BACKGROUND Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy. METHODS ctDNA was analyzed in 112 patients with PDAC (54-73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed. RESULTS The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0-6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85-10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months. CONCLUSIONS Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.

中文翻译：

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胰腺癌中血液循环肿瘤DNA的临床相关性。

背景技术晚期胰腺导管腺癌（PDAC）患者的治疗结果仍然令人沮丧。使用新型的下一代测序技术来了解这种恶性肿瘤的生物学基础存在着未满足的需求。在这里，我们调查了这种恶性肿瘤中循环肿瘤DNA（ctDNA）（液体活检）的临床实用性。方法对112例PDAC患者（54-73个基因）的ctDNA进行分析，对66例患者（315个基因）的组织DNA进行分析（均为临床级下一代测序）。评估了改变的数量，％ctDNA，ctDNA与组织DNA之间的一致性以及ctDNA结果与生存的相关性。结果ctDNA中最常见的基因改变是TP53（46％的患者，N = 51）和KRAS（44％，N = 49）。每位患者的特征性ctDNA改变的中位数为1（范围为0-6），但晚期PDAC患者的ctDNA改变数量明显高于可手术切除疾病的患者（中位数，2对0.5，P = 0.04）。总体而言，75％（70/94）的晚期肿瘤具有≥1 ctDNA改变。ctDNA与组织DNA改变之间的一致性率为TP53为61％，KRAS为52％。转移部位的ctDNA与组织DNA之间的KRAS改变的一致性显着高于ctDNA与原发性肿瘤DNA之间的KRAS一致性（72％比39％，P = 0.01）。重要的是，较高的总ctctDNA水平是存活率降低的独立预后因素（危险比：4.35； 95％置信区间：1.85-10.24 [多变量，P = 0.001]）。一名患有三种影响MEK途径的ctDNA改变的患者（GNAS，KRAS和NF1）对曲美替尼单药治疗的反应持续了6个月。结论我们的研究结果表明，ctDNA通常具有独特的改变，其中一些可能是可靶向的，并且在晚期与可切除疾病中发生的ctDNA改变数量明显更多。此外，较高的ctDNA水平是生存的不良预后因素。