title: Decreased expression of ABAT and STC2 hallmarks ER-positive inflammatory breast cancer and endocrine therapy resistance in advanced disease.
abstract: BACKGROUND
  Patients with Estrogen Receptor α-positive (ER+) Inflammatory Breast Cancer (IBC) are less responsive to endocrine therapy compared with ER+ non-IBC (nIBC) patients. The study of ER+ IBC samples might reveal biomarkers for endocrine resistant breast cancer.
  
  
  METHODS
  Gene expression profiles of ER+ samples from 201 patients were explored for genes that discriminated between IBC and nIBC. Classifier genes were applied onto clinically annotated expression data from 947 patients with ER+ breast cancer and validated with RT-qPCR for 231 patients treated with first-line tamoxifen. Relationships with metastasis-free survival (MFS) and progression-free survival (PFS) following adjuvant and first-line endocrine treatment, respectively, were investigated using Cox regression analysis.
  
  
  RESULTS
  A metagene of six genes including the genes encoding for 4-aminobutyrate aminotransferase (ABAT) and Stanniocalcin-2 (STC2) were identified to distinguish 22 ER+ IBC from 43 ER+ nIBC patients and remained discriminatory in an independent series of 136 patients. The metagene and two genes were not prognostic in 517 (neo)adjuvant untreated lymph node-negative ER+ nIBC breast cancer patients. Only ABAT was related to outcome in 250 patients treated with adjuvant tamoxifen. Three independent series of in total 411 patients with advanced disease showed increased metagene scores and decreased expression of ABAT and STC2 to be correlated with poor first-line endocrine therapy outcome. The biomarkers remained predictive for first-line tamoxifen treatment outcome in multivariate analysis including traditional factors or published signatures. In an exploratory analysis, ABAT and STC2 protein expression levels had no relation with PFS after first-line tamoxifen.
  
  
  CONCLUSIONS
  This study utilized ER+ IBC to identify a metagene including ABAT and STC2 as predictive biomarkers for endocrine therapy resistance.
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands. Electronic address: m.p.h.m.jansen@erasmusmc.nl.
authors.forename: Maurice P H M
authors.initials: MP
authors.lastname: Jansen
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals St-Augustinus, Oosterveldlaan 24, Antwerp B2610, Belgium; Department of Medical Oncology, University Hospital Antwerp, Wilrijkstraat 10, B2650 Antwerp, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Sas
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands.
authors.forename: Anieta M
authors.initials: AM
authors.lastname: Sieuwerts
authors.affiliation: Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Caroline
authors.initials: C
authors.lastname: Van Cauwenberghe
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands.
authors.forename: Diana
authors.initials: D
authors.lastname: Ramirez-Ardila
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands.
authors.forename: Maxime
authors.initials: M
authors.lastname: Look
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Ruigrok-Ritstier
authors.affiliation: Marseille Cancer Research Center (CRCM), UMR891 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Marseille, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Finetti
authors.affiliation: Marseille Cancer Research Center (CRCM), UMR891 Inserm, Institut Paoli-Calmettes (IPC), Department of Molecular Oncology, Marseille, France.
authors.forename: François
authors.initials: F
authors.lastname: Bertucci
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands.
authors.forename: Mieke M
authors.initials: MM
authors.lastname: Timmermans
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands.
authors.forename: Carolien H M
authors.initials: CH
authors.lastname: van Deurzen
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands.
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Research and Development, Agendia BV, Amsterdam, The Netherlands.
authors.forename: Iris
authors.initials: I
authors.lastname: Simon
authors.affiliation: Research and Development, Agendia BV, Amsterdam, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Roepman
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Sabine C
authors.initials: SC
authors.lastname: Linn
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals St-Augustinus, Oosterveldlaan 24, Antwerp B2610, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: van Dam
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Kok
authors.affiliation: Department of Medical Oncology, University Hospital Antwerp, Wilrijkstraat 10, B2650 Antwerp, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Lardon
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals St-Augustinus, Oosterveldlaan 24, Antwerp B2610, Belgium.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Vermeulen
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands.
authors.forename: John A
authors.initials: JA
authors.lastname: Foekens
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals St-Augustinus, Oosterveldlaan 24, Antwerp B2610, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Dirix
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3000 CA Rotterdam, The Netherlands.
authors.forename: Els M J J
authors.initials: EM
authors.lastname: Berns
authors.affiliation: Translational Cancer Research Unit, GZA Hospitals St-Augustinus, Oosterveldlaan 24, Antwerp B2610, Belgium; Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Van Laere
mesh_terms: D000612:4-Aminobutyrate Transaminase / Q000096:biosynthesis*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006023:Glycoproteins / Q000096:biosynthesis*; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D015996:Survival Rate; D013629:Tamoxifen / Q000008:administration & dosage*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C114997:STC2 protein, human; D013629:Tamoxifen; D000612:4-Aminobutyrate Transaminase
keywords: ABAT; Endocrine therapy resistance; Inflammatory breast cancer; Metastatic disease; STC2