动态增强MRI预测乳腺癌新辅助化疗疗效及其与乳腺癌分子亚型的关系研究

发布时间：2018-05-28 13:31

本文选题：乳腺肿瘤 + 磁共振成像　；参考：《北京协和医学院》2014年博士论文

【摘要】：第一部分动态增强MRI预测乳腺癌新辅助化疗疗效目的探讨动态对比增强MRI(DCE-MRI)早期预测乳腺癌新辅助化疗(NAC)疗效的可行性。资料与方法收集2011年5月～2014年1月计划在我院行NAC的乳腺癌患者共112例,年龄23～67岁,中位年龄48岁,于化疗前和NAC2周期后行DCE-MRI扫描,分别采用ROIw,ol。法和ROIhs法测量肿瘤三个方位最大径、半定量参数最大上升斜率(MSI)、第二期强化程度(SI2%)、峰值强化程度(SIpeak%)、正性增强积分(PEI)、最大下降斜率(MSD)、达峰时间(TTP)以及R0Iwhole法测量定量参数容量转移常数(Ktrans)、速率常数(Kep)、细胞外血管外间隙容积比(Ve)。按照MillerPayne分级系统,将肿瘤反应性分为组织学显著反应(MHR)和组织学非显著反应(NMHR)。分别比较MHR组及NMHR组化疗前与NAC2周期后的量化参数,并比较MHR组和NMHR组NAC2周期后各参数的变化值以及基线参数值,正态分布者行两独立(或配对)样本t检验,非正态分布者行两独立样本(或配对资料)的非参数检验,绘制受试者工作曲线(ROC),找到早期预测乳腺癌NAC疗效的最佳参数及其诊断阈值,并比较两种ROI选取方法的预测效能。结果最终入组行半定量分析者72例,NMHR组53例,MHR组19例；行定量分析者62例,NMHR组45例,MHR组17例。无论MHR组还是NMHR组,NAC前与化疗2周期后的肿瘤大小均有统计学差异(P0.001)；MHR组NAC前与化疗2周期后的半定量参数及定量参数均有统计学差异(P0.05)；NMHR组除MSD(ROIwhole)、MSD(ROIhs)、TTP(ROIhs)、KepVe外(P值分别为0.615,0.205,0.085,0.118,0.236),其余DCE-MRI参数在NAC前与化疗2周期后的差异均有统计学意义(P0.05)；NAC2周期后肿瘤各径线消退率、半定量参数变化值及定量参数变化值在MHR组和NMHR组间的差异均有统计学意义(P0.05),即MHR组参数下降较NMHR组明显；而化疗前的各参数在两组间的差异无统计学意义(P0.05)。ROC分析显示以肿瘤三径线几何均值的变化值(△G)预测NAC疗效的曲线下面积、敏感度、特异度和诊断阈值分别为0.908、84.2%、92.5%和-43.7%,以K。。的变化值预测的曲线下面积、敏感度、特异度和诊断阈值分别为0.890、76.5%、93.3%和-54.8%。比较ROIwhole法和R0Ihs法测得的半定量参数MSI、SI2%、SIpeak%、PEI和MSD变化值预测NAC疗效的ROC曲线下面积,P值分别为0.769、0.588、0.490、0.807和0.793。结论DCE-MRI量化参数可于化疗2周期预测乳腺癌NAC的疗效,而化疗前的参数尚不能预测化疗的最终疗效,其中△G、△Kep是较好的预测指标,两种ROI选取方法预测乳腺癌NAC疗效的效能相当。第二部分动态增强MRI参数与乳腺癌分子亚型的关系研究目的探讨动态对比增强MRI (DCE-MRI)量化参数与乳腺癌不同分子亚型及预后因子的关系。资料与方法以第一部分中收集的2011年5月-2014年1月计划在我院行新辅助化疗(NAC)的112例乳腺癌患者为研究对象,行DCE-MRI检查,分别采用ROIwhole法和ROIhs法测量半定量参数最大上升斜率(MSI)、第二期强化程度(SI2%)、峰值强化程度(SIpeak%)、正性增强积分(PEI)、最大下降斜率(MSD)、达峰时间(TTP)以及ROIwhole法测量定量参数容量转移常数(Ktrans)、速率常数(Kep)、细胞外血管外间隙容积比(Ve)。采用SP法检测免疫组化指标ER、PR、HER-2及Ki-67,对HER-2(++)者行免疫荧光原位杂交法(FISH)检测,以此将乳腺癌分为Luminal A、Luminal B、HER-2+和三阴性乳腺癌(TNBC)四个亚型。采用两独立样本t检验或Mann-WhitneyU检验比较ER、PR和HER-2不同表达状态时各参数的差别,行单因素方差分析比较不同分子亚型间的半定量参数,行Mann-Whitney U检验对不同分子亚型间定量参数两两比较,P≤0.05为差异有统计学意义。结果最终入组行半定量分析的101例患者,有4例未行FISH检测,Luminal A型15例,Luminal B型56例,HER-2+型12例,TNBC14例。PR+者的MSD高于PR-者(P=0.002,0.016),HER-2+者的MSI高于HER-2-者(P=0.021,0.011),PR-者的SI2%(ROI,,hole)高于PR+者(P=0.031),HER-2-者的TTP(ROIhs)高于HER-2+者(P=0.029),其余半定量参数在不同受体表达状态时的差异无统计学意义(P0.05)。