Prognostic indicators of KRASG12X mutations in pancreatic cancer


Bach Ardalan, Aaron Ciner, Yasmine Baca, Sourat Dourabi, Anup Kasi, Emil Lou, Jose Azqueta, Joanne Xiu, Chadi Nabhan, Anthony Shields, Michael Pishvaian, W. Michael Korn, Sanjay Goel

Background: We have studied the role of KRAS mutations in relation to the prognosis in patients with advanced pancreatic ductal adenocarcinoma (PDAC). KRAS is a well-described oncogenic driver in PDAC, with mutations identified in over 90% of cases, typically involving codon 12. The three predominant missense variants include G12D, G12V and G12R. PDAC has the highest rate of G12R mutations compared to other malignancies, comprising 15-20% of KRAS-mutated tumors. This study presents a new finding in the progression of advanced PDAC utilizing a large clinical and genomic database to further characterize the clinical features of pathogenic KRAS variants in PDAC with a focus on G12R.

Methods: PDAC samples were tested using whole transcriptome sequencing (WTS; Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ). Transcriptomic signatures including MPAS (MAPK activation score), T-cell inflamed score and tumor micro environment (TME) characterization were calculated on WTS data. Significance was determined by X2 and Fisher-Exact and p adjusted for multiple comparisons (q) was < 0.05 (Benjamini-Hochberg). Real-world overall survival (rwOS) was obtained from insurance claims data and calculated from tissue collection to last contact; time-on-treatment (TOT) was calculated from start to finish of specific treatments; comparison was done by Kaplan-Meier test.

Results: A total of 5,555 patients with PDAC harboring either KRAS G12D (n = 2,671), G12V (n = 1,871) G12R (n = 904) or G12C (n = 109) variants were identified. The patients with KRAS G12R mutant tumors had significantly longer median real-world overall survival (mRWOS) compared to G12D (452 vs 358 days, HR 0.82, CI 0.74 – 0.9, p < 0.0001). This difference persisted regardless of treatment with FOLFIRINOX or gemcitabine plus nab-paclitaxel. There was no difference in outcomesbetween patients with KRAS G12R, G12V or G12C. PD-L1 expression was significantly lower in G12R than in G12C or G12D (13% vs 27% vs 19%,) while the prevalence of TMB-H and dMMR was comparable across isoforms.

Conclusions: Patients with KRAS G12R variants has improved rwOS compared to G12D irrespective of the chemotherapy regimen administered. Immune profiling suggested that the immune contexture in G12R-driven tumors are distinct from G12D as reflected by reduced PDL1 staining, decreased levels of multiple checkpoint receptors. We aim to further explore the molecular basis for these differences with a focus on PI3K and MAPK pathways. Based on this data, survivorship studies in patients with advanced PDAC should consider reporting KRAS mutational status.

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