Abstract
BackgroundTriple Negative Breast Cancer (TNBC) represents a heterogeneous group of tumors with poor prognosis owing to aggressive tumor biology and lack of targeted therapies. No clear prognostic biomarkers have been identified to date for this subgroup.Materials and MethodsIn this retrospective study we evaluated the prognostic role of 4 different molecular determinants, including androgen receptor (AR), E-cadherin (CDH1), Ki67 index, and basal cytokeratins (CKs) 5/6, in a cohort of 99 patients with TNBC. All patients received neo/adjuvant chemotherapy (mostly anthracycline/taxane-based). Immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded primary tumor samples. CDH1 expression was considered positive as ≥ 30% of the membrane cells staining. AR positivity was defined as > 10% of positive tumor cells. High Ki67 was defined as ≥20% positive tumor cells. CK5/6 expression was judged positive if the score was ≥1.ResultsThe absence of AR expression was significantly associated with highly undifferentiated tumors. Univariate analyses showed that lack of expression of CDH1, tumor size and nodal status were significantly correlated with worse RFS and OS (p< 0.05). AR expression and low Ki67 showed a trend towards better RFS and OS. Patients with absent CK5/6 expression in univariate and multivariate analyses had poorer RFS (p=0.02 and p=0.002, respectively) and OS (p=0.05 and p=0.02, respectively). Multivariate analysis showed an independent association between CDH1 expression and better RFS and OS (p< 0.05) beyond tumor size, nodal status, and grade. The Kaplan-Meier curves showed that patients with AR and CDH1 negative expression and high Ki-67 levels have a significant correlation with poor outcome.ConclusionsOur study supports the use of IHC expression of AR, CDH1, Ki67, and CK5/6 as prognostic markers in TNBCs and suggests a link between their expression and prognosis and may help to stratify TNBC patients in different prognostic classes.
Highlights
Univariate analyses showed that lack of expression of Cadherin-1 or epithelial cadherin gene (CDH1), tumor size and nodal status were significantly correlated with worse relapse-free survival (RFS) and overall survival (OS) (p< 0.05)
Our study supports the use of IHC expression of androgen receptor (AR), CDH1, Ki67, and Cytokeratin 5/6 (CK5/6) as prognostic markers in Triple Negative Breast Cancer (TNBC) and suggests a link between their expression and prognosis and may help to stratify TNBC patients in different prognostic classes
Increasing evidence shows that the presence or not of a specific molecular phenotype related to the expression a variable number of biomarkers confers the tumor a different degree of aggressiveness
Summary
Triple negative breast cancer (TNBC) represents 10-15% of all breast cancer (BC) subtypes and is defined by the lack of immunohistochemical expression of estrogen receptor, progesterone receptor and absence of overexpression and/or amplification of c-ErbB2 by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) [1,2,3]TNBC is a highly aggressive disease with a poorer prognosis compared to other subtypes of BC and draws no benefits from endocrine and anti-HER2 therapies [4] characterized by shorter disease free intervals and overall survival in the metastatic setting [5].These tumors occur typically in young premenopausal African-American women and are identified as highly undifferentiated tumors with a high proliferation index and early, more frequent visceral or central nervous system metastases relapse than other subtypes [6,7,8]. most TNBCs have a ductal histology, other tumor histological types may occur, including metaplastic [9], medullary [10], adenoic cystic [11], apocrine [12], and secretory carcinomas [13].TNBC is an inter and intra-tumor heterogeneous disease that presents distinct biomolecular prognostic and therapeutic features [14, 15].The TNBC population frequently presents BRCA1/2, TP53(62%) and PI3KCA mutations (10.2%) [16,17,18].The development of gene expression signatures has allowed a better understanding of the heterogeneity of TNBC with different classification systems [19, 20]. TNBC is a highly aggressive disease with a poorer prognosis compared to other subtypes of BC and draws no benefits from endocrine and anti-HER2 therapies [4] characterized by shorter disease free intervals and overall survival in the metastatic setting [5]. These tumors occur typically in young premenopausal African-American women and are identified as highly undifferentiated tumors with a high proliferation index and early, more frequent visceral or central nervous system metastases relapse than other subtypes [6,7,8]. No clear prognostic biomarkers have been identified to date for this subgroup
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