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Background <p>Pancreatic ductal adenocarcinoma (PDAC) lacks consistent biomarkers to monitor treatment response and predict survival. Metabolically active extracellular vesicles (EVs) carrying tumor-specific <i>KRAS</i> mutations offer promise as disease-specific biomarkers.</p> Patients and Methods <p>Informed by genomic profiling of tumor tissue, plasma samples were prospectively collected from 44 patients, with confirmed <i>KRAS</i>-mutated PDAC, undergoing neoadjuvant therapy (NAT) followed by surgery between 2019 and 2021. Samples were obtained at diagnosis, post-NAT, and 1&#xa0;month post surgery. EVs were isolated using lipid nanoprobe technology, and EV-associated <i>KRAS</i> mutations were detected using droplet digital polymerase chain reaction (ddPCR). Patients were grouped on the basis of temporal changes in EV-associated <i>KRAS</i> mutation allele frequency (MAF): no <i>KRAS</i> detected (ND), decreasing MAF (DD), and increasing MAF (ID).</p> Results <p>Among 44 patients, 29 (65.9%) were ND, 8 (18.2%) DD, and 7 (15.9%) ID. Detectable EV-associated <i>KRAS</i> MAF was found in 21%, 30%, and 50% of patients with stages I, II, and III PDAC. No significant differences were noted in demographic or clinical variables (<i>p</i> &gt; 0.05). The ND group had the longest restricted mean disease-free survival (rmDFS: 31.2&#xa0;months), followed by DD (27.8&#xa0;months) and ID (9.8&#xa0;months; <i>p </i>= 0.010). Similarly, restricted mean overall survival (rmOS) was longest in the ND (40.3&#xa0;months), followed by DD (35.7&#xa0;months) and ID (17.7&#xa0;months; <i>p </i>= 0.012). On multivariable analysis, increasing EV-<i>KRAS</i> MAF (ID group) independently predicted inferior rmDFS [hazard ratio (HR): 6.14; <i>p </i>= 0.001] and rmOS (HR: 6.95; <i>p </i>= 0.002).</p> Conclusions <p>Temporal increase of EV-<i>KRAS</i> MAF is a significant predictor of reduced DFS and OS in PDAC. Integrating EV-<i>KRAS</i> mutation allele frequency dynamics analysis with current biomarkers such as carbohydrate antigen 19-9 (CA19-9) could improve treatment monitoring and survival prognostication.</p>

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KRAS Mutation Allele Frequency Dynamics in Plasma Extracellular Vesicles: Association with Survival in Localized Pancreatic Adenocarcinoma

  • 期刊论文

  • 发表日期：

    2025年11月4日

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  • Asmita Chopra,
  • Hong-Zhang He,
  • Jadranka Milosevic,
  • Nikhil Tirukkovalur,
  • Rudy El Asmar,
  • Ibrahim Nassour,
  • Geoffrey Nunns,
  • Mingxi Chen,
  • Jiaqi Chen,
  • Siyu Jiang,
  • Aatur D. Singhi,
  • Anwaar Saeed,
  • Janie Zhang,
  • Kenneth Lee,
  • Amer Zureikat,
  • Si-Yang Zheng,
  • Alessandro Paniccia

摘要

Background

Pancreatic ductal adenocarcinoma (PDAC) lacks consistent biomarkers to monitor treatment response and predict survival. Metabolically active extracellular vesicles (EVs) carrying tumor-specific KRAS mutations offer promise as disease-specific biomarkers.

Patients and Methods

Informed by genomic profiling of tumor tissue, plasma samples were prospectively collected from 44 patients, with confirmed KRAS-mutated PDAC, undergoing neoadjuvant therapy (NAT) followed by surgery between 2019 and 2021. Samples were obtained at diagnosis, post-NAT, and 1 month post surgery. EVs were isolated using lipid nanoprobe technology, and EV-associated KRAS mutations were detected using droplet digital polymerase chain reaction (ddPCR). Patients were grouped on the basis of temporal changes in EV-associated KRAS mutation allele frequency (MAF): no KRAS detected (ND), decreasing MAF (DD), and increasing MAF (ID).

Results

Among 44 patients, 29 (65.9%) were ND, 8 (18.2%) DD, and 7 (15.9%) ID. Detectable EV-associated KRAS MAF was found in 21%, 30%, and 50% of patients with stages I, II, and III PDAC. No significant differences were noted in demographic or clinical variables (p > 0.05). The ND group had the longest restricted mean disease-free survival (rmDFS: 31.2 months), followed by DD (27.8 months) and ID (9.8 months; p = 0.010). Similarly, restricted mean overall survival (rmOS) was longest in the ND (40.3 months), followed by DD (35.7 months) and ID (17.7 months; p = 0.012). On multivariable analysis, increasing EV-KRAS MAF (ID group) independently predicted inferior rmDFS [hazard ratio (HR): 6.14; p = 0.001] and rmOS (HR: 6.95; p = 0.002).

Conclusions

Temporal increase of EV-KRAS MAF is a significant predictor of reduced DFS and OS in PDAC. Integrating EV-KRAS mutation allele frequency dynamics analysis with current biomarkers such as carbohydrate antigen 19-9 (CA19-9) could improve treatment monitoring and survival prognostication.