Clinical predictors of KRAS mutation detection in liquid biopsies for pancreatic ductal adenocarcinoma

Abstract

Background: Liquid biopsy offers an alternative to tissue specimens for comprehensive genomic profiling. However, detection of circulating tumor DNA (ctDNA) remains challenging in pancreatic ductal adenocarcinoma (PDAC). This study assessed predictive ability of CA19-9 and other factors for detecting KRAS mutations on liquid biopsy.

Methods: We retrospectively reviewed clinical and genomic databases for PDAC patients who underwent liquid biopsy between September 2021 and August 2024.

Results: A total of 106 patients were enrolled. The overall detection rate of KRAS mutations was 48 %. Univariate analysis identified hepatic metastases (Odds ratio (OR) 4.50, p < 0.01) and CA19-9 levels ≥2000 U/mL (OR 3.82, p < 0.01) as significantly associated with higher detection of KRAS mutations. These factors remained independent predictors in multivariate analysis: hepatic metastases (OR 4.51, p < 0.01) and CA19-9 ≥ 2000 U/mL (OR 3.91, p < 0.01). KRAS mutations were detected in 79 % of patients with both factors. In an overall survival (OS) analysis of 102 patients, detection of KRAS mutations was associated with worse prognosis (detected vs not-detected: 16.5 vs. 26.9 months, p = 0.02). Further stratification by maximum variant allele frequency (Max VAF) among patients with KRAS mutations revealed significantly shorter OS in patients with Max VAF >10 % compared to those with Max VAF <1 % (10.6 vs. 19.8 months, p < 0.01) or 1-10 % (10.6 vs. 18.0 months, p = 0.02).

Conclusions: CA19-9 levels and hepatic metastases are predictive of KRAS mutation detection in ctDNA. Higher Max VAF may reflect more aggressive disease biology in PDAC.

Keywords: CA19-9; Hepatic metastases; KRAS mutations; Liquid biopsy; Pancreatic ductal adenocarcinoma.