ONCAlert | 2017 San Antonio Breast Cancer Symposium
Melanoma Case Studies

Boris C. Bastian, MD, PhD: Frequency of Missed BRAF Alterations in Melanoma

Boris C. Bastian, MD, PhD
Published Online:Aug 03, 2016
Michelle is a 55-year old who was referred by her primary care physician to receive a biopsy for a suspicious mole during a routine visit. Results of the biopsy and other subsequent tests revealed that she had an M1b stage tumor (lung metastasis and a less than ULN LDH level). Her ECOG PS is 0.

Metastatic Melanoma with Adil Daud, MD and Boris C. Bastian, MD, PhD



How frequently are BRAF alterations missed that are subsequently picked up using a different test?

First of all, there are different types of BRAF alterations that can cause melanoma. So there are mutations. Most of them occur in exon 15 of BRAF. The most frequently mutated codon is 600 and the most frequent prevalent mutation is a V600E. That can actually rise through two types of nucleotide changes, a single and a dinucleotide change, and those account for about 70% of all V600 mutations. So there are additional substitutions. V600K is the most frequent but there are even others that are clearly pathogenic and cause melanoma. Then there are mutations in the immediate vicinity of V600, 601, and 597.

On top of these mutations that can activate BRAF, there are genetic rearrangements of the BRAF gene where there are actually no mutations but the BRAF kinase domain is put behind some other gene. Depending on which BRAF alteration one would like to pick up, one has to pick the right tests. The current FDA-approved tests, like the cobas and the bioMérieux test, really are very distinctly focusing on V600. The cobas test has low sensitivity for non-V600E mutations and the V600E mutations that are caused by dinucleotide mutations. In the literature, the sensitivity for picking up mutations of V600 are about 80%. If the test is actually negative and there is clearly a rationale for using another test, you can really make sure that there is no actionable BRAF mutation.

The bioMérieux test is more sensitive in terms of better detecting V600K but it will also miss any of the other mutations, and specifically none of these tests will detect any of the structural rearrangements of BRAF fusions. In my view, particularly if the result is negative, it’s important to consider those technical limitations of the assay and consider other tests to really confirm that the patient is negative.

The probability that a melanoma is driven by a BRAF mutation is actually highly dependent on where the melanoma arose on the body. The cutaneous melanomas that arise on sun-exposed skin, particularly in younger individuals, younger than 55, have a very high probability of having BRAF V600E mutations. About 60% of those patients have these mutations. The probability is zero if the melanoma originated in the interior of the eye. In this case having a negative test result would not cause concern and I think the test shouldn’t even be ordered for patients with uveal melanoma. And so the site of origin determines the pretest probability and how concerned one should be about a negative result.

CASE: Metastatic Melanoma

Michelle is a 55-year old who was referred by her primary care physician to receive a biopsy for a suspicious mole during a routine visit. Results of the biopsy and other subsequent tests revealed that she had an M1b stage tumor (lung metastasis and a less than ULN LDH level). Her ECOG PS is 0.

  • Initial BRAF testing using a laboratory-developed test was negative for BRAF V600E L
  •  She was referred from the community setting to a tertiary center, at which point a second test was conducted using the bioMérieux HxID-BRAF kit. This assay was positive for the BRAF V600K mutation
  • Following the finding of BRAF-positivity, Michelle was prescribed the combination of dabrafenib (150 mg BID) and trametinib (1 mg daily)
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