Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
Department of Oncology, Shanghai Medical College, Fudan University, No. 270 DongAn Road, Shanghai, 200032, People's Republic of China.
Int J Cancer. 2017 May 15;140(10):2344-2350. doi: 10.1002/ijc.30650. Epub 2017 Mar 9.
Cell-free circulating tumor DNA (ctDNA) in plasma has been used as a potential noninvasive biomarker for various tumors. Our study was performed to evaluate the clinical implications of ctDNA detection in patients with metastatic pancreatic cancer. First, we attempted to prospectively screen a panel of 60 genes in cell-free DNA (cfDNA) from ten metastatic pancreatic cancer patients via exome sequencing. Second, droplet digital PCR (ddPCR) was used to identify potential mutations in a cohort of 188 patients with metastatic pancreatic cancer. Finally, to preliminary evaluate the potential role of ctDNA in monitoring tumor responses following chemotherapy, we detected the presence of ctDNA in serial plasma samples from 13 metastatic pancreatic cancer patients (Clinical trial: NCT02017015). The analysis revealed five somatic mutations at BRCA2, EGFR, KDR and ERBB2 gene loci. The frequencies of ctDNA mutation at BRCA2, KDR, EGFR, ERBB2 exon17 and ERBB2 exon27 were 11.7%, 13.8%, 13.3%, 13.3% and 6.4% respectively. Univariate and multivariate analyses identified the ERBB2 exon17 mutation (p = 0.035, HR = 1.61) as an independent factor associated with overall survival among metastatic pancreatic cancer patients. Furthermore, the rate of coincident detection of ctDNA and response to treatment as assessed by CT imaging was 76.9% (10 of 13 cases), and the presence of ctDNA provided the earliest measure of treatment in 6 of 10 patients (60%). ctDNA sequencing may have clinical value for determining metastatic pancreatic cancer treatment and monitoring the tumor response.
血浆中的无细胞循环肿瘤 DNA (ctDNA) 已被用作各种肿瘤的潜在非侵入性生物标志物。我们的研究旨在评估 ctDNA 检测在转移性胰腺癌患者中的临床意义。首先，我们尝试通过外显子组测序对 10 名转移性胰腺癌患者的无细胞 DNA (cfDNA) 中的 60 个基因进行前瞻性筛选。其次，采用液滴数字 PCR (ddPCR) 鉴定了 188 名转移性胰腺癌患者的潜在突变。最后，为了初步评估 ctDNA 在监测化疗后肿瘤反应中的潜在作用，我们在 13 名转移性胰腺癌患者的系列血浆样本中检测了 ctDNA 的存在（临床试验：NCT02017015）。分析显示 BRCA2、EGFR、KDR 和 ERBB2 基因座存在五个体细胞突变。BRCA2、KDR、EGFR、ERBB2 外显子 17 和 ERBB2 外显子 27 的 ctDNA 突变频率分别为 11.7%、13.8%、13.3%、13.3%和 6.4%。单因素和多因素分析确定 ERBB2 外显子 17 突变（p=0.035，HR=1.61）是转移性胰腺癌患者总生存期的独立相关因素。此外，ctDNA 的检测与 CT 成像评估的治疗反应的一致性率为 76.9%（13 例中的 10 例），并且 ctDNA 的存在为 10 例患者中的 6 例（60%）提供了最早的治疗措施。ctDNA 测序可能具有确定转移性胰腺癌治疗和监测肿瘤反应的临床价值。
