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PurposeThe expression of HAGE as a novel prognostic and predictive tool was assessed in 1,079 triple-negative breast cancers (TNBC).Experimental designHAGE 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.ResultsIn 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(-).ConclusionsHAGE 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.

Original publication




Journal article


Clinical cancer research : an official journal of the American Association for Cancer Research

Publication Date





905 - 914


Clinical Oncology Department, Nottingham University Hospitals, Nottingham, United Kingdom.


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