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Molecular Profiles Count in Therapeutic Choices for BRAF-Mutant Melanoma

By: Celeste L. Dixon
Posted: Wednesday, February 6, 2019

The results of investigations into whether and why BRAF V600E and V600K melanomas differ in their responses to BRAF and MEK inhibition were published in Clinical Cancer Research, adding to work demonstrating that BRAF V600K–mutant tumors are less responsive. Alexander M. Menzies, MD, PhD, of Melanoma Institute Australia, Sydney, New South Wales, and colleagues found that patients with BRAF V600K mutations (n = 15), versus those with BRAF V600E mutations (n = 78), had shorter progression-free survival (median, 5.7 vs. 7.1 months; P = .15) and a lower median tumor regression (−31% vs. −52%; P = .154).

The investigators also examined a second, independent cohort of patients with BRAF V600E/K mutations who received anti–PD-1 immunotherapy. Those with BRAF V600K mutations (n = 19) had better outcomes than those with BRAF V600E mutations (n = 84), in terms of response rate (53% vs. 29%; P = .059), median progression-free survival (19 vs. 2.7 months; P = .049), and overall survival (20.4 vs. 11.7 months; P = .081).

The poorer responses of melanomas with BRAF V600K mutations to BRAF and MEK inhibition, versus melanomas with BRAF V600E mutations, are “potentially due to less reliance on ERK pathway activation and greater use of alternative pathways,” wrote Dr. Menzies and his team. “V600K [mutant] melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6” and higher expression of PI3K-AKT genes.

In contrast, the better responses of melanomas with BRAF V600K mutations to anti–PD-1 immunotherapy could be related to their higher mutational load, including a higher proportion of mutations in PIK3R1 and tumor-suppressor genes. The study’s translational data regarding both BRAF and MEK inhibition and immunotherapy, wrote the authors, “provide further rationale for the selection of one therapy over the other.”

Disclosure: The study authors’ disclosure information may be found at aacrjournals.org.



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