title: Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy.
abstract: The association between CYP2D6 genotype and outcome in breast cancer patients treated with adjuvant tamoxifen remains controversial. We assessed the influence of comprehensive versus limited CYP2D6 genotype in the context of tamoxifen adherence and co-medication in a large cohort of 618 patients. Genotyping of 33 CYP2D6 alleles used two archival cohorts from tamoxifen-treated women with invasive breast cancer (Dundee, n = 391; Manchester, n = 227). Estimates for recurrence-free survival (RFS) were calculated based on inferred CYP2D6 phenotypes using Kaplan-Meier and Cox proportional hazard models, adjusted for nodal status and tumour size. Patients with at least one reduced function CYP2D6 allele (60%) or no functional alleles (6%) had a non-significant trend for worse RFS: hazard ratio (HR) 1.52 (CI 0.98-2.36, P = 0.06). For post-menopausal women on tamoxifen monotherapy, the HR for recurrence in patients with reduced functional alleles was 1.96 (CI 1.05-3.66, P = 0.036). However, RFS analysis limited to four common CYP2D6 allelic variants was no longer significant (P = 0.39). The effect of CYP2D6 genotype was increased by adjusting for adherence to tamoxifen therapy, but not significantly changed when adjusted for co-administration of potent inhibitors of CYP2D6. Comprehensive genotyping of CYP2D6 and adherence to tamoxifen therapy may be useful to identify breast cancer patients most likely to benefit from adjuvant tamoxifen.
authors.affiliation: Department of Surgery and Molecular Oncology, University of Dundee, Dundee DD1 9SY, UK. a.m.thompson@dundee.ac.uk
authors.forename: Alastair M
authors.initials: AM
authors.lastname: Thompson
authors.forename: Andrea
authors.initials: A
authors.lastname: Johnson
authors.forename: Philip
authors.initials: P
authors.lastname: Quinlan
authors.forename: Grantland
authors.initials: G
authors.lastname: Hillman
authors.forename: Marcel
authors.initials: M
authors.lastname: Fontecha
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bray
authors.forename: Colin A
authors.initials: CA
authors.lastname: Purdie
authors.forename: Lee B
authors.initials: LB
authors.lastname: Jordan
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferraldeschi
authors.forename: Ayshe
authors.initials: A
authors.lastname: Latif
authors.forename: Kirsten D
authors.initials: KD
authors.lastname: Hadfield
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
authors.forename: Linda
authors.initials: L
authors.lastname: Ashcroft
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Michele
authors.initials: M
authors.lastname: Nikoloff
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lawrence
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
mesh_terms: D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D018572:Disease-Free Survival; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D020847:Estrogen Receptor Modulators / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D055118:Medication Adherence; D008875:Middle Aged; D010641:Phenotype; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013629:Tamoxifen / Q000378:metabolism / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6