Effects of Gene Mutations on the Prognosis and Treatment Response of Locally Advanced Rectal Cancer Following Neoadjuvant Chemoradiotherapy: A Meta‐Analysis and Systematic Review

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). However, treatment response and long‐term outcomes vary considerably among patients. Increasing evidence suggests that tumor gene mutations may influence therapeutic response and prognosis. Here, we investigated the relationship between gene mutations and clinical outcomes in LARC patients treated with nCRT. A systematic search was performed to identify relevant literature published prior to September 2024 using PubMed, EMBASE, and Web of Science. Studies that investigated the relationship between gene mutations and the prognosis or response of LARC patients were included in this study. Pooled odds ratios (ORs), hazard ratios (HR) and 95% confidence intervals (CIs) were calculated for the gene mutations and clinical outcomes. The KRAS gene was investigated in 21 studies; the mutated rate ranged from 13.2% to 73.3%. Meta‐analysis revealed that KRAS mutation was associated with a higher risk of poorer overall survival (OS) (HR = 1.23, 95% CI: 1.01–1.49, p = 0.04) in LARC patients receiving nCRT. Moreover, a negative relationship was identified between KRAS mutation and a good response (OR = 0.52, 95% CI: 0.31–0.86, p = 0.01) or pathological complete response (OR = 0.75, 95% CI: 0.59–0.96, p = 0.02). Patients with mutations in the RAS pathway had better responses than those with wild‐type variants (OR = 0.28, 95% CI: 0.13–0.57, p < 0.001). Three‐year OS and disease‐free survival did not differ significantly between patients with wild‐type and mutated KRAS. KRAS mutational status may therefore be a useful indicator of the response to nCRT but not of long‐term outcomes (e.g., 3‐year OS and disease‐free survival). What’s more, APC‐mutated LARC patients did not achieve better OS than those with the wild‐type genotype. Further integrative analyses of multiple genes and molecular pathways are required to improve prognostic stratification in LARC.