摘要
乳腺癌是全世界女性肿瘤相关致死率第二高的恶性肿瘤，以手术切除为主，化疗、内分泌治疗为辅的综合治疗有效的提高了乳腺癌的5年生存率。手术前的新辅助化疗目前已经成为乳腺癌的标准治疗方案，新辅助化疗能降低肿瘤的级别、缩小肿瘤的体积，从而使更多的患者可行手术切除瘤灶，而且肿瘤对新辅助化疗的病理反应可以做为患者预后的指标。但新辅助化疗所使用的细胞毒性化疗药物引起的包括严重的过敏反应、周围神经病变等多种细胞毒副作用在临床应用中经常发生，因此临床上需要寻找降低新辅助化疗的细胞毒性药物剂量、提高新辅助化疗疗效的途经。
自上世纪七十年代Folkman研究发现实体肿瘤包括乳腺癌必须建立新生血管网以获得生长和转移所需的营养，抗血管生成逐渐成为临床新兴的一种肿瘤治疗方法。而血管内皮抑素是一种内源性广谱血管生成抑制因子，能特异性的抑制内皮细胞增殖、迁移，从而抑制血管生成并抑制肿瘤生长。恩度(endostar)是重组人血管内皮抑制素注射液(recombinant humanendostatin injection, rh-endostatin)，中国研究人员罗永章等在原始内皮抑素序列N端基础上添加了9个氨基酸，创造性解决了重组生产内皮抑素中蛋白质复性问题，并且通过大量实验研究证明了这一结构的改变并没有改变内皮抑素的生物效应。恩度已于2005年被中国国家药品食品监督局批准用于恶性肿瘤的治疗。恩度联合化疗治疗多种晚期肿瘤取得较好疗效已见较多报道，但在乳腺癌治疗中的应用尚未有相关报道。
在本II期临床实验中，课题组使用恩度联合新辅助化疗治疗进展期乳腺癌病例，并使用磁共振成像技术观察在接受恩度联合新辅助化疗后乳腺癌的影像学变化，以研究恩度能否在乳腺癌中发挥其抗血管生成作用、恩度能否提高新辅助化疗的抗肿瘤效应，以及磁共振功能成像评价恩度联合新辅助化疗的抗血管生成作用与抗肿瘤作用的可行性。
实验一MRI扩散加权成像评价恩度在乳腺癌中的抗血管生成与抗肿瘤作用
目的:探讨MRI扩散加权成像评价恩度在乳腺癌中的抗血管生成与抗肿瘤作用的应用价值。方法:选取2008年3月～2010年8月60例乳腺癌作为研究对象，随机分为实验组与对照组，分别接受恩度联合新辅助化疗、单独新辅助化疗治疗3个周期，分别在治疗前、后使用SIEMENS公司MAGNETOM Trio Tim3.0T超导型磁共振进行扫描，成像方法包括常规SE序列和扩散加权成像，治疗结束后一周内行手术切除病灶或者乳腺癌改良根治术。比较两组病例治疗后瘤灶扩散加权成像的影像学改变，并将影像学结果与手术病理结果相对照。结果：根据肿瘤治疗组织反应标准，实验组即恩度联合新辅助化疗组治疗后组织学反应评分4级以上的为23例，而对照组即新辅助化疗组则仅为18例，实验组高于对照组。组织学显著反应率为77%，高于对照组的60%的反应率。治疗后两组病例的肿瘤MVD分别为（3.7±1.7）、(5.1±2.8)，两者之间的差异具有统计学意义（P<0.05）。两组在治疗前ADC值无显著性差异（P=0.86），治疗后恩度组ADC值为(1.83±0.17)×10-3(mm2/s)，较治疗前上升了42%（P<0.05）。而新辅助化疗组ADC值为(1.66±0.24)×10-3(mm2/s)，较治疗前上升了39%（P<0.05）。治疗后恩度组ADC值上升了(0.62±0.21)×10-3(mm2/s)，而新辅助化疗组ADC值上升了(0.47±0.15)×10-3(mm2/s)，两者之间无显著性差异（P=0.45）。
实验二MRI动态增强扫描评价恩度在乳腺癌中的抗血管生成与抗肿瘤作用
