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- Title
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.
- Authors
Schreuer, Max; Meersseman, Geert; Van Den Herrewegen, Sari; Jansen, Yanina; Chevolet, Ines; Bott, Ambre; Wilgenhof, Sofie; Seremet, Teofila; Jacobs, Bart; Buyl, Ronald; Maertens, Geert; Neyns, Bart
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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).<bold>Conclusions: </bold>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.
- Subjects
MELANOMA treatment; BRAF genes; CIRCULATING tumor DNA; BIOMARKERS; TUMOR treatment; PROTEIN kinase inhibitors; AMINES; CELLS; DNA; DRUG monitoring; HETEROCYCLIC compounds; IMIDAZOLES; MELANOMA; METASTASIS; GENETIC mutation; PYRIDINE; TRANSFERASES; DISEASE progression; KAPLAN-Meier estimator; PHARMACODYNAMICS; METABOLISM; THERAPEUTICS
- Publication
Journal of Translational Medicine, 2016, Vol 14, p1
- ISSN
1479-5876
- Publication type
journal article
- DOI
10.1186/s12967-016-0852-6