Clinicopathological features and outcomes for colorectal carcinomas with KRAS codon 146 mutations

Background: KRAS-activating mutations characterize ∼40% of colorectal carcinomas (CRCs) and predict resistance to anti-epidermal growth factor receptor therapy. Because the location of KRAS mutations conveys distinct biophysical consequences, we investigated whether CRCs’ clinicopathological features varied by KRAS mutation codon. Patients and methods: CRC patients from 2018 to 2022 were identified from the United States National Cancer Database, which reports KRAS as wild-type versus codon 12/13/61-mutant versus codon 146-mutant. KRAS codon mutations were compared using multivariable logistic regression for clinicopathological features and multivariable Cox regression for overall survival (OS). Notable limitations include a lack of granular codon characterization and detailed treatment data. Results: Nationally, n = 76 581 CRC patients were identified, 43.3% of whom were KRAS mutated (including n = 16 366 at codon 12/13/61 and n = 784 at codon 146). Among tumor characteristics, codon 146-mutated CRCs were less likely poorly differentiated (12.1%) and more likely moderately differentiated (80.7%) than codon 12/13/61-mutated CRCs (15.9% and 76.0%, respectively; P = 0.003). Additionally, codon 146-mutated CRCs less likely involved the sigmoid colon (14.4% versus 18.1% of codon 12/13/61-mutated CRCs; P = 0.004). KRAS codon 146-mutated CRCs were enriched with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) (10.1% versus 5.9% of codon 12/13/61-mutated; P < 0.001) and were less likely concurrently NRAS mutant (1.5% versus 8.0% of codon 12/13/61-mutated; chi-square P < 0.001). Adjusting for patient characteristics and treatments, no OS difference was observed between KRAS codon 146-mutated and 12/13/61-mutated stage IV CRCs (hazard ratio 0.97, 95% confidence interval 0.84-1.12, P = 0.69). Conclusion: Nationally, CRCs with KRAS mutations at codon 146 exhibited select pathological and MSI/MMR differences—illustrating that KRAS mutations have codon-specific manifestations that warrant further investigation, particularly as the armamentarium of alteration-specific KRAS inhibitors grows.