HAGE in Triple-Negative Breast Cancer Is a Novel Prognostic, Predictive, and Actionable Biomarker: A Transcriptomic and Protein Expression Analysis

Clin Cancer Res. 2016 Feb 15;22(4):905-14. doi: 10.1158/1078-0432.CCR-15-0610. Epub 2015 Aug 3.

Abstract

Purpose: The expression of HAGE as a novel prognostic and predictive tool was assessed in 1,079 triple-negative breast cancers (TNBC).

Experimental design: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Carcinoma, Ductal, Breast / genetics
  • Carcinoma, Ductal, Breast / metabolism*
  • Carcinoma, Ductal, Breast / mortality
  • Carcinoma, Ductal, Breast / therapy
  • Chemotherapy, Adjuvant
  • Comparative Genomic Hybridization
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • DNA Copy Number Variations
  • Disease-Free Survival
  • Female
  • Gene Expression Profiling
  • Humans
  • Kaplan-Meier Estimate
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Middle Aged
  • Multivariate Analysis
  • Neoadjuvant Therapy
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Prognosis
  • Transcriptome*
  • Treatment Outcome
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / mortality
  • Triple Negative Breast Neoplasms / therapy

Substances

  • Biomarkers, Tumor
  • Neoplasm Proteins
  • DDX43 protein, human
  • DEAD-box RNA Helicases