title: Improved outcome of high-risk early HER2 positive breast cancer with high CXCL13-CXCR5 messenger RNA expression.
abstract: The CXCL13-CXCR5 is a chemokine axis that is activated in some breast cancers. A total of 321 tissue blocks from a group of patients who received adjuvant, dose-dense chemotherapy for high-risk early breast cancer were examined. Activation of this axis was found to be associated with determinants of poor prognosis but also with improved outcome in the human epidermal growth factor receptor 2 overexpressing subpopulation.
  
  
  BACKGROUND
  Chemokines are important in cell migration and are thought to play a key role in metastasis. We explored the prognostic significance of C-X-C ligand-motif (CXCL) 12, CXCL13, and receptor (CXCR) 5 on disease-free survival (DFS) and overall survival (OS) in early breast cancer.
  
  
  METHODS
  A total of 595 patients with high risk, [corrected] early breast cancer were treated in a 2-arm trial (HE10/97) with dose-dense sequential epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without paclitaxel. RNA was extracted from 321 formalin-fixed paraffin-embedded primary tumor tissue samples and quantitative reverse-transcriptase polymerase chain reaction was used to assess messenger RNA (mRNA) expression of CXCL12, CXCL13, and CXCR5; estrogen receptor; progesterone receptor (PgR); microtubule-associated protein tau and human epidermal growth factor receptor 2 (HER2).
  
  
  RESULTS
  CXCL13 and CXCR5 were found to be negatively associated with estrogen receptor and microtubule-associated protein tau mRNA expression and with dense lymphocytic infiltration, and were positively associated with nuclear grade. Only CXCL13 was positively associated with HER2. Multivariate analysis revealed an association between high CXCL13 mRNA expression and improved DFS (hazard ratio [HR] 0.48 [95% CI, 0.25-0.90]; Wald, P = .023) but not OS; whereas high CXCL12 expression was significantly associated with increased OS (HR 0.53 [95% CI, 0.33-0.85]; Wald, P = .009). In the HER2 mRNA overexpressing subgroup, high CXCL13 mRNA expression was associated with improved DFS (P < .001), whereas high CXCR5 was associated with increased DFS and OS (P = .004 and P = .049, respectively).
  
  
  CONCLUSIONS
  The CXCL13-CXCR5 axis is associated with classic determinants of poor prognosis, such as high grade, hormone receptor negativity, and axillary node involvement. Interestingly, this chemokine axis seems to be strongly associated with improved outcome in patients with HER2(+) disease.
authors.affiliation: Third Department of Medical Oncology, Hygeia Hospital, Stavrou and Kifissias Ave., Maroussi, Athens, Greece. e.razis@hygeia.gr
authors.forename: Evangelia
authors.initials: E
authors.lastname: Razis
authors.forename: Konstantine T
authors.initials: KT
authors.lastname: Kalogeras
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.forename: Anastasia G
authors.initials: AG
authors.lastname: Eleftheraki
authors.forename: Nikitas
authors.initials: N
authors.lastname: Nikitas
authors.forename: Ralf
authors.initials: R
authors.lastname: Kronenwett
authors.forename: Eleni
authors.initials: E
authors.lastname: Timotheadou
authors.forename: Christos
authors.initials: C
authors.lastname: Christodoulou
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Wirtz
authors.forename: Thomas
authors.initials: T
authors.lastname: Makatsoris
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bafaloukos
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Aravantinos
authors.forename: Despina
authors.initials: D
authors.lastname: Televantou
authors.forename: Nicholas
authors.initials: N
authors.lastname: Pavlidis
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D002277:Carcinoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D054382:Chemokine CXCL13 / Q000235:genetics* / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000235:genetics* / Q000378:metabolism; D012189:Retrospective Studies; D012306:Risk; D016896:Treatment Outcome; D015854:Up-Regulation / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D054382:Chemokine CXCL13; D003520:Cyclophosphamide; D005472:Fluorouracil; D008727:Methotrexate; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D054380:Receptors, CXCR5; C110663:CXCL13 protein, human; C095085:CXCR5 protein, human; C508053:ERBB2 protein, human