双模态超声评估维吾尔族乳腺癌新辅助化疗疗效及其与TSC、EMT表达的关联

Uygur patients with breast cancer often still receive preoperative neoadjuvant chemotherapy because of large lesions and late tumor staging. Their sensitivity to chemotherapy is poor, suggesting that neoadjuvant chemotherapy for Uygur breast cancer may have their own characteristics. Tumor stem cells and epithelial mesenchymal transition is the key to obtain the invasiveness of breast cancer.This is the focus of this study. Changes of Uighur patients with breast cancerlesions before and after neoadjuvant chemotherapy will be analysed by contrast enhanced ultrasound and shear wave elasticity imaging. To draw materials from the regional of rich microcirculation perfusion and the highest elastic modulus，the regional on the contrary and the lesion area adjacent mammary gland tissue. They will be subjected to primary culture and the following cytological and histological detection of molecular mass markers related to tumor stem cells and epithelial mesenchymal transformation. Neoadjuvant chemotherapy effect of stem cells and epithelial mesenchymal transition in breast cancer and its association with contrast-enhanced ultrasonography and shear wave elasticity imaging features are the research focus. The study will discuss the relationship and the changes of breast cancer stem cells and epithelial mesenchymal on the specific environment of neoadjuvant chemotherapy, and clarify the correlation of the changes and the microvascular architecture and tumor hardness. The micro world of tumor stem cells and epithelial mesenchymal transition in neoadjuvant chemotherapy of breast cancer will be explored by the macroscopic method of ultrasonic quantitative analysis. This study will provide imaging basis for individualized treatment of breast cancer in Uygur.

维吾尔族乳腺癌肿块大、分期晚，常需术前进行新辅助化疗，但其对化疗的敏感性欠佳，提示维吾尔族乳腺癌新辅助化疗可能具有自身特点。肿瘤干细胞和上皮间质转化是乳腺癌获得侵袭性的关键事件，本研究拟以此为着眼点，采用超声造影及剪切波弹性成像技术定量分析新辅助化疗前后维吾尔族患者乳腺癌病灶的变化，对微循环灌注丰富和弹性模量最高的区域、与之相反的区域、病灶旁乳腺组织分别取材，进行原代培养，通过细胞学及组织学检测肿瘤细胞及上皮间质转化的相关分子标志物，研究新辅助化疗对乳腺癌肿瘤干细胞上皮间质转化的影响及其与超声造影及剪切波弹性成像特征的关联，探讨在新辅助化疗的特定环境中乳腺癌肿瘤干细胞与上皮间质转化的关系与变化，阐明这种变化与微血管构筑和肿瘤硬度的关联，以期通过超声定量分析的宏观方法探索乳腺癌新辅助化疗中肿瘤干细胞上皮间质转化的微观世界，为维吾尔族乳腺癌的个体化治疗提供影像学依据。

乳腺癌NAC后肿瘤血供及硬度的改变早于大小的改变，对其疗效评估存在影像学高估及病理学低估， TSC及EMT被视为乳腺癌获得侵袭性的关键事件，是优于临床病理指标的预后因子。本课题利用超声造影及剪切波弹性成像（SWE）与微观世界的TSC及EMT表达进行关联性分析，探讨超声造影及SWE预测乳腺癌NAC疗效的可行性并筛选评估疗效的可靠指标。研究表明：（1）双模态超声在乳腺癌的术前诊断及预后评估都有价值：超声造影后病灶范围增大具有显著的术前诊断价值；超声造影后病灶范围扩大与激素受体阳性相关；超声造影特征对乳腺癌的分子分型具有预测价值，尤其是病灶范围扩大与灌注缺损；超声造影对伴原位癌的乳腺癌范围的评估优于常规超声；剪切波弹性成像较单纯剪切波对小于1cm的乳腺癌有更高诊断价值；乳腺癌超声造影后出现增强扩大及灌注缺损，时间强度曲线呈快进高增强、高灌注与TSC及EMT高表达有关；乳腺癌SWE存在各向异性，横切面的SWE参数与超声恶性征象的相关性高于纵切面；SWE的各向异性越大，乳腺癌硬度越高，越倾向于TSC及EMT高表达，提示预后不良。（2）双模态超声对评估NAC疗效具有价值：NAC前超声造影测量病灶大于常规超声，NAC后则小于常规超声，与病理大小最接近；NAC后病灶增强范围的变化和病理反应MP评分呈正相关；化疗应答好的乳腺癌由高增强变为等增强或低增强，由向心性增强变为整体增强，由快进慢退变为慢进慢退，但灌注缺损改变不明显；NAC后，SWE各弹性指标均显著缩小，其中Emax可用于乳腺NAC疗效的预测。（3）乳腺癌NAC前后的超声造影表现与TSC及EMT的表达相关：化疗前超声造影呈现快进高增强、高灌注、病灶范围扩大及灌注缺损的乳腺癌与TSC及EMT高表达有关，倾向于疗效不佳及预后不良，但非Luminal型乳腺癌在化疗前呈低灌注与TSC及EMT高表达有关；超声造影对化疗后呈非向心性退缩的非Luminal型乳腺癌的疗效评估价值优于常规超声。研究结果支持超声造影及SWE征象与乳腺癌的TSC及EMT表达相关，提示双模态超声宏观影像可预测乳腺癌NAC疗效并评估预后。