Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab

Tol, Jolien; Dijkstra, Jeroen R.; Klomp, Marjolein; Teerenstra, Steven; Dommerholt, Martin; Vink-Börger, M. Elisa; Cleef, P.H. van; Krieken, J. Han van; Punt, Cornelis J.A.; Nagtegaal, Irıs D.

doi:10.1016/j.ejca.2010.03.036

Cited by 186 publications

(155 citation statements)

References 40 publications

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“…This variability in the series can be partly explained by the fact that BRAF mutations are associated with poor clinical features and worse OS in mCRC patients (30,31), limiting the inclusion of BRAF-mutated tumors in series of chemorefractory advanced patients treated beyond the first line setting. As a negative prognostic marker, BRAF mutations can act as a confounding variable when assessing their predictive value in the first line setting of advanced disease (32)(33)(34). In our series, we detected a BRAF mutation in five patients by both techniques (5%).…”

Section: Discussionmentioning

confidence: 71%

Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies

Azuara

Santos

López-Dóriga

et al. 2016

Molecular Cancer Therapeutics

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The clinical significance of low-frequent RAS pathwaymutated alleles and the optimal sensitivity cutoff value in the prediction of response to anti-EGFR therapy in metastatic colorectal cancer (mCRC) patients remains controversial. We aimed to evaluate the added value of genotyping an extended RAS panel using a robust nanofluidic digital PCR (dPCR) approach. A panel of 34 hotspots, including RAS (KRAS and NRAS exons 2/3/4) and BRAF (V600E), was analyzed in tumor FFPE samples from 102 mCRC patients treated with anti-EGFR therapy. dPCR was compared with conventional quantitative PCR (qPCR). Response rates, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutated allele fraction. Tumor response evaluations were not available in 9 patients and were excluded for response rate analysis. Twenty-two percent of patients were positive for one mutation with qPCR (mutated alleles ranged from 2.1% to 66.6%). Analysis by dPCR increased the number of positive patients to 47%. Mutated alleles for patients only detected by dPCR ranged from 0.04% to 10.8%. An inverse correlation between the fraction of mutated alleles and radiologic response was observed. ROC analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value for all combinations of RAS and BRAF analysis. In addition, this threshold also optimized prediction both PFS and OS. We conclude that mutation testing using an extended gene panel, including RAS and BRAF with a threshold of 1% improved prediction of response to anti-EGFR therapy.

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Section: Discussionmentioning

confidence: 71%

Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies

Azuara

Santos

López-Dóriga

et al. 2016

Molecular Cancer Therapeutics

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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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“…With an estimated prevalence of 8 % in mCRC tumours [4,7,[13][14][15], BRAF mutations are approximately 7-fold less prevalent in mCRC than malignant melanoma. In this case, the clinical utility of the assay is noticeably altered; the PPV can be calculated to be 41.4 % and the NPV 99.9 % for the same assay used for a different condition.…”

Section: Relevance Of Predictive Values In a Diagnostic Settingmentioning

confidence: 99%

Predictive Values for Molecular Diagnostics: Converting Unknown Unknowns to Known Unknowns

et al. 2013

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Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab

Cited by 186 publications

References 40 publications

Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies

Nanofluidic Digital PCR and Extended Genotyping of RAS and BRAF for Improved Selection of Metastatic Colorectal Cancer Patients for Anti-EGFR Therapies

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

Predictive Values for Molecular Diagnostics: Converting Unknown Unknowns to Known Unknowns

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