Background: We recently provided evidences that HAGE is immunogenic. In current study, the expression of HAGE as a prognostic and predictive tool was assessed in 1079 TNBC patients. Methods: HAGE protein and mRNA expressions were investigated in two cohorts of BC who received adjuvant chemotherapy (CT) with 10 year median follow up: (1) early primary TNBC (EP TNBC; n = 520) and (2) the METABRIC TNBC (n = 317) cohorts, respectively. The relationship between HAGE protein and mRNA expressions and response to CT was explored in two TNBC cohorts in whom pathological complete response (pCR) was the endpoint: (3) the multicentre phase II clinical trial cohort (NCT00455533; n = 132) received doxorubicin/cyclophosphamide neoadjuvant-CT (Neo-ACT), followed by 1:1 randomisation to ixabepilone (n = 68) or paclitaxel (n = 64) and (4) a locally advanced primary TNBC cohort (LAP TNBC, n = 110) received anthracycline-based Neo-ACT (AC-Neo-ACT), respectively. To investigate HAGE interactome in TNBC, a non-linear, artificial neural network (ANN) modelling based, data mining approach was applied. Results: In CT naïve EP TNBC, high (+) HAGE protein expression had a higher risk of death compared to low (-) HAGE expression (HR (95% CI) = 1.4 (1.2-1.7, p = 0.0000004). While in EP TNBC patients who received adjuvant CT, HAGE mRNA+ level exhibited lower risk of death compared to HAGE mRNA- (HR (95% CI) = 0.56 (0.36-0.86), p = 0.0.008). In LAP TNBC received AC-Neo-ACT, pre CT HAGE+ expression was: linked to tumour infiltration lymphocytes (TILs, p < 0.001), found to be independent predictor for pCR [OR (95%CI) = 5.1 (1.2-22.4), p = 0.03] and significantly associated with prolonged survival (HR (95% CI) = 0.54 (0.41-0.85), p = 0.0.005). Following AC-Neo-ACT, loss of HAGE protein expression was found (p = 0.002) and patients with HAGE+ residual disease exhibited no TILs and had two fold increase in the risk of death (HR (95% CI) = 1.66 (1.10-2.52), p = 0.0.018) compared to HAGE- residual tumours. HAGE interactome included genes that involved in protein degradation and antigen presentation Conclusions: The expression of HAGE is a potential prognostic marker and a predictor of response to AC CT in TNBC.