Study of Breast Cancer Angiogenesis Using Dynamic Contrast Enhanced MRI

動態對比顯影磁振造影為利用快速掃描，獲得組織接受顯影劑灌流時之系列影像，藉此可以反應組織血液灌流之狀況，亦可經由對比劑顯影程度而觀察到腫瘤血管特性。動態對比顯影磁振造影為非侵襲性腫瘤血管新生性的評估方式，藉由藥物動力學模式之應用，可反應腫瘤之血管新生性特徵及滲漏度，無外科或經皮切片只能獲得小體積標本的限制。我們使用以像素為基礎獲得之整體乳房彩色參數圖示，可以提供整體乳房組織與病灶具有血管新生性特點分布之評估。 在本論文中，我們使用新方法評估乳癌之整體血管新生特性，針對由二隔間模式衍算之磁振造影參數進行乳房病灶整體之組織圖分析。我們的研究結果顯示在良性惡性乳房病灶及腫瘤間，包括輻度、組織間交換速率及最大訊號顯影度，均存在明顯差異。使用此技術與評估方式，我們針對局部侵襲性乳癌的治療反應進行研究，結果顯示在化學治療前或在化學治療第一療程後施行顯影磁振造影檢查，可以藉由內在腫瘤磁振造影參數組成來預估術前化學治療之腫瘤反應。本研究亦發現化學治療有反應者之腫瘤，其血管新生性參數組成較常為不均質，而化學治療不反應之腫瘤，其血管新生性參數組成為較均質。在治療過程中，化學治療有反應者之腫瘤可由連續縱向磁振造影檢查中觀察到腫瘤變小，伴隨磁振造影血管新生參數組成也由不均質變為較均質。就我們所知，本研究為首先以動態對比顯影磁振造影研究乳癌內在組成在化學治療過程中變化的情況。 本論文顯示使用動態顯影乳房磁振造影以磁振造影參數組織圖分析來評估腫瘤血管新生性，具有能夠提供腫瘤整體異質性之評估與內在組成血管新生性特徵之優點。未來研究方向應針對磁振造影腫瘤影像分析平台之研發，及發展相關標的磁振造影顯影劑，來探討功能性磁振造影，並結合腫瘤磁振造影分子影像之研究。Dynamic contrast enhanced (DCE) MRI acquires sequential images during contrast perfusion of tissue of interest. Gadolinium chelates enable visualization of tumor vasculature through the degree of contrast enhancement, which reflects angiogenic properties and permeability of tumor. DCE MRI provides a window of noninvasive assessment of tumor angiogenesis without the limitation of small size of surgical specimen or percutaneous tumor sampling. Pixel-by-pixel high-resolution parametric color mapping of the whole breast provides good spatial assessment of angiogenic characters of breast lesions. We used a new approach for assessing global angiogenic character of breast cancer with quantitative analysis of MR parametric histogram obtained from compartmental model. With this analysis of MR parametric histogram, we demonstrated that there existed significant differences of parametric amplitude, compartmental exchange rate kout and maximal signal enhancement between benign and malignant breast lesions. Using this technique, tumor response of locally advanced breast cancer (LABC) may be predicted from the results of MR parametric histograms in the initial study before neoadjuvant chemotherapy or the study after the first course of neoadjuvant chemotherapy. Heterogeneity of internal parametric tumor composition was more commonly observed in responders. In contrast, tumor composition of nonresponders was more homogeneous. Involution of heterogeneous to more homogeneous tumor parametric composition was found in responders associated with reduction of tumor size in longitudinal MR studies. To our knowledge, this is the first report about the internal composition change of breast cancer on DCE MRI. Our results suggest that MR parametric histogram analysis may assess global tumor angiogenesis and tumor heterogeneity. Further development of analytic platform of MR-based tumor imaging with perfusion model and clinically relevant targeted MR contrast agents may explore the capability of functional and molecular imaging in the near future.1. An overview of breast MRI 8 1.1 History of breast MRI 8 1.2 Dynamic contrast enhanced (DCE) breast MRI 13 1.3 Interpretation of breast MRI 18 1.4 Pharmacokinetic models of DCE MRI analysis 23 1.5 Outline 28 2. MR parametric histogram and color mapping for benign and malignant tumors 29 2.1 Rationale of parametric analysis of DCE MRI based on two-compartment model 29 2.2 Materials and methods 32 2.3 Results 36 2.4 Discussion 41 3. MR angiogenic response of locally advanced breast cancer to neoadjuvant chemotherapy 47 3.1 Introduction 47 3.2 Materials and methods 49 3.3 Results 53 3.4 Discussion 54 4. Discussion and conclusion 61 4.1 Summary 61 4.2 Tumor segmentation using independent component analysis: work in progress 64 4.3 DCE MRI on tumor imaging and link with targeted MR imaging 68 4.4 Future work 69 Bibliography 7