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

Richman, Susan D.; Seymour, Matthew T.; Chambers, Philip; Elliott, Faye; Daly, Catherine L.; Meade, Angela M.; Taylor, Graham; Barrett, Jennifer H.; Quirke, Philip

doi:10.1200/jco.2009.22.4295

Cited by 560Colorectal Cancer Treatments and StudiesColorectal Cancer Surgical TreatmentsGenetic factors in colorectal cancer

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

Richman, Susan D., Seymour, Matthew T., Chambers, Philip, Elliott, Faye, Daly, Catherine L., Meade, Angela M., Taylor, Graham, Barrett, Jennifer H. +1 more·2009·Journal of Clinical Oncology

DOI 10.1200/jco.2009.22.4295

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Abstract

Purpose: Activating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies. Patients and Methods: The Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry. Results: Three hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012). Conclusion: KRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.

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The 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.”
From The Prognostic Impact of KRAS G12C Mutation in Patients with Metastatic Colorectal Cancer: A Multicenter Retrospective Observational Study (2021) · cites this paper as [15]

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Authors: Richman, S. D., Seymour, M. T., Chambers, P., Elliott, F., Daly, C. L., Meade, A. M., Taylor, G., Barrett, J. H., & Quirke, P.
Affiliations: University of Leeds (GB)
From the Leeds Institute of Molecular Medicine, St. James's Institute of Oncology, Cancer Research UK Genomic Services, University of Leeds, Leeds; and the Medical Research Council Clinical Trials Unit, London, United Kingdom.
ORCID: Richman, Susan D.
Chambers, Philip
Elliott, Faye
Meade, Angela M.
Barrett, Jennifer H.
Quirke, Philip
Venue: Journal of Clinical Oncology
Publisher: American Society of Clinical Oncology (ASCO)
Published: 2009-12-10
Volume: 27
Issue: 35
Pages: 5931-5937
ISSN: 0732-183X (ISSN-L)
1527-7755
DOI: 10.1200/jco.2009.22.4295
OpenAlex: W2135800465
Cited by: 560
References: 41
Citations by year: 2026: 3 · 2025: 9 · 2024: 11 · 2023: 14 · 2022: 23 · 2021: 38 · 2020: 29 · 2019: 38 · 2018: 31 · 2017: 35 · 2016: 34 · 2015: 64 · 2014: 52 · 2013: 58 · 2012: 50
FWCI: 20.01
Type: journal article
Language: en
Open access: closed
Locations: Journal of Clinical Oncology (publishedVersion)
PubMed (publishedVersion)
Funders: Cancer Research UK
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 mutation, BRAF mutation, advanced colorectal cancer, predictive biomarkers, oxaliplatin, irinotecan, 5-fluorouracil, first-line chemotherapy, prognostic factors, MLH1 loss, mismatch repair deficiency, overall survival, progression-free survival, anti-EGFR therapy resistance, treatment sequencing, pyrosequencing
MeSH terms: MutL Protein Homolog 1, Irinotecan, Oxaliplatin, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, DNA Mutational Analysis, Fluorouracil, Humans, Immunohistochemistry, Mutation, Nuclear Proteins, Organoplatinum Compounds, Proto-Oncogene Proteins, Time Factors, Biomarkers, Tumor, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Proportional Hazards Models, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Risk Assessment, Disease-Free Survival, Patient Selection, ras Proteins, Proto-Oncogene Proteins B-raf, Adaptor Proteins, Signal Transducing, Kaplan-Meier Estimate, Microsatellite Instability, Precision Medicine

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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

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