title: CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8.
abstract: OBJECTIVE
  Controversy exists about CYP2D6 genotype and tamoxifen efficacy.
  
  
  METHODS
  A matched case-control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor-node-metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism.
  
  
  RESULTS
  The common CYP2D6*4 allele was in Hardy-Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05-5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95-2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86-6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03-2.30).
  
  
  CONCLUSIONS
  In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole.
authors.affiliation: Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. goetz.matthew@mayo.edu
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Hoskin
authors.forename: Michael
authors.initials: M
authors.lastname: Gnant
authors.forename: Martin
authors.initials: M
authors.lastname: Filipits
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Safgren
authors.forename: Mary
authors.initials: M
authors.lastname: Kuffel
authors.forename: Raimund
authors.initials: R
authors.lastname: Jakesz
authors.forename: Margaretha
authors.initials: M
authors.lastname: Rudas
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.forename: Otto
authors.initials: O
authors.lastname: Dietze
authors.forename: Alois
authors.initials: A
authors.lastname: Lang
authors.forename: Felix
authors.initials: F
authors.lastname: Offner
authors.forename: Carol A
authors.initials: CA
authors.lastname: Reynolds
authors.forename: Richard M
authors.initials: RM
authors.lastname: Weinshilboum
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: James N
authors.initials: JN
authors.lastname: Ingle
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017698:Postmenopause; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D019389:Cytochrome P-450 CYP2D6