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Intricacies of BRAF Testing in Advanced Melanoma

Sigrid Eckardt
Published Online: May 21,2016
metastatic melanoma

Keith T. Flaherty, MD

About half of all melanomas contain somatic mutations that result in constitutive activation of the BRAF kinase, leading to hyperactive signaling of the growth-promoting mitogen-activated protein kinase (MAPK) pathway. Systemic therapies with selective small-molecule inhibitors of the BRAF kinase, both in monotherapy and in combination with inhibitors of the MEK kinase, can extend survival and reduce recurrence risk in patients with BRAF-mutant tumors.1 BRAF mutation testing has therefore become an essential tool in the diagnostic workup and management of patients with advanced melanoma. 

According to Keith T. Flaherty, MD, with the Massachusetts General Hospital Cancer Center in Boston, “At the moment, the only molecular feature in melanoma that is critical to treatment decision making is the presence or absence of a V600 BRAF mutation.”  Activating mutations of BRAF are present in 40% to 60% of all melanoma cases, with more than 90% of mutations found at codon 600 in exon 15. The activating V600E amino acid substitution is by far the most common V600 mutation and accounts for 74% to 95% of these mutations, followed by V600K in 5% to 30%, V600R in 5% to 7%, and V600M in about 4%.2,3 More rare mutations include V600D and mutations in other codons with activating, impairing, or unknown effects on kinase activity.3,4 

TABLE. BRAF Mutations in Melanoma

Mutation Frequency FDA-Approved Tests





70% to 90%

cobas test BRAFV600D & THxID BRAF Kit





7% to 20%



1% to 3%



3% to 7%


Activity of Selective BRAF Inhibitors Beyond BRAF V600E Mutations 

Clinical evidence for the activity selective BRAF inhibitors derives from trials that were largely restricted to patients with V600E- and V600K-mutant tumors, as concurrently developed BRAF mutation testing assays were optimized for the detection of these two most common mutations. 

Prospective testing of the BRAF inhibitors vemurafenib and dabrafenib as single agents in phase III trials was conducted among patients with V600E-positive metastatic melanoma, demonstrating response rates in the range of 50%, clinical benefit rates close to 90%, and prolongation of progression-free survival (PFS) and overall survival (OS) compared with dacarbazine.5,6 

Similarly, phase III studies with combination regimens of dabrafenib and trametinib or vemurafenib with cobimetinib revealed significant PFS and OS benefits with dual BRAF/MEK inhibition over single agent BRAF inhibitors. Patients with V600E- or V600K-mutant melanoma represented the majority of the study population.7-9 

Indications for these agents based on phase III trial data therefore incorporate the presence of specific mutations: Combination dabrafenib/trametinib and vemurafenib/cobimetinib therapies and single agent trametinib are indicated for the treatment of patients with V600E or V600K mutations, whereas approved use of single-agent vemurafenib or dabrafenib is limited to the treatment of patients with V600E mutant melanoma. 

This rationale is supported by findings that BRAF mutation type can affect response to treatment with selective BRAF inhibitors. Phase II study findings have shown that although dabrafenib is active in patients with V600K-mutant tumors, ORR and PFS in this subgroup were lower than in patients with V600E-mutant tumors.10,11 However, evidence also exists that patients with less common BRAF mutations not represented in phase III trials can benefit from BRAF inhibitor therapy.2,12,13 

In a cohort study including patients with BRAF V600R mutations (n = 9), objective responses to monotherapy with selective BRAF inhibitors (dabrafenib or vemurafenib) were seen in 5 of 6 patients evaluable for response assessment. The V600R mutation is common in males and those with ulcerated primary melanomas. Similar to V600K melanoma, V600R is more frequently observed in older individuals.2 

According to study author Oliver Klein, MD, with Westmead Hospital, Sydney, Australia, and co-authors, these partial responses occurred rapidly and included “a reduction in the size of lung metastases, liver metastases, stabilization of brain metastases, and a marked reduction in subcutaneous metastases to the scalp. The rapid clinical responses of patients with V600R BRAF mutation-positive melanoma mirror those observed in patients with V600E and V600K mutations, indicating that selective BRAF inhibitors are active against melanoma with this genotype.”

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Intricacies of BRAF Testing in Advanced Melanoma
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