Clinicopathologic characteristics, co-mutation landscape, and survival outcomes of KRAS-G12D mutant lung adenocarcinoma in comparison to KRAS-G12C and EGFR-mutated subtypes.

Given the ongoing clinical development of KRAS specific inhibitors, we aimed to explore the clinicopathologic characteristics of KRAS mutant tumors. We analyzed 1,225 surgically resected LUAD from a large cohort of a French-Canadian cohort. Tumors were classified into five mutually exclusive molecular groups: KRAS (n = 82), KRAS (n = 311), KRAS (n = 324), EGFR-mutant (n = 175), and WT (n = 333). Clinicopathological features, survival outcomes, and co-mutational profiles were compared across groups. KRAS tumors had the highest frequency of invasive mucinous adenocarcinoma (IMA) (17.1 %, p < 0.00001), spread through air spaces (STAS, p = 0.0001), lymphovascular invasion (LVI, p < 0.00001), and presentation at advanced stages compared to EGFR-mutant and other groups (p = 0.0031). TP53 was the most frequently co-mutated gene across all subgroups; however, it was significantly less frequent in KRAS tumors (47.8 %) compared to KRAS (68.1 %) and EGFR-mutant tumors (83.0 %) (p = 0.041). KRAS also exhibited a broader spectrum of low-frequency co-mutations, including BRAF (8.7 %) and GNAS (4.3 %). In the unstratified cohort, both KRAS and KRAS mutations were associated with significantly worse overall survival (OS) and recurrence-free survival (RFS) compared to EGFR-mutant tumors. In multivariable Cox models, KRAS remained independently associated with poorer OS (HR = 1.778, 95 % CI: 1.418-2.186, p = 0.021) and RFS (HR = 1.665, 95 % CI: 1.267-2.193, p = 0.045) when compared to EGFR. These associations were particularly evident in stage I disease. This study identifies KRAS as a clinically and pathologically distinct LUAD subtype, characterized by more aggressive histologic features, a unique co-mutation profile, and independently poorer survival outcomes compared to EGFR-mutant tumors. These findings support the need for refined molecular classification of LUAD and underscore the prognostic importance of KRAS mutations in risk stratification and clinical management, particularly in early-stage disease.