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

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 205; p. 108596
• Main Authors: Abolfathi, Hanie, Kordahi, Manal, Armero, Victoria Saavedra, Gagné, Andréanne, Desmeules, Patrice, Orain, Michèle, Fiset, Pierre Oliver, Boudreau, Dominique K., Gaudreault, Nathalie, Lamaze, Fabien Claude, Bossé, Yohan, Joubert, Philippe
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.07.2025
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - mortality; Adenocarcinoma - pathology; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - mortality; Adenocarcinoma of Lung - pathology; Adult; Aged; Aged, 80 and over; EGFR; ErbB Receptors - genetics; Female; Humans; KRAS-G12C; KRAS-G12D; Lung adenocarcinoma; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Male; Middle Aged; Mutation; Neoplasm Staging; Overall survival; Prognosis; Proto-Oncogene Proteins p21(ras) - genetics; Recurrence-free survival; TNM stage; KRAS-G12C; TNM stage; Lung adenocarcinoma; Recurrence-free survival; Overall survival; EGFR; KRAS-G12D
• ISSN: 0169-5002; 1872-8332; 1872-8332
• DOI: 10.1016/j.lungcan.2025.108596

•KRAS-G12D defines a distinct lung adenocarcinoma subtype with aggressive clinicopathologic features.•KRAS-G12D exhibits a unique co-mutation profile with significantly fewer TP53 mutations compared to EGFR and KRAS-G12C.•KRAS-G12D was independently associated with poorer overall and recurrence-free survival compared to EGFR and KRAS-G12C.•Findings support integrating KRAS-G12D into future lung adenocarcinoma TNM staging refinements. Given the ongoing clinical development of KRASG12D specific inhibitors, we aimed to explore the clinicopathologic characteristics of KRASG12D 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: KRASG12D (n = 82), KRASG12C (n = 311), KRASnon-G12C/G12D (n = 324), EGFR-mutant (n = 175), and WT (n = 333). Clinicopathological features, survival outcomes, and co-mutational profiles were compared across groups. KRASG12D 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 KRASG12D tumors (47.8 %) compared to KRASG12C (68.1 %) and EGFR-mutant tumors (83.0 %) (p = 0.041). KRASG12D also exhibited a broader spectrum of low-frequency co-mutations, including BRAF (8.7 %) and GNAS (4.3 %). In the unstratified cohort, both KRASG12D and KRASG12C mutations were associated with significantly worse overall survival (OS) and recurrence-free survival (RFS) compared to EGFR-mutant tumors. In multivariable Cox models, KRASG12D 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 KRASG12D 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 KRASG12D mutations in risk stratification and clinical management, particularly in early-stage disease.