title: Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study.
abstract: OBJECTIVE
  Among postmenopausal women with endocrine-responsive breast cancer, the aromatase inhibitor letrozole, when compared with tamoxifen, has been shown to significantly improve disease-free survival (DFS) and time to distant recurrence (TDR). We investigated whether letrozole monotherapy prolonged overall survival (OS) compared with tamoxifen monotherapy.
  
  
  METHODS
  Of 8,010 postmenopausal women with hormone receptor-positive, early breast cancer enrolled on the Breast International Group (BIG) 1-98 study, 4,922 were randomly assigned to 5 years of continuous adjuvant therapy with either letrozole or tamoxifen. Of 2,459 patients enrolled in the tamoxifen treatment arm, 619 (25.2%) selectively crossed over to either adjuvant or extended letrozole after initial trial results were presented in January 2005. To gain better estimates of relative treatment effects in the presence of selective crossover, we used inverse probability of censoring weighted (IPCW) modeling.
  
  
  RESULTS
  Weighted Cox models, by using IPCW, estimated a statistically significant, 18% reduction in the hazard of an OS event with letrozole treatment (hazard ratio [HR], 0.82; 95% CI, 0.70 to 0.95). Estimates of 5-year OS on the basis of IPCW were 91.8% and 90.4% for letrozole and tamoxifen, respectively. The HRs of DFS and TDR events by using IPCW modeling were 0.83 (95% CI, 0.74 to 0.94) and 0.80 (95% CI, 0.67 to 0.94), respectively (P < .05 for DFS, OS, and TDR). Median follow-up was 74 months.
  
  
  CONCLUSIONS
  Adjuvant treatment with letrozole, compared with tamoxifen, significantly reduces the risk of death, the risk of recurrent disease, and the risk of recurrence at distant sites in postmenopausal women with hormone receptor-positive breast cancer.
authors.affiliation: European Institute of Oncology, Milan, Italy. marco.colleoni@ieo.it
authors.forename: Marco
authors.initials: M
authors.lastname: Colleoni
authors.forename: Anita
authors.initials: A
authors.lastname: Giobbie-Hurder
authors.forename: Meredith M
authors.initials: MM
authors.lastname: Regan
authors.forename: Beat
authors.initials: B
authors.lastname: Thürlimann
authors.forename: Henning
authors.initials: H
authors.lastname: Mouridsen
authors.forename: Louis
authors.initials: L
authors.lastname: Mauriac
authors.forename: John F
authors.initials: JF
authors.lastname: Forbes
authors.forename: Robert
authors.initials: R
authors.lastname: Paridaens
authors.forename: István
authors.initials: I
authors.lastname: Láng
authors.forename: Ian
authors.initials: I
authors.lastname: Smith
authors.forename: Jacquie
authors.initials: J
authors.lastname: Chirgwin
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Pienkowski
authors.forename: Andrew
authors.initials: A
authors.lastname: Wardley
authors.forename: Karen N
authors.initials: KN
authors.lastname: Price
authors.forename: Richard D
authors.initials: RD
authors.lastname: Gelber
authors.forename: Alan S
authors.initials: AS
authors.lastname: Coates
authors.forename: Aron
authors.initials: A
authors.lastname: Goldhirsch
mesh_terms: D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077289:Letrozole; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D009570:Nitriles / Q000627:therapeutic use*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D015996:Survival Rate; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole