Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors
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Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors. / Ahlborn, Lise Barlebo; Tuxen, Ida Viller; Mouliere, Florent; Kinalis, Savvas; Schmidt, Ane Y; Rohrberg, Kristoffer Staal; Santoni-Rugiu, Eric; Nielsen, Finn Cilius; Lassen, Ulrik; Yde, Christina Westmose; Oestrup, Olga; Mau-Sorensen, Morten.
In: OncoTarget, Vol. 9, No. 66, 2018, p. 32570-32579.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors
AU - Ahlborn, Lise Barlebo
AU - Tuxen, Ida Viller
AU - Mouliere, Florent
AU - Kinalis, Savvas
AU - Schmidt, Ane Y
AU - Rohrberg, Kristoffer Staal
AU - Santoni-Rugiu, Eric
AU - Nielsen, Finn Cilius
AU - Lassen, Ulrik
AU - Yde, Christina Westmose
AU - Oestrup, Olga
AU - Mau-Sorensen, Morten
PY - 2018
Y1 - 2018
N2 - Purpose: We evaluated longitudinal tracking of BRAF V600E in circulating cell-free DNA (cfDNA) as a marker of treatment response to BRAF inhibitor (BRAFi) combination therapies in non-melanoma solid tumors included in the Copenhagen Prospective Personalized Oncology (CoPPO) program.Experimental design: Patients with BRAF V600E-mutated tumors were treated with combination therapies including BRAFi. Quantification of mutant cfDNA from plasma was determined and correlated to clinical outcomes. Exome sequencing was performed to identify possible resistance mutations.Results: Twenty-three patients had BRAF-mutated tumors out of 455 patients included in CoPPO and 17 started BRAFi combination (EGFRi/MEKi) therapy. Tumor responses were achieved in 8 out of 16 evaluable patients and the median overall- and progression-free survival (OS and PFS) was 15 and 4.8 months, respectively. Longitudinal measurements of BRAF V600E-mutant cfDNA indicated disease progression prior to radiological evaluation and a reduction in the mutant fraction of more than 50% after 4 and 12 weeks of therapy was associated with a significantly longer PFS (p=0.003 and p=0.029) and OS (p=0.029 and p=0.017). Furthermore, the baseline mutant fraction and total level of cfDNA positively correlated with tumor burden (p=0.026 and p=0.024). Finally, analysis of cfDNA at progression revealed novel mutations potentially affecting the MAPK pathway.Conclusion: BRAFi combination therapies showed a response rate of 50% in BRAF V600E-mutated non-melanoma tumors. The fraction of BRAF-mutant cfDNA represent a sensitive indicator for clinical outcomes with plasma collected at week 4 and 12 as crucial time points for monitoring response and disease progression.
AB - Purpose: We evaluated longitudinal tracking of BRAF V600E in circulating cell-free DNA (cfDNA) as a marker of treatment response to BRAF inhibitor (BRAFi) combination therapies in non-melanoma solid tumors included in the Copenhagen Prospective Personalized Oncology (CoPPO) program.Experimental design: Patients with BRAF V600E-mutated tumors were treated with combination therapies including BRAFi. Quantification of mutant cfDNA from plasma was determined and correlated to clinical outcomes. Exome sequencing was performed to identify possible resistance mutations.Results: Twenty-three patients had BRAF-mutated tumors out of 455 patients included in CoPPO and 17 started BRAFi combination (EGFRi/MEKi) therapy. Tumor responses were achieved in 8 out of 16 evaluable patients and the median overall- and progression-free survival (OS and PFS) was 15 and 4.8 months, respectively. Longitudinal measurements of BRAF V600E-mutant cfDNA indicated disease progression prior to radiological evaluation and a reduction in the mutant fraction of more than 50% after 4 and 12 weeks of therapy was associated with a significantly longer PFS (p=0.003 and p=0.029) and OS (p=0.029 and p=0.017). Furthermore, the baseline mutant fraction and total level of cfDNA positively correlated with tumor burden (p=0.026 and p=0.024). Finally, analysis of cfDNA at progression revealed novel mutations potentially affecting the MAPK pathway.Conclusion: BRAFi combination therapies showed a response rate of 50% in BRAF V600E-mutated non-melanoma tumors. The fraction of BRAF-mutant cfDNA represent a sensitive indicator for clinical outcomes with plasma collected at week 4 and 12 as crucial time points for monitoring response and disease progression.
U2 - 10.18632/oncotarget.25948
DO - 10.18632/oncotarget.25948
M3 - Journal article
C2 - 30220966
VL - 9
SP - 32570
EP - 32579
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 66
ER -
ID: 216558603