J Natl Cancer Inst. 2012 Mar 6. [Epub ahead of print]
CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial.
Regan MM, Leyland-Jones B, Bouzyk M, Pagani O, Tang W, Kammler R, Dell'orto P, Biasi MO, Thürlimann B, Lyng MB, Ditzel HJ, Neven P, Debled M, Maibach R, Price KN, Gelber RD, Coates AS, Goldhirsch A, Rae JM, Viale G; on behalf of the Breast International Group (BIG) 1-98 Collaborative Group.
SourceAffiliations of authors: International Breast Cancer Study Group (IBCSG) Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA (MMR, RDG, KNP); Harvard School of Public Health and Harvard Medical School, Boston, MA (MMR, RDG); Emory University School of Medicine, Atlanta, GA (BL-J); Formerly of Emory University School of Medicine, Atlanta, GA (MB); AKESOgen, Inc, Atlanta, GA (MB); Institute of Oncology of Southern Switzerland, Viganello, Switzerland (OP); Department of Medical Oncology/Clinical Research, Ospedale Italiano, Viganello, Switzerland (OP); Swiss Group for Clinical Cancer Research, Bern, Switzerland (OP, BT); Formerly of Emory Biomarker Service Center, Emory University Winship Cancer Institute, Atlanta, GA (WT); Omega Bio-tek, Inc, Norcross, GA (WT); IBCSG Coordinating Center, Bern, Switzerland (RK, RM); IBCSG Central Pathology Office, Bern, Switzerland (RK); IBCSG Central Pathology Office, Milan, Italy (PD'O, GV); Division of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy (PD'O, MOB, GV); Breast Center, Kantonsspital, St Gallen, Switzerland (BT); Department of Cancer and Inflammation, institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark (MBL, HJD); Danish Breast Cancer Cooperative Group, Copenhagen, Denmark (MBL, HJD); Department of Oncology, Odense University Hospital, Odense, Denmark (HD); Multidisciplinary Breast Unit, Department of Gynecologic Oncology, UZ Leuven, Belgium (PN); Department of Medical Oncology, Institut Bergonié, South-West Comprehensive Cancer Center, Bordeaux, France (MD); Frontier Science and Technology Research Foundation, Boston, MA (KNP, RDG); IBCSG, Sydney, Australia (ASC); School of Public Health, University of Sydney, Sydney, Australia (ASC); Department of Medicine, European Institute of Oncology, Milan, Italy (AG); Swiss Center for Breast Health, Sant'Anna Clinics, Lugano-Sorengo, Switzerland (AG); Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI (JMR); University of Milan, Milan, Italy (GV).
AbstractBackgroundAdjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms.MethodsWe obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor-positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction-based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.ResultsNo association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43).ConclusionsCYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen.
- [PubMed - as supplied by publisher]