title: Endometrial Carcinoma Recurrence Score (ECARS) validates to identify aggressive disease and associates with markers of epithelial-mesenchymal transition and PI3K alterations.
abstract: OBJECTIVE
  Our previously reported 29-gene expression signature identified an aggressive subgroup of endometrial cancer patients with PI3K activation. We here wanted to validate these findings by independent patient series.
  
  
  METHODS
  The 29-gene expression signature was assessed in fresh frozen tumor tissue from 280 primary endometrial carcinomas (three independent cohorts), 19 metastatic lesions and in 333 primary endometrial carcinomas using TCGA data, and expression was related to clinico-pathologic features and survival. The 29-gene signature was assessed by real-time quantitative PCR, DNA oligonucleotide microarrays, or RNA sequencing. PI3K alterations were assessed by immunohistochemistry, DNA microarrays, DNA sequencing, SNP arrays or fluorescence in situ hybridization. A panel of markers of epithelial-mesenchymal transition (EMT) was also correlated to the 29-gene signature score.
  
  
  RESULTS
  High 29-gene Endometrial Carcinoma Recurrence Score (ECARS) values consistently validated to identify patients with aggressive clinico-pathologic phenotype and reduced survival. Within the presumed favorable subgroups of low grade, endometrioid tumors confined to the uterus, high ECARS still predicted a poor prognosis. The score was higher in metastatic compared to primary lesions (P<0.001) and was significantly associated with potential measures of PI3K activation, markers of EMT and vascular invasion as an indicator of metastatic spread (all P<0.001).
  
  
  CONCLUSIONS
  ECARS validates to identify aggressive endometrial carcinomas in multiple, independent patients cohorts. The higher signature score in metastatic compared to primary lesions, and the potential link to PI3K activation and EMT, support further studies of ECARS in relation to response to PI3K and EMT inhibitors in clinical trials of metastatic endometrial carcinoma.
authors.affiliation: Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway. Electronic address: elisabeth.wik@med.uib.no.
authors.forename: E
authors.initials: E
authors.lastname: Wik
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Trovik
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Computational Biology Unit, University of Bergen, Bergen, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Kusonmano
authors.affiliation: Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Birkeland
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: M B
authors.initials: MB
authors.lastname: Raeder
authors.affiliation: Department of Radiation Oncology, Dana-Farber/Brigham and Women's Cancer Center, Boston, MA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Pashtan
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: E A
authors.initials: EA
authors.lastname: Hoivik
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: C
authors.initials: C
authors.lastname: Krakstad
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: H M J
authors.initials: HM
authors.lastname: Werner
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: F
authors.initials: F
authors.lastname: Holst
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Mjøs
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: M K
authors.initials: MK
authors.lastname: Halle
authors.affiliation: Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Mannelqvist
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: K K
authors.initials: KK
authors.lastname: Mauland
authors.affiliation: Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
authors.forename: A M
authors.initials: AM
authors.lastname: Oyan
authors.affiliation: Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway.
authors.forename: I M
authors.initials: IM
authors.lastname: Stefansson
authors.affiliation: Computational Biology Unit, University of Bergen, Bergen, Norway.
authors.forename: K
authors.initials: K
authors.lastname: Petersen
authors.affiliation: Department of Pathology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Simon
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Cherniack
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway; Department of Microbiology, Haukeland University Hospital, Bergen, Norway.
authors.forename: K H
authors.initials: KH
authors.lastname: Kalland
authors.affiliation: Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway.
authors.forename: L A
authors.initials: LA
authors.lastname: Akslen
authors.affiliation: Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Norway.
authors.forename: H B
authors.initials: HB
authors.lastname: Salvesen
mesh_terms: D014408:Biomarkers, Tumor; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases
keywords: ECARS; Endometrial Carcinoma Recurrence Score; Epithelial–mesenchymal transition; PI3K; Prognosis