title: A BRCA1 deficient-like signature is enriched in breast cancer brain metastases and predicts DNA damage-induced poly (ADP-ribose) polymerase inhibitor sensitivity.
abstract: BACKGROUND
  There is an unmet clinical need for biomarkers to identify breast cancer patients at an increased risk of developing brain metastases. The objective is to identify gene signatures and biological pathways associated with human epidermal growth factor receptor 2-positive (HER2+) brain metastasis.
  
  
  METHODS
  We combined laser capture microdissection and gene expression microarrays to analyze malignant epithelium from HER2+ breast cancer brain metastases with that from HER2+ nonmetastatic primary tumors. Differential gene expression was performed including gene set enrichment analysis (GSEA) using publicly available breast cancer gene expression data sets.
  
  
  RESULTS
  In a cohort of HER2+ breast cancer brain metastases, we identified a gene expression signature that anti-correlates with overexpression of BRCA1. Sequence analysis of the HER2+ brain metastases revealed no pathogenic mutations of BRCA1, and therefore the aforementioned signature was designated BRCA1 Deficient-Like (BD-L). Evaluation of an independent cohort of breast cancer metastases demonstrated that BD-L values are significantly higher in brain metastases as compared to other metastatic sites. Although the BD-L signature is present in all subtypes of breast cancer, it is significantly higher in BRCA1 mutant primary tumors as compared with sporadic breast tumors. Additionally, BD-L signature values are significantly higher in HER2-/ER- primary tumors as compared with HER2+/ER + and HER2-/ER + tumors. The BD-L signature correlates with breast cancer cell line pharmacologic response to a combination of poly (ADP-ribose) polymerase (PARP) inhibitor and temozolomide, and the signature outperformed four published gene signatures of BRCA1/2 deficiency.
  
  
  CONCLUSIONS
  A BD-L signature is enriched in HER2+ breast cancer brain metastases without pathogenic BRCA1 mutations. Unexpectedly, elevated BD-L values are found in a subset of primary tumors across all breast cancer subtypes. Evaluation of pharmacological sensitivity in breast cancer cell lines representing all breast cancer subtypes suggests the BD-L signature may serve as a biomarker to identify sporadic breast cancer patients who might benefit from a therapeutic combination of PARP inhibitor and temozolomide and may be indicative of a dysfunctional BRCA1-associated pathway.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: McMullin
authors.forename: Ben S
authors.initials: BS
authors.lastname: Wittner
authors.forename: Chuanwei
authors.initials: C
authors.lastname: Yang
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Denton-Schneider
authors.forename: Daniel
authors.initials: D
authors.lastname: Hicks
authors.forename: Raj
authors.initials: R
authors.lastname: Singavarapu
authors.forename: Sharon
authors.initials: S
authors.lastname: Moulis
authors.forename: Jeongeun
authors.initials: J
authors.lastname: Lee
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Akbari
authors.forename: Steven A
authors.initials: SA
authors.lastname: Narod
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Sgroi
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D004249:DNA Damage; D004252:DNA Mutational Analysis; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D020411:Oligonucleotide Array Sequence Analysis; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000077204:Temozolomide; D059467:Transcriptome
chemical_list: D019313:BRCA1 Protein; D014408:Biomarkers, Tumor; D003606:Dacarbazine; D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077204:Temozolomide; C508053:ERBB2 protein, human; C531550:olaparib