除MSD(ROI,,hole)外(P=0.045),其余半定量参数在不同分子亚型间的差异无统计学意义,但进一步两两比较,各组间差异均无统计学意义。最终入组行定量分析的82例患者,有3例未行FISH检测,Luminal A型13例,Luminal B型42例,HER-2+型11例,TNBC13例。不同受体表达状态时定量参数的差异无统计学意义(P0.05)。Lumianl A型和TNBC、LumianlA型和HER-2+型的Ktrans值有统计学差异(P=0.026,0.047),Luminal B型和TNBC的Kep值有统计学差异(P=0.013),其余任何两型间的定量参数值均无统计学差异。结论不同PR表达状态时的MSD不同,PR+者高于PR-者,HER-2过表达者的MSI较正常表达者显著性增高；TNBC和HER-2+型的Ktrans值高于Luminal A型,TNBC的K。。值高于Luminal B型,即TNBC和HER-2+型的局部血流灌注较高,Luminal A和Luminal B型则相反,揭示了各分子亚型的不同生物学特性。第三部分不同分子亚型对动态增强MRI预测乳腺癌NAC疗效准确性的影响目的探讨乳腺癌不同分子亚型对动态对比增强MRI(DCE-MRI)量化参数预测乳腺癌新辅助化疗(NAC)疗效准确性的影响。资料与方法收集2011年5月～2014年1月计划在我院行NAC的乳腺癌患者共112例,分别于化疗前和NAC2周期后行DCE-MR T扫描,分别采用R0Iwhole法和R0Ihs法测量肿瘤三个方位最大径、半定量参数最大上升斜率(MSI)、第二期强化程度(SI：%)、峰值强化程度(SIpeak%)、正性增强积分(PEI)、最大下降斜率(MSD)、达峰时间(TTP)以及ROIwhole法测量定量参数容量转移常数(Ktrans)、速率常数(Kep)、细胞外血管外间隙容积比(V。)。按照MillerPayne分级系统,将肿瘤反应性分为组织学显著反应(MHR)和组织学非显著反应(NMHR)。采用SP法检测免疫组化指标ER.PR.HER-2及Ki-67,对HER-2(++)者行免疫荧光原位杂交法(FISH)检测,以此将乳腺癌分为Luminal A、Luminal B、HER-2+和三阴性乳腺癌(TNBC)四个亚型。行二分类Logi stic回归,从患者年龄、肿瘤形态、化疗方案和分子亚型中筛选出影响病理与影像预测结果一致性的因素；计算DEC-MRI参数预测乳腺癌不同分子亚型NAC疗效的敏感度、特异度、阳性预测值、阴性预测值和准确度。结果最终入组69例,MHR组19例,NMIIR组50例；Luminal A型9例,Luminal B型39例,HER2+型8例,TNBC13例。经过筛选,分子分型是影响I)CEMRl预测乳腺癌NAC疗效准确性的因素,对SIpenk%(ROIwhole)、MSD(ROIwhone)及SI：%(ROIts)三个参数的影响较大,比值比分别为2.580、0.437和2.569。定量参数(Ktrans、Kep、Vec)及左右径预测不同分子亚型乳腺癌NAC疗效的准确性均较高；对于肿瘤前后径和MSD(ROIwhole),Lumianl的准确度较高,分别为87.5%和89.6%,高于HER-2+型(75.0%和87.5%)和TNBC(76.9%和61.5%)；对于上下径及半定量参数MSI(ROIwhole)、SI2%(ROIwhols)、SIpeak%(ROIwhole)、PEI(ROIwhole)、MSI(ROIhs)、SI2%(R0Ihs)、SIpeak%(ROIh、)、PEI(ROIhs)、MSD(ROIhs),Luminal型乳腺癌预测的准确性较差(分别为68.7%,77.1%,70.8%,62.5%,73.0%,79.2%,64.6%,64.6%,66.7%,72.9%),HER-2+(分别为100.0%,87.5%,87.5%,87.5%,87.5%,100.0%,100.0%,87.5%,87.5%,100.0%)和TNBC的准确性较高(分别为92.3%,100.0%,100.0%,100.0%,100.0%,100.0%,100.0%,100.0%,92.3%,84.6%)。结论定量参数和在延迟MRI图像(高分辨率)上测得的肿瘤左右径预测NAC疗效的准确性较高,不受分子亚型影响；通过大多数半定量参数预测TNBC和HER-2+型NAC疗效的准确性较高,Luminal型则较低。
[Abstract]:Part I dynamic contrast-enhanced MRI predicts the efficacy of neoadjuvant chemotherapy for breast cancer.
