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.

Figure 1

The clinical outcome of HAGE protein expression in the training set of primary early breast cancer. (A) (1–3) Photomicrographs showing weak nuclear expression of HAGE in normal breast tissue (A-1), breast cancer tissue (A2–3) showing negative expression of HAGE in neoplastic cells (A-2), positive expression of HAGE in neoplastic cells (A-3) (magnification × 200). (B) (1–4) Kaplan–Meier curves showing the relationship between HAGE expression and breast cancer-specific and disease-free survival in the training set of primary early breast cancer (PE-BC). See text for details.

Figure 2

The clinical outcome of HAGE protein expression in the test set of primary early breast cancer (PE-BC). Kaplan–Meier curves showing the relationship between HAGE expression and breast cancer-specific survival and disease-free survival in the test set of primary early breast cancer (PE-BC). (A) Whole cohort; (B) LN− (C) ER+ (D) high-risk ER− subpopulation. See text for details.

Figure 3

The effect of Tamoxifen treatment on the clinical outcome of HAGE protein expression in high risk oestrogen receptor positive (ER+) primary early breast cancer (PE-BC). (A, B) Kaplan–Meier curves showing the effect of tamoxifen on breast cancer-specific survival (BCSS) and disease-free survival (DFS) in high-risk primary ER+ breast cancer, stratified according to the HAGE status. (A) HAGE negative and (B) HAGE positive. See text for details.

Figure 4

The clinical outcome of HAGE protein expression in high risk oestrogen receptor negative (ER-) primary early breast cancer (PE-BC). (A–C) Kaplan–Meier curves showing the relationship between HAGE expression and breast cancer-specific survival (BCSS) and disease-free survival (DFS) in primary oestrogen receptor-negative breast cancer (PER-BC), stratified according to the received adjuvant chemotherapy protocols. (A) Whole cohort, (B) no chemotherapy/or less effective CMF and (C) anthracycline combination therapy (ACT). See text for details.

Figure 5

The clinical outcome of HAGE protein expression in primary locally advanced breast cancer (PLA-BC) before and after receiving neoadjuvant chemotherapy. (A) Kaplan–Meier curves illustrating the relationship between prechemotherapy expression of HAGE and disease-free survival (DFS) in the entire PLA-BC cohort (A-1) and in the ER− subgroup (A-2). (B) Kaplan–Meier curves illustrating the relationship between HAGE expression and DFS in patients who exhibited evidence of pathological residual disease after receiving neoadjuvant-ACT in the entire PLA-BC cohort (B-1) and in the ER+ subgroup (B-2).