{"doi":"10.1371/journal.pone.0320783","title":"Prognostic significance of KRAS, NRAS, BRAF, and PIK3CA mutations in stage II/III colorectal cancer: A retrospective study and meta-analysis","abstract":"<jats:p>The prognostic significance of <jats:italic>KRAS</jats:italic> and <jats:italic>BRAF</jats:italic> mutations is well-established in metastatic colorectal cancer (CRC) but remains uncertain in early-stage tumors. This study retrospectively analyzed 47 stage II/III CRC patients undergoing curative surgery to assess the association of mutations in <jats:italic>KRAS</jats:italic>, <jats:italic>NRAS</jats:italic>, <jats:italic>BRAF</jats:italic>, and <jats:italic>PIK3CA</jats:italic> with overall survival (OS) and disease-free survival (DFS). Additionally, a meta-analysis was conducted to validate the prognostic relevance of these gene mutations. We included post hoc analyses of phase III randomized controlled trials (RCTs) in stage II/III patients receiving adjuvant therapy after curative resection in the meta-analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated using a random-effect model in the overall population, stratified subgroups adjusted for microsatellite instability (MSI) status, and within MSI-high (MSI-H) and microsatellite-stable (MSS) populations. In the retrospective cohort, mutations in <jats:italic>KRAS</jats:italic>, <jats:italic>NRAS</jats:italic>, <jats:italic>BRAF</jats:italic>, and <jats:italic>PIK3CA</jats:italic> were identified in 29.8%, 4.3%, 8.5%, and 14.9% of patients, respectively. No significant association between individual genes and survival was observed. However, in MSS patients, concurrent mutations were significantly associated with shorter OS and DFS (log-rank test, P &lt; 0.05). The meta-analysis incorporated 13 eligible studies, including 15,034 patients. Pooled analyses revealed that <jats:italic>KRAS</jats:italic> and <jats:italic>BRAF</jats:italic> mutations were significantly linked to poor OS (<jats:italic>KRAS</jats:italic>: HR = 1.25, 95%CI: 1.06-1.47, P = 0.008; <jats:italic>BRAF</jats:italic>: HR = 1.43, 95%CI: 1.26-1.63, P &lt; 0.001) and DFS (<jats:italic>KRAS</jats:italic>: HR = 1.36, 95%CI: 1.21-1.53, P &lt; 0.001; <jats:italic>BRAF</jats:italic>: HR = 1.21, 95%CI: 1.02-1.44, P = 0.032). The prognostic impact of <jats:italic>BRAF</jats:italic> mutation increased with MSI adjustment compared those without MSI adjustment. In MSS tumors, <jats:italic>KRAS</jats:italic>-mutant patients demonstrated significantly shorter DFS (HR = 1.63, 95%CI: 1.25-2.13, P &lt; 0.001), while <jats:italic>BRAF</jats:italic>-mutant patients exhibited reduced OS (HR = 1.53, 95%CI: 1.24-1.89, P &lt; 0.001) and DFS (HR = 1.72, 95%CI: 1.20-2.46, P = 0.003) compared to wildtype patients. Conversely, no significant survival differences were found between mutant and wildtype patients in the MSI-H population. Although <jats:italic>PIK3CA</jats:italic> mutation was nominally associated with OS (HR = 0.86, 95%CI: 0.75-1.00, P = 0.046), the pooled result lacked robustness. In conclusion, <jats:italic>KRAS</jats:italic> and <jats:italic>BRAF</jats:italic> mutations had a negative prognostic impact on MSS stage II/III CRC patients receiving adjuvant therapy following curative resection. These patients may benefit from more effective adjuvant treatment strategies.</jats:p>","journal":"PLOS One","year":2025,"id":607050,"datarank":0.4566783656585135,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":0.0,"self_endowment_contribution":0.4566783656585135,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1346179,"name":"Jing Li","orcid":"0000-0003-3209-8973","position":1,"is_corresponding":false},{"id":1107522,"name":"Yangyang Li","orcid":"0000-0002-2922-1005","position":2,"is_corresponding":false},{"id":1558604,"name":"Jingquan Xu","orcid":null,"position":3,"is_corresponding":false},{"id":1558605,"name":"Jianlei Yang","orcid":null,"position":4,"is_corresponding":false},{"id":1009710,"name":"Zili Zhang","orcid":"0000-0003-1204-1857","position":5,"is_corresponding":false},{"id":459155,"name":"Di Kang","orcid":"0000-0002-9553-769X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Prognostic significance of KRAS, NRAS, BRAF, and PIK3CA mutations in stage II/III colorectal cancer: A retrospective study and meta-analysis","abstract":"<jats:p>The prognostic significance of <jats:italic>KRAS</jats:italic> and <jats:italic>BRAF</jats:italic> mutations is well-established in metastatic colorectal cancer (CRC) but remains uncertain in early-stage tumors. This study retrospectively analyzed 47 stage II/III CRC patients undergoing curative surgery to assess the association of mutations in <jats:italic>KRAS</jats:italic>, <jats:italic>NRAS</jats:italic>, <jats:italic>BRAF</jats:italic>, and <jats:italic>PIK3CA</jats:italic> with overall