title: Constitutive phosphorylated STAT3-associated gene signature is predictive for trastuzumab resistance in primary HER2-positive breast cancer.
abstract: BACKGROUND
  The likelihood of recurrence in patients with breast cancer who have HER2-positive tumors is relatively high, although trastuzumab is a remarkably effective drug in this setting. Signal transducer and activator of transcription 3 protein (STAT3), a transcription factor that is persistently tyrosine-705 phosphorylated (pSTAT3) in response to numerous oncogenic signaling pathways, activates downstream proliferative and anti-apoptotic pathways. We hypothesized that pSTAT3 expression in HER2-positive breast cancer will confer trastuzumab resistance.
  
  
  METHODS
  We integrated reverse phase protein array (RPPA) and gene expression data from patients with HER2-positive breast cancer treated with trastuzumab in the adjuvant setting.
  
  
  RESULTS
  We show that a pSTAT3-associated gene signature (pSTAT3-GS) is able to predict pSTAT3 status in an independent dataset (TCGA; AUC = 0.77, P = 0.02). This suggests that STAT3 induces a characteristic set of gene expression changes in HER2-positive cancers. Tumors characterized as high pSTAT3-GS were associated with trastuzumab resistance (log rank P = 0.049). These results were confirmed using data from the prospective, randomized controlled FinHer study, where the effect was especially prominent in HER2-positive estrogen receptor (ER)-negative tumors (interaction test P = 0.02). Of interest, constitutively activated pSTAT3 tumors were associated with loss of PTEN, elevated IL6, and stromal reactivation.
  
  
  CONCLUSIONS
  This study provides compelling evidence for a link between pSTAT3 and trastuzumab resistance in HER2-positive primary breast cancers. Our results suggest that it may be valuable to add agents targeting the STAT3 pathway to trastuzumab for treatment of HER2-positive breast cancer.
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.
authors.forename: Amir
authors.initials: A
authors.lastname: Sonnenblick
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brohée
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.
authors.forename: Debora
authors.initials: D
authors.lastname: Fumagalli
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Vincent
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Venet
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.|Medical Oncology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Bld de Waterloo, 1000, Brussels, Belgium.
authors.forename: Michail
authors.initials: M
authors.lastname: Ignatiadis
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salgado
authors.affiliation: Molecular Immunology Lab, Institut Jules Bordet, Université Libre de Bruxelles, 1000, Brussels, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Van den Eynden
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.
authors.forename: Françoise
authors.initials: F
authors.lastname: Rothé
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Desmedt
authors.affiliation: Multidisciplinary Breast Center, KULeuven, University Hospitals, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.affiliation: German Breast Group, Neu-Isenburg and Sana-Klinikum, Offenbach, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.affiliation: Institute of Pathology, Charité Hospital Campus Mitte, and German Cancer Consortium (DKTK), Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: Department of Oncology, Helsinki University, Hospital and Helsinki University, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Division of Cancer Medicine and Research, Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia.
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
authors.affiliation: Pathology Department, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sirtaine
authors.affiliation: Department of Oncology, University of Tampere and Tampere University Hospital, PO Box 607, FIN 33101, Tampere, Finland.
authors.forename: Pirkko-Liisa
authors.initials: PL
authors.lastname: Kellokumpu-Lehtinen
authors.affiliation: Medical Oncology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Bld de Waterloo, 1000, Brussels, Belgium.
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.affiliation: Breast Cancer Translational Research Laboratory J-C Heuson, Institut Jules Bordet, Bld de Waterloo, Université Libre de Bruxelles, 1000, Brussels, Belgium. christos.sotiriou@bordet.be.|Medical Oncology Unit, Institut Jules Bordet, Université Libre de Bruxelles, Bld de Waterloo, 1000, Brussels, Belgium. christos.sotiriou@bordet.be.
authors.forename: Christos
authors.initials: C
authors.lastname: Sotiriou
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010766:Phosphorylation; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D014157:Transcription Factors; D000068878:Trastuzumab; C060759:enhancer-binding protein AP-3