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.
Introduction: SPAG5 has been found to be involved in the functional and dynamic regulation of mitotic spindles, and to be essential for chromosome segregation fidelity. Recently we found by using neural network and pathways analysis of a gene expression array data that SPAG5 was among top 10 ranked genes out of 48,000 of transcripts, that accurately predicted worse clinical outcome based on a 10-fold external cross-validation analysis with an average classification accuracy of >99.999%. Moreover we found that 5% of BC showed amplification of SPAG5 locus at chromosome 17q11.2 and SPAG5 mRNA expression levels displayed a statistically significant correlation with its copy number. Methods: In the current study the molecular and clinicopathological features of SPAG5 expression and its effect on management of BC have been investigated in 2800 BC patients with primary operable invasive BCs constituted four cohorts: 1) A series of 1650 BC patients received adjuvant endocrine and/or CMF chemotherapy according to NPI.2) A series of 256 BC received adjuvant anthracycline-based chemotherapy (ATC-CT)3) A series of 140 primary BC HER2+ patients treated with ATC-CT+ Herceptin 4) To validate SPAG5 as a predictor factor for ATC-CT, 260 patients with locally advanced primary breast cancer treated with neoadjuvant ATC-CT were included and the pathological complete response (pCR) was used to evaluate the response to chemotherapy. Immunohistochemical staining was performed using Anti–SPAG5 rabbit polyclonal (HPA022479; Sigma). Results: i) By using dual immunoflurescent in BC cell lines, co-expression of SPAG5 and proliferating cell nuclear antigen (PCNA) was detected in 4 out of 5 of the breast cancer cell lines screened (MCF7, T47D, MDA468 and MDA231) providing evidence for the importance of SPAG5 in cell proliferation. ii) 20% of breast cancer showed SPAG5 protein overexpression. SPAG5 overexpression showed a statistically significant association with ER−, PR−, triple negative phenotype, high grade tumour, high ki67, basal like phenotype and epithelial mesenchymal transition phenotype, p53 mutation and absence of DNA repair genes (BRCA1, ATM and XRCC1); p values <0.0001. iii) In high risk ER− BC patients who did not received any adjuvant therapy or received ineffective CMF chemotherapy, SPAG5+ protein expression had a similar risk of death and recurrence. Receiving ATC-CT had a positive impact on high risk ER− BC patients with SPAG5 protein + expression as SPAG5+ protein expression showed 72–65% less of death, recurrence and metastases compared to SPAG5−; p < 0.0001. The positive impact of ATC-CT on SPAG5+BC has also been confirmed in HER2+ who either received ATC-CT only or ACT-CT plus Herceptin. iv) Moreover, BC received neoadjuvantATC-CT, SPAG5+ BC achieved 39% pCR vs., 6% of SPAG5-negative BC (p < 0.00001). After controlling to other validated predictors for pCR, SPAG5 remained as a powerful independent predictor (HR; 2.4, CI 95%; 1.5–3.9; p = 0.00001). Conclusion: SPAG5 is an important novel gene implicated in the survival of BC cells and its protein expression is an independent predictor for ATC- CT. SPAG5 may provide new avenues for the discovery of new predictive marker to guide therapeutic intervention. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-18.
Introduction: Recently, TOPO2A alteration was found to be a predictor for ATC-CT and by using neural network and pathways analysis of gene expression array data, TROAP gene was revealed as a major hub in TOPO2A pathway and strongly related to genes that are involved in mitotic cell cycle regulation. In addition, we found that TROAP gene was among top 10 ranked genes out of 48,000 of transcripts, that accurately predicted worse clinical outcome, and differentiated between low and high grade based on a 10-fold external cross-validation analysis with an average classification accuracy of >99.999%. TROAP protein is essential for centrosome integrity and proper bipolar organisation of spindle assembly during mitosis and plays essential role in cell proliferation. In the current study the molecular and clinicopathological functions of TROAP expression and its effect on management of breast cancer have been investigated. Methods: The co-expression of TROAP and TOPO2A protein was evaluated by using dual immunoflurescent in BC cell lines. In addition both TROAP and TOP2A protein expressions were immunohistochemically (IHC) assessed in 40 normal breast tissues and a well characterised series of 1650 primary BC and were correlated to clinicopathological and other biomarkers. IHC staining was performed using Anti-TROAP rabbit polyclonal (HPA044102; Sigma). The association between TROAP and response to chemotherapy was investigated in 350 ER negative BC treated with adjuvant ATC-CT and 260 locally advanced BC treated with neoadjuvant ATC-CT. In addition the clinical outcome of TROAP expression was evaluated in a series of 180 ER− high risk BC patients