Prognostic value of KRAS and PI3K pathway mutations for advanced pancreatic ductal adenocarcinoma (PDAC) patients (pts).

Abstract

424 Background: KRAS mutation (MUT) variants (var) have been associated with differential clinical outcomes in advanced PDAC pts (Hendifar, 2020). Recent data from PDAC cell lines suggests that, unlike KRAS G12D/V, the KRAS G12R var is unable to interact with p110α PI3Kα and relies on KRAS-independent p110γ PI3K activity to support macropinocytosis, a nutrient uptake process necessary for tumor growth (Hobbs, 2020). Methods: We retrospectively reviewed advanced PDAC pts who received at least first-line (1L) systemic therapy and underwent next generation sequencing (NGS) at University of Washington between 2013 and 2020. We analyzed, using Fisher’s exact test, whether KRAS var were associated with PI3K pathway mutations (PI3K MUT). Using multivariate (Cox proportional hazards) analysis, we compared overall survival (OS) and progression-free survival (PFS) from start of 1L therapy for pts whose tumors harbored any KRAS var with and without stratification by PI3K MUT status. Results: 127 pts had NGS (96% tissue, 4% ctDNA). Median OS (mOS) and PFS were 16.8 months (mos) and 8.6 mos, respectively. 111 PDAC were KRAS MUT (87%): 43 (39%) G12D, 35 (32%) G12V, 23 (21%) G12R, 1 (0.9%) G12C, 6 (5%) Q61. 15 PDAC (12%) had 16 PI3K MUT, including 7 PIK3CA, 3 AKT2, 3 RICTOR, 1 PTEN, 1 PIK3C2B, and 1 PIK3R1. PI3K MUT occurred in 26% of tumors with KRAS G12R vs 8% in other KRAS var (p=0.0265). In multivariate analysis controlling for age, performance status, stage at diagnosis, type of 1L chemotherapy, TP53 MUT and GATA6 amplification status, pts with KRAS G12R var PDAC vs other variants had longer mOS (20.4 vs 14.5 mos, HR 0.67 (95% CI 0.47 – 0.93), p=0.0215) and mPFS on 1L therapy (12.2 vs 6.8mos, HR 0.60 (95% CI 0.40 – 0.85), p=0.0040). In pts with KRAS G12R var PDAC, concurrent PI3K MUT vs PI3K WT associated with shorter mOS (19.4 vs 24.2mos, HR 2.79 (95% CI 0.97 – 10.6), p=0.0570). In pts with non-G12R KRAS var tumors, PI3K MUT vs WT did not confer shorter OS (mOS 17.6 vs 14.5 mos, HR 1.20 (95% CI 0.72 – 2.0), p=0.55). Conclusions: KRAS G12R PDAC have a higher incidence of PI3K MUT than other KRAS var. KRAS G12R status may confer improved prognosis vs other KRAS variants, albeit this benefit is offset by the presence of concurrent PI3K MUT.