title: Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study.
abstract: BACKGROUND
  Gene amplification of CCND1 is observed in a subgroup of breast cancers with poor prognosis, whereas overexpression of the protein cyclin D1 has been linked to both worse and better clinical outcome. CCND1 amplification and protein overexpression have also been associated with resistance to treatment with tamoxifen or even to a potentially detrimental effect of tamoxifen.
  
  
  METHODS
  To clarify these challenging and partly contrasting treatment predictive and prognostic links for cyclin D1 we analysed a large cohort of postmenopausal breast cancer patients randomised to receive either adjuvant anastrozole or tamoxifen, as part of the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. The CCND1 amplification status and protein expression of cyclin D1 were assessed by chromogenic in situ hybridisation and immunohistochemistry, respectively, in 1,155 postmenopausal, oestrogen-receptor-positive breast cancer patients included in the TransATAC substudy.
  
  
  RESULTS
  Amplification of CCND1 was observed in 8.7% of the tumours and was associated with increased risk of disease recurrence (hazard ratio = 1.61; 95% confidence interval, 1.08 to 2.41) after adjustment for other clinicopathological parameters. In contrast, nuclear expression of cyclin D1 protein was associated with decreased recurrence rate (hazard ratio = 0.6; 95% confidence interval, 0.39 to 0.92). The intensity of nuclear or cytoplasmic expression was not of prognostic value. There was no significant interaction between cyclin D1 status and treatment efficacy, ruling out any major detrimental effect of tamoxifen in CCND1-amplified postmenopausal breast cancer.
  
  
  CONCLUSIONS
  In summary, CCND1 amplification and low nuclear expression of cyclin D1 predicted poor clinical outcome in postmenopausal breast cancer patients treated with either anastrozole or tamoxifen.
  
  
  BACKGROUND
  Current Controlled Trials ISRCTN18233230.
authors.affiliation: Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden.
authors.forename: Katja
authors.initials: K
authors.lastname: Lundgren
authors.forename: Matthew
authors.initials: M
authors.lastname: Brown
authors.forename: Silvia
authors.initials: S
authors.lastname: Pineda
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.forename: Janine
authors.initials: J
authors.lastname: Salter
authors.forename: Lila
authors.initials: L
authors.lastname: Zabaglo
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
mesh_terms: D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009570:Nitriles / Q000008:administration & dosage / Q000627:therapeutic use*; D017698:Postmenopause; D011237:Predictive Value of Tests; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D013629:Tamoxifen / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; C530104:CCND1 protein, human; D019394:Ki-67 Antigen; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D013629:Tamoxifen; D019938:Cyclin D1; D000077384:Anastrozole