AbstractPancreatic ductal adenocarcinoma represents one of the solid tumors showing the worst prognosis worldwide, with a high recurrence rate after adjuvant or neoadjuvant therapy. Circulating tumor DNA analysis raised as a promising non-invasive tool to characterize tumor genomics and to assess treatment response.

摘要胰腺导管腺癌是全球预后最差的实体瘤之一，辅助或新辅助治疗后复发率高。循环肿瘤DNA分析被认为是表征肿瘤基因组学和评估治疗反应的有前途的非侵入性工具。

In this study, surgical tumor tissue and sequential blood samples were analyzed by next-generation sequencing and were correlated with clinical and pathological characteristics. Thirty resectable/borderline pancreatic ductal adenocarcinoma patients treated at the Hospital Universitario de Navarra were included.

在这项研究中，通过下一代测序分析了手术肿瘤组织和连续血液样本，并与临床和病理特征相关。包括在纳瓦拉大学医院接受治疗的30例可切除/交界性胰腺导管腺癌患者。

Circulating tumoral DNA sequencing identified pathogenic variants in KRAS and TP53, and in other cancer-associated genes. Pathogenic variants at diagnosis were detected in patients with a poorer outcome, and were correlated with response to neoadjuvant therapy in borderline pancreatic ductal adneocarcinoma patients.

循环肿瘤DNA测序鉴定了KRAS和TP53以及其他癌症相关基因中的致病变异。在预后较差的患者中检测到诊断时的致病变异，并且与临界胰腺导管癌患者对新辅助治疗的反应相关。

Higher variant allele frequency at diagnosis was associated with worse prognosis, and thesum of variant allele frequency was greater in samples at progression. Our results build on the potential value of circulating tumor DNA for non-metastatic pancreatic ductal adenocarcinoma patients, by complementing tissue genetic information and as a non-invasive tool for treatment decision.

诊断时变异等位基因频率越高，预后越差，进展时样本中变异等位基因频率的总和越大。我们的研究结果基于循环肿瘤DNA对非转移性胰腺导管腺癌患者的潜在价值，通过补充组织遗传信息并作为治疗决策的非侵入性工具。

Confirmatory studies are needed to corroborate these findings..

需要进行验证性研究来证实这些发现。。

IntroductionPancreatic ductal adenocarcinoma (PDAC) represents a worldwide problem. With an all stages 5 year overall survival of 9%1,2, PDAC ranks the seventh-leading cause of cancer-related death3. Furthermore, its incidence has been increasing during the last 20 years and it has been projected to become the third leading cause of cancer-related death by 20254.

简介胰腺导管腺癌（PDAC）是一个世界性的问题。PDAC的所有阶段5年总生存率为9%1,2，是癌症相关死亡的第七大原因3。此外，在过去的20年中，其发病率一直在增加，预计到20254年，它将成为癌症相关死亡的第三大原因。

Curative options for PDAC patients are scarce and, despite research efforts, few advances have been achieved in the last years.Surgery is the only curative treatment option and resectability of PDAC patients relies on the exclusion of vascular tumor involvement, in order to provide an R0 resection1.

PDAC患者的治疗选择很少，尽管进行了研究，但在过去几年中几乎没有取得进展。手术是唯一的治疗选择，PDAC患者的可切除性依赖于排除血管肿瘤受累，以提供R0切除1。

Subsequently, adjuvant chemotherapy is indicated, with an intention to treat possible persistent tumor cells and improve the survival outcomes of these patients5,6. In patients presenting borderline PDAC (defined by limited vascular involvement technically resectable or elevated baseline levels of the carbohydrate antigen (CA) 19-9)7,8, induction chemotherapy and optionally chemoradiotherapy treatment are recommended, with the aim of tumor down staging and potentially eradicating micrometastatic disease, to assure a secondary curative surgery1.

随后，指示辅助化疗，旨在治疗可能的持续性肿瘤细胞并改善这些患者的生存结果5,6。对于出现临界PDAC的患者（定义为有限的血管受累，技术上可切除或碳水化合物抗原（CA）19-9的基线水平升高）7,8，建议进行诱导化疗和选择性放化疗治疗，目的是降低肿瘤分期并可能根除微转移性疾病，以确保二次治愈性手术1。

Although the type of neoadjuvant chemotherapy is still a matter of debate9,10, some genetic alterations may guide treatment decisions, such as the preference of platinum combinations in patients with mutations in the homologous recombination genes11.Unfortunately, even after tumor resection, the vast majority of patients will eventually present recurrence or disease progression.

