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.
Subject(s)
Anthracyclines/administration & dosage , Prognosis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Triple Negative Breast Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Staging , Proto-Oncogene Proteins c-bcl-2/genetics , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathologyABSTRACT
Gene expression microarrays allow for the high throughput analysis of huge numbers of gene transcripts and this technology has been widely applied to the molecular and biological classification of cancer patients and in predicting clinical outcome. A potential handicap of such data intensive molecular technologies is the translation to clinical application in routine practice. In using an artificial neural network bioinformatic approach, we have reduced a 70 gene signature to just 9 genes capable of accurately predicting distant metastases in the original dataset. Upon validation in a follow-up cohort, this signature was an independent predictor of metastases free and overall survival in the presence of the 70 gene signature and other factors. Interestingly, the ANN signature and CA9 expression also split the groups defined by the 70 gene signature into prognostically distinct groups. Subsequently, the presence of protein for the principal prognosticator gene was categorically assessed in breast cancer tissue of an experimental and independent validation patient cohort, using immunohistochemistry. Importantly our principal prognosticator, CA9, showed that it is capable of selecting an aggressive subgroup of patients who are known to have poor prognosis.
