title: Identification of biology-based breast cancer types with distinct predictive and prognostic features: role of steroid hormone and HER2 receptor expression in patients treated with neoadjuvant anthracycline/taxane-based chemotherapy.
abstract: BACKGROUND
  Reliable predictive and prognostic markers for routine diagnostic purposes are needed for breast cancer patients treated with neoadjuvant chemotherapy. We evaluated protein biomarkers in a cohort of 116 participants of the GeparDuo study on anthracycline/taxane-based neoadjuvant chemotherapy for operable breast cancer to test for associations with pathological complete response (pCR) and disease-free survival (DFS). Particularly, we evaluated if interactions between hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression might lead to a different clinical behavior of HR+/HER2+ co-expressing and HR+/HER2- tumors and whether subgroups of triple negative tumors might be identified by the help of Ki67 labeling index, cytokeratin 5/6 (CK5/6), as well as cyclooxygenase-2 (COX-2), and Y-box binding protein 1 (YB-1) expression.
  
  
  METHODS
  Expression analysis was performed using immunohistochemistry and silver-enhanced in situ hybridization on tissue microarrays (TMAs) of pretherapeutic core biopsies.
  
  
  RESULTS
  pCR rates were significantly different between the biology-based tumor types (P = 0.044) with HR+/HER2+ and HR-/HER2- tumors having higher pCR rates than HR+/HER2- tumors. Ki67 labeling index, confirmed as significant predictor of pCR in the whole cohort (P = 0.001), identified HR-/HER- (triple negative) carcinomas with a higher chance for a pCR (P = 0.006). Biology-based tumor type (P = 0.046 for HR+/HER2+ vs. HR+/HER2-), Ki67 labeling index (P = 0.028), and treatment arm (P = 0.036) were independent predictors of pCR in a multivariate model. DFS was different in the biology-based tumor types (P < 0.0001) with HR+/HER2- and HR+/HER2+ tumors having the best prognosis and HR-/HER2+ tumors showing the worst outcome. Biology-based tumor type was an independent prognostic factor for DFS in multivariate analysis (P < 0.001).
  
  
  CONCLUSIONS
  Our data demonstrate that a biology-based breast cancer classification using estrogen receptor (ER), progesterone receptor (PgR), and HER2 bears independent predictive and prognostic potential. The HR+/HER2+ co-expressing carcinomas emerged as a group of tumors with a good response rate to neoadjuvant chemotherapy and a favorable prognosis. HR+/HER2- tumors had a good prognosis irrespective of a pCR, whereas patients with HR-/HER- and HR-/HER+ tumors, especially if they had not achieved a pCR, had an unfavorable prognosis and are in need of additional treatment options.
authors.affiliation: Institute of Pathology, Charité Universitätsmedizin Berlin, Charitéplatz 1, Berlin, 10117, Germany. Silvia.Darb-Esfahani@charite.de
authors.forename: Silvia
authors.initials: S
authors.lastname: Darb-Esfahani
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Berit M
authors.initials: BM
authors.lastname: Müller
authors.forename: Marc
authors.initials: M
authors.lastname: Roller
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.forename: Martina
authors.initials: M
authors.lastname: Komor
authors.forename: Karsten
authors.initials: K
authors.lastname: Schlüns
authors.forename: Jens Uwe
authors.initials: JU
authors.lastname: Blohmer
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.forename: Bernd
authors.initials: B
authors.lastname: Gerber
authors.forename: Aurelia
authors.initials: A
authors.lastname: Noske
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.forename: Manfred
authors.initials: M
authors.lastname: Dietel
authors.forename: Klaus
authors.initials: K
authors.lastname: Richter
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001706:Biopsy; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D044584:Carcinoma, Ductal / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D003520:Cyclophosphamide / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D018572:Disease-Free Survival; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009687:Nuclear Proteins / Q000096:biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D011960:Receptors, Estrogen / Q000096:biosynthesis*; D011980:Receptors, Progesterone / Q000096:biosynthesis*; D043823:Taxoids / Q000008:administration & dosage; D051840:Y-Box-Binding Protein 1
chemical_list: D051546:Cyclooxygenase 2; D003520:Cyclophosphamide; D004268:DNA-Binding Proteins; D000077143:Docetaxel; D004317:Doxorubicin; D009687:Nuclear Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D043823:Taxoids; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human