Jerjees Dena A, Alabdullah M, Green Andrew R, Alshareeda Alaa, Macmillan R D, Ellis Ian O, Rakha Emad A
Department of Histopathology, University of Nottingham and Nottingham University Hospitals NHS Trust, Nottingham, UK,
Breast Cancer Res Treat. 2014 Jun;145(2):317-30. doi: 10.1007/s10549-014-2941-7. Epub 2014 Apr 18.
The definition of Luminal-B subclass of breast cancer (BC) varies in literature. In this study, we have compared the proliferation status; assessed using KI67 labeling index (KI67-LI), and HER2-expression in estrogen receptor positive (ER+) BC to assess their impact on the biological and clinical characteristics of luminal-BC. 1547 (73.8 %) well-characterized clinically annotated stage I-III ER + BC were assessed for expression of KI67, HER2 (ASCO guidelines), and a large panel of relevant biomarkers (no = 37). 46.3 % of the cases show high KI67-LI (>13 %) and 8.4 % show HER2+ and both markers are positively associated with younger age, higher tumor grade and poorer outcome. High KI67-LI and HER2+ are associated with upregulation of ER-coactivators and proliferation-related markers and with downregulation of good prognostic markers. High KI67-LI is associated with larger size, advanced stage, and lymphovascular invasion (LVI) and with downregulation of luminal-enriched and DNA-damage repair markers. In contrast, HER2+ is associated with upregulation of ER-regulated proteins and E-cadherin. When analysis is restricted to high KI67-LI subgroup, HER2+ shows an association with upregulation of differentiation-associated proteins and E-cadherin. Conversely, within HER2+ class, high KI67-LI maintains its association with downregulation of differentiation-associated/luminal-enriched proteins. Outcome analyses indicate that both markers are independently associated with shorter survival but HER2+ is associated with a worse outcome. Although both are associated with high proliferation and poor prognosis within ER + BC, HER2+ is less frequent than high KI67-LI. Unlike KI67, HER2 seems to independently drive the aggressive behavior of ER+ tumors without downregulation of luminal proteins.
乳腺癌（BC）腔面B亚类的定义在文献中存在差异。在本研究中，我们比较了增殖状态（使用Ki67标记指数（Ki67-LI）评估）以及雌激素受体阳性（ER+）乳腺癌中的HER2表达，以评估它们对腔面B型乳腺癌生物学和临床特征的影响。对1547例（73.8%）临床特征明确的I-III期ER+乳腺癌进行了Ki67、HER2（美国临床肿瘤学会指南）以及大量相关生物标志物（共37种）表达的评估。46.3%的病例显示Ki67-LI高（>13%），8.4%显示HER2阳性，且这两种标志物均与较年轻的年龄、较高的肿瘤分级及较差的预后呈正相关。高Ki67-LI和HER2阳性与ER共激活因子及增殖相关标志物的上调以及良好预后标志物的下调有关。高Ki67-LI与更大的肿瘤大小、晚期及淋巴管浸润（LVI）相关，且与腔面富集和DNA损伤修复标志物的下调有关。相比之下，HER2阳性与ER调节蛋白和E-钙黏蛋白的上调有关。当分析仅限于高Ki67-LI亚组时，HER2阳性与分化相关蛋白和E-钙黏蛋白的上调有关。相反，在HER2阳性组中，高Ki67-LI与分化相关/腔面富集蛋白的下调保持相关。预后分析表明，这两种标志物均与较短的生存期独立相关，但HER2阳性与更差的预后相关。尽管在ER+乳腺癌中两者均与高增殖和不良预后相关，但HER2阳性的频率低于高Ki67-LI。与Ki67不同，HER2似乎独立驱动ER+肿瘤的侵袭性，而不会使腔面蛋白下调。
