生物标志物联合检测对早期乳腺癌曲妥珠单抗联合化疗心脏毒性的预测价值

发布时间：2018-06-16 22:12

本文选题：生物标志物 + 乳腺癌　；参考：《中国人民解放军军事医学科学院》2017年硕士论文

【摘要】：目的曲妥珠单抗作为靶向治疗药物,于1988年被批准用于治疗转移性及早期乳腺癌。目前,一年曲妥珠单抗辅助治疗的标准治疗已广泛用于早期HER2阳性乳腺癌患者,显著提高了患者的总生存期,使得乳腺癌患者成为“慢性病”。但临床研究对曲妥珠单抗所致心脏毒性的报道也越来越多,心脏毒性事件往往发病隐匿、临床发现时较晚常发生心功能不全甚至心脏衰竭,是一部分肿瘤存活者的主要非乳腺癌死亡原因。左室射血分数是抗肿瘤治疗患者心脏毒性评价的最常用指标,但越来越来的研究表明心肌细胞坏死导致的心脏损害在LVEF降低之前已经发生,其对心脏毒性亚临床损害并不敏感,而识别心脏结构与功能早期微细变化是防止晚期心脏毒性事件风险的关键环节。尽管学者们在心脏亚临床损伤的早期敏感指标做了一些研究,但应用哪种指标早期预测抗肿瘤治疗心脏毒性的发生尚无定论。本研究通过检测hs-cTnI、Tβ4和NT-proBNP,探讨其在预测曲妥珠单抗联合化疗致心脏毒性中的临床价值。方法收集2013年至2015年我院确诊的her-2阳性早期乳腺癌,并安排接受AC-TH辅助化疗方案的患者,根据入排标准收集病例,进行了入组。在基线(visit1)蒽环类药物用药前、3个月(visit2)即曲妥珠单抗+紫杉类用药前、6个月(visit3)即曲妥珠单抗用药期间,测定hs-cTnI、Tβ4和NT-proBNP水平,从基线到15个月,每3个月进行一次超声心动图检查和问卷调查(共6次)。采用SPSS19.0软件进行数据分析,使用汇总统计、平均数和标准差的描述计量资料,使用百分比和率描述计数资料,组间基线病理资料比较方法,连续变量使用t检验,分类变量使用卡方检验。hs-cTnI、Tβ4和NT-proBNP这三项指标在不同时间点的组间比较采用Wilcoxon秩和检验,组内前后比较采用Wilcoxon符号秩检验。将心脏毒性的发生视为终点事件,为了描述简洁,我们将hs-cTnI、Tβ4和NT-proBNP动态变化差值(visit1至visit3)分别表示为Δhs-cTnI、ΔTβ4和ΔNT-proBNP。为阐明这多个生物标志物联合检测对随后心脏毒性发生风险的预测价值。利用受试者工作曲线(ROC曲线),对cTnI、Tβ4和NT-proBNP的诊断价值进行比较,选出意义较大的指标做COX生存分析,分组如两个指标均高于阈值定义为“两高组”或其中任一达到阈值定义为“一高组”,分别赋值为1、0,定义为新变量后做COX生存分析。结果本研究共有129例HER2阳性早期乳腺癌患者入组,随访时间最长15个月,因化疗方案中途更改、电话错误失访和关键指标缺失等原因,共剔除12人,实际完成117例。患者年龄从24-75岁,平均年龄47.95±8.94,共有16例发生心脏毒性(13.67%),发生心脏毒性事件的中位时间为9.8个月(四分位数间距:2至15个月)。心脏毒性患者LVEF变化的中位数是15.35%(四分位数间距:12.57%至19.19%),其中3例LVEF下降≥5%降至55%,伴随CHF症状和体征,其余13例中,有11例下降≥10%降至降至55%无症状和体征,2例下降≥10%55%,伴随症状和体征。根据有无发生心脏毒性将患者分为两组,即心脏毒性组和非心脏毒性组,两组在基线的一般病理资料特征无统计学差异(P0.05)。比较两组化疗前后生物标志物的动态变化,发现hs-ctnI和Tβ4的动态变化和随后的心脏毒性显著正相关,且hs-cTnI的浓度变化较Tβ4早,而NT-proBNP的浓度变化与心脏毒性的关系不大。ROC曲线分析hs-cTnI、Tβ4指标下面积分别为0.964、0.930,分别与面积0.500比较有显著统计学差异(P值0.01);NT-proBNP指标ROC曲线下面积为0.656,与面积0.500比较有统计学差异(P0.05),且各有统计学意义的指标曲线下面积由大到小排列为hs-cTnITβ4NT-proBNP,说明hs-cTnI对心脏毒性的预测效果最好,Tβ4次之,NT-proBNP最差。COX生存分析,显示NT-proBNP对心脏毒性风险的预测几乎没有价值。而hs-cTnI与Tβ4联合检测与单一检测指标的的风险比分析中,显示“两高组”随后发生心脏毒性事件的风险是“一高组”的9.486倍(HR=9.486),可以认为两指标的联合检测在曲妥珠单抗联合化疗心脏毒性风险的预测上更加高效。结论本研究证实在接受曲妥珠单抗联合蒽环类化疗的早期乳腺患者中1.hs-cTnI和Tβ4的升高与心脏毒性早期损伤显著相关。2.就单一指标对心脏毒性的预测价值比较,hs-cTnI的预测价值最好,Tβ4较好,NT-proBNP较差;且在抗肿瘤治疗期间,hs-cTnI的浓度升高最早,能更早期预测心脏毒性。3.就多指标的价值而言,hs-cTnI和Tβ4的联合预测显然比单一指标更有价值,可以更高效的识别随后一年发生心脏毒性高风险的患者。
[Abstract]:Objective trastuzumab, as a target drug, was approved for the treatment of metastatic and early breast cancer in 1988. At present, the standard treatment for the first year of trastuzumab adjuvant therapy has been widely used in early HER2 positive breast cancer patients, significantly improving the total survival time of the patients and making the patients with breast cancer become "chronic disease". More and more reports of cardiac toxicity caused by trastuzumab are also reported. Cardiac toxicity is often occult, cardiac insufficiency or heart failure often occurs later in clinical discovery, which is the main cause of non breast cancer death in some tumor survivors. Left ventricular ejection fraction is the most commonly used assessment of cardiac toxicity in antitumor patients. But a growing number of studies have shown that cardiac damage caused by cardiomyocyte necrosis has occurred before LVEF decreased, and it is not sensitive to subclinical cardiac damage, and the identification of cardiac structure and early functional changes is the key link to prevent the risk of advanced cardiac toxicity. Early sensitivity indicators have been studied, but it is not conclusive of which indicators to predict early antitumor cardiotoxicity. This study examined the clinical value of hs-cTnI, T beta 4 and NT-proBNP in predicting the cardiac toxicity of trastuzumab combined with chemotherapy. The method collected HER-2 positive in our hospital from 2013 to 2015. Patients with early breast cancer and arranged with AC-TH adjuvant chemotherapy were enrolled in the group. Before the baseline (visit1) anthracycline medication, 3 months (visit2) before the use of trastuzumab + paclitaxel and 6 months (visit3), the levels of hs-cTnI, T beta 4, and NT-proBNP were measured, from the baseline, from the baseline. 