Objective to explore the feasibility of dynamic contrast-enhanced MRI (DCE-MRI) in predicting the efficacy of neoadjuvant chemotherapy (NAC) in breast cancer.
Materials and methods 112 cases of breast cancer were collected from May 2011 to January 2014 in our hospital. The age of 112 cases of breast cancer was 23~67 years old. The median age was 48 years old. DCE-MRI scan was performed before and after the chemotherapy and NAC2 cycle. The maximum diameter of three azimuth, the maximum slope of semi quantitative parameters (MSI), and second phases of strengthening of the tumor were measured by ROIw, ol. and ROIhs. Degree (SI2%), peak Intensification (SIpeak%), positive enhancement integral (PEI), maximum descent slope (MSD), peak time (TTP) and quantitative parameter volume transfer constant (Ktrans), rate constant (Kep) and extracellular space volume ratio (Ve) of extracellular blood vessel (Ve) measured by R0Iwhole method. According to MillerPayne grading system, the tumor reactivity was divided into a significant histological response (MHR) and histology non significant response (NMHR). Compare the quantitative parameters of the MHR and NMHR groups before and after the NAC2 cycle, and compare the changes of the parameters and the baseline parameters of the MHR and NMHR groups after NAC2 cycle, the normal distribution of the two independent (or paired) sample t test, and the non normal distribution of the two independent samples (or paired data). Nonparametric test, the subject work curve (ROC) was drawn to find the best parameters for early prediction of breast cancer NAC and its diagnostic threshold, and to compare the predictive effectiveness of the two ROI selection methods.
Results in the final group, there were 72 semi quantitative analysts, 53 cases in group NMHR and 19 in group MHR, 62 cases of quantitative analysis, 45 cases in group NMHR, 17 cases in group MHR. The tumor size before NAC before and after 2 cycles of chemotherapy was statistically significant (P0.001); the semi quantitative parameters and quantitative parameters of MHR group before and after 2 cycles of chemotherapy were statistically significant. Difference (P0.05); group NMHR except MSD (ROIwhole), MSD (ROIhs), TTP (ROIhs), KepVe (P value was 0.615,0.205,0.085,0.118,0.236), and the difference between the remaining DCE-MRI parameters before and after 2 cycles of chemotherapy. The difference between the NMHR group and the NMHR group was statistically significant (P0.05), that is, the parameters of the MHR group were significantly lower than those in the NMHR group, but the difference between the parameters before the chemotherapy was not statistically significant (P0.05).ROC analysis showed that the variation value of the geometric mean of the tumor (delta G) predicted the area under the curve of the NAC efficacy, sensitivity, specificity and diagnostic threshold, respectively. For 0.908,84.2%, 92.5% and -43.7%, the area under the curve, sensitivity, specificity and diagnostic threshold were 0.890,76.5%, 93.3% and -54.8%. compared with the ROIwhole method and the R0Ihs method to determine the semi quantitative parameter MSI, and the SI2%, SIpeak%, PEI and MSD variations predicted the area under the curve. .807 and 0.793.
Conclusion DCE-MRI quantized parameters can be used to predict the curative effect of breast cancer NAC in 2 cycle of chemotherapy, and the parameters before chemotherapy can not predict the final curative effect of chemotherapy, of which Delta G and delta Kep are good predictors, and the effectiveness of the two ROI selection methods to predict the effect of breast cancer NAC is quite effective.
The second part is the relationship between dynamic enhanced MRI parameters and molecular subtypes of breast cancer.
Objective to explore the relationship between dynamic contrast enhanced MRI (DCE-MRI) quantification parameters and different molecular subtypes and prognostic factors of breast cancer.
Materials and methods: in the first part, 112 cases of breast cancer who were planned in January -2014 May 2011 in January -2014 were studied. The DCE-MRI examination was performed. The maximum slope of semi quantitative parameters (MSI) was measured by ROIwhole method and ROIhs method respectively. The second phase intensification degree (SI2%), and the peak intensification degree (SIpeak%) were taken. Sex enhancement score (PEI), maximum descent slope (MSD), peak time (TTP) and quantitative parameter volume transfer constant (Ktrans), rate constant (Kep), extracellular space volume ratio (Ve) of extracellular blood vessel (Ve) were measured by ROIwhole method. Immunochemical index ER, PR, HER-2 and Ki-67 were detected by SP method, and the immunofluorescence in situ hybridization (+ +) was detected by SP method. Breast cancer was divided into four subtypes of Luminal A, Luminal B, HER-2+ and three negative breast cancer (TNBC). Two independent samples t test or Mann-WhitneyU test were used to compare the difference of the parameters when ER, PR and HER-2 were expressed in different states. Single factor variance analysis was used to compare the semi quantitative parameters of different molecular subtypes. There was a significant difference between the quantitative parameters of sub subtypes 22 and P < 0.05.
