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. 2025 Apr 17;18(1):44.
doi: 10.1186/s13045-025-01696-0.

KRAS mutation detection by liquid biopsy for pancreatic ductal adenocarcinoma

Mahmoud Yousef  1 , Abdelrahman Yousef  1 , Mark W Hurd  2 , Ashwathy Pillai  3 , Saikat Chowdhury  1 , Rebecca Snyder  4 , Mark Knafl  5 , Ryan L Lewis  6 , Paul M Roy  6 , Mohammad Fanaeian  1 , Sali Albarouki  7 , Luca F Castelnovo  1 , Jennifer Peterson  1 , Brandon G Smaglo  1 , Robert A Wolff  1 , Shubham Pant  1 , Jason Willis  1 , Ryan Huey  1 , Michael Overman  1 , Ching-Wei Tzeng  4 , Michael P Kim  4 , Naruhiko Ikoma  4 , Jess E Maxwell  4 , Matthew H G Katz  4 , Huamin Wang  8 , Anirban Maitra  2   8 , Eugene Koay  9 , Ethan B Ludmir  9   10 , Anthony Chen  1 , Camila Lopez  1 , Haoqiang Ying  11 , John Paul Shen  1 , Dan Zhao  12
Affiliations

KRAS mutation detection by liquid biopsy for pancreatic ductal adenocarcinoma

Mahmoud Yousef et al. J Hematol Oncol. .

Abstract

The clinical utility of liquid biopsy (LB) for pancreatic ductal adenocarcinoma (PDAC) remain understudied. Our single-institution cohort of 311 PDAC patients with non-tumor tissues informed LB found 81.2% positivity (N = 186) in metastatic cases and in 52.4% (N = 43) of localized disease. KRAS mutations were detected in 64.6% (N = 148) of metastatic cases and 16% (N = 13) for localized disease. Positive LB, especially KRAS mutation detection, is associated with worse overall survival (OS) in metastatic PDAC (median 14.5 vs. 31.3 months, HR = 2.7, 95%CI = 1.7-4.3, P < 0.0001). The positive concordance rates of KRAS and TP53 mutations were 63% and 68% in metastatic disease but only 7% (KRAS) and 33% (TP53) in localized disease, respectively. Among the 41 patients who underwent serial liquid biopsy testing, 25% tested positive after an initial negative result. LB detects therapeutically targetable mutations in 58.5% of PDAC patients and is associated with OS.

Keywords: KRAS; Liquid biopsy; Molecular profiling; Mutation; OS; PDAC; Pancreatic cancer.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the MD Anderson Institutional Review Board (IRB), protocol number 2023-0091. A waiver of informed consent was granted per the USA federal regulation 45 CFR 46.116(f) for this retrospective study. Competing interests: Brandon Smaglo: Consulting for Ipsen.Shubham Pant: Advisory for Zymeworks, Ipsen, Novartis, Janssen, Boehringer Ingelheim, and AskGene Pharma; and he receives research funding from Mirati Therapeutics, Lilly, Xencor, Novartis, Rgenix, Bristol-Myers Squibb, Astellas Pharma, Framewave, 4D Phar-ma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, Bionte, Ipsen, Zymeworks, Pfizer, ImmunoMET, Imuneering, and Amal Therapeutics. Anirban Maitra: Consultant for Tezcat Biosciences is listed as an inventor of a patent licensed to Thrive Earlier Detection (an Exact Sciences Company) relevant to early detection of pancreatic cancer. John Paul Shen: Grant/research support/collaboration: Celsius Therapeutics, BostonGene, Caris Life Sciences, Natera, Xilis, Palantir, Genentech. Consulting/stock ownership: Engine Biosciences, NaDeNo Nanoscience.Dan Zhao: Clinical trials with hMirati/BMS, Phanes, CARsgen, TriSalus and Affini-T; Consulting for Ipsen.

Figures

Fig. 1
Fig. 1
Mutations detected in LB and OS. A- Oncoplot for mutations detected in metastatic disease at LB. B- Oncoplot for mutations detected in localized disease at LB. C- Difference in median VAF of mutations detected in LB between localized disease and metastatic disease. D-Rates of actionable mutations detected in LB by OncoKB therapeutic levels
Fig. 2
Fig. 2
Outcomes with positivity of LB and with KRAS mutations detection. A- OS with positive LB in metastatic disease. B- OS with positive LB in localized disease. C- Hazard ratios (HRs) of OS with mutation detection by LB in metastatic disease. D- HRs of OS with mutation detection in LB in localized disease. E- OS of patients with positive KRAS mutation vs. other mutations in LB for metastatic disease. F- OS of metastatic disease patients with positive KRAS mutation detected by tissue NGS stratified by KRAS mutation detection in LB. G- Frequencies of detected KRAS mutation subtypes. H- OS of patients with KRAS mutation detected in LB by KRAS mutation subtypes
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