目的:探讨MRI动态增强扫描评价恩度在乳腺癌中的抗血管生成与抗肿瘤作用的应用价值。方法:研究对象与治疗方案与实验一相同，分别在治疗前、后使用SIEMENS公司MAGNETOM Trio Tim3.0T超导型磁共振进行扫描，在常规成像的基础上进行动态增强扫描。并引入T1－FCM药物动力学模型，对动态增强的时间信号曲线进行定量分析，对比两组病例治疗前后瘤灶相应指标的变化，并将动态增强扫描结果与病理结果对照。结果：治疗前实验组与对照组之间的最大强化率ER无差异，治疗后两组病灶的信号强化率均下降，但实验组的ER为(0.93±0.35)，低于对照组的(1.02±0.29)（P<0.05），治疗前后的ER降低量治疗组大于对照组（P<0.05）。且治疗后实验组的TIC曲线更加平滑，高度较对照组低，实验组的治疗后的最大线性斜率仅为(21.3±9.5)，低于对照组的(34.0±7.3)（P<0.05）。反应肿瘤的血管通透性指标Ktrans在治疗后两组均较治疗前下降（P <0.05），实验组下降了（0.32±0.11）ml/min/100cm3，对照组下降了(0.14±0.08)ml/min/100cm3，实验组高于对照组(P<0.05)。两组肿瘤的血管外细胞外间隙Ve在治疗后均较治疗前缩小(P<0.05)，但实验组缩小了(0.40±0.14)，而对照组仅缩小(0.19±0.12)，两者之间差异具有统计学意义（P<0.05）。
结论：
1、新辅助化疗的多西他赛、吡柔比星化疗药物通过细胞毒性作用的抑制肿瘤生长的同时也能抑制肿瘤血管内皮细胞的增生，使乳腺癌瘤灶体积缩小，肿瘤的微血管密度降低。
2、恩度能抑制乳腺癌的血管生成，间接导致肿瘤休眠或退缩。与新辅助化疗联合治疗乳腺癌能增强新辅助化疗的抗肿瘤作用，加剧肿瘤的退缩。
3、磁共振成像的多参数、任意角度成像在乳腺癌的诊断中能精确定位、准确定性，并且能观察恩度联合新辅助化疗治疗乳腺癌后肿瘤体积等形态学改变。DWI成像更能在肿瘤治疗发生形态学改变之前检测出瘤灶内细胞外水分子扩散运动、肿瘤的微循环灌注等肿瘤微环境的改变。能够更加早期准确的评价肿瘤对于治疗的反应，但对于恩度在乳腺癌中的抗血管作用的观察能力有限。
4、DCE－MRI通过临床常用的对比剂与图像后处理获得的数据进行半定量分析，其最大强化率与最大线性斜率的改变与肿瘤治疗后的体积改变、肿瘤的MVD一致，能反映出恩度在乳腺癌中的抗血管作用与抗肿瘤作用。
5、通过引入合适的药物动力学模型，对DCE－MRI所获得的数据定量分析，可以获得反应血管通透性的指标传输常数（Ktrans）和反应肿瘤内的渗漏空间的指标血管外细胞外间隙(Ve)。恩度、新辅助化疗后的乳腺癌瘤灶的Ktrans、Ve与肿瘤的MVD具有相关性，两者之间的改变具有一致性。说明DCE－MRI可以作为抗血管生成治疗药物的疗效评价手段，Ktrans与Ve可以作为肿瘤微血管密度、血管通透性的代替生物标志。
The use of neoadjuvant chemotherapy (NAC) has become the standardtreatment of breast cancer, especially locally advanced breast cancer. NAC maydownstage the tumor, decrease tumor size and render the tumor resectable. Inaddition, the pathological response of primary breast cancers to NAC is asurrogate biomarker for patient outcome; a major impact on survival is onlyobserved in the patients who achieve a pathologically complete response aftersurgery. So lots of explorations have been done by previous researchers toimprove the CR ratio of neoadjuvant chemotherapy.
