Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore.
Division of Pathology, Singapore General Hospital, 20 College Road, Academia, Level 7, Diagnostics Tower, Singapore, 169856, Singapore.
Virchows Arch. 2019 Dec;475(6):709-725. doi: 10.1007/s00428-019-02635-4. Epub 2019 Aug 12.
The proliferation marker Ki-67 is frequently used to assess aggressiveness in the pathological evaluation of cancer, but its role remains uncertain in triple-negative breast cancer (TNBC). We aimed to quantify and localize Ki-67 expression in both epithelial and immune compartments in TNBC and investigate its association with clinicopathological parameters and survival outcomes. A total of 406 TNBC cases diagnosed between 2003 and 2015 at Singapore General Hospital were recruited. Using state-of-the-art, 7-colour multiplex immunofluorescence (mIF) tissue microarrays (TMAs) were stained to assess the abundance, density and spatial distribution of Ki-67-positive tumour cells and immune cells co-decorated with cytokeratin (CK) and leukocyte common antigen (CD45) respectively. Furthermore, MKI67 mRNA profiles were analysed using NanoString technology. In multivariate analysis adjusted for tumour size, histologic grade, age at diagnosis, and lymph node stage, a high Ki-67 labelling index (LI) > 0.3% was associated with improved disease-free survival (DFS; HR = 0.727; p = 0.027). High Ki-67-positive immune cell count per TMA was a favourable prognostic marker for both DFS (HR = 0.379; p = 0.00153) and overall survival (OS; HR = 0.473; p = 0.0482). The combination of high Ki-67 LI and high MKI67 expression was associated with improved DFS (HR = 0.239; p = 0.00639) and OS (HR = 0.213; p = 0.034). This study is among the first to highlight that Ki-67 is associated with favourable prognosis in an adjuvant setting in TNBC, and the mIF-based evaluation of Ki-67 expression on both tumour and immune cells represents a novel prognostic approach.
Ki-67 增殖标志物常用于评估癌症的病理侵袭性，但在三阴性乳腺癌（TNBC）中其作用仍不确定。我们旨在定量和定位 TNBC 中上皮和免疫细胞中 Ki-67 的表达，并研究其与临床病理参数和生存结局的关系。本研究共纳入了 2003 年至 2015 年在新加坡综合医院诊断的 406 例 TNBC 病例。使用最先进的 7 色多重免疫荧光（mIF）组织微阵列（TMA）进行染色，以评估 Ki-67 阳性肿瘤细胞的丰度、密度和空间分布，以及分别与细胞角蛋白（CK）和白细胞共同抗原（CD45）共染色的免疫细胞。此外，还使用 NanoString 技术分析了 MKI67 mRNA 谱。在多变量分析中，根据肿瘤大小、组织学分级、诊断时年龄和淋巴结分期调整后，高 Ki-67 标记指数（LI）>0.3%与无病生存（DFS）改善相关（HR=0.727；p=0.027）。TMA 中每高 Ki-67 阳性免疫细胞计数是 DFS（HR=0.379；p=0.00153）和总生存（OS；HR=0.473；p=0.0482）的有利预后标志物。高 Ki-67 LI 和高 MKI67 表达的组合与改善的 DFS（HR=0.239；p=0.00639）和 OS（HR=0.213；p=0.034）相关。本研究是首次强调 Ki-67 在 TNBC 辅助治疗中与预后良好相关的研究之一，基于 mIF 的肿瘤和免疫细胞中 Ki-67 表达的评估代表了一种新的预后方法。
