Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K BRAF-Mutant Melanoma.

Pires da Silva, I; 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

Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K BRAF-Mutant Melanoma.

Pires da Silva, I 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

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Publisher:: American Association for Cancer Research (AACR)
Publication Type:: Journal Article
Citation:: Clin Cancer Res, 2019, 25, (4), pp. 1272-1279
Issue Date:: 2019-02-15

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Field	Value	Language
dc.contributor.author	Pires da Silva, I
dc.contributor.author	Wang, KYX
dc.contributor.author	Wilmott, JS
dc.contributor.author	Holst, J
dc.contributor.author	Carlino, MS
dc.contributor.author	Park, JJ
dc.contributor.author	Quek, C
dc.contributor.author	Wongchenko, M
dc.contributor.author	Yan, Y
dc.contributor.author	Mann, G
dc.contributor.author	Johnson, DB
dc.contributor.author	McQuade, JL
dc.contributor.author	Rai, R
dc.contributor.author	Kefford, RF
dc.contributor.author	Rizos, H
dc.contributor.author	Scolyer, RA
dc.contributor.author	Yang, JYH
dc.contributor.author	Long, GV
dc.contributor.author	Menzies, AM
dc.date.accessioned	2022-05-25T01:51:12Z
dc.date.available	2018-11-01
dc.date.available	2022-05-25T01:51:12Z
dc.date.issued	2019-02-15
dc.identifier.citation	Clin Cancer Res, 2019, 25, (4), pp. 1272-1279
dc.identifier.issn	1078-0432
dc.identifier.issn	1557-3265
dc.identifier.uri	http://hdl.handle.net/10453/157678
dc.description.abstract	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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	American Association for Cancer Research (AACR)
dc.relation.ispartof	Clin Cancer Res
dc.relation.isbasedon	10.1158/1078-0432.CCR-18-1680
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Female
dc.subject.mesh	Humans
dc.subject.mesh	Immunotherapy
dc.subject.mesh	MAP Kinase Signaling System
dc.subject.mesh	Male
dc.subject.mesh	Melanoma
dc.subject.mesh	Middle Aged
dc.subject.mesh	Mutant Proteins
dc.subject.mesh	Mutation
dc.subject.mesh	Oncogene Protein v-akt
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Proto-Oncogene Proteins B-raf
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Humans
dc.subject.mesh	Melanoma
dc.subject.mesh	Proto-Oncogene Proteins B-raf
dc.subject.mesh	Protein Kinase Inhibitors
dc.subject.mesh	Treatment Outcome
dc.subject.mesh	Immunotherapy
dc.subject.mesh	Signal Transduction
dc.subject.mesh	MAP Kinase Signaling System
dc.subject.mesh	Mutation
dc.subject.mesh	Middle Aged
dc.subject.mesh	Female
dc.subject.mesh	Male
dc.subject.mesh	Mutant Proteins
dc.subject.mesh	Oncogene Protein v-akt
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.title	Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K BRAF-Mutant Melanoma.
dc.type	Journal Article
utslib.citation.volume	25
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
utslib.copyright.status	closed_access	*
dc.date.updated	2022-05-25T01:51:11Z
pubs.issue	4
pubs.publication-status	Published
pubs.volume	25
utslib.citation.issue	4

Abstract:

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.

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http://hdl.handle.net/10453/157678