HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer

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.