Limits...
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 from plasma in 5 patients (a–e) with advanced melanoma during targeted therapy. Treatment with dabrafenib (dabra, 150 mg BID) and trametinib (trame, 2 mg QD) was initiated after obtaining the baseline plasma sample. The left y-axis represents the BRAF V600mut ctDNA copy number per milliliter (solid line), the right y-axis represents the BRAF V600mut ctDNA fraction to the total amount of cfDNA (dashed line). SD, PR and PD respectively denote stable disease, partial response and progressive disease according to RECIST v1.1. a The BRAF V600mut ctDNA copy number and fraction dropped after treatment initiation. After 40 days, no BRAF V600mut ctDNA could be detected anymore, and CT body showed a PR. The BRAF V600mut ctDNA fraction reappeared after 96 days and increased on day 124, although an ongoing PR was reported on PET–CT. PET–CT showed PD, 50 days after the reappearance of BRAF V600mut ctDNA in plasma. bBRAF V600mut ctDNA remained detectable from treatment initiation until PD was detected after 89 days. c At baseline, no BRAF V600mut ctDNA was detected in plasma. BRAF V600mut ctDNA appeared after 28 days, 35 days prior to the detection of PD on CT body. d At baseline, no BRAF V600mut ctDNA was detected in plasma. After 168 days, PD was detected in a gallbladder metastasis, and BRAF V600mut ctDNA was detected concomitantly. The only other lesion, a lung metastasis, had remained strictly stable. After resection of the gallbladder metastasis, the BRAF V600mut ctDNA fraction could not be detected until PD occurred in the remaining lung metastasis. e Five days after treatment initiation, BRAF V600mut ctDNA could not be detected anymore. Brain MRI showed a new millimetric brain lesion on the first response evaluation, while PET–CT showed clear regression of all liver and lung metastases. Subsequent MRI’s showed ongoing slow PD in the brain, while liver and lung lesions showed ongoing PR. No BRAF V600mut ctDNA was detected during PD in this patient
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Serial measurement of BRAF V600mut ctDNA from plasma in 5 patients (a–e) with advanced melanoma during targeted therapy. Treatment with dabrafenib (dabra, 150 mg BID) and trametinib (trame, 2 mg QD) was initiated after obtaining the baseline plasma sample. The left y-axis represents the BRAF V600mut ctDNA copy number per milliliter (solid line), the right y-axis represents the BRAF V600mut ctDNA fraction to the total amount of cfDNA (dashed line). SD, PR and PD respectively denote stable disease, partial response and progressive disease according to RECIST v1.1. a The BRAF V600mut ctDNA copy number and fraction dropped after treatment initiation. After 40 days, no BRAF V600mut ctDNA could be detected anymore, and CT body showed a PR. The BRAF V600mut ctDNA fraction reappeared after 96 days and increased on day 124, although an ongoing PR was reported on PET–CT. PET–CT showed PD, 50 days after the reappearance of BRAF V600mut ctDNA in plasma. bBRAF V600mut ctDNA remained detectable from treatment initiation until PD was detected after 89 days. c At baseline, no BRAF V600mut ctDNA was detected in plasma. BRAF V600mut ctDNA appeared after 28 days, 35 days prior to the detection of PD on CT body. d At baseline, no BRAF V600mut ctDNA was detected in plasma. After 168 days, PD was detected in a gallbladder metastasis, and BRAF V600mut ctDNA was detected concomitantly. The only other lesion, a lung metastasis, had remained strictly stable. After resection of the gallbladder metastasis, the BRAF V600mut ctDNA fraction could not be detected until PD occurred in the remaining lung metastasis. e Five days after treatment initiation, BRAF V600mut ctDNA could not be detected anymore. Brain MRI showed a new millimetric brain lesion on the first response evaluation, while PET–CT showed clear regression of all liver and lung metastases. Subsequent MRI’s showed ongoing slow PD in the brain, while liver and lung lesions showed ongoing PR. No BRAF V600mut ctDNA was detected during PD in this patient

Mentions: During treatment, the BRAF V600mut ctDNA fraction and copy number decreased significantly compared to baseline in all 12 patients (p < 0.01, Fig. 3), and became undetectable (n = 7) or <1 % (n = 5) after a median of 13 days (range 6–40 days). At the time when no ctDNA could be measured any more, none of the patients had obtained a complete radiological remission (e.g. Fig.  4a, e). In 3 patients, BRAF V600mut ctDNA remained detectable from the initiation of targeted therapy until PD was diagnosed (e.g. Fig. 4b). Median PFS was not significantly longer for patients in whom BRAF V600mut ctDNA became undetectable 1 month after the initiation of targeted therapy, as compared to patients in whom ctDNA remained detectable during the first month of therapy (p = 0.56). Progression free survival was significantly shorter for patients in whom BRAF V600mut ctDNA remained detectable throughout the treatment with targeted therapy compared to patients in whom BRAF V600mut ctDNA became undetectable (p < 0.001) (Fig. 5).Fig. 3


