Distinct KRAS Mutations are Enriched in Early-Stage Resected Pancreatic Ductal Adenocarcinoma

Introduction: KRAS is altered in over 90% of pancreatic ductal adenocarcinomas (PDAC), yet the significance of specific KRAS alleles has not been well studied. Herein, we evaluate associations between KRAS variants and clinical outcomes. Methods: Patients with PDAC who underwent resection and had targeted genomic sequencing with MSK-IMPACT between 2004-2019 were included. Early-stage tumors were defined as T1/2 and N0, whereas T3/4 or N1/2 specified more advanced resected disease. Pathologic variables, recurrence patterns and survival outcomes were compared between specific KRAS variants. Results: There were 403 patients included and KRAS was altered in 91%. There were 146 (36%) patients with KRAS G12D mutations, 130 (32%) with G12V, 56 (14%) with G12R, 33 (8%) had other alterations and 38 (9%) were KRAS wildtype. Tumor size (p=0.056) and positive lymph nodes (p=0.067) did not differ between patients with different KRAS alterations (Table). Early-stage PDAC was associated with increased incidence of G12R mutations (23% vs 11%) whereas G12V was more common in late-stage disease (35% vs 24%, p=0.017). Patients who received neoadjuvant therapy were more likely to have G12R alterations than those who did not (22% vs 12%, p=0.028). Patients with G12D and G12V mutations were more likely to have distant recurrences at 2-years as compared to G12R (45% and 35% vs 26%, p=0.008), but there was no difference in local recurrence. KRAS mutation status was not associated with overall or recurrence free survival (p=NS). Conclusion: KRAS alterations in PDAC are associated with distinct clinical presentation, tumor biology, and recurrence patterns.Tabled 1EP02C-064G12D (n=146)G12V (n=130)G12R (n=56)Other KRAS (n=33)Wildtype (n=38)p-valueTumor diameter, cm2.9 (2.2-3.5)2.9 (2.2-3.7)2.5 (2.2-3.5)2.7 (2.2-4.0)2.3 (1.8-3.0)0.056Lymph NodesPositive108 (38)95 (34)30 (11)22 (8)26 (9)0.067Negative38 (31)35 (29)26 (21)11 (9)12 (10)StageEarly Stage34 (33)25 (24)24 (23)10 (10)11 (11)0.017Late Stage112 (37)105 (35)32 (11)23 (8)27 (9)Neoadjuvant TherapyYes26 (28)29 (31)20 (22)5 (5)13 (14)0.028No120 (39)101 (33)36 (12)28 (9)25 (8)*displayed as n (%) or median (IQR); percentages displayed by row Open table in a new tab *displayed as n (%) or median (IQR); percentages displayed by row