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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

Swimmer plot showing the interval between increase of the BRAF V600mut ctDNA fraction and progressive disease according to RECIST v1.1 on imaging (PD), for all 36 patients patients from start of ctDNA monitoring. In 12 patients, an increase in the BRAF V600mut ctDNA fraction was detected prior to PD. In 7 patients, an increase of the BRAF V600mut ctDNA fraction was detected simultaneously with PD. In 8 patients, no increase in the BRAF V600mut ctDNA fraction was detected prior to or simultaneously with PD. None of the patients with an ongoing response showed an increase of the BRAF V600mut ctDNA fraction
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Fig6: Swimmer plot showing the interval between increase of the BRAF V600mut ctDNA fraction and progressive disease according to RECIST v1.1 on imaging (PD), for all 36 patients patients from start of ctDNA monitoring. In 12 patients, an increase in the BRAF V600mut ctDNA fraction was detected prior to PD. In 7 patients, an increase of the BRAF V600mut ctDNA fraction was detected simultaneously with PD. In 8 patients, no increase in the BRAF V600mut ctDNA fraction was detected prior to or simultaneously with PD. None of the patients with an ongoing response showed an increase of the BRAF V600mut ctDNA fraction

Mentions: During the course of plasma BRAF V600mut ctDNA monitoring, clinical PD was diagnosed in 27 of 36 patients after a median of 111 days [95 % CI 98–124] (Figs. 1b, 6). An increase of the BRAF V600mut ctDNA copy number and fraction was diagnosed in 19 of 27 (70 %) patients with PD and in none of the patients with an ongoing response, resulting in a sensitivity of 70 % and a specificity of 100 % (Kappa 0.54 [0.26–0.82]).Fig. 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.

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)

Swimmer plot showing the interval between increase of the BRAF V600mut ctDNA fraction and progressive disease according to RECIST v1.1 on imaging (PD), for all 36 patients patients from start of ctDNA monitoring. In 12 patients, an increase in the BRAF V600mut ctDNA fraction was detected prior to PD. In 7 patients, an increase of the BRAF V600mut ctDNA fraction was detected simultaneously with PD. In 8 patients, no increase in the BRAF V600mut ctDNA fraction was detected prior to or simultaneously with PD. None of the patients with an ongoing response showed an increase of the BRAF V600mut ctDNA fraction
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: Swimmer plot showing the interval between increase of the BRAF V600mut ctDNA fraction and progressive disease according to RECIST v1.1 on imaging (PD), for all 36 patients patients from start of ctDNA monitoring. In 12 patients, an increase in the BRAF V600mut ctDNA fraction was detected prior to PD. In 7 patients, an increase of the BRAF V600mut ctDNA fraction was detected simultaneously with PD. In 8 patients, no increase in the BRAF V600mut ctDNA fraction was detected prior to or simultaneously with PD. None of the patients with an ongoing response showed an increase of the BRAF V600mut ctDNA fraction
Mentions: During the course of plasma BRAF V600mut ctDNA monitoring, clinical PD was diagnosed in 27 of 36 patients after a median of 111 days [95 % CI 98–124] (Figs. 1b, 6). An increase of the BRAF V600mut ctDNA copy number and fraction was diagnosed in 19 of 27 (70 %) patients with PD and in none of the patients with an ongoing response, resulting in a sensitivity of 70 % and a specificity of 100 % (Kappa 0.54 [0.26–0.82]).Fig. 6

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