Reference Detail

Ref Type

Journal Article

PMID

(30630828)

Authors

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

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	25	4	2019 Feb 15	1272-1279	Clin Cancer Res

URL

Abstract Text

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.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.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).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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600K	melanoma	predicted - sensitive	Nivolumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, patients with melanoma harboring BRAF V600K (n=19) had increased tumor mutational burden and greater response rates (53% vs. 29%, p=0.059), progression-free survival (19 vs. 2.7 months, p=0.049), and overall survival (20.4 vs. 11.7 months, p=0.081) relative to patients with BRAF V600E (n=84) when treated with Keytruda (pembrolizumab) (n=17 and 62 for BRAF V600K and V600E, respectively) or Opdivo (nivolumab) (n=2 and 22 for BRAF V600K and V600E, respectively) (PMID: 30630828).	30630828
BRAF V600E	melanoma	decreased response	Pembrolizumab	Clinical Study	Actionable	In a retrospective analysis, patients with melanoma harboring BRAF V600E (n=84) had decreased response rates (29% vs. 53%, p=0.059), progression-free survival (2.7 vs. 19 months, p=0.049), and overall survival (11.7 vs. 20.4 months, p=0.081) relative to patients with BRAF V600K (n=19) when treated with Keytruda (pembrolizumab) (n=62 and 17 for BRAF V600E and V600K, respectively) or Opdivo (nivolumab) (n=22 and 2 for BRAF V600E and V600K, respectively) (PMID: 30630828).	30630828
BRAF V600E	melanoma	decreased response	Nivolumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, patients with melanoma harboring BRAF V600E (n=84) had decreased response rates (29% vs. 53%, p=0.059), progression-free survival (2.7 vs. 19 months, p=0.049), and overall survival (11.7 vs. 20.4 months, p=0.081) relative to patients with BRAF V600K (n=19) when treated with Keytruda (pembrolizumab) (n=62 and 17 for BRAF V600E and V600K, respectively) or Opdivo (nivolumab) (n=22 and 2 for BRAF V600E and V600K, respectively) (PMID: 30630828).	30630828
BRAF V600K	melanoma	predicted - sensitive	Pembrolizumab	Clinical Study - Cohort	Actionable	In a retrospective analysis, patients with melanoma harboring BRAF V600K (n=19) had increased tumor mutational burden and greater response rates (53% vs. 29%, p=0.059), progression-free survival (19 vs. 2.7 months, p=0.049), and overall survival (20.4 vs. 11.7 months, p=0.081) relative to patients with BRAF V600E (n=84) when treated with Keytruda (pembrolizumab) (n=17 and 62 for BRAF V600K and V600E, respectively) or Opdivo (nivolumab) (n=2 and 22 for BRAF V600K and V600E, respectively) (PMID: 30630828).	30630828

Reference Detail

Contact

Filtering

Sorting