<i>KRAS</i> and <i>BRAF</i> 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, Michel; Chambers, P; Elliott, Faye; Daly, Catherine; Meade, Angela; Taylor, Graham R.; Barrett, Jennifer; Quirke, Philip

doi:10.1200/jco.2009.22.4295

Cited by 516 publications

(419 citation statements)

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“…RAS mutations represent the only, molecular, predictive biomarker approved for clinical use, while their prognostic role is still debated. Several randomized studies have shown no significant survival differences between KRAS mutated and KRAS wild-type, CRC patients, independently of anti-EGFR therapy (Price et al, 2011;Hecht et al, 2009;Kastrinakis et al, 1995;Russo et al, 1998;Tol et al, 2010), while others have demonstrated a prognostic role of KRAS in advanced disease (Richman et al, 2009;Maughan et al, 2011;Tejpar et al, 2012). BRAF mutations have been described in about 10% of primary CRC, representing a well-known negative prognostic factor, associated with worse survival outcomes, regardless of any treatment received (Ahn et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

Passiglia

Bronte

Bazan

et al. 2016

Critical Reviews in Oncology/Hematology

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Background: Clinical trials investigated the potential role of both KRAS and BRAF mutations, as prognostic biomarkers, in colorectal cancer (CRC) patients who underwent surgical treatment of CRC-related liver metastases (CLM), showing conflicting results. This meta-analysis aims to review all the studies reporting survival outcomes (recurrence free survival (RFS), and/or overall survival (OS)) of patients undergoing resection of CLM, stratified according to KRAS and/or BRAF mutation status. Materials and methods: Data from all published studies reporting survival outcomes (RFS and/or OS) of CRC patients who received resection of CLM, stratified by KRAS and/or BRAF mutation status were collected, according to the PRISMA guidelines. Pooled HRs were calculated for both the OS and/or RFS. Results: Seven eligible trials (1403 patients) were included. Pooled analysis showed that KRAS mutations predicted a significantly worse both RFS (HR: 1.65; 95% CI: 1.23-2.21) and OS (HR: 1.86; 95% CI: 1.51-2.30) in patients who underwent surgical resection of CLM. BRAF mutations were also associated with a significantly worse OS (HR: 3.90; 95% CI: 1.96-7.73) in this subgroup of patients. Conclusions: This meta-analysis suggests both KRAS and BRAF mutations as poor, prognostic biomarkers, associated with worse survival outcomes, in patients undergoing hepatic resection of CLM

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Section: Introductionmentioning

confidence: 99%

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

Passiglia

Bronte

Bazan

et al. 2016

Critical Reviews in Oncology/Hematology

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“…7,10,11 The overwhelming majority of KRAS mutations (90%) occur in codons 12 and 13 of exon 2, with the most frequent alteration being a G4A transition in codon 12. 12 The clinical significance of KRAS mutation in colorectal carcinoma patients is controversial; some studies reported no association with survival, 13,14 whereas others suggested that patients with KRASmutated colorectal carcinoma have poorer outcome for any mutation subtype, 15 mutation in codon 12 only 16,17 or codon 13 only. 11 There is more definitive evidence for a negative predictive value of KRAS mutation in patients with advanced stage disease treated with targeted anti-EGFR monoclonal antibody drugs.…”

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confidence: 99%

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

et al. 2013

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KRAS-mutated carcinomas comprise 35-40% of all colorectal carcinomas but little is known about their characteristics. The aim of this study was to examine the pathological and molecular features of KRAS-mutated colorectal carcinomas and to compare them with other carcinoma subgroups. KRAS mutation testing was performed in 776 incident tumors from the Melbourne Collaborative Cohort Study. O 6 -methylguanine DNA methyltransferase (MGMT) status was assessed using both immunohistochemistry and MethyLight techniques. Microsatellite instability (MSI) phenotype and BRAF V600E mutation status were derived from earlier studies. Mutation in KRAS codon 12 or codon 13 was present in 28% of colorectal carcinomas. Compared with KRAS wildtype carcinomas, KRAS-mutated carcinomas were more frequently observed in contiguity with a residual polyp (38 vs 21%; Po0.001), demonstrated mucinous differentiation (46 vs 31%; P ¼ 0.001) and were associated with different MSI status (Po0.001) and with MGMT methylation (47 vs 21%; P ¼ 0.001). Compared with tumors demonstrating neither BRAF nor KRAS mutation, KRAS-mutated carcinomas showed more frequent location in the proximal colon (41 vs 27%; P ¼ 0.001), mucinous differentiation (46 vs 25%; Po0.001), presence of a contiguous polyp (38 vs 22%; Po0.001), MGMT methylation (47 vs 26%; P ¼ 0.01) and loss of MGMT immunohistochemical expression (27 vs 19%; P ¼ 0.02). KRAS-mutated carcinomas were distributed in a bimodal pattern along the proximal-distal axis of the colorectum. Compared with male subjects, female subjects were more likely to have KRAS-mutated carcinoma in the transverse colon and descending colon (39 vs 15%; P ¼ 0.02). No difference in overall survival was observed in patients according to their tumor KRAS mutation status. In summary, KRAS-mutated carcinomas frequently develop in contiguity with a residual polyp and show molecular features distinct from other colorectal carcinomas, in particular from tumors with neither BRAF nor KRAS mutation.

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“…In CRC, the incidence of KRAS mutations has been reported to be 40% and that of BRAF mutations 5%-10% (Bokemeyer et al, 2009;Richman et al, 2009). However, these data were mainly derived from studies of patient populations in Western countries.…”

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confidence: 99%

Gene Mutations in Epidermal Growth Factor Receptor Signaling Network and Their Association With Survival in Chinese Patients With Metastatic Colorectal Cancers

Liao

Zhou³

et al. 2010

The Anatomical Record

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Mutations of the KRAS, BRAF, and PIK3CA genes have been reported in colorectal cancer (CRC), associated with resistance to epidermal growth factor receptor (EGFR)-targeted monoclonal antibody therapy. These reports have mainly emanated from Western countries, however, and little is known about the mutation frequencies of these genes and their prognostic value in Asian patients with CRC. In this study, we analyzed the mutation frequencies of these three genes together with EGFR, and their association with overall survival in 61 Chinese patients with metastatic CRC (mCRC). Gene mutations were examined using pyrosequencing. Kaplan-Meier survival analysis and multivariate Cox proportional hazard analysis were used to assess the prognostic significance of mutations of these four genes for patients' survival. We found that the mutations of KRAS, BRAF, PIK3CA, and EGFR were present in 12 (19.7%), 3 (4.9%), 3 (4.9%), and 0 patients, respectively. Kaplan-Meier survival analysis showed that none of these gene mutations correlated significantly with patients' overall survival. Multivariate Cox proportional hazard analysis showed only treatment regimens and age to be independent prognostic factors. Our findings indicate that EGFR signaling network genes are frequently mutated in Chinese mCRC patients, and these gene mutations do not seem to be associated with patients' overall survival. Anat Rec, 293:1506Rec, 293: -1511

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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

Abstract: 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.

Cited by 516 publications

References 38 publications

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features

Gene Mutations in Epidermal Growth Factor Receptor Signaling Network and Their Association With Survival in Chinese Patients With Metastatic Colorectal Cancers

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