title: A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low-dose tamoxifen.
abstract: Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with 'study' as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16-0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman's hormonal context and CYP2D6 genotype are warranted.
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy. harriet.johansson@ieo.it.
authors.forename: Harriet
authors.identifier: 0000-0002-4131-2030
authors.initials: H
authors.lastname: Johansson
authors.affiliation: Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gandini
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Serrano
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gjerde
authors.affiliation: Medical Systems S.p.A., Genoa, Italy.
authors.forename: Monia
authors.initials: M
authors.lastname: Lattanzi
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Macis
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Aliana
authors.initials: A
authors.lastname: Guerrieri-Gonzaga
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Aristarco
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Mellgren
authors.affiliation: Department of Clinical Science, University of Bergen, Bergen, Norway.|Hormone Laboratory, Haukeland University Hospital, Bergen, Norway.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lien
authors.affiliation: Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy.|Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: DeCensi
authors.affiliation: Division of Cancer Prevention and Genetics, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Bonanni
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001943:Breast Neoplasms / Q000235:genetics / Q000517:prevention & control*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; C583557:IGF1 protein, human; D013629:Tamoxifen; D007334:Insulin-Like Growth Factor I; D019389:Cytochrome P-450 CYP2D6
keywords: Biomarkers; Breast cancer; CYP2D6; IGF-I; Pharmacogenetics; Prevention; Tamoxifen