RT Journal Article
SR Electronic
T1 Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K <em>BRAF</em>-Mutant Melanoma
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 1272
OP 1279
DO 10.1158/1078-0432.CCR-18-1680
VO 25
IS 4
A1 Pires da Silva, Inês
A1 Wang, Kevin Y.X.
A1 Wilmott, James S.
A1 Holst, Jeff
A1 Carlino, Matteo S.
A1 Park, John J.
A1 Quek, Camelia
A1 Wongchenko, Matthew
A1 Yan, Yibing
A1 Mann, Graham
A1 Johnson, Douglas B.
A1 McQuade, Jennifer L.
A1 Rai, Rajat
A1 Kefford, Richard F.
A1 Rizos, Helen
A1 Scolyer, Richard A.
A1 Yang, Jean Y.H.
A1 Long, Georgina V.
A1 Menzies, Alexander M.
YR 2019
UL http://clincancerres.aacrjournals.org/content/25/4/1272.abstract
AB Purpose: BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFi±MEKi. We investigated mechanisms for this and explored whether genotype affects response to immunotherapy.Experimental Design: Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with BRAFi±MEKi underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti–PD-1 immunotherapy was examined.Results: Baseline tissue and clinical outcome with BRAFi±MEKi were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, −31% vs. −52%, P = 0.154) and shorter progression-free survival (PFS; median, 5.7 vs. 7.1 months, P = 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in PIK3R1 and tumor-suppressor genes. In patients treated with anti–PD-1, V600K (n = 19) had superior outcomes than V600E (n = 84), including response rate (53% vs. 29%, P = 0.059), PFS (median, 19 vs. 2.7 months, P = 0.049), and overall survival (20.4 vs. 11.7 months, P = 0.081).Conclusions: BRAF V600K melanomas appear to benefit less from BRAFi±MEKi than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.