Clinical utility and outcomes associated with mutations detection in liquid biopsy for patients with pancreatic ductal adenocarcinoma: Real-world data evidence from a single institution.
Authors: Yousef Mahmoud M.G. , Hurd Mark W. , Yousef Abdelrahman M.G. , Balachandran Pillai Ashwathy , Snyder Rebecca A , Knafl Mark , Chacko Ray , Smaglo Brandon George , Wolff Robert A. , Pant Shubham , Willis Jason , Huey Ryan W , Overman Michael J. , Tzeng Ching-Wei D. , Katz Matthew H. G. , Wang Huamin , Maitra Anirban , Ludmir Ethan B. , Shen John Paul Y.C. , Zhao Dan 
Published: June 2024

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Background: The clinical utility of liquid biopsy in pancreatic ductal adenocarcinoma (PDAC) and its association with clinical outcome remains understudied. We investigated the detection rate and association of mutations with overall survival (OS) in patients with PDAC who had liquid biopsy. Methods: The Foundry software platform was used to extract clinical information and disease outcomes for patients with PDAC who underwent our in-house tumor non-informed liquid biopsy, the panel detects somatic mutations in 70 genes, copy number gains in 19 genes and gene fusions in 6 genes in circulating cell free DNA isolated from plasma. Results: Liquid biopsy was performed for 311 patients with PDAC from 2018 to 2023 with median follow-up time of 25 months, and median OS of 24 months (95%CI=21-29). 73% (N=229) of patients had metastatic disease at time of liquid biopsy. Among patients with metastatic disease at liquid biopsy, 81.2% (N=186) tested positive, but only 52.4% (N= 43) tested positive in localized disease. KRAS mutation was detected in 68% (N=148) of patients with metastatic disease, while only in 16% (N=13) for localized disease. Any mutation detection was associated with worse OS (HR=2, 95%CI=1.2-3.2, P=0.009) in metastatic disease. However, in localized disease the difference was not significant (HR=1.3, 95%CI=0.67-2.6, P=0.43). In addition, KRAS detection in metastatic disease compared to other mutations was associated with worse OS (median 16 vs 31 months, HR=2.3, 95%CI=1.4-3.8, P=0.001). The most frequent KRAS mutation detected was G12D (N=66, 40.7% of KRAS mutations) followed by G12V (N=58, 35.8%), G12R (N=15, 9.3%), and Q61 mutations (N=10, 6.2%). G12D and Q61 mutations detection was associated with worse OS (median 13 and 10 months respectively, overall P<0.001). The most frequently co-occurring mutations detected with KRAS were TP53 (N=126, 77.8%), CDKN2A (N=34, 21%), SMAD4 (N=33, 20.4%), and ARID1A (N=12, 7.4%). Among 122 and 107 patients tested for KRAS and TP53 in solid biopsy respectively, concordance rate for positive mutations in patients treated for metastatic disease was 61% and 68%, while 7% and 33% for localized disease respectively. Furthermore, among 40 Patients who underwent serial liquid biopsy testing; 25% tested positive after a negative result with disease progression, but none of the patients with positive tests converted to negative (N=22) after chemotherapy. Conclusions: Detection of any mutation in liquid biopsy was associated with worse OS in patients with metastatic PDAC. Moreover, KRASmutation detection especially G12D or Q61, is associated with worse OS compared to other mutations. Repeating liquid biopsy for patients with initial negative result at disease progression might be beneficial. These data highlight the utility and importance of liquid biopsy in patients with PDAC.