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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.

Schreuer M, Meersseman G, Van Den Herrewegen S, Jansen Y, Chevolet I, Bott A, Wilgenhof S, Seremet T, Jacobs B, Buyl R, Maertens G, Neyns B - J Transl Med (2016)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium. max.schreuer@uzbrussel.be.

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.

No MeSH data available.


Related in: MedlinePlus

a Flow diagram showing subgroups of patients according to the detection of BRAF V600mut ctDNA after treatment initiation. b Flow diagram showing subgroups of patients according to the evolution of BRAF V600mut ctDNA in relation to disease progression. Pts patients
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Fig1: a Flow diagram showing subgroups of patients according to the detection of BRAF V600mut ctDNA after treatment initiation. b Flow diagram showing subgroups of patients according to the evolution of BRAF V600mut ctDNA in relation to disease progression. Pts patients

Mentions: In 75 % of patients (n = 12/16) BRAF V600mut ctDNA was detected before initiation of dabrafenib and trametinib (median fraction 16.5 %; Q1–Q3 9.8–25 %—median copy number 571 copies/mL; Q1–Q3 79–1610 copies/mL) (Fig. 1a). In 25 % of patients (n = 4/16) no BRAF V600mut ctDNA was detected before initiation of dabrafenib and trametinib.Fig. 1


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.

Schreuer M, Meersseman G, Van Den Herrewegen S, Jansen Y, Chevolet I, Bott A, Wilgenhof S, Seremet T, Jacobs B, Buyl R, Maertens G, Neyns B - J Transl Med (2016)

a Flow diagram showing subgroups of patients according to the detection of BRAF V600mut ctDNA after treatment initiation. b Flow diagram showing subgroups of patients according to the evolution of BRAF V600mut ctDNA in relation to disease progression. Pts patients
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4837559&req=5

Fig1: a Flow diagram showing subgroups of patients according to the detection of BRAF V600mut ctDNA after treatment initiation. b Flow diagram showing subgroups of patients according to the evolution of BRAF V600mut ctDNA in relation to disease progression. Pts patients
Mentions: In 75 % of patients (n = 12/16) BRAF V600mut ctDNA was detected before initiation of dabrafenib and trametinib (median fraction 16.5 %; Q1–Q3 9.8–25 %—median copy number 571 copies/mL; Q1–Q3 79–1610 copies/mL) (Fig. 1a). In 25 % of patients (n = 4/16) no BRAF V600mut ctDNA was detected before initiation of dabrafenib and trametinib.Fig. 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Laarbeeklaan 101, 1090, Brussels, Belgium. max.schreuer@uzbrussel.be.

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.

No MeSH data available.


Related in: MedlinePlus