本文選題：乳腺癌　切入點(diǎn)：循環(huán)腫瘤DNA　出處：《北京協(xié)和醫(yī)學(xué)院》2016年博士論文

【摘要】：目的：探討接受靶向治療的HER2陽性晚期乳腺癌患者循環(huán)腫瘤DNA檢測在預(yù)后、病情監(jiān)測中的作用,探索循環(huán)腫瘤DNA克隆動態(tài)變化與療效的相關(guān)性。方法：選擇臨床試驗BLTN-1b中18例簽署了知情同意的HER2表達(dá)陽性晚期乳腺癌患者,患者均接受不可逆EGFR/HER2雙靶點(diǎn)酪氨酸激酶抑制劑的單藥治療,直至患者疾病進(jìn)展、毒性不可耐受、患者撤回知情或研究者判斷必須終止用藥。給藥前和每2個給藥周期(56±3天,28天為1周期)采血,給藥第1、28天進(jìn)行密集時間點(diǎn)采血,采用實體瘤療效評價標(biāo)準(zhǔn)RECIST1.1以影像學(xué)檢查評價療效。采集血樣分離血漿,應(yīng)用雜交捕獲高通量測序檢測血漿循環(huán)腫瘤的單核苷酸變異、小片段插入和缺失、拷貝數(shù)變異,應(yīng)用統(tǒng)計學(xué)軟件SPSS22.0進(jìn)行Kaplan-Meier生存分析和log-rank檢驗,探討循環(huán)腫瘤DNA與患者無進(jìn)展生存之間的關(guān)系。應(yīng)用Excel軟件繪制散點(diǎn)圖,分析定期隨訪檢測循環(huán)腫瘤DNA與評估疾病進(jìn)展之間的關(guān)系。采用循環(huán)腫瘤DNA亞克隆分析方法PyClone進(jìn)行突變簇聚類,探索治療反應(yīng)不同的患者用藥后循環(huán)腫瘤DNA在克隆層面的動態(tài)變化。結(jié)果：將基因突變和拷貝數(shù)變異個數(shù)相加作為變異數(shù),以變異數(shù)5和≤5為分界,基線變異數(shù)＞5的患者平均PFS為17.3周,中位PFS為8周,基線變異數(shù)≤5的患者平均PFS為50.7周,中位PFS為31.6周,隨訪期間總變異數(shù)5的患者平均PFS為20.4周,中位PFS為15.7周,總變異數(shù)≤5的患者平均PFS為73.9周,中位PFS為77.7周。分別對基線變異和總變異有差異的兩組進(jìn)行生存分析,結(jié)果生存曲線均有顯著性差異(p=0.037和p=0.023),變異數(shù)5的患者PFS更短。6例首次療效評估即為PD的早期進(jìn)展患者中,5例患者ctDNA突變頻率變化趨勢與疾病進(jìn)展情況相符,6例隨訪6個周期后出現(xiàn)疾病進(jìn)展的晚期進(jìn)展組患者,ctDNA突變頻率變化趨勢均與病情進(jìn)展相符,其中3例ctDNA連續(xù)監(jiān)測較臨床提前8周發(fā)現(xiàn)疾病進(jìn)展。早期進(jìn)展和晚期進(jìn)展患者用藥后數(shù)小時內(nèi)ctDNA有所上升,ctDNA突變簇敏感實時地反映了用藥后腫瘤細(xì)胞的死亡,ctDNA以小時為單位的動態(tài)變化很不穩(wěn)定,每種突變和每個亞克隆群的變化復(fù)雜。結(jié)論：1.接受靶向治療的HER2陽性晚期乳腺癌患者血漿循環(huán)腫瘤DNA基線變異個數(shù)和總變異個數(shù)與患者無進(jìn)展生存相關(guān),變異個數(shù)超過5的患者無進(jìn)展生存更短。2.循環(huán)腫瘤DNA定期監(jiān)測能夠反映接受靶向治療的HER2陽性晚期乳腺癌患者病情變化,有較臨床提前發(fā)現(xiàn)病情進(jìn)展的潛能3.接受靶向治療的HER2陽性晚期乳腺癌患者血漿循環(huán)腫瘤DNA在給藥后短時間內(nèi)即出現(xiàn)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 鹵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，

本文編號：1698195