Results there were 101 cases of semi quantitative analysis. There were 4 cases without FISH detection, 15 cases of Luminal A, 56 cases of Luminal B, 12 cases of HER-2+ type, and MSD higher than PR- in TNBC14 case.PR+. R-2+ (P=0.029), the difference of the other semi quantitative parameters in the expression of different receptors was not statistically significant (P0.05). Except MSD (ROI, hole), the difference between the other semi quantitative parameters was not statistically significant in the subtypes of different molecules, but there was no statistical significance in the further 22 ratio, and the final group was 8. In 2 cases, there were 3 cases without FISH detection, 13 cases of Luminal A, 42 cases of Luminal B, 11 cases of HER-2+ type, and TNBC13 cases. There was no statistical difference between the quantitative parameters of the expression of different receptors (P0.05).Lumianl A and TNBC. Difference (P=0.013), no significant difference was found in the quantitative parameters between the other two types.
Conclusion the MSD of different PR expressions is different, the PR+ is higher than the PR-, the MSI of HER-2 overexpression is significantly higher than that of the normal expression. The Ktrans value of TNBC and HER-2+ is higher than that of Luminal A. Different biological characteristics of subtypes.
The third part of the impact of different molecular subtypes on the accuracy of dynamic enhanced MRI in predicting the efficacy of NAC in breast cancer
Objective to investigate the effect of different molecular subtypes of breast cancer on the accuracy of dynamic contrast enhanced MRI (DCE-MRI) in predicting the efficacy of neoadjuvant chemotherapy (NAC) in breast cancer.
Data and methods 112 cases of breast cancer were collected from May 2011 to January 2014 in our hospital. DCE-MR T scan was performed before and after the chemotherapy of NAC. The maximum diameter of three azimuth, the maximum slope of semi quantitative parameter (MSI), the second intensification degree (SI:%) and the peak strengthening process were measured by R0Iwhole and R0Ihs respectively. Degree (SIpeak%), positive enhancement integral (PEI), maximum descent slope (MSD), peak time (TTP) and quantitative parameter volume transfer constant (Ktrans) measured by ROIwhole, rate constant (Kep), extracellular space volume ratio (V.) in extracellular space (V.). According to the MillerPayne grading system, the tumor reactivity was divided into histological significant reaction (MHR) and histology nonsignificant. Reaction (NMHR). The immunofluorescence index ER.PR.HER-2 and Ki-67 were detected by SP, and the HER-2 (+ +) was detected by immunofluorescence in situ hybridization (FISH), and the breast cancer was divided into four subtypes: Luminal A, Luminal B, HER-2+ and three negative breast cancer (TNBC). The factors that affect the consistency of the pathological and image prediction results were screened, and the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the DEC-MRI parameters were calculated to predict the efficacy of different molecular subtypes of NAC in breast cancer.
The results were 69 cases, 19 cases in group MHR, 50 cases in group NMIIR, 9 cases of Luminal A, 39 cases of Luminal B, 8 cases of HER2+, TNBC13 case. The molecular typing is the factor influencing the accuracy of I) CEMRl to predict the NAC effect of breast cancer. The accuracy of the 37 and 2.569. quantitative parameters (Ktrans, Kep, Vec) and the left and right diameters for the prediction of NAC for different molecular subtypes of breast cancer were higher. The accuracy of Lumianl was higher for the anterior and posterior diameter of the tumor and MSD (ROIwhole), 87.5% and 89.6%, respectively, higher than the HER-2+ (75% and 87.5%) and TNBC (76.9% and 61.5%), and MSI (ROI) for the upper and lower diameter and the semi quantitative parameter (ROI). Whole), SI2% (ROIwhols), SIpeak% (ROIwhole), PEI (ROIwhole), MSI (ROIhs), SI2% (R0Ihs), SIpeak% (R0Ihs), poor prediction accuracy (68.7%, 77.1%, 70.8%, 62.5%, 73%, 79.2%, 64.6%, 64.6%, 66.7%, 72.9% respectively). %, 100%) and TNBC were of high accuracy (92.3%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 92.3%, 84.6%) respectively.
Conclusion the accuracy of the quantitative parameters and the predicted NAC effect in the delayed MRI image (high resolution) is higher, not affected by the molecular subtype, and the accuracy of the TNBC and HER-2+ type NAC is higher and the Luminal type is lower by most semi quantitative parameters.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2014
【分类号】：R737.9;R445.2

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