Association of KRAS G13D Tumor Mutations With Outcome in Patients With Metastatic Colorectal Cancer Treated With First-Line Chemotherapy With or Without Cetuximab
Abstract
Purpose: We investigated in the first-line setting our previous finding that patients with chemorefractory KRAS G13D–mutated metastatic colorectal cancer (mCRC) benefit from cetuximab treatment. Methods: Associations between tumor KRAS mutation status (wild-type, G13D, G12V, or other mutations) and progression-free survival (PFS), survival, and response were investigated in pooled data from 1,378 evaluable patients from the CRYSTAL and OPUS studies. Multivariate analysis correcting for differences in baseline prognostic factors was performed. Results: Of 533 patients (39%) with KRAS-mutant tumors, 83 (16%) had G13D, 125 (23%) had G12V, and 325 (61%) had other mutations. Significant variations in treatment effects were found for tumor response (P = .005) and PFS (P = .046) in patients with G13D-mutant tumors versus all other mutations (including G12V). Within KRAS mutation subgroups, cetuximab plus chemotherapy versus chemotherapy alone significantly improved PFS (median, 7.4 v 6.0 months; hazard ratio [HR], 0.47; P = .039) and tumor response (40.5% v 22.0%; odds ratio, 3.38; P = .042) but not survival (median, 15.4 v 14.7 months; HR, 0.89; P = .68) in patients with G13D-mutant tumors. Patients with G12V and other mutations did not benefit from this treatment combination. Patients with KRAS G13D–mutated tumors receiving chemotherapy alone experienced worse outcomes (response, 22.0% v 43.2%; odds ratio, 0.40; P = .032) than those with other mutations. Effects were similar in the separate CRYSTAL and OPUS studies. Conclusion: The addition of cetuximab to first-line chemotherapy seems to benefit patients with KRAS G13D–mutant tumors. Relative treatment effects were similar to those in patients with KRAS wild-type tumors but with lower absolute values.
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Colorectal cancer patients with the KRASG13D mutation showed efficacy with first-line chemotherapy combined with cetuximab in a previous retrospective analysis.
“A previous retrospective analysis indicated that colorectal cancer (CRC) patients with the KRASG13D mutation showed efficacy with first-line chemotherapy combined with cetuximab [62,63]”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [63]
Not all KRAS alleles confer resistance to anti-EGFR therapy.
“it has been suggested that not all KRAS alleles confer resistance to anti-EGFR therapy”
From The Role of KRAS Mutations in Colorectal Cancer: Biological Insights, Clinical Implications, and Future Therapeutic Perspectives (2025) · cites this paper as [63]
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- Authors
- Tejpar, S., Celik, I., Schlichting, M., Sartorius, U., Bokemeyer, C., & Van Cutsem, E.
- Affiliations
- University Medical Center Hamburg-Eppendorf (DE)
- Sabine Tejpar and Eric Van Cutsem, University Hospital Gasthuisberg, Leuven, Belgium; Ilhan Celik, Michael Schlichting, and Ute Sartorius, Merck KGaA, Darmstadt; and Carsten Bokemeyer, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Venue
- Journal of Clinical Oncology
- Published
- 2012-10-10
- Volume
- 30
- Issue
- 29
- Pages
- 3570-3577
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2141801755
- Cited by
- 353
- References
- 30
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 16 · 2023: 9 · 2022: 9 · 2021: 19 · 2020: 18 · 2019: 24 · 2018: 13 · 2017: 19 · 2016: 32 · 2015: 40 · 2014: 59 · 2013: 58 · 2012: 25
- FWCI
- 28.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- KRAS G13D mutation, metastatic colorectal cancer, cetuximab, first-line chemotherapy, progression-free survival, KRAS G12V mutation, tumor response, CRYSTAL trial, OPUS trial
- MeSH terms
- Cetuximab, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Female, Follow-Up Studies, Humans, Male, Middle Aged, Mutation, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Staging, Proto-Oncogene Proteins, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Multivariate Analysis, Likelihood Functions, Proportional Hazards Models, Survival Analysis, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Risk Assessment, Disease-Free Survival, ras Proteins, Young Adult, Antibodies, Monoclonal, Humanized
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