本文選題：生物標(biāo)志物 + 乳腺癌��； 參考：《中國人民解放軍軍事醫(yī)學(xué)科學(xué)院》2017年碩士論文

【摘要】：目的曲妥珠單抗作為靶向治療藥物,于1988年被批準(zhǔn)用于治療轉(zhuǎn)移性及早期乳腺癌。目前,一年曲妥珠單抗輔助治療的標(biāo)準(zhǔn)治療已廣泛用于早期HER2陽性乳腺癌患者,顯著提高了患者的總生存期,使得乳腺癌患者成為“慢性病”。但臨床研究對曲妥珠單抗所致心臟毒性的報道也越來越多,心臟毒性事件往往發(fā)病隱匿、臨床發(fā)現(xiàn)時較晚常發(fā)生心功能不全甚至心臟衰竭,是一部分腫瘤存活者的主要非乳腺癌死亡原因。左室射血分?jǐn)?shù)是抗腫瘤治療患者心臟毒性評價的最常用指標(biāo),但越來越來的研究表明心肌細(xì)胞壞死導(dǎo)致的心臟損害在LVEF降低之前已經(jīng)發(fā)生,其對心臟毒性亞臨床損害并不敏感,而識別心臟結(jié)構(gòu)與功能早期微細(xì)變化是防止晚期心臟毒性事件風(fēng)險的關(guān)鍵環(huán)節(jié)。盡管學(xué)者們在心臟亞臨床損傷的早期敏感指標(biāo)做了一些研究,但應(yīng)用哪種指標(biāo)早期預(yù)測抗腫瘤治療心臟毒性的發(fā)生尚無定論。本研究通過檢測hs-cTnI、Tβ4和NT-proBNP,探討其在預(yù)測曲妥珠單抗聯(lián)合化療致心臟毒性中的臨床價值。方法收集2013年至2015年我院確診的her-2陽性早期乳腺癌,并安排接受AC-TH輔助化療方案的患者,根據(jù)入排標(biāo)準(zhǔn)收集病例,進(jìn)行了入組。在基線(visit1)蒽環(huán)類藥物用藥前、3個月(visit2)即曲妥珠單抗+紫杉類用藥前、6個月(visit3)即曲妥珠單抗用藥期間,測定hs-cTnI、Tβ4和NT-proBNP水平,從基線到15個月,每3個月進(jìn)行一次超聲心動圖檢查和問卷調(diào)查(共6次)。采用SPSS19.0軟件進(jìn)行數(shù)據(jù)分析,使用匯總統(tǒng)計、平均數(shù)和標(biāo)準(zhǔn)差的描述計量資料,使用百分比和率描述計數(shù)資料,組間基線病理資料比較方法,連續(xù)變量使用t檢驗,分類變量使用卡方檢驗。hs-cTnI、Tβ4和NT-proBNP這三項指標(biāo)在不同時間點的組間比較采用Wilcoxon秩和檢驗,組內(nèi)前后比較采用Wilcoxon符號秩檢驗。將心臟毒性的發(fā)生視為終點事件,為了描述簡潔,我們將hs-cTnI、Tβ4和NT-proBNP動態(tài)變化差值(visit1至visit3)分別表示為Δhs-cTnI、ΔTβ4和ΔNT-proBNP。為闡明這多個生物標(biāo)志物聯(lián)合檢測對隨后心臟毒性發(fā)生風(fēng)險的預(yù)測價值。利用受試者工作曲線(ROC曲線),對cTnI、Tβ4和NT-proBNP的診斷價值進(jìn)行比較,選出意義較大的指標(biāo)做COX生存分析,分組如兩個指標(biāo)均高于閾值定義為“兩高組”或其中任一達(dá)到閾值定義為“一高組”,分別賦值為1、0,定義為新變量后做COX生存分析。結(jié)果本研究共有129例HER2陽性早期乳腺癌患者入組,隨訪時間最長15個月,因化療方案中途更改、電話錯誤失訪和關(guān)鍵指標(biāo)缺失等原因,共剔除12人,實際完成117例�；颊吣挲g從24-75歲,平均年齡47.95±8.94,共有16例發(fā)生心臟毒性(13.67%),發(fā)生心臟毒性事件的中位時間為9.8個月(四分位數(shù)間距:2至15個月)。心臟毒性患者LVEF變化的中位數(shù)是15.35%(四分位數(shù)間距:12.57%至19.19%),其中3例LVEF下降≥5%降至55%,伴隨CHF癥狀和體征,其余13例中,有11例下降≥10%降至降至55%無癥狀和體征,2例下降≥10%55%,伴隨癥狀和體征。根據(jù)有無發(fā)生心臟毒性將患者分為兩組,即心臟毒性組和非心臟毒性組,兩組在基線的一般病理資料特征無統(tǒng)計學(xué)差異(P0.05)。比較兩組化療前后生物標(biāo)志物的動態(tài)變化,發(fā)現(xiàn)hs-ctnI和Tβ4的動態(tài)變化和隨后的心臟毒性顯著正相關(guān),且hs-cTnI的濃度變化較Tβ4早,而NT-proBNP的濃度變化與心臟毒性的關(guān)系不大。ROC曲線分析hs-cTnI、Tβ4指標(biāo)下面積分別為0.964、0.930,分別與面積0.500比較有顯著統(tǒng)計學(xué)差異(P值0.01);NT-proBNP指標(biāo)ROC曲線下面積為0.656,與面積0.500比較有統(tǒng)計學(xué)差異(P0.05),且各有統(tǒng)計學(xué)意義的指標(biāo)曲線下面積由大到小排列為hs-cTnITβ4NT-proBNP,說明hs-cTnI對心臟毒性的預(yù)測效果最好,Tβ4次之,NT-proBNP最差。COX生存分析,顯示NT-proBNP對心臟毒性風(fēng)險的預(yù)測幾乎沒有價值。而hs-cTnI與Tβ4聯(lián)合檢測與單一檢測指標(biāo)的的風(fēng)險比分析中,顯示“兩高組”隨后發(fā)生心臟毒性事件的風(fēng)險是“一高組”的9.486倍(HR=9.486),可以認(rèn)為兩指標(biāo)的聯(lián)合檢測在曲妥珠單抗聯(lián)合化療心臟毒性風(fēng)險的預(yù)測上更加高效。結(jié)論本研究證實在接受曲妥珠單抗聯(lián)合蒽環(huán)類化療的早期乳腺患者中1.hs-cTnI和Tβ4的升高與心臟毒性早期損傷顯著相關(guān)。2.就單一指標(biāo)對心臟毒性的預(yù)測價值比較,hs-cTnI的預(yù)測價值最好,Tβ4較好,NT-proBNP較差;且在抗腫瘤治療期間,hs-cTnI的濃度升高最早,能更早期預(yù)測心臟毒性。3.就多指標(biāo)的價值而言,hs-cTnI和Tβ4的聯(lián)合預(yù)測顯然比單一指標(biāo)更有價值,可以更高效的識別隨后一年發(fā)生心臟毒性高風(fēng)險的患者。
[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.
【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R737.9

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本文編號：2028278