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. 2025 Nov 4:10.1245/s10434-025-18633-7.
doi: 10.1245/s10434-025-18633-7. Online ahead of print.

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

Asmita Chopra #  1 , Hong-Zhang He #  2   3 , Jadranka Milosevic  2   3 , Nikhil Tirukkovalur  1 , Rudy El Asmar  1 , Ibrahim Nassour  4 , Geoffrey Nunns  1 , Mingxi Chen  2 , Jiaqi Chen  2 , Siyu Jiang  2 , Aatur D Singhi  1   5 , Anwaar Saeed  6 , Janie Zhang  6 , Kenneth Lee  1 , Amer Zureikat  1 , Si-Yang Zheng #  2   7 , Alessandro Paniccia #  8
Affiliations

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

Asmita Chopra et al. Ann Surg Oncol. .

Abstract

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.

Keywords: KRAS mutation; Adenocarcinoma; Extracellular vesicle; Mutation allele frequency; Pancreatic cancer; Survival outcome.

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Conflict of interest statement

Ethical Approval: IRB-approved protocol (STUDY20020051) developed at the University of Pittsburgh Medical Center (UPMC) and Carnegie Mellon University utilizing samples from biorepository study (STUDY19060127).

Figures

Figure 1:
Figure 1:
Kaplan-Meier survival estimate curve depicting DFS (1A) and OS (1B) in the three groups: EV-KRAS mutation non-detected (ND), the decreasing EV-KRAS MAF detection (DD), and the increasing EV-KRAS MAF detection (ID).
Figure 2:
Figure 2:
Kaplan-Meier survival estimate curve showing the combined impact of EV-KRAS MAF and CA19–9 on DFS (2A) and OS (2B) in the three patient cohorts
See this image and copyright information in PMC

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