The clinicopathologic characteristics and outcomes of uncommon KRAS mutations in patients with non-small cell lung cancer

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations occur in 25-30% of non-small cell lung cancer (NSCLC) patients. Pooled analyses in previous research have largely focused on the prognostic and predictive value of overall or common KRAS mutation status. Uncommon KRAS variants regarding their clinicopathologic features and associations with clinical outcomes following treatment are largely unexplored. This study characterizes the clinicopathologic features and outcomes associated with uncommon KRAS mutations in NSCLC. Of 4661 NSCLC patients subjected to oncogenic mutation profiling, 378 (8.1%) harbored KRAS mutations. Among the 209 cases with confirmed specific KRAS subtypes, 14 (6.7%, 14/209) presented with uncommon KRAS mutations. G12F was the most prevalent subtype, identified in 4 cases (28.6%, 4/14), followed by G12S and G12R, each detected in 2 cases (14.3%, respectively). Concomitant mutations were observed in 4 additional cases (28.6%), including G12D&G12V, G12A&G13R, G12V&G12C, and G12R&G12C. G12Y and G13R were each identified in 1 case (7.1% each). Compared with a matched cohort of patients with common KRAS mutations, no significant differences were observed in age, sex, smoking history, clinical stage, TTF-1 expression, or pathological subtypes. The uncommon KRAS mutation group had numerically inferior progression-free survival (PFS) and overall survival (OS); however, this difference did not reach statistical significance in our study (mean PFS: 15.14 months vs. 30.39 months, p = 0.074; mean OS: 24.50 months vs. 38.79 months, p = 0.157). These findings underscore the value of broad molecular profiling in establishing critical links between specific morphologic features, genetic alterations, and clinical behavior for tumors harboring these uncommon KRAS variants.