Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma

Inês Pires da Silva, Kevin Y. X. Wang, James S. Wilmott, Jeff Holst, Matteo S. Carlino, John J. Park, Camelia Quek, Matthew Wongchenko, Yibing Yan, Graham Mann, Douglas B. Johnson, Jennifer L. McQuade, Rajat Rai, Richard F. Kefford, Helen Rizos, Richard A. Scolyer, Jean Y. H. Yang, Georgina V. Long, Alexander M. Menzies

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose: BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFiMEKi. 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 ¼ 0.049), and overall survival (20.4 vs. 11.7 months, P = 0.081). Conclusions: BRAF V600K melanomas appear to benefit less from BRAFiMEKi 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.

LanguageEnglish
Pages1272-1279
Number of pages8
JournalClinical Cancer Research
Volume25
Issue number4
DOIs
Publication statusPublished - 15 Feb 2019

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Immunotherapy
Melanoma
MAP Kinase Signaling System
Atlases
Dual Specificity Phosphatase 6
Neoplasms
Genome
Gene Expression Profiling
Tumor Suppressor Genes
Phosphatidylinositol 3-Kinases
DNA Sequence Analysis
Paraffin
Formaldehyde
Disease-Free Survival
Research Design
Genotype
Mutation
Survival
Genes

Cite this

da Silva, I. P., Wang, K. Y. X., Wilmott, J. S., Holst, J., Carlino, M. S., Park, J. J., ... Menzies, A. M. (2019). Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma. Clinical Cancer Research, 25(4), 1272-1279. https://doi.org/10.1158/1078-0432.CCR-18-1680
da Silva, Inês Pires ; Wang, Kevin Y. X. ; Wilmott, James S. ; Holst, Jeff ; Carlino, Matteo S. ; Park, John J. ; Quek, Camelia ; Wongchenko, Matthew ; Yan, Yibing ; Mann, Graham ; Johnson, Douglas B. ; McQuade, Jennifer L. ; Rai, Rajat ; Kefford, Richard F. ; Rizos, Helen ; Scolyer, Richard A. ; Yang, Jean Y. H. ; Long, Georgina V. ; Menzies, Alexander M. / Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 4. pp. 1272-1279.
@article{d884c642edc04642ae1407d1dbac0038,
title = "Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma",
abstract = "Purpose: BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFiMEKi. 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 ¼ 0.049), and overall survival (20.4 vs. 11.7 months, P = 0.081). Conclusions: BRAF V600K melanomas appear to benefit less from BRAFiMEKi 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.",
author = "{da Silva}, {In{\^e}s Pires} and Wang, {Kevin Y. X.} and Wilmott, {James S.} and Jeff Holst and Carlino, {Matteo S.} and Park, {John J.} and Camelia Quek and Matthew Wongchenko and Yibing Yan and Graham Mann and Johnson, {Douglas B.} and McQuade, {Jennifer L.} and Rajat Rai and Kefford, {Richard F.} and Helen Rizos and Scolyer, {Richard A.} and Yang, {Jean Y. H.} and Long, {Georgina V.} and Menzies, {Alexander M.}",
year = "2019",
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doi = "10.1158/1078-0432.CCR-18-1680",
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da Silva, IP, Wang, KYX, Wilmott, JS, Holst, J, Carlino, MS, Park, JJ, Quek, C, Wongchenko, M, Yan, Y, Mann, G, Johnson, DB, McQuade, JL, Rai, R, Kefford, RF, Rizos, H, Scolyer, RA, Yang, JYH, Long, GV & Menzies, AM 2019, 'Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma', Clinical Cancer Research, vol. 25, no. 4, pp. 1272-1279. https://doi.org/10.1158/1078-0432.CCR-18-1680

Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma. / da Silva, Inês Pires; Wang, Kevin Y. X.; Wilmott, James S.; Holst, Jeff; Carlino, Matteo S.; Park, John J.; Quek, Camelia; Wongchenko, Matthew; Yan, Yibing; Mann, Graham; Johnson, Douglas B.; McQuade, Jennifer L.; Rai, Rajat; Kefford, Richard F.; Rizos, Helen; Scolyer, Richard A.; Yang, Jean Y. H.; Long, Georgina V.; Menzies, Alexander M.

In: Clinical Cancer Research, Vol. 25, No. 4, 15.02.2019, p. 1272-1279.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Distinct molecular profiles and immunotherapy treatment outcomes of V600E and V600K BRAF-mutant melanoma

AU - da Silva, Inês Pires

AU - Wang, Kevin Y. X.

AU - Wilmott, James S.

AU - Holst, Jeff

AU - Carlino, Matteo S.

AU - Park, John J.

AU - Quek, Camelia

AU - Wongchenko, Matthew

AU - Yan, Yibing

AU - Mann, Graham

AU - Johnson, Douglas B.

AU - McQuade, Jennifer L.

AU - Rai, Rajat

AU - Kefford, Richard F.

AU - Rizos, Helen

AU - Scolyer, Richard A.

AU - Yang, Jean Y. H.

AU - Long, Georgina V.

AU - Menzies, Alexander M.

PY - 2019/2/15

Y1 - 2019/2/15

N2 - Purpose: BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFiMEKi. 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 ¼ 0.049), and overall survival (20.4 vs. 11.7 months, P = 0.081). Conclusions: BRAF V600K melanomas appear to benefit less from BRAFiMEKi 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.

AB - Purpose: BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFiMEKi. 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 ¼ 0.049), and overall survival (20.4 vs. 11.7 months, P = 0.081). Conclusions: BRAF V600K melanomas appear to benefit less from BRAFiMEKi 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.

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U2 - 10.1158/1078-0432.CCR-18-1680

DO - 10.1158/1078-0432.CCR-18-1680

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VL - 25

SP - 1272

EP - 1279

JO - Clinical Cancer Research

T2 - Clinical Cancer Research

JF - Clinical Cancer Research

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