Expression profile and prognostic value of CCR5,HS1 and SMMin triple negative breast carcinoma

Objective: Invasive breast carcinoma is the 2nd most frequent malignancy and the first cause of cancer among women. It is also the 4th cause of cancer-related deaths worldwide. Treatment choice is based on histopathological evaluation, including histological subtype, histological grade, tumor size, vascular invasion, and lymph node status as well as immunohistochemical expression of estrogen receptor (ER), progesteron receptor (PR), human epidermal growth factor reseptor 2 (HER2/cerbB2) and Ki-67 proliferation index. Breast carcinomas are usually classified based on their expression of receptors (ER, PR) and cerbB2. The subgroup without ER, PR and cerbB2 expression are 'triple negative' breast tumors. Although triple negative breast carcinomas (TNBC) are a heterogeneous group in terms of morphological and molecular features, they are generally high-grade and aggressive. Standard therapy includes cytotoxic chemotherapeutic agents. Based on current genetic studies and emerging molecular classification, new biomarkers that are both expressed in tumor cells and tumor microenvironment and have a potential role in prognosis and treatment, have been identified and targeted therapies have been suggested. Because high expression of C-C chemokine ligand 5 (CCL5) related receptor (CCR5) and its ligands play a role in mechanisms behind tumor development and tumor spread, CCR5 related chemokine pathway is outstanding as a prognostic marker and a potential therapeutic target. Overexpression of hematopoetic lineage cell specific protein (HS1), which is identified in hematopoetic cells and is homologous to cortactin, and the related protein (HAX-1) is related to worse prognosis in hematopoetic malignancies as well as ovarian and laryngeal carcinomas. Tumors with myoepithelial differentiation have a worse prognosis compared to those without and better prognosis compared to those with basal phenotype. In our study, we aimed to determine the relationship between expression of CCR5, HS1 and smooth muscle myosin (SMM) and prognosis in a heterogeneous group of triple negative breast carcinomas and tried to estimate prognosis using these biomarkers. Materials and Methods: Archive records between January 2000-May 2018 were retrieved from Istanbul University Istanbul Faculty of Medicine Department of General Surgery and Istanbul University Oncology Institute. The records were compared to computer-based archive records in Department of Pathology, Istanbul Faculty of Medicine. Triple negative breast carcinoma cases were chosen among these records to constitute the study group. A total of 310 tumors blocks of 304 patients were available and 39 tissue microarray blocks were prepared. Immunohistochemical analyses were performed on these blocks using CCR5, HS1 and SMM antibodies. Clinicopathological characteristics of the study group were retrieved from archive records. Some patient records were completed over telephone calls. Information on the patients' medical history, tumor stage, recurrence or metastasis, treatment regimens and survival data were updated. Results: Average follow-up time was 72.61 (5-239, median: 65) months. A total of 104 (34.2%) patients died of disease, and 200 (65.8%) patients were alive. One hundred and six patients (34.9%) showed progression, either as local recurrence or systemic metastasis. Fifty three patients (17%) received neoadjuvant therapy and showed minimal or no response. The 5-year-overall survival (OS) and 10-year-OS were 75.1% and 58%; 5-year-disease free survival (DFS) and 10-year-DFS were 67.1% and 60.7%, respectively. OS and DFS rates were lower in larger sized tumors compared to smaller ones. OS and DFS were also lower in cases with lymph node metastases compared to those without. TNM stage were correlated with survival and survival rates decreased as TNM stages increased. No correlation was shown between CCR5 positivity and lymhpovascular invasion and lymph node metastasis. Correlation between CCR5 expression and local recurrence, systemic metastasis, OS and DFS were statistically significant. Cases with CCR5 expression demonstrated higher rates of local recurrence and systemic metastasis. OS and DFS rates were lower in cases with CCR5 expression. HS1 positive cases showed lower rate of systemic metastases compared to HS1 negative cases. HS1 positive cases also showed higher OS and DFS rates. Correlation between SMM immunohistochemical expression, percentage and ratio of positive cells, H score and lymphovascular invasion, lymph node metastases, local recurrence, systemic metastases, OS and DFS were investigated and no statistically significant relationship was shown. Conclusion: Tumors unresponsive to neoadjuvant treatment are associated with aggressive clinical course. In addition to well-known prognostic parameters like tumor size, lymph node metastasis and stage, OS and DFS are lower in CCR5 positive cases compared to CCR5 negative cases. In multivariate analysis, tumor size (>30.26 mm), lymph node metastasis and CCR5 positivity are found to be independent factors for predicting OS in patients without receiving neoadjuvant therapy. OS and DFS rates are higher in HS1 positive cases compared to HS1 negative group. No prognostic difference is found related to immunohistochemical expression of SMM.