KRAS mutation subtypes influence response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Background: KRAS mutations are common in colorectal cancer, but the impact of KRAS mutation subtypes on treatment response remains poorly understood. This research aimed to investigate whether different KRAS mutations influence pathological complete response (pCR) rates after neoadjuvant chemoradiotherapy (nCRT) in locally-advanced rectal cancer (LARC). Method: A systematic review and meta-analysis of studies describing genetic determinants of response to nCRT in LARC was conducted, searching for manuscripts published up to March 2026. The primary outcome of interest was the odds ratio (OR) for KRAS mutation and pCR. A random-effects model estimated the pooled effect size of KRAS mutations within and outside exon 2 on pCR. Genomic datasets were analysed to investigate the molecular characteristics of KRAS exon 2- and non-exon 2-mutant rectal cancers and their impact on overall (OS) and disease-free (DFS) survival. Finally, a transcriptomic dataset was analysed to elucidate the underlying response mechanisms. Results: Out of 11537 manuscripts identified, 15 studies (3354 patients) were included in the meta-analysis. The OR for any KRAS mutation and pCR was 0.48 (95%-CI 0.32-0.70), indicating reduced odds of pCR in KRAS-mutant LARC. Subgroup analysis revealed that KRAS mutations in exon 2 accounted for this effect, whereas variants outside exon 2 had no influence (OR 0.96, 95% CI 0.11-8.49. Analysis confirmed poorer DFS in patients with exon 2 alterations (P=0.019) as well as poorer OS (P=0.047). Transcriptomic analysis revealed that non-exon 2 KRAS-mutant tumours were enriched for inflammatory signalling pathways, suggesting that these tumours represent a subgroup with high immune infiltration. Conclusion: The presence of KRAS mutations adversely affects pCR odds after nCRT in LARC, but this effect is specific to exon 2 mutations.