Abstract P6-09-25: Circulating tumor cell clusters-associated gene plakoglobin is a novel prognostic predictor in patients with breast cancer
Authors: W Goto, S Kashiwagi, Y Asano, K Takada, T Takashima, T Morisaki, S Noda, N Onoda, M Ohsawa, K Hirakawa, M Ohira
Journal: Cancer Research (2017)

Abstract Background: Accumulating evidence shows that circulating tumor cells (CTC) are linked to metastatic relapse and are regarded as a prognostic marker for human cancer. It was reported that CTC clusters (CTCc) have more metastatic potential than single CTC. Lately, studies also show that the high expression of plakoglobin, a cell adhesion protein, within the primary tumor are positively associated with CTCc in breast cancer patients. In addition, it is thought that insufficient expression of plakoglobin could promote epithelial-mesenchymal transition (EMT). In this study, we investigated the correlation between plakoglobin expression and survival of breast cancer. Materials and Methods:A total of 126 patients with resectable early-stage breast cancer were treated with neoadjuvant chemotherapy (NAC). All patients received a standardized protocol of NAC consisting of four courses of FEC100 (500 mg/m2 fluorouracil, 100 mg/m2 epirubicin, and 500 mg/m2 cyclophosphamide) every 3 weeks, followed by 12 courses of 80 mg/m2 paclitaxel administered weekly. The expression of plakoglobin were identified by immunohistochemical staining properties in cell membrane. Staining with plakoglobin (clone 4C12) was scored according to the percentage of cells that stained positively: low, 0-25%; medium, 26-75%; high, &amp;gt;75%. We investigated the correlation between the plakoglobin expression in primary tumor specimen and clinical outcomes including overall-survival (OS), disease-free-survival (DFS), distant-metastasis-free-survival (DMFS), the efficacy of NAC. And we examined the relation between the expression of plakoglobin and E-cadherin, EMT marker. Results: The patient with high plakoglobin expression had significantly worse OS (p=0.021, log-rank) and DFS (p=0.015, log-rank), DMFS (p=0.040, log-rank). And the plakoglobin expression had no correlation with pathological complete response (pCR) rate (p=0.596). Also, there was not a statistically significant relationship between the plakoglobin expression and other clinicopathological parameters including tumor size (p=0.708), lymph node status (p=0.479), subtype (p=0.413), nuclear grade (p=0.642), Ki67 (p=0.202), tumor infiltrating lymphocytes (p=0.828). On univariate analysis with respect to distal metastasis, high plakoglobin expression showed worse prognosis than low plakoglobin expression (p=0.013, hazard ratio=4.221). And multivariate analysis found the same result (p=0.015, hazard ratio=4.070). In addition, there was a significant relationship between the expression of plakoglobin and E-cadherin (p=0.023). Conclusions: Plakoglobin expression is an independent prognostic factor in the patients with breast cancer; particularly for DMFS, and this mechanism related to EMT.Background: Accumulating evidence shows that circulating tumor cells (CTC) are linked to metastatic relapse and are regarded as a prognostic marker for human cancer. It was reported that CTC clusters (CTCc) have more metastatic potential than single CTC. Lately, studies also show that the high expression of plakoglobin, a cell adhesion protein, within the primary tumor are positively associated with CTCc in breast cancer patients. In addition, it is thought that insufficient expression of plakoglobin could promote epithelial-mesenchymal transition (EMT). In this study, we investigated the correlation between plakoglobin expression and survival of breast cancer. Materials and Methods:A total of 126 patients with resectable early-stage breast cancer were treated with neoadjuvant chemotherapy (NAC). All patients received a standardized protocol of NAC consisting of four courses of FEC100 (500 mg/m2 fluorouracil, 100 mg/m2 epirubicin, and 500 mg/m2 cyclophosphamide) every 3 weeks, followed by 12 courses of 80 mg/m2 paclitaxel administered weekly. The expression of plakoglobin were identified by immunohistochemical staining properties in cell membrane. Staining with plakoglobin (clone 4C12) was scored according to the percentage of cells that stained positively: low, 0-25%; medium, 26-75%; high, &amp;gt;75%. We investigated the correlation between the plakoglobin expression in primary tumor specimen and clinical outcomes including overall-survival (OS), disease-free-survival (DFS), distant-metastasis-free-survival (DMFS), the efficacy of NAC. And we examined the relation between the expression of plakoglobin and E-cadherin, EMT marker. Results: The patient with high plakoglobin expression had significantly worse OS (p=0.021, log-rank) and DFS (p=0.015, log-rank), DMFS (p=0.040, log-rank). And the plakoglobin expression had no correlation with pathological complete response (pCR) rate (p=0.596). Also, there was not a statistically significant relationship between the plakoglobin expression and other clinicopathological parameters including tumor size (p=0.708), lymph node status (p=0.479), subtype (p=0.413), nuclear grade (p=0.642), Ki67 (p=0.202), tumor infiltrating lymphocytes (p=0.828). On univariate analysis with respect to distal metastasis, high plakoglobin expression showed worse prognosis than low plakoglobin expression (p=0.013, hazard ratio=4.221). And multivariate analysis found the same result (p=0.015, hazard ratio=4.070). In addition, there was a significant relationship between the expression of plakoglobin and E-cadherin (p=0.023). Conclusions: Plakoglobin expression is an independent prognostic factor in the patients with breast cancer; particularly for DMFS, and this mechanism related to EMT. Citation Format: Goto W, Kashiwagi S, Asano Y, Takada K, Takashima T, Morisaki T, Noda S, Onoda N, Ohsawa M, Hirakawa K, Ohira M. Circulating tumor cell clusters-associated gene plakoglobin is a novel prognostic predictor in patients with breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-25.