Clinical utility of liquid <i>KRAS</i> -mutation screening in advanced pancreatic cancer patients referred for early-phase trials.

Abstract

3049 Background: Approximately 90% of pancreatic ductal adenocarcinomas (PDAC) harbor a KRAS mutation. Clinical trials targeting oncogenic KRAS mutations, including mutant-specific, pan-KRAS/-RAS inhibitors, have shown promising activity. As tissue next-generation sequencing (NGS) is a multi-step process that can affect turnaround time (TAT), a liquid biopsy (LB) approach is of interest. We investigated the clinical utility of LB testing for common KRAS variants to facilitate matching pts with PDAC to early phase trials. Methods: In this single-center, prospective enrollment/retrospective analysis study, we included pts with locally advanced (LA) or metastatic PDAC seen at Princess Margaret Cancer Centre (PM) phase I clinical trials and gastrointestinal (GI) cancer clinics between Jan 2025 - Jan 2026. Medical records were reviewed to collect clinicopathologic characteristics and treatment data. Plasma ddPCR assessed 4 KRAS codon 12 variants (G12C/D/R/V) at the CAP-CLIA-accredited Advanced Molecular Diagnostics Laboratory at PM. TATs for KRAS ddPCR vs tissue NGS were compared using the Wilcoxon signed-rank test. Results: Of 98 pts with LA/metastatic PDAC, the median age was 67 years, 59% were male, and 67 pts were ECOG 1 (88%). 84 pts had disease stage IV (86%), 43 (44%) pts were chemotherapy-naïve, and 33 (34%) pts had 1 prior L of therapy. Median number of metastatic sites was 2 (range [r] 1-5), and median CA19-9 was 343 (IQR 35-1767). KRAS G12 mts were detected by ddPCR in 38% (37/98) of pts: G12D (46%), G12V (46%), G12R (5%), G12C (2.7%). The median ddPCR VAF was 4.8% (r: 0.4 - 42.2), median TAT of 5 days (r: 1 - 8). Among pts with KRAS detected by ddPCR, 4 (11%) were enrolled in phase I trials targeting KRAS . Tissue NGS was performed in 40 pts (41%), KRAS was detected in 90% (36 pts), with a median VAF of 45% (r: 5-90), and median TAT of 54 days (r: 10-92; p&lt;0.0001 compared to ddPCR TAT). Reported KRAS variants: G12D (50%), G12V (19.4%), G12R (19.4%), Q61H (8.3%), G12C (2.8%). Co-mts in TP53 were seen in 22/36 pts (61%). Concordance between ddPCR and tumor NGS metrics are shown in Table 1. Median NGS VAF of concordant vs discordant cases: 48% vs 21% (p=0.047). Conclusions: Plasma-based KRAS screening using ddPCR was significantly faster than tissue NGS in advanced PDAC. A liquid-first strategy can accelerate matching pts to RAS-targeted trials, but intense competition for trial allocations limits access to these agents. ddPCR has excellent specificity and PPV across KRAS variants but limited sensitivity, thus serves as a rapid rule-in assay. Tissue NGS remains relevant, especially in ddPCR negative pts, and to assess co-mutations. N=36 pts ddPCR(+/-) NGS (+/-) Sens Spec PPV NPV Concordance Discordance G12C 1 / 35 1 / 35 100% 100% 100% 100% 100% 0% G12D 11 / 25 18 / 18 61% 100% 100% 72% 81% 19% G12R 1 / 35 7 / 29 14% 100% 100% 83% 84% 16% G12V 5 / 31 6 / 30 83% 100% 100% 97% 97% 3% All 4 variants 19 / 17 32 / 4 59% 100% 100% 24% 64% 36%