title: The prognostic value ofBRCA1promoter methylation in early stage triple negative breast cancer.
abstract: BACKGROUND
  Methylation of theBRCA1promoter is frequent in triple negative breast cancers (TNBC) and results in a tumor phenotype similar toBRCA1-mutated tumors.BRCA1mutation-associated cancers are more sensitive to DNA damaging agents as compared to conventional chemotherapy agents. It is not known if there is an interaction between the presence ofBRCA1promoter methylation (PM) and response to chemotherapy agents in sporadic TNBC. We sought to investigate the prognostic significance ofBRCA1PM in TNBC patients receiving standard chemotherapy.
  
  
  METHODS
  Subjects with stage I-III TNBC treated with chemotherapy were identified and their formalin-fixed paraffin-embedded (FFPE) tumor specimens retrieved. Genomic DNA was isolated and subjected to methylation-specific PCR (MSPCR).
  
  
  RESULTS
  DNA was isolated from primary tumor of 39 subjects.BRCA1PM was detected in 30% of patients. Presence ofBRCA1PM was associated with lowerBRCA1transcript levels, suggesting epigeneticBRCA1silencing. All patients received chemotherapy (anthracycline:90%, taxane:69%). At a median follow-up of 64 months, 46% of patients have recurred and 36% have died. On univariate analysis, African-American race, node positivity, stage, andBRCA1PM were associated with worse RFS and OS. Five year OS was 36% for patients withBRCA1PM vs. 77% for patients withoutBRCA1PM (p=0.004). On multivariable analysis,BRCA1PM was associated with significantly worse RFS and OS.
  
  
  CONCLUSIONS
  We show thatBRCA1PM is common in TNBC and has the potential to identify a significant fraction of TNBC patients who have suboptimal outcomes with standard chemotherapy.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.|The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Shane R
authors.initials: SR
authors.lastname: Stecklein
authors.affiliation: Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA.|Breast Cancer Prevention Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Bruce F
authors.initials: BF
authors.lastname: Kimler
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.|Department of Biochemistry and Molecular Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Geetika
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.|Breast Cancer Prevention Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Petroff
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.|Breast Cancer Prevention Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Phillips
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.|The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Ossama W
authors.initials: OW
authors.lastname: Tawfik
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.|The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Godwin
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.|The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Roy A
authors.initials: RA
authors.lastname: Jensen
keywords: BRCA1 promoter methylation; Triple negative breast cancer; biomarker; chemosensitivity; prognosis