High-Sensitivity ctDNA Analysis Uncovers Relevant Signals Missed by NGS in Pancreatic Cancer

Area of Science:

• Oncology
• Molecular Diagnostics
• Biomarker Discovery

Background:

• Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate despite current treatments.
• There is a critical need for improved biomarkers to guide perioperative care in PDAC.
• KRAS mutations are common in PDAC and can be detected in circulating tumor DNA (ctDNA).

Purpose of the Study:

• To evaluate the prognostic significance of KRAS-mutant ctDNA in localized PDAC.
• To compare the detection capabilities of next-generation sequencing (NGS) and digital droplet PCR (ddPCR) for KRAS-mutant ctDNA.
• To assess the impact of ctDNA detection on overall survival (OS) in PDAC patients.

Main Methods:

• A prospective cohort study enrolled 106 patients with localized PDAC undergoing neoadjuvant chemotherapy (NAC).
• Blood samples were collected at diagnosis, post-NAC, and post-resection for ctDNA analysis.
• ctDNA was assessed using tumor-agnostic NGS and ddPCR targeting KRAS G12D/V/R mutations, with OS analyzed by Kaplan-Meier.

Main Results:

• KRAS ctDNA was detected by NGS in 17.2% and by ddPCR in 64.9% of patients at diagnosis.
• Detection of KRAS ctDNA by either NGS or ddPCR was associated with significantly shorter OS.
• The higher-sensitivity ddPCR assay identified additional patients with poor outcomes not detected by NGS, demonstrating greater prognostic discrimination.

Conclusions:

• KRAS-mutant ctDNA detection, particularly by ddPCR, is a significant prognostic biomarker in localized PDAC.
• Integrating ddPCR with NGS ctDNA analysis may enhance perioperative risk stratification for PDAC patients.
• Further validation is required before clinical implementation of these ctDNA assays for PDAC management.