循环肿瘤DNA在接受靶向治疗的HER2阳性晚期乳腺癌患者中的临床价值

发布时间：2018-04-02 01:28

  本文选题：乳腺癌　切入点：循环肿瘤DNA　出处：《北京协和医学院》2016年博士论文

【摘要】：目的：探讨接受靶向治疗的HER2阳性晚期乳腺癌患者循环肿瘤DNA检测在预后、病情监测中的作用,探索循环肿瘤DNA克隆动态变化与疗效的相关性。方法：选择临床试验BLTN-1b中18例签署了知情同意的HER2表达阳性晚期乳腺癌患者,患者均接受不可逆EGFR/HER2双靶点酪氨酸激酶抑制剂的单药治疗,直至患者疾病进展、毒性不可耐受、患者撤回知情或研究者判断必须终止用药。给药前和每2个给药周期(56±3天,28天为1周期)采血,给药第1、28天进行密集时间点采血,采用实体瘤疗效评价标准RECIST1.1以影像学检查评价疗效。采集血样分离血浆,应用杂交捕获高通量测序检测血浆循环肿瘤的单核苷酸变异、小片段插入和缺失、拷贝数变异,应用统计学软件SPSS22.0进行Kaplan-Meier生存分析和log-rank检验,探讨循环肿瘤DNA与患者无进展生存之间的关系。应用Excel软件绘制散点图,分析定期随访检测循环肿瘤DNA与评估疾病进展之间的关系。采用循环肿瘤DNA亚克隆分析方法PyClone进行突变簇聚类,探索治疗反应不同的患者用药后循环肿瘤DNA在克隆层面的动态变化。结果：将基因突变和拷贝数变异个数相加作为变异数,以变异数5和≤5为分界,基线变异数＞5的患者平均PFS为17.3周,中位PFS为8周,基线变异数≤5的患者平均PFS为50.7周,中位PFS为31.6周,随访期间总变异数5的患者平均PFS为20.4周,中位PFS为15.7周,总变异数≤5的患者平均PFS为73.9周,中位PFS为77.7周。分别对基线变异和总变异有差异的两组进行生存分析,结果生存曲线均有显著性差异(p=0.037和p=0.023),变异数5的患者PFS更短。6例首次疗效评估即为PD的早期进展患者中,5例患者ctDNA突变频率变化趋势与疾病进展情况相符,6例随访6个周期后出现疾病进展的晚期进展组患者,ctDNA突变频率变化趋势均与病情进展相符,其中3例ctDNA连续监测较临床提前8周发现疾病进展。早期进展和晚期进展患者用药后数小时内ctDNA有所上升,ctDNA突变簇敏感实时地反映了用药后肿瘤细胞的死亡,ctDNA以小时为单位的动态变化很不稳定,每种突变和每个亚克隆群的变化复杂。结论：1.接受靶向治疗的HER2阳性晚期乳腺癌患者血浆循环肿瘤DNA基线变异个数和总变异个数与患者无进展生存相关,变异个数超过5的患者无进展生存更短。2.循环肿瘤DNA定期监测能够反映接受靶向治疗的HER2阳性晚期乳腺癌患者病情变化,有较临床提前发现病情进展的潜能3.接受靶向治疗的HER2阳性晚期乳腺癌患者血浆循环肿瘤DNA在给药后短时间内即出现上升
[Abstract]:Objective: to investigate the role of circulating tumor DNA in prognosis and disease monitoring in patients with advanced breast cancer with HER2 positive, and to explore the correlation between the dynamic changes of DNA clone and the therapeutic effect.Methods: eighteen patients with advanced breast cancer with HER2 positive expression were selected from clinical trial BLTN-1b. All patients were treated with irreversible EGFR/HER2 double target tyrosine kinase inhibitor until the disease progressed and the toxicity was intolerable.The patient withdraws knowledge or the researcher decides that the medication must be terminated.Blood samples were collected before administration and every 2 drug administration cycles (56 卤3 days to 28 days). Blood samples were collected at a dense time point at 28 days after administration. RECIST1.1 was used to evaluate the efficacy of solid tumor.Blood samples were collected to isolate plasma samples. Single nucleotide variation, small fragment insertion and deletion, copy number variation were detected by hybridization capture high-throughput sequencing. Kaplan-Meier survival analysis and log-rank test were performed by statistical software SPSS22.0.To investigate the relationship between circulating tumor DNA and progressive survival.Excel software was used to draw scatter plot and to analyze the relationship between DNA detection of circulating tumors and the evaluation of disease progression.Using DNA subclone analysis of circulating tumors, PyClone was used to cluster mutation clusters to explore the dynamic changes of circulating tumor DNA at clone level in patients with different therapeutic reactions.Results: the mean PFS of patients with baseline variance > 5 was 17.3 weeks, the median PFS was 8 weeks, and the average PFS of patients with baseline variance 鈮，

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