title: HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer.
abstract: BACKGROUND
  HAGE protein is a known immunogenic cancer-specific antigen.
  
  
  METHODS
  The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated.
  
  
  RESULTS
  Eight percent of patients with EP-BC exhibited high HAGE expression (HAGE+) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGE+expression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+residual disease (P=0.0003).
  
  
  CONCLUSIONS
  This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC.
authors.affiliation: Department of Clinical Oncology, University of Nottingham City Hospital NHS Trust, Nottingham, UK.
authors.forename: T M A
authors.initials: TM
authors.lastname: Abdel-Fatah
authors.affiliation: John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK.
authors.forename: S E B
authors.initials: SE
authors.lastname: McArdle
authors.affiliation: John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK.
authors.forename: C
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Department of Clinical Oncology, University of Nottingham City Hospital NHS Trust, Nottingham, UK.
authors.forename: P M
authors.initials: PM
authors.lastname: Moseley
authors.affiliation: John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK.
authors.forename: G R
authors.initials: GR
authors.lastname: Ball
authors.affiliation: John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK.
authors.forename: A G
authors.initials: AG
authors.lastname: Pockley
authors.affiliation: Department of Histopathology, University of Nottingham City Hospital NHS Trust, Nottingham, UK.
authors.forename: I O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: John van Geest Cancer Research Centre, Nottingham Trent University, Nottingham, UK.
authors.forename: R C
authors.initials: RC
authors.lastname: Rees
authors.affiliation: Department of Clinical Oncology, University of Nottingham City Hospital NHS Trust, Nottingham, UK.
authors.forename: S Y T
authors.initials: SY
authors.lastname: Chan
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000401:mortality / Q000628:therapy; D002277:Carcinoma / Q000737:chemistry* / Q000188:drug therapy / Q000401:mortality / Q000628:therapy; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D053487:DEAD-box RNA Helicases / Q000032:analysis*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating; D008408:Mastectomy; D008593:Menopause; D008727:Methotrexate / Q000008:administration & dosage; D008940:Mitotic Index; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis*; D009376:Neoplasms, Hormone-Dependent / Q000737:chemistry / Q000188:drug therapy / Q000401:mortality / Q000628:therapy; D011379:Prognosis; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D011960:Receptors, Estrogen / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D013629:Tamoxifen / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D003520:Cyclophosphamide; D053487:DEAD-box RNA Helicases; D005472:Fluorouracil; D008727:Methotrexate; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen; C508053:ERBB2 protein, human; C412324:DDX43 protein, human
references.citation: Nat Rev Immunol. 2008 Jan;8(1):59-73
references.pmid: 18097448
references.citation: J Natl Cancer Inst. 2005 Aug 17;97(16):1180-4
references.pmid: 16106022
references.citation: Breast Cancer Res Treat. 2011 May;127(1):53-63
references.pmid: 20499159
references.citation: Oncology (Williston Park). 2010 Oct;24(11 Suppl 4):1-15
references.pmid: 21284351
references.citation: Histopathology. 1994 Jan;24(1):41-7
references.pmid: 8144141
references.citation: Cancer Res. 2007 Aug 15;67(16):7572-8
references.pmid: 17699760
references.citation: Cancer Res. 2000 Jul 15;60(14):3848-55
references.pmid: 10919659
references.citation: Cancer Immun. 2007 Jul 12;7:11
references.pmid: 17625806
references.citation: Blood. 2004 Mar 1;103(5):1635-40
references.pmid: 14604977
references.citation: Cancer Immunol Immunother. 2007 Dec;56(12):1885-95
references.pmid: 17487488
references.citation: J Biol Chem. 2012 Apr 20;287(17):13633-43
references.pmid: 22393060
references.citation: Mutat Res. 1999 Jan 25;423(1-2):91-101
references.pmid: 10029684
references.citation: PLoS One. 2011;6(7):e22203
references.pmid: 21765952
references.citation: J Clin Oncol. 2007 Nov 20;25(33):5287-312
references.pmid: 17954709
references.citation: Cancer. 1994 Aug 1;74(3):893-9
references.pmid: 8039116
references.citation: J Clin Oncol. 2010 Jan 1;28(1):105-13
references.pmid: 19917869
references.citation: J Pathol. 2010 Dec;222(4):388-99
references.pmid: 20922713
references.citation: Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011 Oct;19(5):1171-5
references.pmid: 22040965
references.citation: Int J Cancer. 2009 Jan 15;124(2):352-7
references.pmid: 18942708
references.citation: Leukemia. 2002 Nov;16(11):2238-42
references.pmid: 12399967
references.citation: Clin Breast Cancer. 2010;10 Suppl 1:E8-15
references.pmid: 20587409
references.citation: Haematologica. 2007 Feb;92(2):153-62
references.pmid: 17296563
references.citation: Cancer Immun. 2010 Jan 11;10:2
references.pmid: 20058853
references.citation: Cancer. 1999 Jan 1;85(1):112-8
references.pmid: 9921982
references.citation: Clin Cancer Res. 2003 Dec 15;9(17):6453-60
references.pmid: 14695148
references.citation: J Clin Oncol. 2007 Jan 1;25(1):118-45
references.pmid: 17159189
references.citation: J Pathol. 2010 Mar;220(4):419-34
references.pmid: 20044801
references.citation: Cancer Res. 2001 Jun 15;61(12):4671-4
references.pmid: 11406534
references.citation: Histopathology. 1991 Nov;19(5):403-10
references.pmid: 1757079
references.citation: J Exp Med. 2005 Jan 17;201(2):249-57
references.pmid: 15657294
references.citation: Int J Cancer. 2006 May 1;118(9):2269-75
references.pmid: 16331618
references.citation: J Oncol Pract. 2010 Jul;6(4):195-7
references.pmid: 21037871
references.citation: Oncogene. 2009 Nov 19;28(46):4053-64
references.pmid: 19718048
references.citation: Cancer Res. 2001 Sep 15;61(18):6682-7
references.pmid: 11559535
references.citation: Lancet. 2008 Jan 5;371(9606):29-40
references.pmid: 18177773
references.citation: Mol Cancer Res. 2005 Jun;3(6):355-63
references.pmid: 15972854
references.citation: Cancer Treat Rev. 2010 Dec;36(8):584-94
references.pmid: 20554119
references.citation: Hum Pathol. 2001 Aug;32(8):856-62
references.pmid: 11521231
references.citation: Nucleic Acids Res. 1990 Sep 25;18(18):5413-7
references.pmid: 2216714
references.citation: PLoS One. 2011 Mar 18;6(3):e17876
references.pmid: 21437249