title: HAGE in Triple-Negative Breast Cancer Is a Novel Prognostic, Predictive, and Actionable Biomarker: A Transcriptomic and Protein Expression Analysis.
abstract: OBJECTIVE
  The expression of HAGE as a novel prognostic and predictive tool was assessed in 1,079 triple-negative breast cancers (TNBC).
  
  
  METHODS
  HAGE protein expression was investigated in an early primary TNBC (EP-TNBC; n = 520) cohort who received adjuvant chemotherapy (ACT) and in a locally advanced primary TNBC cohort who received anthracycline combination Neo-ACT (n = 110; AC-Neo-ACT). HAGE-mRNA expression was evaluated in the METABRIC-TNBC cohort (n = 311) who received ACT and in a cohort of patients with TNBC who received doxorubicin/cyclophosphamide Neo-ACT, followed by 1:1 randomization to ixabepilone (n = 68) or paclitaxel (n = 64) as part of a phase II clinical trial. Furthermore, a cohort of 128 tumors with integrated HAGE gene copy number changes, mRNA, and protein levels were analyzed.
  
  
  RESULTS
  In patients with EP-TNBC, who were chemotherapy-naïve, high HAGE protein expression (HAGE(+)) was associated with a higher risk of death [HR, 1.3; 95% confidence interval (CI), 1.2-1.5; P = 0.000005] when compared with HAGE(-) cases. Patients who received ACT and expressed mRNA-HAGE(+) were at a lower risk of death than those who were mRNA-HAGE(-) (P = 0.004). The expression of HAGE was linked to the presence of tumor-infiltrating lymphocytes (TIL), and both features were found to be independent predictors for pathologic complete response (pCR, P < 0.001) and associated with prolonged survival (P < 0.01), following AC-Neo-ACT. In patients with residual disease, HAGE(+) had a 2-fold death risk increase (P = 0.018) compared with HAGE(-).
  
  
  CONCLUSIONS
  HAGE expression is a potential prognostic marker and a predictor of response to anthracycline treatment in TNBC. A prospective clinical trial to examine the therapeutic value of HAGE for TNBC cases is warranted.
authors.affiliation: Clinical Oncology Department, Nottingham University Hospitals, Nottingham, United Kingdom.
authors.forename: Tarek M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, United Kingdom.
authors.forename: Stephanie E B
authors.initials: SE
authors.lastname: McArdle
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, United Kingdom.
authors.forename: Devika
authors.initials: D
authors.lastname: Agarwal
authors.affiliation: Clinical Oncology Department, Nottingham University Hospitals, Nottingham, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Moseley
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, United Kingdom.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Green
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, United Kingdom.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Ball
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, United Kingdom.
authors.forename: A Graham
authors.initials: AG
authors.lastname: Pockley
authors.affiliation: Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, United Kingdom.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, United Kingdom.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rees
authors.affiliation: Clinical Oncology Department, Nottingham University Hospitals, Nottingham, United Kingdom. steve.chan@nuh.nhs.uk.
authors.forename: Stephen Y T
authors.initials: SY
authors.lastname: Chan
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D055028:Comparative Genomic Hybridization; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D056915:DNA Copy Number Variations; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008875:Middle Aged; D015999:Multivariate Analysis; D020360:Neoadjuvant Therapy; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D059467:Transcriptome; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000628:therapy
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; C412324:DDX43 protein, human; D053487:DEAD-box RNA Helicases