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Case Report/Case Series |

Identification of a Novel Complex BRAF Mutation Associated With Major Clinical Response to Vemurafenib in a Patient With Metastatic Melanoma

Benoit Busser, PharmD, PhD1; Marie Therese Leccia, MD, PhD1; Guillaume Gras-Combe, MD2; Ivan Bricault, MD, PhD3; Isabelle Templier, MD4; Antoine Claeys, MD4; Marie Jeanne Richard, PharmD, PhD5; Florence de Fraipont, PharmD, PhD5; Julie Charles, MD, PhD1
[+] Author Affiliations
1Institut Albert Bonniot INSERM/UJF U823, Grenoble, France
2Department of Neurosurgery, CHRU Grenoble University Hospital, Grenoble, France
3Department of Medical Imaging, CHRU Grenoble University Hospital, Grenoble, France
4Department of Dermatology, CHRU Grenoble University Hospital, Grenoble, France
5Department of Cancer Clinical Chemistry, CHRU Grenoble University Hospital, Grenoble, France
JAMA Dermatol. 2013;149(12):1403-1406. doi:10.1001/jamadermatol.2013.8198.
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Importance  There is an increasing interest in BRAF V600 mutations in melanomas and their associated sensitivity to vemurafenib, a BRAF inhibitor. However, physicians cannot find information in the literature about vemurafenib response for rare and/or atypical BRAF mutations.

Observations  We describe the identification of a novel complex BRAF mutation associated with major clinical response to vemurafenib in a patient with metastatic melanoma. Using a pyrosequencing method, we determined that the tumor positive for mutated BRAF, uncovering a novel c.1799_1803delinsAT; p.V600-K601>D variant. We uncovered this atypical BRAF mutation with 2 different sequencing methods, both in the primary lesion and in 1 metastasis. The patient was immediately treated with vemurafenib as monotherapy and achieved a prolonged (5.5-month) positive response.

Conclusions and Relevance  We analyzed the consequences of the BRAF V600-K601>D mutation in terms of amino acids. We referred to the published data and databases to screen chemical properties of well-known BRAF V600 mutations and other complex BRAF mutations to find common features of activated BRAF mutations. Importantly, we highlighted that both the site of the mutation and the involved amino acids are important to predict vemurafenib response. Our conclusion is that complex BRAF mutation surrounding codon 600 could also be sensitive to BRAF inhibitors.

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Figure 1.
BRAF Pyrograms After Reverse-Strand Pyrosequencing

The pyrograms correspond to the reference BRAF wild type (WT), BRAF V600E mutation, and the novel BRAF V600-K601>D mutation. Black arrowheads and open arrowheads indicate lower base incorporation and new/higher base incorporation, respectively, compared with the expected ratio.

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Figure 2.
BRAF Electropherograms After Sanger Sequencing

Both the wild type (WT) and the novel V600-K601>D mutant DNA were sequenced on the reverse strand. The corresponding amino acids, number of codons, and forward sequences are indicated in the boxes. Ala indicates, alanine; Asp, aspartate; Leu, leucine; Lys, lysine; Ser, serine; Thr, threonine.

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Figure 3.
Computed Tomographic (CT) Scans of the Patient Showing the Positive Response After 3 Months of Vemurafenib Treatment

Axillary (A) and pectoral (B) lesions (arrowheads) seen on CT scans provide evidence for tumor shrinkage after 3 months of vemurafenib treatment.

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