title: Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial.
abstract: BACKGROUND
  The Breast International Group (BIG) 1-98 trial (a randomised double-blind phase III trial) has shown that letrozole significantly improves disease-free survival (DFS) compared with tamoxifen in postmenopausal women with endocrine-responsive early breast cancer. Our aim was to establish whether the benefit of letrozole versus tamoxifen differs according to the ERBB2 status of tumours.
  
  
  METHODS
  The BIG 1-98 trial consists of four treatment groups that compare 5 years of monotherapy with letrozole or tamoxifen, and sequential administration of one drug for 2 years followed by the other drug for 3 years. Our study includes data from the 4922 patients randomly assigned to the two monotherapy treatment groups (letrozole or tamoxifen for 5 years; 51 months median follow-up [range <1 to 90 months]). A central assessment of oestrogen receptor (ER), progesterone receptor (PgR) and ERBB2 status using paraffin-embedded primary tumour material was possible for 3650 (74%) patients. ER, PgR, and ERBB2 expression were measured by immunohistochemistry (IHC) and ERBB2-positivity was confirmed by fluorescence in-situ hybridisation (FISH). Positive staining in at least 1% of cells was considered to show presence of ER or PgR expression. Tumours were deemed ERBB2-positive if amplified by FISH, or, for the few tumours with unassessable or unavailable FISH results, if they were IHC 3+. Hazard ratios (HR) estimated by Cox modelling were used to compare letrozole with tamoxifen for DFS, which was the primary endpoint, and to assess treatment-by-covariate interactions. The BIG 1-98 trial is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00004205.
  
  
  RESULTS
  By central assessment 7% (257 of 3650) of tumours were classified as ERBB2-positive. In 3533 patients with tumours confirmed to express ER, DFS was poorer in patients with ERBB2-positive tumours (n=239) than in those with ERBB2-negative tumours (n=3294; HR 2.09 [95% CI 1.59-2.76]; p<0.0001). There was no statistical evidence of heterogeneity in the treatment effect according to ERBB2 status of the tumour (p=0.60 for interaction), thus, letrozole improves DFS compared with tamoxifen regardless of ERBB2 status. The observed HRs were 0.62 (95% CI 0.37-1.03) for ERBB2-positive tumours and 0.72 (0.59-0.87) for ERBB2-negative tumours.
  
  
  CONCLUSIONS
  A benefit of letrozole over tamoxifen was noted, irrespective of ERBB2 status of the tumour, and, therefore, ERBB2 status does not seem to be a selection criterion for treatment with letrozole versus tamoxifen in postmenopausal women with endocrine-responsive early breast cancer.
authors: Department of Pathology, Nordsjaellands Hospital, Hilleroed, Denmark. bbr@noh.regionh.dk
authors: Birgitte B
authors: BB
authors: Rasmussen
authors: Meredith M
authors: MM
authors: Regan
authors: Anne E
authors: AE
authors: Lykkesfeldt
authors: Patrizia
authors: P
authors: Dell'Orto
authors: Barbara
authors: B
authors: Del Curto
authors: Katrine L
authors: KL
authors: Henriksen
authors: Mauro G
authors: MG
authors: Mastropasqua
authors: Karen N
authors: KN
authors: Price
authors: Eliane
authors: E
authors: Méry
authors: Magali
authors: M
authors: Lacroix-Triki
authors: Stephen
authors: S
authors: Braye
authors: Hans J
authors: HJ
authors: Altermatt
authors: Richard D
authors: RD
authors: Gelber
authors: Monica
authors: M
authors: Castiglione-Gertsch
authors: Aron
authors: A
authors: Goldhirsch
authors: Barry A
authors: BA
authors: Gusterson
authors: Beat
authors: B
authors: Thürlimann
authors: Alan S
authors: AS
authors: Coates
authors: Giuseppe
authors: G
authors: Viale
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D000077289:Letrozole; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017698:Postmenopause; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D011960:Receptors, Estrogen; D014230:Triazoles; D013629:Tamoxifen; D000077289:Letrozole