ONCAlert | 2017 San Antonio Breast Cancer Symposium
Melanoma Case Studies

Boris C. Bastian, MD, PhD: Mutations To Test For 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



What types of mutations are patients with melanoma generally tested for? Is there a role for testing for other genes, such as NRAS, and how might that impact assay selection?

The subtype of melanoma, which is mostly predetermined by the site of origin, drives those considerations. Other genes include NRAS. NRAS, they’re mutations primarily at codon 61 and 12, 13, and those are clearly pathogenic mutations that account for maybe a quarter of all melanomas. There is no current agent to directly treat those, but there are multiple clinical trials pursuing various therapeutic options downstream of mutant NRAS.

Then there are genes in similar categories like GNAQ, GNA11 mutations in uveal melanoma—melanoma arising inside of the eye. Those also are not actionable in the strict sense, they are similar to NRAS in that they are not targetable directly, but there are various clinical trials that evaluate therapeutic targets downstream of those oncoproteins.

Then there are mutations in KIT, activating mutations in a subset of melanoma as they’re more common in melanomas that originate from acral sites or the non-hair-bearing skin of the palms and soles, nail apparatus, mucosal membranes. A small proportion of melanomas originating from chronically sun-damaged skin has KIT mutations. There are multiple clinical trials that show that KIT inhibitors have a positive effect on patients with melanomas that have KIT mutations.

Then there are these gene fusions. I mentioned that BRAF is one of those, but there are also fusions in other kinases, such as ALK, ROS1, NTRK1, and those are therapeutic targets that are on the horizon. Their frequency is difficult to estimate at this point in time because there are no really standardized assays so that one could actually get a firm sense of how common these are. But, if after testing for these main drivers in melanomas, one still doesn’t find a driving mutation, one should be aware of the possibility that there may be a fusion underlying this process as a driver.

One gene that I forgot to mention that is frequently mutated, in particular in melanomas arising on chronically sun-exposed skin is NF1. These are loss of function mutations, difficult to test for because it’s a very large gene. This is definitely currently out of range of these more focused testing approaches.

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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