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.

Molecular profiling of breast cancer in Nigerian women identifies an altered p53 pathway as a major mechanism underlying its poor prognosis compared with British counterpart.

BACKGROUND: Advances in breast cancer (BC) research have demonstrated differences between black and white women with regarding tumour behaviour, patient outcome and response to treatment which can be explained by underlying genetic changes. The tumour suppressor gene p53 has been speculated to be involved in tumour biology of triple negative and/or basal -like BC and more commonly observed in black than caucasian women. MATERIALS AND METHODS: In this study, the protein expression of p53 was investigated in tissue samples from a series of 308 Nigerian women, prepared as a tissue microarray (TMA), using immunohistochemistry. Clinicopathological parameters, biomarkers of functional significance in BC and patient outcome of tumours expressing p53 in Nigerian women were correlated with UK grade matched series. RESULTS: A significantly large proportion of BC from Nigerian women showed high p53 expression compared with UK women (p<0.001). In those tumours showing positive p53 in the Nigerian series, a significant proportion were premenopausal, diagnosed before 50 years, larger in size, with evidence of metastasis into lymphatic vessels ( all p<0.001). In addition, p53 positive expression was also significantly correlated with negative expression of ER and PgR (p<0.001, p<0.03 respectively), BRCA1, MDM2 (all p<0.001), p21 (p=0.006) and E-cadherin (p=0.001) and positively associated with P-cadherin (p=0.001), triple negative phenotype, basal cytokeratin (CK) 5/6 expression (p<0.04) and basal phenotype compared with the UK series (p<0.001). Survival analyses showed Nigerian women with BC were significantly associated with poor BC specific survival (p<0.001, but no significant association with disease free interval was observed. CONCLUSION: In this study, protein expressions of p53 pathways are different between Nigerian and UK BC women and this may also contribute to differences in tumour biology. Therefore, targeting these p53 pathways for therapeutic usage might improve the poor outcome observed in Black Nigerian women.

Bcl2 is an independent prognostic marker of triple negative breast cancer (TNBC) and predicts response to anthracycline combination (ATC) chemotherapy (CT) in adjuvant and neoadjuvant settings.

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.

Molecular characteristics and prognostic features of breast cancer in Nigerian compared with UK women.

Although breast cancer (BC) incidence is lower in African-American women compared with White-American, in African countries such as Nigeria, BC is a common disease. Nigerian women have a higher risk for early-onset, with a high mortality rate from BC, prompting speculation that risk factors could be genetic and the molecular portrait of these tumours are different to those of western women. In this study, 308 BC samples from Nigerian women with complete clinical history and tumour characteristics were included and compared with a large series of BC from the UK as a control group. Immunoprofile of these tumours was characterised using a panel of 11 biomarkers of known relevance to BC. The immunoprofile and patients' outcome were compared with tumour grade-matched UK control group. Nigerian women presenting with BC were more frequently premenopausal, and their tumours were characterised by large primary tumour size, high tumour grade, advanced lymph node stage, and a higher rate of vascular invasion compared with UK women. In the grade-matched groups, Nigerian BC showed over representation of triple-negative and basal phenotypes and BRCA1 deficiency BC compared with UK women, but no difference was found regarding HER2 expression between the two series. Nigerian women showed significantly poorer outcome after development of BC compared with UK women. This study demonstrates that there are possible genetic and molecular differences between an indigenous Black population and a UK-based series. The basal-like, triple negative and BRCA1 dysfunction groups of tumours identified in this study may have implications in the development of screening programs and therapies for African patients and families that are likely to have a BRCA1 dysfunction, basal like and triple negative.

A validated gene expression profile for detecting clinical outcome in breast cancer using artificial neural networks.

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.

Molecular profiling of breast cancer in Nigerian women identifies an altered p53 pathway as a major mechanism underlying its poor prognosis compared with British counterpart

Advances in breast cancer (BC) research have demonstrated differences between black and white women with regarding tumour behaviour, patient outcome and response to treatment which can be explained by underlying genetic changes. The tumour suppressor gene p53 has been speculated to be involved in tumour biology of triple negative and/or basal –like BC and more commonly observed in black than caucasian women. Materials and methods: In this study, the protein expression of p53 was investigated in tissue samples from a series of 308 Nigerian women, prepared as a tissue microarray (TMA), using immunohistochemistry. Clinicopathological parameters, biomarkers of functional significance in BC and patient outcome of tumours expressing p53 in Nigerian women were correlated with UK grade matched series. Results: A significantly large proportion of BC from Nigerian women showed high p53 expression compared with UK women (p<0.001). In those tumours showing positive p53 in the Nigerian series, a significant proportion were premenopausal, diagnosed before 50 years, larger in size, with evidence of metastasis into lymphatic vessels ( all p<0.001). In addition, p53 positive expression was also significantly correlated with negative expression of ER and PgR (p<0.001, p<0.03 respectively), BRCA1, MDM2 (all p<0.001), p21 (p=0.006) and E-cadherin (p=0.001) and positively associated with P-cadherin (p=0.001), triple negative phenotype, basal cytokeratin (CK) 5/6 expression (p<0.04) and basal phenotype compared with the UK series (p<0.001). Survival analyses showed Nigerian women with BC were significantly associated with poor BC specific survival (p<0.001, but no significant association with disease free interval was observed. Conclusion: In this study, protein expressions of p53 pathways are different between Nigerian and UK BC women and this may also contribute to differences in tumour biology. Therefore, targeting these p53 pathways for therapeutic usage might improve the poor outcome observed in Black Nigerian women.