{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T21:48:42Z","timestamp":1782078522225,"version":"3.54.5"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>KRAS G12C mutations occur in approximately 3%-4% of metastatic colorectal cancer (mCRC) cases. While the introduction of KRAS G12C inhibitors has transformed the therapeutic landscape for this molecular subset, conflicting evidence exists regarding the independent prognostic impact of this mutation in inhibitor-na\u00efve settings. Small sample sizes and methodological heterogeneity have limited individual studies, precluding definitive conclusions. To address this knowledge gap, we conducted a systematic review and meta-analysis to establish the prognostic significance of KRAS G12C mutations in mCRC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A comprehensive systematic literature search was conducted across PubMed, Google Scholar, and Cochrane Library through August 2025. Studies comparing overall survival between KRAS G12C and non-G12C RAS-mutant mCRC were included. Hazard ratios (HRs) were extracted or calculated from reconstructed individual patient data. Pooled analyses employed random-effects models. Quality assessment utilized the Newcastle\u2013Ottawa Scale.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Fourteen retrospective studies encompassing 9308 patients (903 KRAS G12C, 8405 non-G12C RAS) were included. The pooled analysis demonstrated that KRAS G12C mutations confer significantly worse prognosis, with a 28% increased risk of mortality compared to non-G12C RAS mutations (HR = 1.28, 95% CI, 1.10-1.48; p\u2009=\u2009.0015). A meta-analysis of difference in medians showed a pooled median overall survival (mOS) difference of \u22124.5\u2009months (95% CI, \u22129.1 to 0.0; P\u2009=\u2009.05) and a pooled median progression-free survival (mPFS) difference of \u22121.3\u2009months (95% CI, \u22122.4 to \u22120.1; P\u2009=\u2009.03) for KRAS G12C versus non-G12C patients. Moderate heterogeneity was observed (I2\u2009=\u200954.3%). Sensitivity analysis restricted to high-quality studies confirmed these findings (HR = 1.31, 95% CI, 1.11-1.54). No publication bias was detected.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>KRAS G12C mutations represent an independent adverse prognostic biomarker in mCRC, with a statistically significant 28% increased risk of mortality compared to other RAS mutations. The consistent HR across multiple sensitivity analyses supports a true prognostic effect. These findings have important implications for patient counseling and risk stratification. While the poor prognosis may provide rationale for prioritizing trial enrollment, translation into therapeutic decision-making requires caution, as prospective data demonstrating benefit from earlier use of KRAS G12C inhibitors are lacking.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/oncolo\/oyag219","type":"journal-article","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T11:40:17Z","timestamp":1780141217000},"source":"Crossref","is-referenced-by-count":0,"title":["Prognostic significance of KRAS G12C versus non-G12C RAS mutations in metastatic colorectal cancer: a systematic review and meta-analysis"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3419-2173","authenticated-orcid":false,"given":"Mohamed M","family":"Khamis","sequence":"first","affiliation":[{"name":"Internal Medicine, Mercy Hospital , St. Louis, MO, 63141,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2259-8261","authenticated-orcid":false,"given":"Mahsa Shirani","family":"Lapari","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Department of Medicine, Johns Hopkins University School of Medicine , Baltimore, MD, 21205,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Alkharabsheh","sequence":"additional","affiliation":[{"name":"Hematology-Oncology, University of Cincinnati, Cincinnati, OH, 45221,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maun R","family":"Baral","sequence":"additional","affiliation":[{"name":"Medical Oncology, Washington University in St. Louis , St. Louis, MO, 63110,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahim Halil","family":"Sahin","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Medical School , Rogel Cancer Center, Ann Arbor, MI, 48109,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Archwamety","sequence":"additional","affiliation":[{"name":"Medical Oncology, Siriraj Hospital , Bangkok, 10700,","place":["Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belal","family":"Firwana","sequence":"additional","affiliation":[{"name":"Medical Oncology, Heartland Cancer Research, Missouri Baptist Medical Center , Saint Louis, MO, 63131,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girijesh Kumar","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Motilal Nehru National Institute of Technology , Prayagraj, UP, 211004,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Singh","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology, University of Mississippi Medical Center , Jackson, MS, 39216,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameer","family":"Al Diffalha","sequence":"additional","affiliation":[{"name":"Pathology, The University of Alabama at Birmingham, O\u2019Neal comprehensive Cancer Center , Birmingham, AL, 35294,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Upender","family":"Manne","sequence":"additional","affiliation":[{"name":"Pathology, The University of Alabama at Birmingham, O\u2019Neal comprehensive Cancer Center , Birmingham, AL, 35294,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moh\u2019d","family":"Khushman","sequence":"additional","affiliation":[{"name":"Medical Oncology, Washington University in St. Louis , St. Louis, MO, 63110,","place":["United States"]},{"name":"Siteman Cancer Center , St. Louis, MO, 63110,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"2026062117364546500_oyag219-B1","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1001\/jama.2021.0106","article-title":"Diagnosis and treatment of metastatic colorectal cancer: a review","volume":"325","author":"Biller","year":"2021","journal-title":"JAMA"},{"key":"2026062117364546500_oyag219-B2","doi-asserted-by":"publisher","first-page":"1453","DOI":"10.1200\/jco.2016.71.9807","article-title":"Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical 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