title: Combination anastrozole and fulvestrant in metastatic breast cancer.
abstract: BACKGROUND
  The aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)-positive metastatic breast cancer.
  
  
  METHODS
  Postmenopausal women with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrant was administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progression-free survival, with overall survival designated as a prespecified secondary outcome.
  
  
  RESULTS
  The median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combination therapy, 0.80; 95% confidence interval [CI], 0.68 to 0.94; P=0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P=0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups.
  
  
  CONCLUSIONS
  The combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard. (Funded by the National Cancer Institute and AstraZeneca; SWOG ClinicalTrials.gov number, NCT00075764.).
authors.affiliation: University of California Irvine Medical Center, Orange, CA 92868, USA. rsmehta@uci.edu
authors.forename: Rita S
authors.initials: RS
authors.lastname: Mehta
authors.forename: William E
authors.initials: WE
authors.lastname: Barlow
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.forename: Ted A
authors.initials: TA
authors.lastname: Vandenberg
authors.forename: Shaker R
authors.initials: SR
authors.lastname: Dakhil
authors.forename: Nagendra R
authors.initials: NR
authors.lastname: Tirumali
authors.forename: Danika L
authors.initials: DL
authors.lastname: Lew
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Hayes
authors.forename: Julie R
authors.initials: JR
authors.lastname: Gralow
authors.forename: Robert B
authors.initials: RB
authors.lastname: Livingston
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077384:Anastrozole; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018592:Cross-Over Studies; D018572:Disease-Free Survival; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004965:Estrogen Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects; D017698:Postmenopause; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D047072:Aromatase Inhibitors; D004965:Estrogen Antagonists; D009570:Nitriles; D014230:Triazoles; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol