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Background: The prognostic value of lymphovascular invasion (LVI) in breast cancer (BC) has been demonstrated in several independent studies. However, identification of driver molecules for LVI remains a challenging task. Large-scale transcriptomic profiling of histologically validated LVI can potentially identify genes that regulate LVI. Methods: Integrative bio-informatics analyses of the METABRIC study were performed utilising a subset of strictly defined LVI using histological and immunohistochemical (IHC) criteria. ARHGAP18 was among the top differentially expressed genes between LVI+ and LVI− BC with a 1.8-fold change. The prognostic impact of ARHGAP18 gene expression was assessed in the METABRIC data set (n=1980) and externally validated using the online BC gene expression data sets utilising bc-GenExMiner v4.0 (n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large cohort of invasive BC (n=959) with long-term follow-up using IHC. Results: Pooled analysis of ARHGAP18 mRNA expression showed that overexpression was associated with better outcome (P<0.001, hazard ratio (HR)=0.82, 95% CI 0.75–0.90). ARHGAP18 protein was expressed in the cytoplasm and nuclei of the tumour cells and its expression was positively associated with good prognostic variables. Lack of cytoplasmic expression showed associations with LVI (P=0.006), epithelial-mesenchymal transition and the HER+ subtype (P=0.01). Loss of nuclear expression was associated with higher grade, HER2+ and high Ki67LI (P=0.001). Cytoplasmic and nuclear expression showed a positive association with improved survival independent of other variables (P=0.01, HR=0.74, 95% CI 0.60–87). Conclusions: ARHGAP18 expression at transcriptomic and protein levels is associated with improved patients’ outcomes whose deregulation may play a role in tumour progression and the development of LVI in BC. Further assessment of its potential therapeutic value in BC is warranted

Background: The prognostic value of lymphovascular invasion (LVI) in breast cancer (BC) has been demonstrated in several independent studies. However, identification of driver molecules for LVI remains a challenging task. Large-scale transcriptomic profiling of histologically validated LVI can potentially identify genes that regulate LVI. Methods:Integrative bio-informatics analyses of the METABRIC study were performed utilising a subset of strictly defined LVI using histological and immunohistochemical (IHC) criteria. ARHGAP18 was amongst the top differentially expressed genes between LVI+ and LVI- BC with a 1.8 fold change. The prognostic impact of ARHGAP18 gene expression was assessed in the METABRIC dataset (n=1980) and externally validated using the online BC gene expression datasets utilising bc-GenExMiner v4.0 (n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large cohort of invasive BC (n=959) with long term follow-up using IHC. Results: Pooled analysis of ARHGAP18 mRNA expression showed that overexpression was associated with better outcome (p<0.001, Hazard ratio (HR) =0.82, 95%CI 0.75-0.90). ARHGAP18 protein was expressed in the cytoplasm and nuclei of the tumour cells and its expression was positively associated with good prognostic variables. Lack of cytoplasmic expression showed associations with LVI (p=0.006), epithelialmesenchymal transition and the HER+ subtype (p=0.01). Loss of nuclear expression was associated higher grade, HER2+ and high Ki67LI (p=0.001). Cytoplasmic and nuclear expression showed a positive association with improved survival independent of other variables (P =0.01, HR = 0.74, 95%CI 0.60-87). Conclusions: ARHGAP18 expression at transcriptomic and protein levels is associated with improved patients’ outcomes whose deregulation may play a role in tumour progression and the development of LVI in BC. Further assessment of its potential therapeutic value in BC is warranted.

In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P\0.001). The least variability between the different slides was observed with HS scoring. Although the associations between Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r = 0.98, P\0.001). In conclusion, assessment of Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.

Background: The prognostic value of lymphovascular invasion (LVI) in breast cancer (BC) has been demonstrated in several independent studies. However, identification of driver molecules for LVI remains a challenging task. Large-scale transcriptomic profiling of histologically validated LVI can potentially identify genes that regulate LVI. Methods:Integrative bio-informatics analyses of the METABRIC study were performed utilising a subset of strictly defined LVI using histological and immunohistochemical (IHC) criteria. ARHGAP18 was amongst the top differentially expressed genes between LVI+ and LVI- BC with a 1.8 fold change. The prognostic impact of ARHGAP18 gene expression was assessed in the METABRIC dataset (n=1980) and externally validated using the online BC gene expression datasets utilising bc-GenExMiner v4.0 (n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large cohort of invasive BC (n=959) with long term follow-up using IHC. Results: Pooled analysis of ARHGAP18 mRNA expression showed that overexpression was associated with better outcome (p<0.001, Hazard ratio (HR) =0.82, 95%CI 0.75-0.90). ARHGAP18 protein was expressed in the cytoplasm and nuclei of the tumour cells and its expression was positively associated with good prognostic variables. Lack of cytoplasmic expression showed associations with LVI (p=0.006), epithelialmesenchymal transition and the HER+ subtype (p=0.01). Loss of nuclear expression was associated higher grade, HER2+ and high Ki67LI (p=0.001). Cytoplasmic and nuclear expression showed a positive association with improved survival independent of other variables (P =0.01, HR = 0.74, 95%CI 0.60-87). Conclusions: ARHGAP18 expression at transcriptomic and protein levels is associated with improved patients’ outcomes whose deregulation may play a role in tumour progression and the development of LVI in BC. Further assessment of its potential therapeutic value in BC is warranted.

Background: The prognostic value of lymphovascular invasion (LVI) in breast cancer (BC) has been demonstrated in several independent studies. However, identification of driver molecules for LVI remains a challenging task. Large-scale transcriptomic profiling of histologically validated LVI can potentially identify genes that regulate LVI. Methods:Integrative bio-informatics analyses of the METABRIC study were performed utilising a subset of strictly defined LVI using histological and immunohistochemical (IHC) criteria. ARHGAP18 was amongst the top differentially expressed genes between LVI+ and LVI- BC with a 1.8 fold change. The prognostic impact of ARHGAP18 gene expression was assessed in the METABRIC dataset (n=1980) and externally validated using the online BC gene expression datasets utilising bc-GenExMiner v4.0 (n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large cohort of invasive BC (n=959) with long term follow-up using IHC. Results: Pooled analysis of ARHGAP18 mRNA expression showed that overexpression was associated with better outcome (p<0.001, Hazard ratio (HR) =0.82, 95%CI 0.75-0.90). ARHGAP18 protein was expressed in the cytoplasm and nuclei of the tumour cells and its expression was positively associated with good prognostic variables. Lack of cytoplasmic expression showed associations with LVI (p=0.006), epithelialmesenchymal transition and the HER+ subtype (p=0.01). Loss of nuclear expression was associated higher grade, HER2+ and high Ki67LI (p=0.001). Cytoplasmic and nuclear expression showed a positive association with improved survival independent of other variables (P =0.01, HR = 0.74, 95%CI 0.60-87). Conclusions: ARHGAP18 expression at transcriptomic and protein levels is associated with improved patients’ outcomes whose deregulation may play a role in tumour progression and the development of LVI in BC. Further assessment of its potential therapeutic value in BC is warranted.

In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P\0.001). The least variability between the different slides was observed with HS scoring. Although the associations between Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r = 0.98, P\0.001). In conclusion, assessment of Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.

Background: The prognostic value of lymphovascular invasion (LVI) in breast cancer (BC) has been demonstrated in several independent studies. However, identification of driver molecules for LVI remains a challenging task. Large-scale transcriptomic profiling of histologically validated LVI can potentially identify genes that regulate LVI. Methods:Integrative bio-informatics analyses of the METABRIC study were performed utilising a subset of strictly defined LVI using histological and immunohistochemical (IHC) criteria. ARHGAP18 was amongst the top differentially expressed genes between LVI+ and LVI- BC with a 1.8 fold change. The prognostic impact of ARHGAP18 gene expression was assessed in the METABRIC dataset (n=1980) and externally validated using the online BC gene expression datasets utilising bc-GenExMiner v4.0 (n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large cohort of invasive BC (n=959) with long term follow-up using IHC. Results: Pooled analysis of ARHGAP18 mRNA expression showed that overexpression was associated with better outcome (p<0.001, Hazard ratio (HR) =0.82, 95%CI 0.75-0.90). ARHGAP18 protein was expressed in the cytoplasm and nuclei of the tumour cells and its expression was positively associated with good prognostic variables. Lack of cytoplasmic expression showed associations with LVI (p=0.006), epithelialmesenchymal transition and the HER+ subtype (p=0.01). Loss of nuclear expression was associated higher grade, HER2+ and high Ki67LI (p=0.001). Cytoplasmic and nuclear expression showed a positive association with improved survival independent of other variables (P =0.01, HR = 0.74, 95%CI 0.60-87). Conclusions: ARHGAP18 expression at transcriptomic and protein levels is associated with improved patients’ outcomes whose deregulation may play a role in tumour progression and the development of LVI in BC. Further assessment of its potential therapeutic value in BC is warranted.

In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P\0.001). The least variability between the different slides was observed with HS scoring. Although the associations between Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r = 0.98, P\0.001). In conclusion, assessment of Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.

Background: The prognostic value of lymphovascular invasion (LVI) in breast cancer (BC) has been demonstrated in several independent studies. However, identification of driver molecules for LVI remains a challenging task. Large-scale transcriptomic profiling of histologically validated LVI can potentially identify genes that regulate LVI. Methods:Integrative bio-informatics analyses of the METABRIC study were performed utilising a subset of strictly defined LVI using histological and immunohistochemical (IHC) criteria. ARHGAP18 was amongst the top differentially expressed genes between LVI+ and LVI- BC with a 1.8 fold change. The prognostic impact of ARHGAP18 gene expression was assessed in the METABRIC dataset (n=1980) and externally validated using the online BC gene expression datasets utilising bc-GenExMiner v4.0 (n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large cohort of invasive BC (n=959) with long term follow-up using IHC. Results: Pooled analysis of ARHGAP18 mRNA expression showed that overexpression was associated with better outcome (p<0.001, Hazard ratio (HR) =0.82, 95%CI 0.75-0.90). ARHGAP18 protein was expressed in the cytoplasm and nuclei of the tumour cells and its expression was positively associated with good prognostic variables. Lack of cytoplasmic expression showed associations with LVI (p=0.006), epithelialmesenchymal transition and the HER+ subtype (p=0.01). Loss of nuclear expression was associated higher grade, HER2+ and high Ki67LI (p=0.001). Cytoplasmic and nuclear expression showed a positive association with improved survival independent of other variables (P =0.01, HR = 0.74, 95%CI 0.60-87). Conclusions: ARHGAP18 expression at transcriptomic and protein levels is associated with improved patients’ outcomes whose deregulation may play a role in tumour progression and the development of LVI in BC. Further assessment of its potential therapeutic value in BC is warranted.

In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P\0.001). The least variability between the different slides was observed with HS scoring. Although the associations between Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r = 0.98, P\0.001). In conclusion, assessment of Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.