title: Side effects associated with ultrarapid cytochrome P450 2D6 genotype among women with early stage breast cancer treated with tamoxifen.
abstract: BACKGROUND
  The side effects of tamoxifen, a drug widely used for the treatment and the prevention of recurrence in patients with estrogen receptor positive breast cancers (ER+), have been reported in clinical trials, but to date no information is available on their possible association with an increased enzymatic activity of CYP2D6 (ultra-metabolizers, UMs). The aim of this study was therefore to evaluate the association between the presence of multiple functional CYP2D6 alleles and the occurrence of side effects.
  
  
  METHODS
  61 women with ER+ breast cancer receiving tamoxifen monotherapy were investigated in order to assess the relationships between CYP2D6 UM phenotype and side effects. Genotyping of 16 CYP2D6 polymorphisms was performed using a new DNA microarray technology.
  
  
  RESULTS
  A highly significant difference was detected (41.2% of difference, 95% CI 6 - 61%, Fisher's exact test, p = 0.030) between the numbers of Ultrarapid Metabolizer patients (UM; high activity) with two or more adverse drug reactions to tamoxifen (7/9; 77.8%), compared to the number of Extensive Metabolizers (EM; normal activity), Intermediate Metabolizers (IM; reduced activity), and Poor Metabolizers (PM; no activity) with at least two side effects (19/52, 36.5%). A similar difference was also observed comparing the two groups (UM vs EM-IM-PM) for the number of side effects (median and inter quartile range, IQR: AM/EM/IM 1, IQR 0-2 vs. ULTRA 2, IQR 2-4; Mann-Whitney p = 0.005).
  
  
  CONCLUSIONS
  Our results suggest a new association between CYP2D6 gene duplication and side effects to tamoxifen, indicating a possible role of CYP2D6 in their occurrence.
authors.affiliation: Departmentt of Medical Sciences, University "Amedeo Avogadro" of East Piedmont, Novara, Italy. roberta.rolla@med.unipmn.it
authors.forename: R
authors.initials: R
authors.lastname: Rolla
authors.forename: M
authors.initials: M
authors.lastname: Vidali
authors.forename: S
authors.initials: S
authors.lastname: Meola
authors.forename: P
authors.initials: P
authors.lastname: Pollarolo
authors.forename: M R
authors.initials: MR
authors.lastname: Fanello
authors.forename: C
authors.initials: C
authors.lastname: Nicolotti
authors.forename: C
authors.initials: C
authors.lastname: Saggia
authors.forename: L
authors.initials: L
authors.lastname: Forti
authors.forename: F D
authors.initials: FD
authors.lastname: Agostino
authors.forename: V
authors.initials: V
authors.lastname: Rossi
authors.forename: G
authors.initials: G
authors.lastname: Borra
authors.forename: F
authors.initials: F
authors.lastname: Stratica
authors.forename: O
authors.initials: O
authors.lastname: Alabiso
authors.forename: G
authors.initials: G
authors.lastname: Bellomo
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D042241:Early Diagnosis; D005260:Female; D005838:Genotype; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D013629:Tamoxifen / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6