title: Gene pathways associated with prognosis and chemotherapy sensitivity in molecular subtypes of breast cancer.
abstract: BACKGROUND
  We hypothesized that distinct biological processes might be associated with prognosis and chemotherapy sensitivity in the different types of breast cancers.
  
  
  METHODS
  We performed gene set analyses with BRB-ArrayTools statistical software including 2331 functionally annotated gene sets (ie, lists of genes that correspond to a particular biological pathway or biochemical function) assembled from Ingenuity Pathway Analysis and Gene Ontology databases corresponding to almost all known biological processes. Gene set analysis was performed on gene expression data from three cohorts of 234, 170, and 175 patients with HER2-normal lymph node-negative breast cancer who received no systemic adjuvant therapy to identify gene sets associated prognosis and three additional cohorts of 198, 85, and 62 patients with HER2-normal stage I-III breast cancer who received preoperative chemotherapy to identify gene sets associated with pathological complete response to therapy. These analyses were performed separately for estrogen receptor (ER)-positive and ER-negative breast cancers. Interaction between gene sets and survival and treatment response by breast cancer subtype was assessed in individual datasets and also in pooled datasets. Statistical significance was estimated with permutation test. All statistical tests were two-sided.
  
  
  RESULTS
  For ER-positive cancers, from 370 to 434 gene sets were associated with prognosis (P ≤ .05) and from 209 to 267 gene sets were associated with chemotherapy response in analysis by individual dataset. For ER-positive cancers, 131 gene sets were associated with prognosis and 69 were associated with pathological complete response (P ≤.001) in pooled analysis. Increased expression of cell cycle-related gene sets was associated with poor prognosis, and B-cell immunity-related gene sets were associated with good prognosis. For ER-negative cancers, from 175 to 288 gene sets were associated with prognosis and from 212 to 285 gene sets were associated with chemotherapy response. In pooled analyses of ER-negative cancers, 14 gene sets were associated with prognosis and 23 were associated with response. Gene sets involved in sphingolipid and glycolipid metabolism were associated with better prognosis and those involved in base excision repair, cell aging, and spindle microtubule regulation were associated with chemotherapy response.
  
  
  CONCLUSIONS
  Different biological processes were associated with prognosis and chemotherapy response in ER-positive and ER-negative breast cancers.
authors.affiliation: Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77230-1439, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Bianchini
authors.forename: Daniel
authors.initials: D
authors.lastname: Booser
authors.forename: Yuan
authors.initials: Y
authors.lastname: Qi
authors.forename: Charles
authors.initials: C
authors.lastname: Coutant
authors.forename: Christine Ya-Hui
authors.initials: CY
authors.lastname: Shiang
authors.forename: Libero
authors.initials: L
authors.lastname: Santarpia
authors.forename: Junji
authors.initials: J
authors.lastname: Matsuoka
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: William Fraser
authors.initials: WF
authors.lastname: Symmans
authors.forename: Frankie A
authors.initials: FA
authors.lastname: Holmes
authors.forename: Joyce
authors.initials: J
authors.lastname: O'Shaughnessy
authors.forename: Beth
authors.initials: B
authors.lastname: Hellerstedt
authors.forename: John
authors.initials: J
authors.lastname: Pippen
authors.forename: Fabrice
authors.initials: F
authors.lastname: Andre
authors.forename: Richard
authors.initials: R
authors.lastname: Simon
authors.forename: Lajos
authors.initials: L
authors.lastname: Pusztai
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D015986:Confounding Factors, Epidemiologic; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D030541:Databases, Genetic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D065607:Cytochrome P-450 Enzyme Inhibitors; D011960:Receptors, Estrogen; D003577:Cytochrome P-450 Enzyme System; D019204:GTP-Binding Proteins