CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations.
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.
Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, Missouri, USA.
M A
MA
Province
Department of Oncology and Pharmacology, Mayo Clinic, Rochester, Minnesota, USA.
M P
MP
Goetz
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University, Tuebingen, Germany.
H
H
Brauch
Division of Clinical Pharmacology, School of Medicine, Indiana University, Bloomington, Indiana, USA.
D A
DA
Flockhart
Department of Genetics, School of Medicine, Stanford University, Stanford, California, USA.
J M
JM
Hebert
Department of Genetics, School of Medicine, Stanford University, Stanford, California, USA.
R
R
Whaley
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
V J
VJ
Suman
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University, Tuebingen, Germany.
W
W
Schroth
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University, Tuebingen, Germany.
S
S
Winter
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
H
H
Zembutsu
Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama, Japan.
T
T
Mushiroda
Centre for Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
W G
WG
Newman
Laboratory for International Alliance, RIKEN Center for Genomic Medicine, Yokohama, Japan.
M-T M
MT
Lee
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
C B
CB
Ambrosone
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
M W
MW
Beckmann
Department of Biomedical Science, Graduate School, Seoul National University, Seoul, Korea.
J-Y
JY
Choi
Department of Oncology, Catholic University Leuven, Leuven, Belgium.
A-S
AS
Dieudonné
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.
P A
PA
Fasching
Centre for Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
R
R
Ferraldeschi
Department of Genetics, School of Medicine, Stanford University, Stanford, California, USA.
L
L
Gong
University Institute of Medical and Chemical Laboratory Diagnostics, Paracelsus Private Medical University, Salzburg, Austria.
E
E
Haschke-Becher
The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
A
A
Howell
Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK.
L B
LB
Jordan
Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
U
U
Hamann
Laboratory for Pharmacogenetics, RIKEN Center for Genomic Medicine, Yokohama, Japan.
K
K
Kiyotani
Medical University Graz, Graz, Austria.
P
P
Krippl
Vesalius Research Center, VIB and Laboratory of Translational Genetics, Department of Oncology, Catholic University Leuven, Leuven, Belgium.
D
D
Lambrechts
Centre for Genetic Medicine, Manchester Academic Health Science Centre, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
A
A
Latif
Medical University Graz, Graz, Austria.
U
U
Langsenlehner
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.
W
W
Lorizio
Department of Gynecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.
P
P
Neven
Division of Clinical Pharmacology, School of Medicine, Indiana University, Bloomington, Indiana, USA.
A T
AT
Nguyen
Department of Surgery, Yonsei University Health System, Seoul, Korea.
B-W
BW
Park
Department of Pathology, Ninewells Hospital and Medical School, Dundee, UK.
C A
CA
Purdie
Dundee Cancer Centre, Dundee, UK.
P
P
Quinlan
Medical University Graz, Graz, Austria.
W
W
Renner
1] Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University, Tuebingen, Germany [2] Department of Gynecology and Obstetrics, University of Mainz, Mainz, Germany.
M
M
Schmidt
Department of Clinical Pharmacology and Toxicology, University Hospital Tuebingen, Tuebingen, Germany.
M
M
Schwab
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.
J-G
JG
Shin
Division of Research, Federal Institute for Drugs and Medical Devices, University of Bonn Medical Faculty, Bonn, Germany.
J C
JC
Stingl
Department of Clinical Medicine, Ö rebro University, Örebro, Sweden.
P
P
Wegman
Department of Clinical Medicine, Ö rebro University, Örebro, Sweden.
S
S
Wingren
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA.
A H B
AH
Wu
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.
E
E
Ziv
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York, USA.
G
G
Zirpoli
Dundee Cancer Centre, Dundee, UK.
A M
AM
Thompson
Department of Oncology, Georgetown University, Washington, DC, USA.
V C
VC
Jordan
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Y
Y
Nakamura
1] Department of Genetics, School of Medicine, Stanford University, Stanford, California, USA [2] Department of Bioengineering, Stanford University, Stanford, California, USA.
R B
RB
Altman
Department of Pharmacology, Mayo Clinic, Rochester, Minnesota, USA.
M M
MM
Ames
Department of Pharmacology, Mayo Clinic, Rochester, Minnesota, USA.
R M
RM
Weinshilboum
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology and University, Tuebingen, Germany.
M
M
Eichelbaum
Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA.
J N
JN
Ingle
Department of Genetics, School of Medicine, Stanford University, Stanford, California, USA.
T E
TE
Klein
D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D016019:Survival Analysis; D013629:Tamoxifen / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6