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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Carcinoma/chemistry , DEAD-box RNA Helicases/analysis , Drug Resistance, Neoplasm , Neoplasm Proteins/analysis , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms/therapy , Carcinoma/drug therapy , Carcinoma/mortality , Carcinoma/therapy , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Kaplan-Meier Estimate , Lymphocytes, Tumor-Infiltrating , Mastectomy , Menopause , Methotrexate/administration & dosage , Mitotic Index , Neoplasm Invasiveness , Neoplasms, Hormone-Dependent/chemistry , Neoplasms, Hormone-Dependent/drug therapy , Neoplasms, Hormone-Dependent/mortality , Neoplasms, Hormone-Dependent/therapy , Prognosis , Proportional Hazards Models , Receptor, ErbB-2/analysis , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Tamoxifen/administration & dosage , Treatment OutcomeABSTRACT
BACKGROUND: TNBC represents a heterogeneous subgroup of BC with poor prognosis and frequently resistant to CT. MATERIAL AND METHODS: The relationship between Bcl2 immunohistochemical protein expression and clinico-pathological outcomes was assessed in 736 TNBC-patients: 635 patients had early primary-TNBC (EP-TNBC) and 101 had primary locally advanced (PLA)-TNBC treated with neo-adjuvant- ATC-CT. RESULTS: Negative Bcl2 (Bcl2-) was observed in 70% of EP-TNBC and was significantly associated with high proliferation, high levels of P-Cadherin, E-Cadherin and HER3 (P's < 0.01), while Bcl2+ was significantly associated with high levels of p27, MDM4 and SPAG5 (P < 0.01). After controlling for chemotherapy and other prognostic factors, Bcl2- was associated with 2-fold increased risk of death (P = 0.006) and recurrence (P = 0.0004). Furthermore, the prognosis of EP-TNBC/Bcl2- patients had improved both BC-specific survival (P = 0.002) and disease-free survival (P = 0.003), if they received adjuvant-ATC-CT. Moreover, Bcl2- expression was an independent predictor of pathological complete response of primary locally advanced triple negative breast cancer (PLA-TNBC) treated with neoadjuvant-ATC-CT (P = 0.008). CONCLUSION: Adding Bcl2 to the panel of markers used in current clinical practice could provide both prognostic and predictive information in TNBC. TNBC/Bcl2- patients appear to benefit from ATC-CT, whereas Bcl2+ TNBC seems to be resistant to ATC-CT and may benefit from a trial of different type of chemotherapy with/without novel-targeted agents.
