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Melanoma BRAF Mutation Type May Affect Response to Targeted Treatments, Immunotherapy

NEW YORK (GenomeWeb) – Melanomas with different types of BRAF alterations appear to differ in their response to two treatment approaches, according to a new analysis appearing in Clinical Cancer Research today.

About 40 percent of cutaneous melanomas harbor a mutation affecting the BRAF gene. Typically, they carry a V600E mutations, but about 20 to 30 percent have V600K alterations. Tumors with V600E and V600K mutations exhibit different clinical and pathological features, with V600K mutations being more common among older patients. Both types, though, are often treated with targeted drugs or immunotherapies.

A team of Australian researchers has now investigated whether those clinical differences translate to differences in response to treatments. "We wanted to explore the molecular basis for differing clinical phenotypes observed between BRAF V600E and V600K melanomas, whether they have distinct response profiles to targeted treatments and immunotherapy, and the biological rationale for different clinical outcomes," senior author Alexander Menzies from the University of Sydney said in a statement.

Menzies and his colleagues enrolled 93 consecutive metastatic melanoma patients with BRAF mutations who were treated with targeted therapies — BRAF inhibitors with or without MEK inhibitors — into their study. Of those patients, 78 had V600E BRAF mutations and 15 had V600K mutations.

The researchers found that even though more patients with V600K mutations were treated with combined BRAF-MEK inhibitors, they were less likely to respond to the treatment or achieve a complete response. They also had a shorter progression-free survival time of 5.7 months, as compared to 7.1 months for V600E mutation patients, though that difference was not statistically significant.

Using NanoString RNA gene expression analysis, the researchers uncovered expression differences between the patient groups. Patients harboring V600K mutations had lower expression levels of DUSP6, a transcription target of ERK that is also involved in its regulation. BRAF, the researchers noted, typically activates the ERK signaling pathway.

They confirmed this decreased DUSP6 expression using RNA sequencing data from The Cancer Genome Atlas.

Additionally, other ERK pathway genes were also expressed at lower levels in V600K mutation melanomas as compared to V600E mutation melanomas. This indicated to the researchers that V600E melanomas might respond better to BRAF-MEK inhibitors because of their increased activation of the MAPK/ERK signaling cascade.

The researchers also found that while ERK pathway genes were expressed at lower levels in V600K mutation melanomas, PI3K-AKT pathway genes were more highly expressed. As V600K tumors also had a higher mutational load, they hypothesized that this type of tumor might better respond to immunotherapy.

Menzies and colleagues then examined a cohort of 103 melanoma patients with V600E or V600K BRAF mutations who were treated with an anti-PD-1 immunotherapy. After nearly 32 months of follow-up, they found that patients with V600K mutation melanoma had a higher response rate than patients with V600E mutation melanoma, 53 percent compared to 23 percent.

They also noted a longer progression-free survival of a median 19 months among V600K mutation patients as compared to 2.7 months among V600E mutation patients.

This could mean that melanoma patients with differing BRAF mutations could benefit from different types of treatments, the researchers said.

"The clinicopathic differences previously observed in V600E and V600K BRAF­mutant melanoma can now be explained by their biology," Menzies said. "These genotypes should be considered as distinct clinical entities with differing responses to treatments, and they should be managed differently."

The researchers cautioned, though, that their study size was small and had a relatively short follow-up time. They also noted ties to a number of pharmaceutical companies, including MetabloQ Pharmaceuticals, Bristol-Myers Squibb, Roche, Amgen, and others.

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