15 months, every 3 months, the echocardiography and questionnaire survey (6 times) were carried out. The data were analyzed with SPSS19.0 software. The statistics, the average and the standard deviation were used to describe the data, the percentage and rate were used to describe the counting data, the comparison method of the baseline pathological data between the groups, the continuous variables using the t test, and the classification variables. The three indexes of.Hs-cTnI, T beta 4 and NT-proBNP were compared with Wilcoxon rank and test at different time points, and Wilcoxon symbol rank test was used in the group before and after group. The occurrence of cardiac toxicity was regarded as an end event. In order to describe the succinct, we would use hs-cTnI, T beta 4 and NT-proBNP dynamic variation (visit1 to visit3), respectively. The value of delta hs-cTnI, Delta T beta 4 and delta NT-proBNP. was used to illustrate the predictive value of the combined detection of these biomarkers on the risk of subsequent cardiac toxicity. The diagnostic value of cTnI, T beta 4 and NT-proBNP was compared by using the receiver's work curve (ROC curve), and a significant index was selected to do COX survival analysis, and the groups such as two indexes were all high. The threshold was defined as "two high groups" or any of the threshold values defined as "one high group", respectively assigned to 1,0, defined as a new variable and COX survival analysis. Results 129 cases of HER2 positive early breast cancer patients were enrolled in the study. The follow-up time was 15 months for the longest time. 12 people were eliminated and 117 cases were actually completed. The age of the patients was 24-75 years old and the average age was 47.95 + 8.94. There were 16 cases of cardiac toxicity (13.67%). The median time of cardiac toxicity was 9.8 months (four in the distance of 2 to 15 months). The median of LVEF changes in the patients with cardiac toxicity was 15.35% (four fraction spacing: 12.57% to 24-75). 19.19%) in 3 cases, LVEF decreased to 55%, accompanied by symptoms and signs. In the remaining 13 cases, 11 cases decreased to 10% to 55% asymptomatic and physical signs, 2 patients decreased more than 10%55%, accompanied by symptoms and signs. The patients were divided into two groups according to or without cardiac toxicity, that is, the cardiac toxicity group and the non cardiac toxicity group, and the two group in the baseline general disease. There was no statistical difference (P0.05). Comparing the dynamic changes of biomarkers before and after chemotherapy in two groups, it was found that the dynamic changes of hs-ctnI and T beta 4 were positively correlated with the subsequent cardiac toxicity, and the concentration of hs-cTnI was earlier than that of T beta 4, but the relationship between the concentration of NT-proBNP and cardiac toxicity was not.ROC curve analysis hs-cTnI, T beta 4 index. The lower area was 0.964,0.930, respectively, compared with area 0.500 (P value 0.01), and the area under ROC curve of NT-proBNP index was 0.656, and there was a statistical difference from area 0.500 (P0.05), and the area under the curve of statistical significance from large to small was hs-cTnIT beta 4NT-proBNP, indicating the toxicity of hs-cTnI to the heart. T beta 4, NT-proBNP's worst.COX survival analysis showed that NT-proBNP was of little value in predicting the risk of heart toxicity, and the risk ratio of hs-cTnI and T beta 4 combined with a single test showed that the risk of subsequent cardio events in the "two high groups" was 9.486 times as high as the "high group" (HR=9.) 486) a combined test of two indicators can be considered to be more efficient in predicting the risk of cardiac toxicity with trastuzumab combined with chemotherapy. Conclusion this study confirms that the increase of 1.hs-cTnI and T beta 4 in early breast patients with trastuzumab combined with anthracycline chemotherapy is significantly related to the early toxicity of cardio toxicity.2. on a single indicator of cardiac toxicity. Hs-cTnI has the best predictive value, T beta 4 is better, NT-proBNP is poorer, and the increase of hs-cTnI concentration is the earliest during antitumor treatment, and the value of the early prediction of cardiac toxicity.3. is more valuable than the single index of hs-cTnI and T beta 4, which can be more efficiently identified for the following year. A patient with high risk of heart toxicity.
【学位授予单位】：中国人民解放军军事医学科学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R737.9

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