Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis

Pietrantonio, Filippo; Petrelli, Fausto; Coinu, Andrea; Bartolomeo, Maria Di; Borgonovo, Karen; Maggi, Claudia; Cabiddu, Mary; Iacovelli, Roberto; Bossi, Ilaria; Lonati, Veronica; Ghilardi, Mara; Braud, Filippo de; Barni, Sandro

doi:10.1016/j.ejca.2015.01.054

Cited by 456 publications

(315 citation statements)

References 42 publications

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“…Gleichzeitige Mutationen von RAS-und BRAF-Genen sind sehr selten (0,001 %) und werden daher als sich gegenseitig ausschließend betrachtet [1057]. Weit überwiegend handelt es sich um BRAF-V600-Mutationen, die mit einer sehr schlechten Prognose assoziiert sind [1055].…”

Section: Braf-mutationunclassified

“…Molekularpathologisch stehen Mikrosatelliteninstabilität und ein "Methylator Phänotyp" im Vordergrund [1055,1118]. Die Prognose der Patienten mit BRAF-V600-Mutation ist außerordentlich schlecht, sodass in zahlreichen Studien mediane PFS-Zeiten von weniger als 6 Monaten und mediane Überlebenszeiten von weniger als einem Jahr berichtet werden [1057].…”

Section: Level Of Evidenceunclassified

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S3-Leitlinie – Kolorektales Karzinom

Schmiegel

Buchberger

Follmann³

et al. 2017

Z Gastroenterol

151

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Section: Braf-mutationunclassified

Section: Level Of Evidenceunclassified

S3-Leitlinie – Kolorektales Karzinom

Schmiegel

Buchberger

Follmann³

et al. 2017

Z Gastroenterol

151

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“…Some authors and guidelines recommend avoiding anti-EGFR therapies in BRAF V600E-positive patients, although clinical evidence for definitive statements are insufficient (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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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“…In contrast, BRAF-V600E mutations also occur in colorectal cancer but BRAF-targeted therapies are not clinically effective (discussed later in this review in the context of extrinsic resistance; refs. 20,21). Identification of sensitizing on-target mutations can stratify patient populations and accelerate clinical trials.…”

Section: Intrinsic Mechanisms Of Drug Response and Resistancementioning

confidence: 99%

“…As mentioned above, targeting the BRAF-V600E mutation in colorectal cancer is ineffective as a single agent because of bypass signaling through EGFR (innate resistance; refs. 20,21). Effective therapies are emerging that combine BRAF-, MEK-, and EGFR-directed drugs.…”

Section: Extrinsic Mechanisms Of Drug Response and Resistancementioning

confidence: 99%

Durability of Kinase-Directed Therapies—A Network Perspective on Response and Resistance

Murray

Miller

2015

Molecular Cancer Therapeutics

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Protein kinase-directed cancer therapies yield impressive initial clinical responses, but the benefits are typically transient. Enhancing the durability of clinical response is dependent upon patient selection, using drugs with more effective pharmacology, anticipating mechanisms of drug resistance, and applying concerted drug combinations. Achieving these tenets requires an understanding of the targeted kinase's role in signaling networks, how the network responds to drug perturbation, and patient-topatient network variations. Protein kinases create sophisticated, malleable signaling networks with fidelity coded into the processes that regulate their presence and function. Robust and reliable signaling is facilitated through network processes (e.g., feedback regulation, and compensatory signaling). The routine use of kinase-directed therapies and advancements in both genomic analysis and tumor cell biology are illuminating the complexity of tumor network biology and its capacity to respond to perturbations. Drug efficacy is attenuated by alterations of the drug target (e.g., steric interference, compensatory activity, and conformational changes), compensatory signaling (bypass mechanisms and phenotype switching), and engagement of other oncogenic capabilities (polygenic disease). Factors influencing anticancer drug response and resistance are examined to define the behavior of kinases in network signaling, mechanisms of drug resistance, drug combinations necessary for durable clinical responses, and strategies to identify mechanisms of drug resistance.

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Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: A meta-analysis

Cited by 456 publications

References 42 publications

S3-Leitlinie – Kolorektales Karzinom

S3-Leitlinie – Kolorektales Karzinom

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

Durability of Kinase-Directed Therapies—A Network Perspective on Response and Resistance

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