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 from plasma in 5 patients (a–e) with advanced melanoma during targeted therapy. Treatment with dabrafenib (dabra, 150 mg BID) and trametinib (trame, 2 mg QD) was initiated after obtaining the baseline plasma sample. The left y-axis represents the BRAF V600mut ctDNA copy number per milliliter (solid line), the right y-axis represents the BRAF V600mut ctDNA fraction to the total amount of cfDNA (dashed line). SD, PR and PD respectively denote stable disease, partial response and progressive disease according to RECIST v1.1. a The BRAF V600mut ctDNA copy number and fraction dropped after treatment initiation. After 40 days, no BRAF V600mut ctDNA could be detected anymore, and CT body showed a PR. The BRAF V600mut ctDNA fraction reappeared after 96 days and increased on day 124, although an ongoing PR was reported on PET–CT. PET–CT showed PD, 50 days after the reappearance of BRAF V600mut ctDNA in plasma. bBRAF V600mut ctDNA remained detectable from treatment initiation until PD was detected after 89 days. c At baseline, no BRAF V600mut ctDNA was detected in plasma. BRAF V600mut ctDNA appeared after 28 days, 35 days prior to the detection of PD on CT body. d At baseline, no BRAF V600mut ctDNA was detected in plasma. After 168 days, PD was detected in a gallbladder metastasis, and BRAF V600mut ctDNA was detected concomitantly. The only other lesion, a lung metastasis, had remained strictly stable. After resection of the gallbladder metastasis, the BRAF V600mut ctDNA fraction could not be detected until PD occurred in the remaining lung metastasis. e Five days after treatment initiation, BRAF V600mut ctDNA could not be detected anymore. Brain MRI showed a new millimetric brain lesion on the first response evaluation, while PET–CT showed clear regression of all liver and lung metastases. Subsequent MRI’s showed ongoing slow PD in the brain, while liver and lung lesions showed ongoing PR. No BRAF V600mut ctDNA was detected during PD in this patient
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig4: Serial measurement of BRAF V600mut ctDNA from plasma in 5 patients (a–e) with advanced melanoma during targeted therapy. Treatment with dabrafenib (dabra, 150 mg BID) and trametinib (trame, 2 mg QD) was initiated after obtaining the baseline plasma sample. The left y-axis represents the BRAF V600mut ctDNA copy number per milliliter (solid line), the right y-axis represents the BRAF V600mut ctDNA fraction to the total amount of cfDNA (dashed line). SD, PR and PD respectively denote stable disease, partial response and progressive disease according to RECIST v1.1. a The BRAF V600mut ctDNA copy number and fraction dropped after treatment initiation. After 40 days, no BRAF V600mut ctDNA could be detected anymore, and CT body showed a PR. The BRAF V600mut ctDNA fraction reappeared after 96 days and increased on day 124, although an ongoing PR was reported on PET–CT. PET–CT showed PD, 50 days after the reappearance of BRAF V600mut ctDNA in plasma. bBRAF V600mut ctDNA remained detectable from treatment initiation until PD was detected after 89 days. c At baseline, no BRAF V600mut ctDNA was detected in plasma. BRAF V600mut ctDNA appeared after 28 days, 35 days prior to the detection of PD on CT body. d At baseline, no BRAF V600mut ctDNA was detected in plasma. After 168 days, PD was detected in a gallbladder metastasis, and BRAF V600mut ctDNA was detected concomitantly. The only other lesion, a lung metastasis, had remained strictly stable. After resection of the gallbladder metastasis, the BRAF V600mut ctDNA fraction could not be detected until PD occurred in the remaining lung metastasis. e Five days after treatment initiation, BRAF V600mut ctDNA could not be detected anymore. Brain MRI showed a new millimetric brain lesion on the first response evaluation, while PET–CT showed clear regression of all liver and lung metastases. Subsequent MRI’s showed ongoing slow PD in the brain, while liver and lung lesions showed ongoing PR. No BRAF V600mut ctDNA was detected during PD in this patient
Mentions: During treatment, the BRAF V600mut ctDNA fraction and copy number decreased significantly compared to baseline in all 12 patients (p < 0.01, Fig. 3), and became undetectable (n = 7) or <1 % (n = 5) after a median of 13 days (range 6–40 days). At the time when no ctDNA could be measured any more, none of the patients had obtained a complete radiological remission (e.g. Fig.  4a, e). In 3 patients, BRAF V600mut ctDNA remained detectable from the initiation of targeted therapy until PD was diagnosed (e.g. Fig. 4b). Median PFS was not significantly longer for patients in whom BRAF V600mut ctDNA became undetectable 1 month after the initiation of targeted therapy, as compared to patients in whom ctDNA remained detectable during the first month of therapy (p = 0.56). Progression free survival was significantly shorter for patients in whom BRAF V600mut ctDNA remained detectable throughout the treatment with targeted therapy compared to patients in whom BRAF V600mut ctDNA became undetectable (p < 0.001) (Fig. 5).Fig. 3

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