Two Case Reports of Rare BRAF Mutations in Exon 11 and Exon 15 with Discussion of Potential Treatment Options

Richtig, Georg; Aigelsreiter, Ariane; Kashofer, Karl; Talakić, Emina; Kupsa, Romana; Schaider, Helmut; Richtig, Erika

doi:10.1159/000449125

Cited by 14 publications

(19 citation statements)

References 13 publications

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“…Interestingly, in vitro sensitivity of class 2 and 3 BRAF mutations to MEK and BRAF inhibition has been proven in melanoma, and a small number of patients with these mutations showed responses to treatment with MEK inhibitors (28)(29)(30)(31). The largest cohort of patients was collected by Boweyer and colleagues describing the antitumor activity of trametinib in 5 patients bearing the rare class 2 or class 3 BRAF mutations (32).…”

Section: Discussionmentioning

confidence: 99%

Class 1, 2, and 3BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization

Schirripa

Biason

Lonardi

et al. 2019

Clinical Cancer Research

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Purpose: BRAF mutations are grouped in activating RASindependent signaling as monomers (class 1-V600E) or as dimers (class 2-codons 597/601), and RAS-dependent with impaired kinase activity (class 3-codons 594/596). Although clinical, pathologic, and molecular features of V600E BRAFmutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes. Experimental Design: Data from 117 patients with BRAF (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected. A total of 540 BRAF wt mCRCs were included as control. IHC profiling was performed to determine the consensus molecular subtypes (CMS), cytokeratin 7/20 profiles, tumor-infiltrating lymphocyte infiltration, and BM1/BM2 categorization. Overall survival (OS) and progression-free survival were evaluated by Kaplan-Meier and log-rank test. Results: Class 3 BRAF-mutated mCRC was more frequently left sided (P ¼ 0.0028), pN0 (P ¼ 0.0159), and without peritoneal metastases (P ¼ 0.0176) compared with class 1, whereas class 2 cases were similar to class 1. Hazard ratio for OS, as compared with BRAF wt, was 2.38 [95% confidence interval (CI), 1.61-3.54] for class 1, 1.90 (95% CI, 0.85-4.26) for class 2, and 0.93 (95% CI, 0.51-1.69) for class 3 (P < 0.0001). Class 2 and 3 tumors were all assigned to CMS2-3. A higher median CD3/CD8-positive lymphocyte infiltration was observed in BRAF-mutated class 2 (P ¼ 0.033) compared with class 3 cases. Conclusions: For the first time, different clinical and pathologic features and outcome data were reported according to the three BRAF mutation classes in mCRC. Specific targeted treatment strategies should be identified in the near future for such patients.

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Section: Discussionmentioning

confidence: 99%

Class 1, 2, and 3BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization

Schirripa

Biason

Lonardi

et al. 2019

Clinical Cancer Research

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“…The major drawback of the clinical management of this patient is a failure to arrange the experimental use of MEK inhibitors. Several melanoma patients with BRAF K601E substitution are described in the literature, and some of them benefited from MEK-targeted drugs [6, 7, 8, 9]. Furthermore, a recent report, which was released after the treatment failure in this patient, demonstrated potential utility of combined use of dabrafenib and trametinib for the management of BRAF K601E mutated melanoma both in vitro and in a single clinical case [10].…”

Section: Discussionmentioning

confidence: 99%

Lack of Response to Vemurafenib in Melanoma Carrying BRAF K601E Mutation

Moiseyenko¹,

Egorenkov²,

Kramchaninov³

et al. 2019

Case Rep Oncol

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Vemurafenib has been developed to target common BRAF mutation V600E. It also exerts activity towards some but not all rare BRAF substitutions. Proper cataloguing of drug-sensitive and -insensitive rare mutations remains a challenge, due to low occurrence of these events and inability of commercial PCR-based diagnostic kits to detect the full spectrum of BRAF gene lesions. We considered the results of BRAF exon 15 testing in 1872 consecutive melanoma patients. BRAF mutation was identified in 1,090 (58.2%) cases. While drug-sensitive codon 600 substitutions constituted the majority of BRAF gene lesions (V600E: 962 [51.4%]; V600K: 86 [4.6%]; V600R: 17 [0.9%]), the fourth common BRAF allele was K601E accounting for 9 (0.5%) melanoma cases. The data on BRAF inhibitor sensitivity of tumors with K601E substitution are scarce. We administered single-agent vemurafenib to a melanoma patient carrying BRAF K601E mutation as the first-line treatment. Unfortunately, this therapy did not result in a tumor response. Taken together with already published data, this report indicates lack of benefit from conventional BRAF inhibitors in patients with BRAF K601E mutated melanoma.

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“…We postulated that BRAF inhibition and/or MEK inhibition would not be beneficial for patients with such mutations because the BRAF G466E mutation is kinase‐dead (Fig. d) . Indeed, Girotti et al .…”

Section: Dead‐kinase‐/low‐activity‐kinase Braf Mutationsmentioning

confidence: 96%

Beyond the BRAF ^V ^600E hotspot: biology and clinical implications of rare BRAF gene mutations in melanoma patients

et al. 2017

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BRAF gene mutations can be found in approximately 50% of melanomas, but the most common BRAF mutation leads to substitution at residue 600 of the protein, from valine to glutamic acid. BRAF occurs in up to 95% of all melanoma cases and can be successfully blocked by using a combination of BRAF- and MEK inhibitors. The wider availability of next-generation sequencing is revealing more non-V600 BRAF mutations, and the clinical implications of these mutations are widely unknown. In this review, we will discuss the biology of the MAPK pathway and the different types of BRAF mutations as well as their effect on MEK activation. Current literature will be reviewed including in vitro data, case reports and case series.

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Two Case Reports of Rare BRAF Mutations in Exon 11 and Exon 15 with Discussion of Potential Treatment Options

Cited by 14 publications

References 13 publications

Class 1, 2, and 3BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization

Class 1, 2, and 3BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization

Lack of Response to Vemurafenib in Melanoma Carrying BRAF K601E Mutation

Beyond the BRAF ^V ^600E hotspot: biology and clinical implications of rare BRAF gene mutations in melanoma patients

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Two Case Reports of Rare BRAF Mutations in Exon 11 and Exon 15 with Discussion of Potential Treatment Options

Cited by 14 publications

References 13 publications

Class 1, 2, and 3BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization

Class 1, 2, and 3BRAF-Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization

Lack of Response to Vemurafenib in Melanoma Carrying BRAF K601E Mutation

Beyond the BRAF V 600E hotspot: biology and clinical implications of rare BRAF gene mutations in melanoma patients

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Beyond the BRAF ^V ^600E hotspot: biology and clinical implications of rare BRAF gene mutations in melanoma patients