title: Prevalence and predictors of loss of wild type BRCA1 in estrogen receptor positive and negative BRCA1-associated breast cancers.
abstract: BACKGROUND
  The majority of breast cancers that occur in BRCA1 mutation carriers (BRCA1 carriers) are estrogen receptor-negative (ER-). Therefore, it has been suggested that ER negativity is intrinsic to BRCA1 cancers and reflects the cell of origin of these tumors. However, approximately 20% of breast cancers that develop in BRCA1 carriers are ER-positive (ER+); these cancers are more likely to develop as BRCA1 carriers age, suggesting that they may be incidental and unrelated to BRCA1 deficiency. The purpose of this study was to compare the prevalence of loss of heterozygosity due to loss of wild type (wt) BRCA1 in ER+ and ER- breast cancers that have occurred in BRCA1 carriers and to determine whether age at diagnosis or any pathologic features or biomarkers predict for loss of wt BRCA1 in these breast cancers.
  
  
  METHODS
  Relative amounts of mutated and wt BRCA1 DNA were measured by quantitative polymerase chain reaction performed on laser capture microdissected cancer cells from 42 ER+ and 35 ER- invasive breast cancers that developed in BRCA1 carriers. BRCA1 gene methylation was determined on all cancers in which sufficient DNA was available. Immunostains for cytokeratins (CK) 5/6, 14, 8 and 18, epidermal growth factor receptor and p53 were performed on paraffin sections from tissue microarrays containing these cancers.
  
  
  RESULTS
  Loss of wt BRCA1 was equally frequent in ER+ and ER- BRCA1-associated cancers (81.0% vs 88.6%, respectively; P = 0.53). One of nine cancers tested that retained wt BRCA1 demonstrated BRCA1 gene methylation. Age at diagnosis was not significantly different between first invasive ER+ BRCA1 breast cancers with and without loss of wt BRCA1 (mean age 45.2 years vs 50.1 years, respectively; P = 0.51). ER+ BRCA1 cancers that retained wt BRCA1 were significantly more likely than those that lost wt BRCA1 to have a low mitotic rate (odds ratio (OR), 5.16; 95% CI, 1.91 to ∞). BRCA1 cancers with loss of wt BRCA1 were more likely to express basal cytokeratins CK 5/6 or 14 (OR 4.7; 95% CI, 1.85 to ∞).
  
  
  CONCLUSIONS
  We found no difference in the prevalence of loss of wt BRCA1 between ER+ and ER- invasive BRCA1-associated breast cancers. Our findings suggest that many of the newer therapies for BRCA1 breast cancers designed to exploit the BRCA1 deficiency in these cancers may also be effective in ER+ cancers that develop in this population.
authors.affiliation: Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. ntung@bidmc.harvard.edu
authors.forename: Nadine
authors.initials: N
authors.lastname: Tung
authors.forename: Alexander
authors.initials: A
authors.lastname: Miron
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Schnitt
authors.forename: Shiva
authors.initials: S
authors.lastname: Gautam
authors.forename: Katharina
authors.initials: K
authors.lastname: Fetten
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kaplan
authors.forename: Yosuf
authors.initials: Y
authors.lastname: Yassin
authors.forename: Ayodele
authors.initials: A
authors.lastname: Buraimoh
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Attila M
authors.initials: AM
authors.lastname: Szász
authors.forename: Ruiyang
authors.initials: R
authors.lastname: Tian
authors.forename: Zhigang C
authors.initials: ZC
authors.lastname: Wang
authors.forename: Laura C
authors.initials: LC
authors.lastname: Collins
authors.forename: Jane
authors.initials: J
authors.lastname: Brock
authors.forename: Karen
authors.initials: K
authors.lastname: Krag
authors.forename: Robert D
authors.initials: RD
authors.lastname: Legare
authors.forename: Dennis
authors.initials: D
authors.lastname: Sgroi
authors.forename: Paula D
authors.initials: PD
authors.lastname: Ryan
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Silver
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Richardson
mesh_terms: D000367:Age Factors; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D019398:Genes, BRCA1; D006801:Humans; D007633:Keratins / Q000032:analysis; D046228:Microarray Analysis; D009154:Mutation; D016133:Polymerase Chain Reaction; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen; D016159:Tumor Suppressor Protein p53; D007633:Keratins; D066246:ErbB Receptors