Antiangiogenesis targeting turmor became a novel frontier for the treatmentof malignant disease since1971when Judah Folkman hypothesized that tumorgrowth is angiogenesis dependent. Cell experiments and animal models havemanifested the antiangiogenic and antitumor effect of dozens of antiangiogenicagents such as avastin. Since reported for the first time in1997, Endostatin, a20 kDa C-terminal fragment of collagen XVIII, has been known as a broadspectrum antiangiogenic agent to inhibit vascular endothelial cell proliferationspecifically, thereby inhibiting endothelial cell proliferation, migration,angiogenesis and tumor growth. It has been demonstrated to be effective indifferent tumor models including breast cancer in vivo. endostar, a recombinanthuman Endostatin, was approved by the state food and drug administration ofChina. And it was proved to be at least twice as potent as endostatin in animaltumor models by Judah Folkman. It is hypothesized in our study that endostarcan exert antiangeiogenetic effect in local advanced breast tumor.
To assess the tumour vascularity is a logical approach to evaluate the effectof angiogenesis inhibitors. Measurement of microvessel density (MVD) ontissue samples is the current gold standard technique to determine tumourvascularity. However, it is an invasive method and unsuitable for serialmeasurements. Dynamic contrast-enhanced MRI(DCE-MRI) has been proved tobe a noninvasive imaging technique that can be used to derive microcirculationproperties that mark tumour angiogenesis. Moreover, DCE-MRI can provideinformation on whole tumour volumes while MVD only assess focal regionswhereas tumour vasculature is heterogeneous. Implying a pharmacokinetictwo-compartment analysis, DCE-MRI can yield parameters, the tumor transfercoefficient (Ktrans) and the extravascular extracellulor volume (Ve), which can beused to evaluate microvascular density in tumour and the permeability of thevascular.
Using endostar to treat patient with local advanced breast cancer in clinichas not been performed yet, though there were reports about treating patientswith endostar in NSCLC and other cases. Therefore in the context of a phase IItrial, we prospectively treated patients with local advanced breast cancer usingendostar combined with neochemothrapy, and used DCE-MRI to evaluate the Ktransand Ve of the tumour. The aim of our study is to determine whetherendostar can exert its ant-angiogenesis effect and synergy anti-tumour effect ofNAC in local advanced breast cancer, and investigate the feasibility offunctional MRI to evaluate the anti-angiogenesis effect and anti-tumour effect ofendostar.
Experimental Ⅰ: Application of DWI in valuating anti-angiogenesisand anti-tumor effect of endostar in breast cancer
Objective: To evaluate the application of DWI in valuating anti-angiogenesisand anti-tumor effect of endostar in breast cancer. Methods: From March2008to August2010,60cases of breast cancer were enrolled in as research subjectsand randomly divided into experimental and control group. These two groupswere treated with endostar combined with neoadjuvant chemotherapy andneoadjuvant chemotherapy for3cycles respectively. We scanned all patientswith MAGNETOM Trio Tim3.0T scanning system from SIEMENS companybefore and after the treatment. Imaging methods included conventional SEsequence and diffusion-weighted imaging. All patients received surgicalresection of lesions or modified radical mastectomy in one week after the end oftreatment. Afterward we compared two groups of patients’ diffusion-weightedimaging of tumors, and contrast imaging results with the pathological results.Results: According to tissue response to cancer therapy standard,23cases’histological response scored more than grade4in the experimental group, whileonly18cases in the control group scored beyond grade4. Major histologicalresponse rate was77%in the experimental group, significantly higher thanmajor histological response rate in the control group. After treatment, the MVDof tumor were (3.7±1.7) in the experiment group, and (5.1±2.8) in the controlgroup. The difference between these two groups was statistically significant(P<0.05). ADC values of the two groups before treatment had no significantdifference (P=0.86). After treatment, ADC values in the experiment group were (1.83±0.17)×10-3(mm2/s), increased by42%(P<0.05). ADC value in thecontol group were (1.66±0.24)×10-3(mm2/s), increased by39%. IncreasedADC value in the experiment group was (0.62±0.21)×10-3(mm2/s), and theincreased ADC value in the control was (0.47±0.15)×10-3(mm2/s), and therewas no significant difference between them (P=0.45).
