title: Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome.
abstract: BACKGROUND
  The association between BRCA1 germ-line mutations and breast cancer prognosis is controversial. A historical cohort study was designed to determine the prognosis for women with axillary lymph node negative hereditary breast cancer.
  
  
  METHODS
  We tested pathology blocks from 118 Ashkenazi Jewish women with axillary lymph node negative breast cancer for the presence of the two common BRCA1 founder mutations, 185delAG and 5382insC. Patients were followed up for a median of 76 months. Somatic TP53 mutations were screened for by immunohistochemistry, and direct sequencing was performed in the BRCA1-positive tumours.
  
  
  RESULTS
  Sixteen breast cancer blocks (13.6%) carried a BRCA1 mutation. Young age of onset, high nuclear grade, negative estrogen receptor status and over-expression of p53 were highly associated with BRCA1-positive status (P-values all <0.01). BRCA1 mutation carriers had a higher mortality than non-carriers (five-year overall survival, 50% and 89.6%, respectively, P = 0.0001). Young age of onset, estrogen receptor negative status, nuclear grade 3, and over-expression of p53 also predicted a poor outcome. Cox multivariate analyses showed that only germ-line BRCA1 mutation status was an independent prognostic factor for overall survival (P = 0.01). Among nuclear grade 3 tumours, the BRCA1 mutation carrier status was a significant prognostic factor of death (risk ratio 5.8, 95% confidence interval: 1.5-22, P = 0.009). Sequencing of BRCA1-related breast cancers revealed one TP53 missense mutation not previously reported in breast cancer.
  
  
  CONCLUSIONS
  Using a historical cohort approach, we have identified BRCA1 mutation status as an independent prognostic factor for node negative breast cancer among the Ashkenazi Jewish women. Those managing women carrying a BRCA1 mutation may need take these findings into consideration. Additionally, our preliminary results, taken together with the work of others suggest a different carcinogenic pathway in BRCA1-related breast cancer, compared to non-hereditary cases.
authors.affiliation: Department of Medicine, Sir M. B. Davis-Jewish General Hospital, Montreal, Quebec, Canada. MDWF@musica.mcgill.ca
authors.forename: W D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: P O
authors.initials: PO
authors.lastname: Chappuis
authors.forename: N
authors.initials: N
authors.lastname: Wong
authors.forename: J S
authors.initials: JS
authors.lastname: Brunet
authors.forename: D
authors.initials: D
authors.lastname: Vesprini
authors.forename: F
authors.initials: F
authors.lastname: Rozen
authors.forename: Z Q
authors.initials: ZQ
authors.lastname: Yuan
authors.forename: M N
authors.initials: MN
authors.lastname: Pollak
authors.forename: G
authors.initials: G
authors.lastname: Kuperstein
authors.forename: S A
authors.initials: SA
authors.lastname: Narod
authors.forename: L R
authors.initials: LR
authors.lastname: Bégin
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D024682:BRCA2 Protein; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D015331:Cohort Studies; D005260:Female; D019398:Genes, BRCA1 / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D007585:Jews / Q000235:genetics; D008198:Lymph Nodes / Q000473:pathology; D008875:Middle Aged; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D012307:Risk Factors; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics
chemical_list: D024682:BRCA2 Protein; D009363:Neoplasm Proteins; D014157:Transcription Factors