Adamo Barbara, Ricciardi Giuseppina Rosaria Rita, Ieni Antonio, Franchina Tindara, Fazzari Carmine, Sanò Maria Vita, Angelico Giuseppe, Michele Caruso, Tuccari Giovanni, Adamo Vincenzo
Department of Medical Oncology, Hospital Clínic of Barcelona, Barcelona, Spain.
Medical Oncology Unit A.O. Papardo & Department of Human Pathology University of Messina, Messina, Italy.
Oncotarget. 2017 Aug 16;8(44):76974-76986. doi: 10.18632/oncotarget.20293. eCollection 2017 Sep 29.
Triple 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.
In 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.
The 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.
Our 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.
三阴性乳腺癌（TNBC）是一组异质性肿瘤，因其侵袭性的肿瘤生物学行为和缺乏靶向治疗，预后较差。迄今为止，尚未确定该亚组明确的预后生物标志物。
在这项回顾性研究中，我们评估了雄激素受体（AR）、E-钙黏蛋白（CDH1）、Ki67指数和基底细胞角蛋白（CK）5/6这4种不同分子决定因素在99例TNBC患者队列中的预后作用。所有患者均接受新辅助/辅助化疗（大多基于蒽环类/紫杉类）。在福尔马林固定石蜡包埋的原发性肿瘤样本中进行免疫组织化学（IHC）检测。CDH1表达≥30%的膜细胞染色被视为阳性。AR阳性定义为阳性肿瘤细胞>10%。高Ki67定义为阳性肿瘤细胞≥20%。如果评分≥1，则判断CK5/6表达为阳性。
AR表达缺失与高度未分化肿瘤显著相关。单因素分析显示，CDH1表达缺失、肿瘤大小和淋巴结状态与较差的无复发生存期（RFS）和总生存期（OS）显著相关（p<0.05）。AR表达和低Ki67显示出RFS和OS有改善的趋势。在单因素和多因素分析中，CK5/6表达缺失的患者RFS较差（分别为p=0.02和p=0.002），OS也较差（分别为p=0.05和p=0.02）。多因素分析显示，除肿瘤大小、淋巴结状态和分级外，CDH1表达与较好的RFS和OS独立相关（p<0.05）。Kaplan-Meier曲线显示，AR和CDH1阴性表达且Ki-67水平高的患者与不良预后显著相关。
我们的研究支持将AR、CDH1、Ki67和CK5/6的IHC表达用作TNBC的预后标志物，并表明它们的表达与预后之间存在联系，可能有助于将TNBC患者分层到不同的预后类别中。
