Impact of <i>KRAS</i> sub-mutations in metastatic colorectal cancer patients (mCRC).

Abstract

e15535 Background: KRAS mutations are established predictive and prognostic biomarkers in metastatic colorectal cancer (mCRC). However, the clinical relevance of specific KRAS sub-mutations and their interaction with chemotherapy regimens remains incompletely defined. We evaluated the impact of distinct KRAS sub-mutations on overall survival (OS) and progression-free survival (PFS) in a consecutive cohort of patients with mCRC. Methods: We retrospectively analyzed 126 consecutive patients with mCRC treated at a single institution. Tumor molecular profiling was performed using Next Generation Sequencing (NGS) and Polymerase Chain Reaction (PCR) to identify KRAS and NRAS mutations. Survival outcomes were analyzed according to KRAS sub-mutation status and first-line chemotherapy regimen (oxaliplatin- vs irinotecan-based). OS and PFS were estimated using the Kaplan–Meier method and compared with the log-rank test. Hazard ratios (HRs) were calculated using Cox proportional hazards models. All tests were two-sided. Results: Forty-nine patients (39%) harbored KRAS mutations. Median age was 68 years. Liver was the most common metastatic site (51%); 29% of patients had ≥2 metastatic sites. First-line treatment consisted of oxaliplatin-based regimens in 69% and irinotecan-based regimens in 16% of patients.Codon 12 KRAS mutations were associated with inferior OS compared with other variants. Median PFS for codon 12 mutations was longer with irinotecan-based therapy than with oxaliplatin-based therapy (22.5 vs 8 months, p sign &lt; 0.05). Codon 13 mutations demonstrated similar median PFS (12 months) regardless of chemotherapy regimen or specific variant (G13D vs G13V). Non-canonical KRAS sub-mutations (codons 61 and 146) were associated with improved outcomes with oxaliplatin-based therapy (median PFS 17 vs 13 months, p sign &lt; 0.05). Median OS was longest in non-canonical sub-mutations (23 months), followed by codon 13 (18 months) and codon 12 mutations (15 months). Concomitant genomic alterations were detected in 38% of cases, most frequently involving PIK3CA (10%) and TP53 (8%). Conclusions: KRAS mutations in mCRC are clinically heterogeneous. Codon 12 mutations confer poorer survival, whereas codon 13 and non-canonical mutations exhibit distinct prognostic and predictive profiles on the basis that codon 13 mutations do not completely abolish RAS GTPase activity, in contrast to codon 12 mutations, which result in a more profound functional impairment.Comprehensive molecular characterization may refine prognostic stratification and support personalized first-line treatment selection in mCRC.