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J Transl Med. 2016 Apr 19;14:95. doi: 10.1186/s12967-016-0852-6.

Quantitative assessment of BRAF V600 mutant circulating cell-free tumor DNA as a tool for therapeutic monitoring in metastatic melanoma patients treated with BRAF/MEK inhibitors.

Author information

1
Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium. max.schreuer@uzbrussel.be.
2
Biocartis, Generaal De Wittelaan 11 B3, 2800, Mechelen, Belgium.
3
Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium.
4
Department of Dermatology, Universitair ziekenhuis Gent (UZ Gent), Universiteit Gent (UGent), De Pintelaan 185, 9000, Ghent, Belgium.
5
Department of Biostatistics and Medical Informatics, Vrije Universiteit Brussel (VUB), Laarbeeklaan, 103, 1090, Brussels, Belgium.

Abstract

BACKGROUND:

BRAF V600 mutant circulating cell-free tumor DNA (BRAF V600mut ctDNA) could serve as a specific biomarker in patients with BRAF V600 mutant melanoma. We analyzed the value of BRAF V600mut ctDNA from plasma as a monitoring tool for advanced melanoma patients treated with BRAF/MEK inhibitors.

METHODS:

Allele-specific quantitative PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on DNA extracted from plasma of patients with known BRAF V600 mutant melanoma who were treated with dabrafenib and trametinib.

RESULTS:

245 plasma samples from 36 patients were analyzed. In 16 patients the first plasma sample was obtained before the first dosing of dabrafenib/trametinib. At baseline, BRAF V600mut ctDNA was detected in 75 % of patients (n = 12/16). BRAF V600mut ctDNA decreased rapidly upon initiation of targeted therapy (p < 0.001) and became undetectable in 60 % of patients (n = 7/12) after 6 weeks of treatment. During treatment, disease progression (PD) was diagnosed in 27 of 36 patients. An increase of the BRAF V600mut ctDNA copy number and fraction, identified PD with a sensitivity of 70 % (n = 19/27) and a specificity of 100 %. An increase in the BRAF V600mut ctDNA fraction was detected prior to clinical PD in 44 % of cases (n = 12/27) and simultaneously with PD in 26 % of patients (n = 7/27).

CONCLUSIONS:

Quantitative analysis of BRAF V600mut ctDNA in plasma has unique features as a monitoring tool during treatment with BRAF/MEK inhibitors. Its potential as an early predictor of acquired resistance deserves further evaluation.

KEYWORDS:

BRAF V600; Biomarkers; Dabrafenib; Melanoma; Trametinib; cfDNA; ctDNA

PMID:
27095081
PMCID:
PMC4837559
DOI:
10.1186/s12967-016-0852-6
[Indexed for MEDLINE]
Free PMC Article

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