24060820
PMCID: PMC3904554
DOI: 10.1038/clpt.2013.186

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.

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Figures

**Figure 1**
Individual site estimates of hazard ratios of *CYP2D6* genotype on clinical outcome, along with the meta-analyses for the criterion 1 subset. (a) Invasive disease–free survival (IDFS) outcome. (b) Breast cancer–free interval (BCFI) outcome.

**Figure 2**
Site-specific effects of CYP2D6 metabolizer status on clinical outcomes for subjects meeting inclusion criterion 1 (outcome = invasive disease–free survival (IDFS)).

**Figure 3**
Site-specific effects of CYP2D6 metabolizer status on clinical outcomes for subjects meeting inclusion criterion 1 (outcome = breast cancer–free interval (BCFI)).

See this image and copyright information in PMC

Comment in

CYP2D6 genotype and adjuvant tamoxifen.
Berry DA. Berry DA. Clin Pharmacol Ther. 2014 Aug;96(2):138-40. doi: 10.1038/clpt.2014.96. Clin Pharmacol Ther. 2014. PMID: 25056391 No abstract available.

References

1. Jordan V.C. Tamoxifen: a most unlikely pioneering medicine. Nat. Rev. Drug Discov. 2003;2:205–213. - PubMed
1. Davies C., et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771–784. - PMC - PubMed
1. Johnson M.D., et al. Pharmacological characterization of 4-hydroxy-N-desmethyl tamoxifen, a novel active metabolite of tamoxifen. Breast Cancer Res. Treat. 2004;85:151–159. - PubMed
1. Stearns V., et al. Active tamoxifen metabolite plasma concentrations after coadministration of tamoxifen and the selective serotonin reuptake inhibitor paroxetine. J. Natl. Cancer Inst. 2003;95:1758–1764. - PubMed
1. Goetz M.P., Berry D.A., Klein T.E. 31136 Findings from the International Tamoxifen Pharmacogenomics Consortium. Proceedings of the San Antonio Breast Cancer Symposium, San Antonio, Texas. 9–13 December. 2009. Abstract 33

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

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

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