who did not received any CT. Results: No expression of TROAP protein was observed in normal breast tissue while, 25% of BC showed TROAP protein overexpression. By using dual immunoflurescent in BC cell lines, The MCF7 cells showed strong cytoplasmic TROAP staining with no TOPO2A expression, while The T47D cells did not express TROAP but expressed TOPO2A. SKBr3, MDA468 and MDA231 cell lines showed co-expression of TROAP and TOPO2A. TROAP overexpression was significantly associated with aggressive clinico-pathological features including; high grade, high mitotic rate, absence of hormonal receptors, overexpression of HER2, TOP2A and EGFR (p < 0.001), Triple negative phenotype (p < 0.001), basal-like BC (p < 0.001), p53 mutation (p < 0.001) and inactive p16 (p < 0.001). With regard to outcome, receiving anthracycline chemotherapy had a positive impact on high risk ER− BC patients with TROAP protein over-expression as TROAP protein overexpression showed 50% less risk of recurrence compared to TROAP negative expression; p < 0.0001. Moreover, in locally advanced BC who received anthracycline-based neoadjuvant chemotherapy, 31/81 (39%) of BC with co-expression of TROAP+/TOPO2A+ achieved pCR while none of those with absence of both TROAP−/TOPO2A− (0/51) had achieved pCR (p < 0.00001). Conclusion: TROAP is an important novel gene implicated in the survival of BC cells and its protein expression is a predictor for Anthracycline CT. TROAP may provide new avenues for the discovery of new predictive marker to guide therapeutic intervention. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-07-09.
Introduction Gene expression microarrays, artificial neural network (ANN), tissue microarray and immunohistochemistry (IHC) techniques allow for the analysis of huge numbers of gene transcripts and their corresponding proteins and have been widely applied in predicting clinical outcome. Methods 1- In this study, we analysed 48,000 gene transcripts of 171 unselected series of BC using ANN and pathways analysis to identify genes that can be used to predict clinical outcome of BC. 2- The clinic-pathological outcome of candidate genes were validated by using IHC in 4 independent primary BC data sets: a) a series of 379 consecutive high risk BC (NPI>3.4) who treated with surgery (S)+ radiotherapy (RT) and did not received neither endocrine (ET) nor chemo-therapies (CT), b) A series of 1650 consecutive cases of BC who treated with S + RT and received adjuvant CMF and/or ET according to Nottingham prognostic index (NPI), menopausal and ER status, c) 250 locally advanced BC treated with anthracycline-based combination with or without Taxane followed by S + RT and d) 145 BC overexpressing HER-2 treated with S + RT followed by sequential adjuvant anthracycline combination CT + trastuzumab. Results Gene expression analysis ANN analysis revealed that KIF2C gene was the highest ranked gene that predicted clinical outcome and accurately differentiated between low and high grade BC based on a 10-fold external cross-validation analysis with an average classification accuracy of >98%. High KIF2C gene expression level was associated with shortest BC specific survival (BCSS), disease free (DFS) and distal metastasis free survivals (DM-FS); p<0.0001. In univariate analysis, high level of KIF2C gene expression was associated with large tumour size, higher lymph node stage, negative ER, positive p53 expression and HER2 overexpression. However in multivariate analysis, KIF2C gene expression level was only statistically associated with histological grade (p<00001) and mitosis (p<0.0001). Pathways analysis revealed that KIF2C is likely to play a significant role in cytokinesis, cell division and cell cycle regulations. Immunohistochemistry 75% of BC showed overexpression of KIF2C protein. KIF2C protein overexpression was associated with unfavourable clinic-pathological features including high grade, high mitotic index, basal like phenotype, triple negative phenotype, HER2 overexpression, TOP2A overexpression, p53 mutation, and loss of BRCA1 (adjusted p<0.0001). In univariate analysis, KIF2C protein overexpression was associated with patient's BCSS in both ER+/high risk patients (NPI > 3.4) who did not received ET (HR: 3.3, 95% CI: 1.2−9.3, p=0.02) and ER-/high risk patients who did not received CT (HR: 3.2, 95% CI: 1.1−8.8, p=0.025). In 1650 BC series, multivariate Cox regression model including validated prognostic factors, confirmed that KIF2C overexpression is an independent prognostic factor. KIF2C overexpression showed increase in the risk of death (HR: 1.5, 95% CI: 1.1−2.0, p=0.009), recurrence (HR: 1.4, 95% CI: 1.1−1.8, p=0.017) and DM (HR: 1.6, 95% CI: 1.2−2.3, p=0.005). In conclusion, our findings provide a new insight to a better understanding of mammary carcinogenesis and that KIF2C is a promising molecular prognostic factor and a potential therapeutic target. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-11.
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