Oncology · Medical Literature
Influence of KRAS mutation subtypes on response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: meta-analysis.
Abstract
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 in locally advanced rectal cancer (LARC). A systematic review and meta-analysis of studies describing genetic determinants of response to neoadjuvant chemoradiotherapy in LARC was conducted, searching for manuscripts published up to March 2026. The primary outcome of interest was the odds ratio for KRAS mutations and pCR. A random-effects model estimated the pooled effect size of KRAS mutations within and outside exon 2 on pCR. Genomic data sets were analysed to investigate the molecular characteristics of KRAS exon 2 and non-exon 2 mutant rectal cancers and their impact on overall and disease-free survival. Finally, a transcriptomic data set was analysed to elucidate the underlying response mechanisms. Out of 11 537 manuscripts identified, 15 studies (3354 patients) were included in the meta-analysis. The odds ratio for any KRAS mutation and pCR was 0.48 (95% confidence interval 0.32 to 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 (odds ratio 0.96, 95% confidence interval 0.11 to 8.49). Analysis confirmed poorer disease-free survival in patients with exon 2 alterations (P = 0.019) as well as poorer overall survival (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. The presence of KRAS mutations adversely affects pCR odds after neoadjuvant chemoradiotherapy in LARC, but this effect is specific to exon 2 mutations.
Clinical relevance
Do different KRAS mutation subtypes—specifically exon 2 versus non-exon 2 mutations—differentially influence pathological complete response (pCR) rates after neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer (LARC)? __SNAPSHOT__ {"studyDesign":"Systematic review and meta-analysis, supplemented by secondary genomic dataset analysis (molecular characteristics, overall survival, disease-free survival) and transcriptomic dataset analysis (mechanistic exploration)","setting":"Not reported (multi-study aggregate; manuscripts searched up to March 2026)","sampleSize":"15 studies included in the meta-analysis; n=3,354 patients (subgroup allocation by KRAS mutation subtype not reported in abstract)","population":"Adult patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy; genetic determinants of treatment response were the primary inclusion criterion for constituent studies","intervention":"KRAS mutation status (any mutation; further stratified into exon 2 vs. non-exon 2 subtypes) in patients receiving neoadjuvant chemoradiotherapy","comparator":"KRAS wild-type (for primary meta-analytic comparison); KRAS exon 2 mutant vs. KRAS non-exon 2 mutant (for subtype subgroup analysis)","primaryOutcome":"Pathological complete response (pCR) rate; reported as odds ratio for KRAS mutation vs. wild-type","followUp":"Not reported (cross-sectional pathological endpoint; survival analyses conducted using secondary genomic datasets, duration not specified in abstract)","fundingSource":"Not reported"}
Key findings
The pooled odds ratio for any KRAS mutation and pCR was 0.48 (95% CI: 0.32–0.70), indicating that patients harboring any KRAS mutation had approximately half the odds of achieving pCR compared to KRAS wild-type patients; this result was statistically significant. The NNH (number needed to identify as KRAS-mutant for one fewer pCR compared to wild-type) cannot be calculated from the abstract alone, as absolute pCR rates per group are not provided. A key novel contribution of this study was the subgroup stratification by exon location: the study used a random-effects model to separately estimate the pooled effect of KRAS exon 2 mutations and non-exon 2 mutations on pCR. The specific OR estimates for each subtype (exon 2 vs. non-exon 2) and whether their effects differed significantly from one another are not reported in the abstract provided. Genomic dataset analyses were performed to characterize the molecular landscape of KRAS exon 2 and non-exon 2 mutant rectal cancers, including their association with overall survival and disease-free survival; numerical results from these analyses are not reported in the abstract. A transcriptomic dataset was additionally analyzed to explore underlying mechanistic differences in treatment response; specific findings are not reported in the abstract. No adverse event or treatment toxicity data are reported, consistent with the study's design as a retrospective meta-analysis of pathological response. All values above are as reported in the abstract; no values have been independently calculated.