尽管新辅助化疗的类型仍存在争议[9,10]，但一些基因改变可能会指导治疗决策，例如同源重组基因突变患者对铂类组合的偏好11。不幸的是，即使在肿瘤切除后，绝大多数患者最终也会出现复发或疾病进展。

In this scenario, non-invasive biomarkers that provide real-time information on tumor biology represent a valuable tool to monitor tumor evolution and improve patient follow-up. In line with this, the.

在这种情况下，提供肿瘤生物学实时信息的非侵入性生物标志物代表了监测肿瘤进展和改善患者随访的有价值的工具。与此相一致的是。

Data availability

数据可用性

The data underlying this article cannot be shared publicly due to ethical restrictions. The data will be shared on reasonable request to the corresponding author.

由于道德限制，本文的基础数据无法公开共享。数据将在合理的要求下共享给通讯作者。

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Download referencesAcknowledgementsThe authors thank the Biobank of Navarrabiomed for sample processing and storage and the patients who participated in this study and their families.FundingThis research was founded by two projects of the local Government of Navarra, Spain (DIANA (ref: 0011-1411-2017-000033) and AGATA (ref: 0011-1411-2020-000013).

下载参考文献致谢作者感谢Navarrabiomed生物库的样品处理和储存以及参与本研究的患者及其家人。资助这项研究是由西班牙纳瓦拉地方政府（DIANA（参考号：0011-1411-2017-000033）和AGATA（参考号：0011-1411-2020-000013）的两个项目建立的。

IL is financed by National Agency of Research (AEI) in the “Juan de la Cierva-Postdoctoral formación” (FJC2021-046521-I); MA is financed by the Government of Navarra in the La Caixa Program. HA is supported by the Clínico Junior 2019 scholarship from the Spanish Association Against Cancer (AECC) (CLJUN19010ARAS); AL is supported by the “Clínico Junior en el Territorio AECC 2023” grant from the Spanish Association Against Cancer (AECC) (CLJUN234885LECU); IGB was supported by a predoctoral fellowship from the Department of Economic Development of Navarre, “Ayudas para la contratación de doctorandos y doctorandos por empresas y organismos de investigación y difusión de conocimientos: doctorandos industriales 2018–2020” (0011-1408-2017-000026).Author informationAuthors and AffiliationsOncobiona Group, Navarrabiomed-Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008, Pamplona, SpainIbone Labiano, Ana E.

IL由国家研究机构在“Juan de la Cierva-博士后培训”（FJC2021-046521-I）中资助；MA由纳瓦拉政府在La Caixa计划中资助。HA得到西班牙癌症协会2019年临床青年奖学金（CLJUN19010ARAS）的支持；AL得到西班牙癌症协会（AECC）颁发的“2023年AECC地区初级诊所”的支持（CLJUN234885LECU）；IGB得到了纳瓦雷经济发展部的一个博士前奖学金的支持，“帮助公司和研究机构招聘博士和博士以及传播知识：2018-2020年工业博士”（0011-1408-2017-00026）。作者信息作者和附属机构Cobiona集团，纳瓦拉生物医学-纳瓦拉健康研究所），Irunlarrea 3，31008，潘普洛纳，西班牙拉比亚诺，Ana E。

Huerta, Maria Alsina, Hugo Arasanz, Natalia Castro, Saioa Mendaza, Arturo Lecumberri, Iranzu Gonzalez-Borja, Irene Hernández-Garcia, Virginia Arrazubi, Elena Mata, David Gomez, Antonio Viudez & Ruth VeraMedical Oncology Department, Hospital Universitario de Navarra (HUN), Irunlarrea 3, 31008, Pamplona, SpainMaria Alsina, Hugo Arasanz, Arturo Lecumberri, Irene Hernández-Garcia, Virginia Arrazubi, Elena Mata, David Gomez & Ruth VeraMolecular Pathology of Cancer Group, Navarrabiomed, Hospital .

