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.
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.
Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium. max.schreuer@uzbrussel.be.
Max
M
Schreuer
Biocartis, Generaal De Wittelaan 11 B3, 2800, Mechelen, Belgium.
Geert
G
Meersseman
Biocartis, Generaal De Wittelaan 11 B3, 2800, Mechelen, Belgium.
Sari
S
Van Den Herrewegen
Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium.
Yanina
Y
Jansen
Department of Dermatology, Universitair ziekenhuis Gent (UZ Gent), Universiteit Gent (UGent), De Pintelaan 185, 9000, Ghent, Belgium.
Ines
I
Chevolet
Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium.
Ambre
A
Bott
Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium.
Sofie
S
Wilgenhof
Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium.
Teofila
T
Seremet
Biocartis, Generaal De Wittelaan 11 B3, 2800, Mechelen, Belgium.
Bart
B
Jacobs
Department of Biostatistics and Medical Informatics, Vrije Universiteit Brussel (VUB), Laarbeeklaan, 103, 1090, Brussels, Belgium.
Ronald
R
Buyl
Biocartis, Generaal De Wittelaan 11 B3, 2800, Mechelen, Belgium.
Geert
G
Maertens
Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium.
Bart
B
Neyns
D002474:Cell-Free System; D004273:DNA, Neoplasm / Q000097:blood*; D018450:Disease Progression; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use
D004273:DNA, Neoplasm; D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
BRAF V600; Biomarkers; Dabrafenib; Melanoma; Trametinib; cfDNA; ctDNA