survival (OS) and disease-free survival (DFS). Additionally, a meta-analysis was conducted to validate the prognostic relevance of these gene mutations. We included post hoc analyses of phase III randomized controlled trials (RCTs) in stage II/III patients receiving adjuvant therapy after curative resection in the meta-analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) was calculated using a random-effect model in the overall population, stratified subgroups adjusted for microsatellite instability (MSI) status, and within MSI-high (MSI-H) and microsatellite-stable (MSS) populations. In the retrospective cohort, mutations in <jats:italic>KRAS</jats:italic>, <jats:italic>NRAS</jats:italic>, <jats:italic>BRAF</jats:italic>, and <jats:italic>PIK3CA</jats:italic> were identified in 29.8%, 4.3%, 8.5%, and 14.9% of patients, respectively. No significant association between individual genes and survival was observed. However, in MSS patients, concurrent mutations were significantly associated with shorter OS and DFS (log-rank test, P &lt; 0.05). The meta-analysis incorporated 13 eligible studies, including 15,034 patients. Pooled analyses revealed that <jats:italic>KRAS</jats:italic> and <jats:italic>BRAF</jats:italic> mutations were significantly linked to poor OS (<jats:italic>KRAS</jats:italic>: HR = 1.25, 95%CI: 1.06-1.47, P = 0.008; <jats:italic>BRAF</jats:italic>: HR = 1.43, 95%CI: 1.26-1.63, P &lt; 0.001) and DFS (<jats:italic>KRAS</jats:italic>: HR = 1.36, 95%CI: 1.21-1.53, P &lt; 0.001; <jats:italic>BRAF</jats:italic>: HR = 1.21, 95%CI: 1.02-1.44, P = 0.032). The prognostic impact of <jats:italic>BRAF</jats:italic> mutation increased with MSI adjustment compared those without MSI adjustment. In MSS tumors, <jats:italic>KRAS</jats:italic>-mutant patients demonstrated significantly shorter DFS (HR = 1.63, 95%CI: 1.25-2.13, P &lt; 0.001), while <jats:italic>BRAF</jats:italic>-mutant patients exhibited reduced OS (HR = 1.53, 95%CI: 1.24-1.89, P &lt; 0.001) and DFS (HR = 1.72, 95%CI: 1.20-2.46, P = 0.003) compared to wildtype patients. Conversely, no significant survival differences were found between mutant and wildtype patients in the MSI-H population. Although <jats:italic>PIK3CA</jats:italic> mutation was nominally associated with OS (HR = 0.86, 95%CI: 0.75-1.00, P = 0.046), the pooled result lacked robustness. In conclusion, <jats:italic>KRAS</jats:italic> and <jats:italic>BRAF</jats:italic> mutations had a negative prognostic impact on MSS stage II/III CRC patients receiving adjuvant therapy following curative resection. These patients may benefit from more effective adjuvant treatment strategies.</jats:p>","is_dataset_classified":null,"base_score":2.995732273553991,"endowment":2.995732273553991,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40279317","pmcid":"PMC12027030","openalex_id":"https://openalex.org/W4409798793","authors":[],"funders":[],"total_grants":0,"fwci":9.5471,"citation_percentile":0.98599196,"influential_citations":0,"citation_trend":[{"year":2025,"count":8},{"year":2026,"count":11}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://doi.org/10.1371/journal.pone.0320783","host_type":"journal"},{"url":"https://doi.org/10.1371/journal.pone.0320783","host_type":"publisher"},{"url":"https://dx.plos.org/10.1371/journal.pone.0320783","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40279317","host_type":"repository"},{"url":"https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0320783","host_type":"repository"},{"url":"https://doaj.org/article/eaae50a3cadb4a378445a6ea48d4aef6","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12027030","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12027030","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12027030?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Colorectal Cancer Treatments and Studies","Genetic factors in colorectal cancer","Colorectal Cancer Surgical Treatments"],"mesh_terms":["Adult","Aged","Female","Humans","Male","Membrane Proteins","Middle Aged","Mutation","Neoplasm Staging","Prognosis","Retrospective Studies","Colorectal Neoplasms","Proto-Oncogene Proteins p21(ras)","Disease-Free Survival","Phosphatidylinositol 3-Kinases","GTP Phosphohydrolases","Proto-Oncogene Proteins B-raf","Microsatellite Instability","Class I Phosphatidylinositol 3-Kinases"],"keywords":["KRAS","Neuroblastoma RAS viral oncogene homolog","Medicine","Internal medicine","Hazard ratio","Oncology","Colorectal cancer","Microsatellite instability","Retrospective cohort study","Confidence interval","Population","Meta-analysis","Cancer","Biology","Allele","Microsatellite","Gene","Genetics"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"No poverty"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-07-30T05:39:53.171289Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}