Practice implications
This meta-analysis establishes that any KRAS mutation is significantly associated with substantially reduced odds of achieving pCR after neoadjuvant chemoradiotherapy in LARC (OR 0.48; 95% CI 0.32–0.70), extending and strengthening prior meta-analytic evidence in this area. The study's primary methodological advance is the attempt to disaggregate this effect by KRAS mutation subtype (exon 2 vs. non-exon 2), which addresses a clinically important gap, since exon 2 mutations (codons 12 and 13) are biologically distinct from non-exon 2 variants in their degree of GTPase impairment and downstream MAPK signaling intensity. Whether the predictive impact on pCR differs meaningfully between exon 2 and non-exon 2 subtypes cannot be determined from the abstract alone, as subtype-specific ORs are not reported there. The study did not establish whether KRAS mutation subtype-stratified pCR differences translate into differential overall survival or disease-free survival benefit, though genomic and transcriptomic datasets were explored for mechanistic context. The findings most directly apply to patients with microsatellite-stable or unselected LARC receiving standard fluoropyrimidine-based long-course chemoradiotherapy; patients receiving cetuximab-based or novel total neoadjuvant therapy regimens may not be adequately represented. Critically, this summary is based solely on the supplied abstract; the full subtype-specific effect estimates, heterogeneity statistics (I²), assessment of publication bias, and survival data are not available for evaluation. Practice should not change on the basis of the abstract alone; access to the full publication is required before any subtype-specific clinical conclusions can be drawn. __LIMITATIONS__ Only the abstract was available for review; subtype-specific odds ratios for KRAS exon 2 vs. non-exon 2 mutations, heterogeneity estimates (I²), and publication bias assessments are not reported and cannot be critically appraised.,The meta-analysis pools 15 studies (n=3,354), which likely comprises predominantly retrospective cohorts with variable molecular testing methodologies (Sanger sequencing vs. next-generation sequencing), differing definitions of KRAS mutation status, and heterogeneous neoadjuvant regimens—all sources of substantial between-study heterogeneity.,Non-exon 2 KRAS mutations (exons 3 and 4; codons 61, 117, 146) are substantially less common than exon 2 mutations, raising concern about statistical power in the subgroup analysis, particularly for rarer individual mutation subtypes.,pCR is a surrogate endpoint; although associated with improved survival at an individual patient level, the abstract notes that survival analyses were conducted in separate genomic datasets rather than within the meta-analytic cohort itself, limiting integration of survival data.,The constituent studies likely varied in radiotherapy dose/fractionation, chemotherapy backbone (fluoropyrimidine with or without oxaliplatin), interval to surgery, and pCR grading criteria—all of which confound the KRAS-pCR association.,No adjustment for co-occurring mutations (e.g., TP53, APC, PIK3CA, SMAD4) or consensus molecular subtypes (CMS) is described, raising confounding concerns.,Generalizability is uncertain: the geographic and ethnic composition of included studies, as well as the proportion receiving modern total neoadjuvant therapy (TNT) regimens, are not described in the abstract.,Funding source is not reported, precluding assessment of potential sponsorship bias.,Statistical significance (OR 0.48; CI 0.32–0.70) is demonstrated for any KRAS mutation overall, but absolute effect sizes (absolute pCR rate differences) needed to assess clinical magnitude are not reported. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ This systematic review and meta-analysis (15 studies; n=3,354) confirms that any KRAS mutation is associated with approximately half the odds of achieving pCR after neoadjuvant chemoradiotherapy in LARC (OR 0.48; 95% CI 0.32–0.70), providing the strongest pooled evidence to date. The study's novel contribution—subtype stratification by exon 2 versus non-exon 2 KRAS mutations—cannot be fully evaluated from the abstract alone, and access to the full publication is essential before subtype-specific clinical or treatment-selection inferences are made. Routine KRAS mutation testing in LARC is already clinically warranted; whether the specific exon location should further refine neoadjuvant strategy or patient selection for watch-and-wait protocols requires confirmation from the complete dataset and prospective validation.