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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

Serial measurement of BRAF V600mut ctDNA in plasma of 2 patients (a, b = patient 1; c, d = patient 2) with advanced melanoma during targeted therapy. The y-axis represents the BRAF V600mut ctDNA copy number per millilitre. Results obtained with the Idylla™ system (Biocartis) and digital PCR (Bio-rad) are shown.  a Treatment with dabrafenib and trametinib (dabra 2 × 150 mg + trame 2 mg) was initiated after obtaining the baseline plasma sample. Within 1 week the BRAF V600mut ctDNA copy number dropped significantly. After switching targeted therapy to pembrolizumab (Pem 2 mg/kg) due to side effects on the moment of best response (PR PET–CT), an increase of the BRAF v600mut ctDNA copy number was detected within 9 days. After reintroducing dabrafenib and trametinib, due to rapid clinical disease progression (Clinical PD), the BRAF V600mut ctDNA copy number dropped again. b The evolution of the BRAF V600mut ctDNA copy number in patient 1 during the first 2 days of treatment. c Treatment with dabrafenib and trametinib (dabra 2 × 150 mg + trame 2 mg) was initiated after obtaining the baseline plasma sample. Within 1 week the BRAF V600mut ctDNA copy number dropped significantly. d The evolution of the BRAF V600mut ctDNA copy number in patient 2 during the first day of treatment
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Fig2: Serial measurement of BRAF V600mut ctDNA in plasma of 2 patients (a, b = patient 1; c, d = patient 2) with advanced melanoma during targeted therapy. The y-axis represents the BRAF V600mut ctDNA copy number per millilitre. Results obtained with the Idylla™ system (Biocartis) and digital PCR (Bio-rad) are shown. a Treatment with dabrafenib and trametinib (dabra 2 × 150 mg + trame 2 mg) was initiated after obtaining the baseline plasma sample. Within 1 week the BRAF V600mut ctDNA copy number dropped significantly. After switching targeted therapy to pembrolizumab (Pem 2 mg/kg) due to side effects on the moment of best response (PR PET–CT), an increase of the BRAF v600mut ctDNA copy number was detected within 9 days. After reintroducing dabrafenib and trametinib, due to rapid clinical disease progression (Clinical PD), the BRAF V600mut ctDNA copy number dropped again. b The evolution of the BRAF V600mut ctDNA copy number in patient 1 during the first 2 days of treatment. c Treatment with dabrafenib and trametinib (dabra 2 × 150 mg + trame 2 mg) was initiated after obtaining the baseline plasma sample. Within 1 week the BRAF V600mut ctDNA copy number dropped significantly. d The evolution of the BRAF V600mut ctDNA copy number in patient 2 during the first day of treatment

Mentions: To assess changes in the BRAF V600mut ctDNA concentration during the first hours after treatment initiation, five samples were collected in the first 24 h of treatment in 2 patients treated ‘‘in hospital’’ (Fig. 2). In both patients the BRAF V600mut ctDNA copy number decreased significantly within 5 days after treatment initiation. In one patient only a transient increase in the BRAF V600mut ctDNA copy number was observed within the first 24 h on therapy (Fig. 2b, d).Fig. 2


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)

Serial measurement of BRAF V600mut ctDNA in plasma of 2 patients (a, b = patient 1; c, d = patient 2) with advanced melanoma during targeted therapy. The y-axis represents the BRAF V600mut ctDNA copy number per millilitre. Results obtained with the Idylla™ system (Biocartis) and digital PCR (Bio-rad) are shown.  a Treatment with dabrafenib and trametinib (dabra 2 × 150 mg + trame 2 mg) was initiated after obtaining the baseline plasma sample. Within 1 week the BRAF V600mut ctDNA copy number dropped significantly. After switching targeted therapy to pembrolizumab (Pem 2 mg/kg) due to side effects on the moment of best response (PR PET–CT), an increase of the BRAF v600mut ctDNA copy number was detected within 9 days. After reintroducing dabrafenib and trametinib, due to rapid clinical disease progression (Clinical PD), the BRAF V600mut ctDNA copy number dropped again. b The evolution of the BRAF V600mut ctDNA copy number in patient 1 during the first 2 days of treatment. c Treatment with dabrafenib and trametinib (dabra 2 × 150 mg + trame 2 mg) was initiated after obtaining the baseline plasma sample. Within 1 week the BRAF V600mut ctDNA copy number dropped significantly. d The evolution of the BRAF V600mut ctDNA copy number in patient 2 during the first day of treatment
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Related In: Results  -  Collection

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Fig2: Serial measurement of BRAF V600mut ctDNA in plasma of 2 patients (a, b = patient 1; c, d = patient 2) with advanced melanoma during targeted therapy. The y-axis represents the BRAF V600mut ctDNA copy number per millilitre. Results obtained with the Idylla™ system (Biocartis) and digital PCR (Bio-rad) are shown. a Treatment with dabrafenib and trametinib (dabra 2 × 150 mg + trame 2 mg) was initiated after obtaining the baseline plasma sample. Within 1 week the BRAF V600mut ctDNA copy number dropped significantly. After switching targeted therapy to pembrolizumab (Pem 2 mg/kg) due to side effects on the moment of best response (PR PET–CT), an increase of the BRAF v600mut ctDNA copy number was detected within 9 days. After reintroducing dabrafenib and trametinib, due to rapid clinical disease progression (Clinical PD), the BRAF V600mut ctDNA copy number dropped again. b The evolution of the BRAF V600mut ctDNA copy number in patient 1 during the first 2 days of treatment. c Treatment with dabrafenib and trametinib (dabra 2 × 150 mg + trame 2 mg) was initiated after obtaining the baseline plasma sample. Within 1 week the BRAF V600mut ctDNA copy number dropped significantly. d The evolution of the BRAF V600mut ctDNA copy number in patient 2 during the first day of treatment
Mentions: To assess changes in the BRAF V600mut ctDNA concentration during the first hours after treatment initiation, five samples were collected in the first 24 h of treatment in 2 patients treated ‘‘in hospital’’ (Fig. 2). In both patients the BRAF V600mut ctDNA copy number decreased significantly within 5 days after treatment initiation. In one patient only a transient increase in the BRAF V600mut ctDNA copy number was observed within the first 24 h on therapy (Fig. 2b, d).Fig. 2

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