title: A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment.
abstract: BACKGROUND
  The prognostic significance of germline mutations in BRCA1 and BRCA2 in women with breast cancer remains unclear. A combined analysis was performed to address this uncertainty.
  
  
  METHODS
  Two retrospective cohorts of Ashkenazi Jewish women undergoing breast-conserving treatment for invasive cancer between 1980 and 1995 (n = 584) were established. Archived tissue blocks were used as the source of DNA for Ashkenazi Jewish BRCA1/BRCA2 founder mutation analysis. Paraffin-embedded tissue and follow-up information was available for 505 women.
  
  
  RESULTS
  Genotyping was successful in 496 women, of whom 56 (11.3%) were found to carry a BRCA1/BRCA2 founder mutation. After a median follow-up period of 116 months, breast cancer specific survival was worse in women with BRCA1 mutations than in those without (62% at 10 years versus 86%; P < 0.0001), but not in women with the BRCA2 mutation (84% versus 86% at 10 years; P = 0.76). Germline BRCA1 mutations were an independent predictor of breast cancer mortality in multivariate analysis (hazard ratio 2.4, 95% confidence interval 1.2-4.8; P = 0.01). BRCA1 status predicted breast cancer mortality only among women who did not receive chemotherapy (hazard ratio 4.8, 95% confidence interval 2.0-11.7; P = 0.001). The risk for metachronous ipsilateral cancer was not greater in women with germline BRCA1/BRCA2 founder mutations than in those without mutations (P = 0.68).
  
  
  CONCLUSIONS
  BRCA1 mutations, but not BRCA2 mutations, are associated with reduced survival in Ashkenazi women undergoing breast-conserving treatment for invasive breast cancer, but the poor prognosis associated with germline BRCA1 mutations is mitigated by adjuvant chemotherapy. The risk for metachronous ipsilateral disease does not appear to be increased for either BRCA1 or BRCA2 mutation carriers, at least up to 10 years of follow up.
authors.affiliation: Research Institute of McGill University Health Centre, Cancer Prevention Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Robson
authors.forename: Pierre O
authors.initials: PO
authors.lastname: Chappuis
authors.forename: Jaya
authors.initials: J
authors.lastname: Satagopan
authors.forename: Nora
authors.initials: N
authors.lastname: Wong
authors.forename: Jeff
authors.initials: J
authors.lastname: Boyd
authors.forename: John R
authors.initials: JR
authors.lastname: Goffin
authors.forename: Clifford
authors.initials: C
authors.lastname: Hudis
authors.forename: David
authors.initials: D
authors.lastname: Roberge
authors.forename: Larry
authors.initials: L
authors.lastname: Norton
authors.forename: Louis R
authors.initials: LR
authors.lastname: Bégin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D005500:Follow-Up Studies; D018095:Germ-Line Mutation; D006801:Humans; D007585:Jews / Q000235:genetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein