The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study
Open accessAbstract
Background: KRAS is one of the most frequently mutated oncogenes in colorectal cancer (CRC). Recently, a novel therapy targeting KRAS G12C mutation has demonstrated promising activities for corresponding advanced solid tumors, including metastatic CRC (mCRC). However, the prognostic impact of the KRAS G12C mutation remains unclear in patients with mCRC. Materials and Methods: We retrospectively reviewed medical records of patients with mCRC who received first-line chemotherapy between January 2005 and December 2017 at four large oncology facilities in Japan. Survival outcomes were compared between patients with KRAS G12C and those with non-G12C mutations. Results: Among 2,457 patients with mCRC, 1,632 met selection criteria, and of these, 696 had KRAS exon 2 mutations, including 45 with KRAS G12C mutation tumors. Patient characteristics were not significantly different between the KRAS G12C and non-G12C groups. At a median follow-up of 64.8 months, patients with the KRAS G12C mutation showed significantly shorter first-line progression-free survival (PFS; median, 9.4 vs. 10.8 months; p = .015) and overall survival (OS; median, 21.1 vs. 27.3 months; p = .015) than those with non-G12C mutations. Multivariate analysis also showed that KRAS G12C mutation was significantly associated with shorter PFS (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.04–1.96, p = .030) and OS (HR, 1.42; 95% CI, 1.01–2.00; p = .044). Conclusion: We demonstrate that, compared with non-G12C mutations, KRAS G12C mutation is significantly correlated with shorter first-line PFS and OS. These findings indicate the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC. Implications for Practice: Among patients with KRAS exon 2 mutated metastatic colorectal cancer (mCRC), median progression-free survival (PFS) and overall survival (OS) were 9.4 and 21.1 months, respectively, for G12C mutation and 10.8 and 27.3 months, respectively, for patients with non-G12C mutations, indicating significantly shorter PFS (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.08–2.01; p = .015) and OS (HR, 1.50; 95% CI, 1.08–2.08; p = .015) in patients with G12C mutation than in those with non-G12C mutations. Furthermore, multivariate analysis showed that KRAS G12C mutation was independently associated with shorter first-line PFS and OS. Thus, these findings underscore the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC.
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- Findingown data
In multivariate analysis of patients with KRAS exon 2 mutations, the KRAS G12C mutation was independently associated with shorter progression-free survival (HR 1.43, 95% CI 1.04-1.96, p=.030).
“Multivariate analysis also showed that KRAS G12C mutation was significantly associated with shorter PFS (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.04-1.96,p = .030)”
- Also stated in: § Prognostic Impact of the KRAS G12C Mutation and Non-G12C Mutations · plain
“Multivariate analysis identified the following factors as significantly associated with PFS: KRAS G12C mutation (vs.non-G12C mutation: HR, 1.43; 95% CI, 1.04-1.96;p = .030)”
- Also stated in: § CONCLUSION · plain
“KRAS exon 2 mutation: G12C vs. non-G12C | 1.47 (1.08-2.01) | .015 | 1.43 (1.04-1.96) | .030”
Quote in the paperSubstantial claim - Also stated in: § Prognostic Impact of the KRAS G12C Mutation and Non-G12C Mutations · plain
- Findingown data
In patients with KRAS exon 2 mutated metastatic colorectal cancer, the KRAS G12C mutation was associated with significantly shorter overall survival than non-G12C mutations (median 21.1 vs 27.3 months; HR 1.50, 95% CI 1.08-2.08, p=.015).
“overall survival (OS; median, 21.1 vs. 27.3months; p = .015)”
- Also stated in: § Prognostic Impact of the KRAS G12C Mutation and Non-G12C Mutations · plain
“median OS, 21.1 months [95% CI, 12.8-27.9]vs. 27.3months [95% CI, 24.8-28.9];HR, 1.50 [95% CI, 1.08-2.08],p = .015”
- Also stated in: § Abstract · plain
“and OS (HR, 1.50; 95% CI, 1.08-2.08;p = .015)in patients with G12C mutation than in those with non-G12C mutations.”
Quote in the paperSubstantial claim - Also stated in: § Prognostic Impact of the KRAS G12C Mutation and Non-G12C Mutations · plain
- Findingown data
In multivariate analysis of patients with KRAS exon 2 mutations, the KRAS G12C mutation was independently associated with shorter overall survival (HR 1.42, 95% CI 1.01-2.00, p=.044).
“and OS (HR, 1.42; 95% CI, 1.01-2.00;p = .044)”
- Also stated in: § Prognostic Impact of the KRAS G12C Mutation and Non-G12C Mutations · plain
“multivariate analysis yielded significant association between OS and the following variables: KRAS G12C mutation (vs.non-G12C mutation: HR, 1.42; 95% CI, 1.01-2.00;p = .044)”
- Also stated in: § CONCLUSION · plain
“KRAS exon 2 mutation: G12C vs. non-G12C | 1.50 (1.08-2.08) | .015 | 1.42 (1.01-2.00) | .044”
Quote in the paperSubstantial claim - Also stated in: § Prognostic Impact of the KRAS G12C Mutation and Non-G12C Mutations · plain
- Findingown data
In patients with KRAS exon 2 mutated metastatic colorectal cancer, the KRAS G12C mutation was associated with significantly shorter first-line progression-free survival than non-G12C mutations (median 9.4 vs 10.8 months; HR 1.47, 95% CI 1.08-2.01, p=.015).
“patients with the KRAS G12C mutation showed significantly shorter first-line progression-free survival (PFS; median, 9.4 vs. 10.8 months; p = .015)”
- Also stated in: § Prognostic Impact of the KRAS G12C Mutation and Non-G12C Mutations · plain
“those with the G12C mutation had significantly shorter PFS and OS than those with non-G12C mutations (median PFS, 9.4 months [95% CI, 6.4-12.0]vs. 10.8 months [95% CI, 10.1-11.5];HR, 1.47 [95% CI, 1.08-2.01],p = .015;”
- Also stated in: § Abstract · hedged
“median progression-free survival (PFS) and overall survival (OS) were 9.4 and 21.1 months, respectively, for G12C mutation and 10.8 and 27.3 months, respectively, for patients with non-G12C mutations, indicating significantly shorter PFS (hazard ratio [HR], 1.47; 95% confidence interval [CI], 1.08-2.01;p = .015)”
Quote in the paperSubstantial claim - Also stated in: § Prognostic Impact of the KRAS G12C Mutation and Non-G12C Mutations · plain
- Interpretationcitation
The prevalence of KRAS exon 2 mutations and major subtypes, including KRAS G12C, in this study is consistent with previous reports.
“The overall prevalence of KRAS exon 2 mutations and that of the three major KRAS mutation subtypes, along with the targetable subtype KRAS G12C, obtained in this study is consistent with previous reports [16][17][18].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16][17][18]
Not checked in the free run.
- Study design and conductown data
Baseline patient characteristics did not differ significantly between the KRAS G12C and non-G12C groups.
“Patient characteristics were not significantly different between the KRAS G12C and non-G12C groups.”
- Also stated in: § Patient Overview · plain
“There was no significant difference between KRAS G12C and non-G12C mutations; 5% of difference was observed in the following characteristics: gender, ECOG PS, surgery on primary tumor, time of first metastasis, liver metastasis, peritoneal dissemination, number of metastatic sites, and GPS.”
Quote in the paperNot a substantial claim - Also stated in: § Patient Overview · plain
- Interpretationown data
The findings indicate that stratified treatment targeting the KRAS G12C mutation is relevant in metastatic colorectal cancer.
“These findings indicate the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC.”
- Also stated in: § Abstract · boosted
“Thus, these findings underscore the relevance of a stratified treatment targeting KRAS G12C mutation in mCRC.”
- Also stated in: § CONCLUSION · hedged
“These findings indicate the importance of individualized treatment that targets the KRAS G12C mutation.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · boosted
- Interpretationcitation
The study's results may be applied to Western populations as well as Asian populations.
“Therefore, our result may be applied to Western populations as well as Asian populations.”
Quote in the paperSubstantial claim - Study design and conductown data
All patients in the study were Asian.
“Third, all patients in our study were Asian.”
Quote in the paperNot a substantial claim - Study design and conductown data
The number of patients with KRAS G12C mutation tumors was limited.
“Second, although our study included 1,632 patients with mCRC, the number of patients with the KRAS G12C mutation in tumors was limited.”
Quote in the paperSubstantial claim - Study design and conductown data
Among patients who received doublet or triplet chemotherapy, characteristics did not differ significantly between the KRAS G12C and non-G12C groups.
“Furthermore, in the patients who received doublet or triplet chemotherapy, their characteristics were not significantly different between those with KRAS G12C and non-G12C mutations (supplemental online Table 2).”
Quote in the paperNot a substantial claim - Premisecitation
A pooled analysis by the AIO study group found that KRAS G12C mutation was significantly associated with lower overall survival compared with tumors with no KRAS mutations.
“A pooled analysis by the Arbeitsgemeinschaft Internistische Onkologie [AIO] study group revealed that KRAS G12C mutation was significantly associated with lower OS compared with tumors with no KRAS mutations [16]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Modest, 2016, Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants: Pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group, Ann Oncol source
Not checked in the free run.
- Premisecitation
The AIO pooled analysis included patients who received nonstandard treatment regimens, including FUFIRI, FUFOX, and mIROX as induction chemotherapies and bevacizumab monotherapy or observation alone as maintenance therapies in clinical trials.
“however, it must be noted here that this pooled analysis also included patients who had received a nonstandard treatment regimen, including FUFIRI, FUFOX, and mIROX as induction chemotherapies and bevacizumab monotherapy or observation alone as maintenance therapies in clinical trials [22,23].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [22] Venook, 2017, Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: A randomized clinical trial, JAMA source
Not checked in the free run.
- cites [23] Stintzing, 2016, FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): A post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial, Lancet Oncol source
Not checked in the free run.
- Not yet classified. 1
- May combine two claims. 7
- Classified as probably not a substantial claim. 4
Not yet classified.
FindingAmong patients who received doublet or triplet chemotherapy, the KRAS G12C mutation was associated with consistently poor progression-free survival and overall survival.
“Also, consistently poor PFS and OS were observed in those with KRAS G12C mutation (supplemental online Fig. 3).”
Quote in the paperNot yet classifiedMay combine two claims.
Findingown dataAmong 2,457 patients with metastatic colorectal cancer who received systemic chemotherapy, 1,632 met the selection criteria; 696 of these had KRAS exon 2 mutations, and 45 had KRAS G12C mutation tumors.
“Among 2,457 patients with mCRC, 1,632 met selection criteria, and of these, 696 had KRAS exon 2 mutations, including 45 with KRAS G12C mutation tumors.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThe median overall survival for each mutation type in this cohort was consistent with previously reported values, indicating that the cohort is representative of the metastatic colorectal cancer population and that the results reflect clinical practice.
“Median OS for each type of mutation (i.e., KRAS exon 2 wild-type, KRAS exon 2 mutant, and BRAF V600E mutant) was consistent with that reported previously [14,15], indicating that our cohort was representative of the mCRC population and that the results presented here reflect prognosis in clinical practice.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [14] Phipps, 2013, KRAS-mutation status in relation to colorectal cancer survival: The joint impact of correlated tumour markers, Br J Cancer source
Not checked in the free run.
- cites [15] Richman, 2009, KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: Results from the MRC FOCUS trial, J Clin Oncol source
Not checked in the free run.
May combine two claims.
Study design and conductown dataThe study included patients with metastatic colorectal cancer who received standard chemotherapies and performed a multivariate analysis that included important covariate factors.
“We also included data from patients with mCRC receiving standard chemotherapies by performing a multivariate analysis that included important covariate factors.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductreasoningThe study was nonrandomized and retrospective.
“First, as previously noted, this was a nonrandomized retrospective study.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationA recent report found no difference in the distribution of KRAS G12C mutation in colorectal cancer between Asian and Western populations, unlike non-small cell lung cancer.
“However, a recent report has revealed no difference in the distribution of KRAS G12C mutation in CRC between Asian and Western populations, unlike non-small cell lung cancer [18].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Nassar, 2021, Distribution of KRAS G12C somatic mutations across race, sex, and cancer type, N Engl J Med source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSchirripa et al. reported poor prognosis in patients with metastatic colorectal cancer and KRAS G12C mutation.
“Schirripa et al. have recently reported poor prognosis in patients with mCRC and KRAS G12C mutation;”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Schirripa, 2020, KRAS G12C metastatic colorectal cancer: Specific features of a new emerging target population, Clin Colorectal Cancer source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA phase I trial of AMG 510 achieved a partial response in 30% of patients with non-small cell lung cancer and in 7.1% of patients with colorectal cancer.
“A phase I trial of AMG 510, which is the first-in-class KRAS G12C inhibitor, achieved a partial response in 30% of patients with non-small cell lung cancer and in 7.1% of patients with CRC [8].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Hong, 2020, KRASG12C inhibition with sotorasib in advanced solid tumors, N Engl J Med source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAn ongoing clinical trial is testing a combination of a KRAS G12C inhibitor and an anti-EGFR antibody.
“Additionally, an ongoing clinical trial is testing a combination of the KRAS G12C inhibitor and anti-epidermal growth factor receptor (EGFR) antibody [9].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Fakih, 2020, Trial in progress: A phase Ib study of AMG 510, a specific and irreversible KRAS G12C inhibitor, in combination with other anticancer therapies in patients with advanced solid tumors harboring KRAS p.G12C mutation (CodeBreak 101), J Clin Oncol source
Not checked in the free run.
May combine two claims.
InterpretationcitationIn Schirripa et al., the prevalence of KRAS G12C mutation was relatively high at 17.3%, and favorable outcomes such as median overall survival greater than 35 months in non-G12C patients might not reflect real-world clinical practice.
“however, the prevalence of KRAS G12C mutation was relatively high at 17.3%, and favorable outcomes, such as median OS greater than 35 months in patients with KRAS non-G12C mutations, might not reflect real-world clinical practice [21].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Schirripa, 2020, KRAS G12C metastatic colorectal cancer: Specific features of a new emerging target population, Clin Colorectal Cancer source
Not checked in the free run.
The paper relies on this without support.
The prognostic impact of KRAS G12C mutation in metastatic colorectal cancer remains unclear.
“However, the prognostic impact of the KRAS G12C mutation remains unclear in patients with mCRC.”
The paper relies on this without support.
There have been few reports on the prognostic impact of KRAS G12C mutation in metastatic colorectal cancer.
“however, there have been few reports on the prognostic impact of KRAS G12C mutation in mCRC.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
KRAS p.G12C is an exon 2 mutation which is found in approximately 3% of patients with CRC.
“KRAS p.G12C is an exon 2 mutation which is found in approximately 3% of patients with CRC.25”
From Current and emerging concepts for systemic treatment of metastatic colorectal cancer (2025) · cites this paper as [25]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Two upper confidence limits are given for the 21.1-month OS estimate
MinorThe survival overview gives an upper confidence limit of 29.4 months for the 21.1-month OS endpoint among KRAS exon 2 subtypes. The G12C comparison identifies that same endpoint and lower limit but gives an upper limit of 27.9 months.
“from 21.1 months (95% CI, 12.8-29.4)to 29.8 months”
“median OS, 21.1 months [95% CI, 12.8-27.9]vs. 27.3months”
Two upper confidence limits are given for non-G12C PFS
MinorThe results text gives an upper 95% confidence limit of 11.5 months for non-G12C median PFS, whereas the Figure 4 caption gives 11.8 months for the same comparison.
“vs. 10.8 months [95% CI, 10.1-11.5]”
“vs. 10.8 months [95% CI, 10.1-11.8]”
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Yildirim, H. C., Gunenc, D., Almuradova, E., Sutcuoglu, O., & Yalcin, S. (2025) · Medicina · doi:10.3390/medicina61030408 · Cited by 10 · see citing works
- Authors
- Chida, K., Kotani, D., Masuishi, T., Kawakami, T., Kawamoto, Y., Kato, K., Fushiki, K., Sawada, K., Kumanishi, R., Shirasu, H., Matsubara, Y., Yuki, S., Komatsu, Y., Yamazaki, K., & Yoshino, T.
- Affiliations
- National Cancer Centre Japan (JP)
- Aichi Cancer Center (JP)
- Shizuoka Cancer Center (JP)
- Hokkaido University Hospital (JP)
- Kushiro Rosai Hospital (JP)
- Corresponding author
- Kotani, Daisuke
- ORCID
- Venue
- The Oncologist
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-07-07
- Volume
- 26
- Issue
- 10
- Pages
- 845-853
- ISSN
- 1083-7159 (ISSN-L)
- 1549-490X
- PMC
- PMC8488780
- OpenAlex
- W3182174675
- Semantic Scholar
- f03035070b5b482a665a178a70883e1c504234eb
- Cited by
- 50
- References
- 29
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 10 · 2023: 12 · 2022: 7 · 2021: 4
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Oncologist (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- KRAS G12C mutation, metastatic colorectal cancer, prognostic factors, first-line chemotherapy, progression-free survival, overall survival, KRAS exon 2 mutation, KRAS-targeted therapy, survival outcomes, multicenter retrospective study, Japan Clinical Oncology Group
- MeSH terms
- Humans, Mutation, Prognosis, Retrospective Studies, Colorectal Neoplasms, Proto-Oncogene Proteins p21(ras)
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
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