三维超声造影可视化评价乳腺癌Cetuximab靶向治疗中肿瘤血管构架微循环演变的实验研究

Shrinkage of residual lesions was rather heterogeneous after neoadjuvant targeted therapy in breast cancer, and histological changes were also varied. Besides, it has widely been accepted in recent literature that for breast cancer undergoing neoadjuvant therapy, hemodynamic changes were much earlier than morphological changes. Therefore, conventional imaging modalities had some limitations in predicting therapeutic effects of breast cancer. In this research, we attempted to monitor the evolvement of intratumoral perfusion and vascular pattern by three-dimensional contrast-enhanced ultrasound (3D-CEUS) during targeted therapy, neoadjuvant therapy and laser ablation of breast cancer, according to our previous studies, which successfully assessed breast cancer vascular pattern by 3D-CEUS, and subsequently take advantage of visualized three-dimensional computer software to achieve a virtual stereoscopic breast cancer angioarchitecture by reconstructing series of 3D-CEUS images. Regarding dynamic contrast-enhanced MRI and microvascular molding as control, we aimed at dynamically and visually reflecting microcirculation changes of inratumoral perfusion and vascular pattern, then further exploring the feasibility and clinical value of 3D-CEUS in predicting effect of targeted, neoadjuvant and laser ablation therapy. In conclusion, the purpose of our study was to provide theoretical foundation and basic research for non-invasive and standardized imaging prediction of personalized breast cancer therapy effect.

乳腺癌新辅助靶向治疗后残留病灶的退缩方式具有异质性，病理组织学变化也具有多样性，而且，本课题组及大量近期研究均认识到新辅助治疗后肿瘤血流动力学的变化远远早于肿瘤的形态学改变，因此现有常规影像学技术在乳腺癌靶向治疗疗效评价中具有一定局限性。本课题组在前期成功运用三维超声造影评价乳腺肿瘤血管生成的基础上，拟尝试利用三维超声造影监测乳腺癌靶向治疗及新辅助化疗不同阶段的肿瘤内部灌注及肿瘤血管的变化，并通过可视化三维计算机软件拟合三维超声造影系列图像以达到虚拟立体成像乳腺癌血管构架的目的，以三维磁共振、肿瘤血管解剖铸型等方法为对照，动态可视化展现靶向治疗等治疗前后肿瘤内部灌注及肿瘤血管构架微循环演变的一系列变化，进而深入探讨三维超声造影在评价乳腺癌靶向治疗及新辅助化疗疗效中的可行性及临床价值，为制定乳腺癌个体化治疗的无创影像学评估标准提供理论依据和基础研究。

新辅助靶向治疗后残留病灶的血流动力学的变化远早于形态学改变，如何准确判断治疗疗效以及早期进行疗效预测是临床医师密切关注的热点，然而目前临床上尚缺乏一种较理想的疗效评估与预测方法，亟待一种能较好地评估乳腺癌个体化治疗疗效的影像学方法。我们的早期研究已证实三维超声造影结合了三维超声及超声造影的双重优势，能在三维空间立体完整地展示整个病灶的血管分布。因此，本研究利用三维超声造影开展了一系列乳腺癌新辅助治疗的动物实验研究和临床研究，为制定乳腺癌个体化治疗的无创影像学评估标准提供理论依据。首先，通过对乳腺小肿瘤（肿瘤最大径小于1cm）超声造影研究发现乳腺癌的灌注峰值（Peak）与良性肿瘤存在显著差异，Peak值联合BI-RADS分类可为早期乳腺癌的诊断提供全新的评估方法，为超声造影在动物实验瘤体定量分析提供了坚实的基础和丰富的经验。而且，在兔乳腺癌模型消融治疗中发现三维超声造影能较好的评估病灶周围残留组织的血供情况，为实现完全消融提供准确的影像学依据。而在裸鼠新辅助治疗中发现化疗后移植瘤块的造影灌注强度明显降低，曲线下面积明显减少，残留病灶以边缘为主，中央坏死较多。而边缘血管特征的系列研究对于指导后续治疗具有一定的临床意义。通过对3D-CEUS在乳腺癌新辅助治疗疗效评估的临床研究发现3D-CEUS评分和磁共振评分均与病理完全缓解（pathologic complete response, pCR）与组织学显著反应（major histology response, MHR）有较好的相关性，可为新辅助化疗的疗效做出综合的评价，为进一步个性化治疗方案的制定提供依据。总之，本课题利用三维超声造影对乳腺癌新辅助治疗进行疗效评价的动物实验及临床研究取得了一定的成果，为三维超声造影广泛应用于临床及新辅助治疗的疗效评价和个性化治疗方案的制定提供一种新的影像学依据。