Huerta，Sr Maria Alsina，Sr.Hugo Arasanz，Sr.Natalia Castro，Sr.Mendaza，Sr.Arturo Lecumberi，Sr.Iranzu Gonzalez-Borja，Sr.艾琳·赫南德斯-加西亚，Sr.Virginia Arrazubi，Sr.Elena Mata，Sr..David Gomez，Antonio Viudez，Sr Vera医学肿瘤系，纳瓦拉大学（HUN），Irunlarea 3，31008 Virginia Arrazubi、Chalena Mata、Chalenna Gomez&&ChalenRuth Vera纳瓦拉生物医学医院癌症组分子病理学。

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PubMed Google ScholarContributionsIGB, AV, RV: Conception and study design. HA, AL, IHG, VA, EM, DG, AV, RV: Patient recruitment, monitoring and acquisition of clinical data. APG, GA, DGS: Acquisition of raw genomic data. IL, AEH, MA, HA, SM, NC, APG: Data analyses and interpretation of the results.

PubMed谷歌学术贡献SIGB，AV，RV：概念和研究设计。HA，AL，IHG，VA，EM，DG，AV，RV：患者招募，监测和获取临床数据。APG，GA，DGS：获取原始基因组数据。IL，AEH，MA，HA，SM，NC，APG：数据分析和结果解释。

IL, AEH, MA: Drafting of the original version of manuscript. All authors revised and approved the final version of the manuscript.Corresponding authorCorrespondence to.

IL，AEH，MA：起草原稿。所有作者都修改并批准了稿件的最终版本。对应作者对应。

Maria Alsina.Ethics declarations

玛丽亚·阿尔西纳。道德宣言

Competing interests

相互竞争的利益

IL, AEH, SM, IGB, DGS, EM, DG and AV declare no conflict of interest; MA has been involved as a consultant for advisory roles with Amgen, BMS, MSD, Lilly and Servier; HA has been involved as a consultant for advisory roles from Astra Zeneca and for trial coordination from Ferrer Farma; NC: has received speaker honoraria from Roche and Pierre Fabre; AL has received speaker honoraria from Pierre-Fabre; APG has received speaker honoraria from Merck Sharp; GAA has received speaker honoraria from ThermoFisher and Roche; IHG has received speaker honoraria from Astra Zeneca; VA has been involved as a consultant for advisory roles and received speaker honoraria from MSD, Bristol, Lilly, Astra-Zeneca and Pierre-Fabre.

IL，AEH，SM，IGB，DGS，EM，DG和AV声明没有利益冲突；MA曾担任安进、BMS、MSD、礼来和施维雅的顾问；HA曾担任Astra Zeneca的顾问角色和Ferrer Farma的试验协调顾问；NC：收到了罗氏和皮埃尔·法布尔的演讲者酬金；AL收到了皮埃尔·法布尔（PierreFabre）的演讲者酬金；APG已收到默克夏普的演讲者酬金；GAA已获得ThermoFisher和Roche的演讲者酬金；IHG已收到阿斯特拉·捷利康的演讲者酬金；VA曾担任顾问角色，并获得了MSD、布里斯托尔、礼来、阿斯特拉·捷利康和皮埃尔·法布尔的演讲者酬金。

RV has been involved as a consultant for advisory roles with Servier, Roche and Merck Sharp and has received speaker honoraria from Roche, Amgen, Merck Sharp and Dohme, Astra Zeneca..

RV曾担任施维雅（Servier）、罗氏（Roche）和默克（Merck Sharp）的顾问，并获得了罗氏（Roche）、安进（Amgen）、默克（Merck Sharp）和多姆（Dohme）、阿斯特拉捷利康（Astra Zeneca）的演讲者酬金。。

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Reprints and permissionsAbout this articleCite this articleLabiano, I., Huerta, A.E., Alsina, M. et al. Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma.

转载和许可本文引用本文Labiano，I.，Huerta，A.E.，Alsina，M。等人基于ctDNA分析在非转移性胰腺导管腺癌中的临床适用性。

Sci Rep 14, 16203 (2024). https://doi.org/10.1038/s41598-024-67235-yDownload citationReceived: 19 April 2024Accepted: 09 July 2024Published: 13 July 2024DOI: https://doi.org/10.1038/s41598-024-67235-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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KeywordsLiquid biopsyGenomicsBiomarkersPrecision medicineGastrointestinal neoplasms

关键词液体生物学基因组学生物标志物精准医学胃肠道肿瘤

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