title: DNA methylation markers predict outcome in node-positive, estrogen receptor-positive breast cancer with adjuvant anthracycline-based chemotherapy.
abstract: OBJECTIVE
  We have shown that DNA methylation of the PITX2 gene predicts risk of distant recurrence in steroid hormone receptor-positive, node-negative breast cancer. Here, we present results from a multicenter study investigating whether PITX2 and other candidate DNA methylation markers predict outcome in node-positive, estrogen receptor-positive, HER-2-negative breast cancer patients who received adjuvant anthracycline-based chemotherapy.
  
  
  METHODS
  Using a microarray platform, we analyzed DNA methylation in regulatory regions of PITX2 and 60 additional candidate genes in 241 breast cancer specimens. Using Cox regression analysis, we assessed the predictive power of the individual marker/marker panel candidates. Clinical endpoints were time to distant metastasis, disease-free survival, and overall survival. A nested bootstrap/cross-validation strategy was applied to identify and validate marker panels.
  
  
  RESULTS
  DNA methylation of PITX2 and 14 other genes was correlated with clinical outcome. In multivariate models, each methylation marker added significant information to established clinical factors. A four-marker panel including PITX2, BMP4, FGF4, and C20orf55 was identified that resulted in improvement of outcome prediction compared with PITX2 alone.
  
  
  CONCLUSIONS
  This study provides further evidence for the PITX2 biomarker, which has now been successfully confirmed to predict outcome among different breast cancer patient populations. We further identify new DNA methylation biomarkers, three of which can be combined into a panel with PITX2 to increase the outcome prediction performance in our anthracycline-treated primary breast cancer population. Our results show that a well-defined panel of DNA methylation markers enables outcome prediction in lymph node-positive, HER-2-negative breast cancer patients treated with anthracycline-based chemotherapy.
authors.affiliation: Epigenomics AG, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartmann
authors.forename: Frédérique
authors.initials: F
authors.lastname: Spyratos
authors.forename: Nadia
authors.initials: N
authors.lastname: Harbeck
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
authors.forename: Anne
authors.initials: A
authors.lastname: Fassbender
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.forename: Serenella
authors.initials: S
authors.lastname: Eppenberger-Castori
authors.forename: Vincent
authors.initials: V
authors.lastname: Vuaroqueaux
authors.forename: Florence
authors.initials: F
authors.lastname: Lerebours
authors.forename: Katrin
authors.initials: K
authors.lastname: Welzel
authors.forename: Sabine
authors.initials: S
authors.lastname: Maier
authors.forename: Achim
authors.initials: A
authors.lastname: Plum
authors.forename: Stephan
authors.initials: S
authors.lastname: Niemann
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.forename: Ralf
authors.initials: R
authors.lastname: Lesche
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
mesh_terms: D018943:Anthracyclines / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D019175:DNA Methylation; D005260:Female; D018734:Genes, erbB-2; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008207:Lymphatic Metastasis; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome; D000097577:Homeobox Protein PITX2
chemical_list: D018943:Anthracyclines; D015415:Biomarkers; D018398:Homeodomain Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2