Mahadevia Himil, Majeed Umair, Patel Jaydeepbhai, Ahmed Ahmed K, Elhariri Ahmed, Albelal Douaa, Rao Nakka Naga Malleswara, Rachamala Hari Krishnareddy, Mosalem Osama, Mukhopadhyay Debabrata, Jones Jeremy, Mahadevan Daruka, Borad Mitesh J, Ahn Daniel, Sonbol Mohamad Bassam, Tran Nguyen, Mahipal Amit, Wee Ma Wen, McWilliams Robert R, Halfdanarson Thor R, Kankeu Fonkoua Lionel A, Bekaii-Saab Tanios, Mody Kabir, Babiker Hani
Department of Medicine, University of Missouri-Kansas City.
Division of Hematology-Oncology, Department of Medicine, Mayo Clinic Florida, Jacksonville.
JAMA Netw Open. 2025 Sep 2;8(9):e2531373. doi: 10.1001/jamanetworkopen.2025.31373.
The prognosis of advanced pancreaticobiliary tumors is poor. Next-generation sequencing (NGS) of tissue samples is utilized to identify actionable alterations, but there are occasional limitations due to inadequate tissue acquisition. Circulating tumor DNA (ctDNA) is an alternative method, but its correlation with tissue-based NGS remains unexplored.
To assess the mutation concordance (mCR) rates between ctDNA and tissue testing for patients with pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CC) and to evaluate how ctDNA performs as a treatment response biomarker.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted among patients with PDAC and CC treated at academic institutions from January 2014 to January 2025. Patients underwent ctDNA testing using 1 platform and tissue NGS testing using 2 platforms.
mCR, which measures the shared gene alterations observed by both ctDNA and tissue-based NGS testing, was calculated using the Spearman correlation for PDAC and CC. The performance of ctDNA as a treatment response biomarker was assessed by comparing serial ctDNA data with restaging scans and cancer antigen 19-9 levels in patients with PDAC.
Our cohort included 790 patients: 570 with advanced PDAC (265 [46.5%] female; median [IQR] age, 64 [33-84] years) and 220 with advanced CC (95 [43.2%] female; median [IQR] age, 66 [42-88] years). Overall, 461 patients with PDAC (80.9%) and 192 patients with CC (87.2%) underwent ctDNA testing, while 239 patients with PDAC (41.9%) and 70 patients with CC (31.8%) had tissue NGS testing. Among patients with PDAC, 85 of 130 patients (65.4%) showed shared specific gene alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.47 (95% CI, 0.28-0.62; P < .001). For patients with CC, 32 of 48 (66.7%) had shared alterations between ctDNA and tissue testing; there was a significant mCR, with a Spearman correlation of 0.56 (95% CI, 0.35-0.70; P < .001). A subgroup analysis of patients with PDAC who underwent serial ctDNA testing suggested that new TP53 subclones and increased ctDNA variant allele frequency levels of TP53 and KRAS were associated with higher odds of progressive disease (eg, increased TP53 frequency: odds ratio, 7.28; 95% CI, 2.15-24.66; P = .001).
In this cohort study of patients with pancreaticobiliary tumors, there was a significant mCR between ctDNA and tissue NGS testing. Additionally, results suggest that ctDNA might detect resistant clones and enable assessment of treatment response.
晚期胰胆管肿瘤的预后较差。组织样本的二代测序（NGS）用于识别可靶向改变，但由于组织获取不足偶尔会存在局限性。循环肿瘤DNA（ctDNA）是一种替代方法，但其与基于组织的NGS的相关性仍未得到探索。
评估胰腺导管腺癌（PDAC）和胆管癌（CC）患者ctDNA与组织检测之间的突变一致性（mCR）率，并评估ctDNA作为治疗反应生物标志物的表现。
设计、背景和参与者：这项回顾性队列研究在2014年1月至2025年1月期间在学术机构接受治疗的PDAC和CC患者中进行。患者使用1个平台进行ctDNA检测，并使用2个平台进行组织NGS检测。
mCR用于衡量ctDNA和基于组织的NGS检测所观察到的共享基因改变，使用Spearman相关性对PDAC和CC进行计算。通过比较PDAC患者的系列ctDNA数据与重新分期扫描及癌胚抗原19-9水平，评估ctDNA作为治疗反应生物标志物的表现。
我们的队列包括790名患者：570例晚期PDAC（265例[46.5%]为女性；中位[四分位间距]年龄，64岁[33-84岁]）和220例晚期CC（95例[43.2%]为女性；中位[四分位间距]年龄，66岁[42-88岁]）。总体而言，461例PDAC患者（80.9%）和192例CC患者（87.2%）接受了ctDNA检测，而239例PDAC患者（41.9%）和70例CC患者（31.8%）进行了组织NGS检测。在PDAC患者中，130例患者中有85例（65.4%）在ctDNA和组织检测之间显示出共享的特定基因改变；存在显著的mCR，Spearman相关性为0.47（95%CI，0.28-0.62；P＜0.001）。对于CC患者，48例中有32例（66.7%）在ctDNA和组织检测之间存在共享改变；存在显著的mCR，Spearman相关性为0.56（95%CI，0.35-0.70；P＜0.001）。对接受系列ctDNA检测的PDAC患者进行的亚组分析表明，新的TP53亚克隆以及TP53和KRAS的ctDNA变异等位基因频率水平升高与疾病进展的较高几率相关（例如，TP53频率增加：比值比，7.28；95%CI，2.15-24.66；P=0.001）。
在这项针对胰胆管肿瘤患者的队列研究中，ctDNA与组织NGS检测之间存在显著的mCR。此外，结果表明ctDNA可能检测到耐药克隆并能够评估治疗反应。