Experimental Ⅱ: Application of DCE－MRI in valuatinganti-angiogenesis and anti-tumor effect of endostar in breast cancer
Objective: To evaluate the application of dynamic contrast-enhanced MRI inevaluating the anti-angiogenesis and anti-tumor effect of endostar in breastcancer. Methods: The patients and therapy regime were same as in experimentⅠ. All patients underwent MRI examination before and after treatment usingMAGNETOM Trio Tim3.0T superconductive MRI scanning system from theSIEMENS company. Dynamic contrast enhanced magnetic resonance imagingwas administered with Gd-DTPA on the basis of conventional imaging. T1-FCMpharmacokinetic model was introduced to make quantitative analysis of the timesignal enhancement curve. We compared the changes of tumors in the twogroups after treatment and compared dynamic enhanced MRI results withpathologic findings. Results: There was no difference in maximumenhancement rates between the experimental group and control group prior totreatment. ER in both groups declined after treatment, but ER in theexperimental group was (0.93±0.35), lower than the control group (P<0.05).Decrease of ER after treatment in the treatment group was significantly biggerthan the control group (P<0.05). After treatment, TIC curve in the experimentalgroup was more smooth, and lower than that in the control group. The maximumlinear slope in the experimental group after treatment was only (21.3±9.5),significantly lower than that in the control group (34.0±7.3)(P <0.05). Ktranswhich reflected vascular permeability of tumor after treatment was lower than that before in both groups (P<0.05). The experimental group decreased by(0.32±0.11)ml/min/100cm3, and the control group decreased by(0.14±0.08)ml/min/100cm3. The decrease in the experimental groupsignificantly was higher (P<0.05). Ve which reflected tumor extravascularextracellular space reduced after treatment (P<0.05), but the experimental groupreduced by (0.40±0.14), while the control group reduced (0.19±0.12), and thedifference was statistically significant (P<0.05).
Conclusion:
1. Because of cytotoxicity of the docetaxel and pirarubicin, neoadjuvantchemotherapy can reduce the volume of tumors of breast cancer, and decreasetumor microvessel density as well.
2. Endostar inhibit angiogenesis and tumor growth by regulating vascularendothelial growth factor expression and activity of proteolytic enzymes andplay a multi-target anti-angiogenic effect resulting in hypoxic tumor cells,indirectly lead to tumor dormancy or withdrawal. And it can can enhance theantitumor effect when used together with neoadjuvant chemotherapy intreatment breast cancer.
3. Magnetic resonance imaging which has the advantage of multi-parameter,arbitrary angle imaging has been proved to be useful in diagnoing breast cancerand monitoring the morphology change of the tumor after treatment. DWIimaging can detect the changes of the excellular water molecule diffusion withinthe cell, tumor microcirculation and other changes in the tumormicroenvironment prior to morphological changes occurred in the tumor aftertreatment. But it has limited capacity of observing anti-angiogenic effect ofendostatin in breast cancer.
4. Semi-quantitative analysis of the DCE-MRI data can yield parameters including the maximum enhancement rate and the maximum linear slope ofchange and change in tumor volume after treatment. These parameters wereconsistent with tumor MVD, and can reflect antitumor effect and anti-angiogenesis effect of the endostar in breast cancer.
5. By introducing a suitable pharmacokinetic model, We can get parametersincluding Ktransand Ve which can reflect the permeability of the vascular in thetumor through quantitative analyzing the DCE-MRI data. The changes of Ktransand Ve are consistent with MVD. So DCE-MRI can be used as anti-angiogenesistherapy efficacy evaluation tools. Moreover Ktransand Ve can be used assurrogate biomarkers for tumor microvessel density, vascular permeability.
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