Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors

Lise Barlebo Ahlborn, Ida Viller Tuxen, Florent Mouliere, Savvas Kinalis, Ane Y. Schmidt, Kristoffer Staal Rohrberg, Eric Santoni-Rugiu, Finn Cilius Nielsen, Ulrik Lassen, Christina Westmose Yde, Olga Oestrup, Morten Mau-Sorensen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose: We evaluated longitudinal tracking of BRAF V600E in circulating cellfree 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 overalland 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.

Original languageEnglish
Pages (from-to)32570-32579
Number of pages10
JournalOncotarget
Volume9
Issue number66
DOIs
Publication statusPublished - 24 Aug 2018

Cite this

Ahlborn, L. B., Tuxen, I. V., Mouliere, F., Kinalis, S., Schmidt, A. Y., Rohrberg, K. S., ... Mau-Sorensen, M. (2018). Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors. Oncotarget, 9(66), 32570-32579. https://doi.org/10.18632/oncotarget.25948
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. / Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors. In: Oncotarget. 2018 ; Vol. 9, No. 66. pp. 32570-32579.
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title = "Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors",
abstract = "Purpose: We evaluated longitudinal tracking of BRAF V600E in circulating cellfree 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 overalland 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.",
keywords = "BRAF inhibitor, Circulating tumor DNA, Early phase study, Mutant allele fraction, Solid cancer",
author = "Ahlborn, {Lise Barlebo} and Tuxen, {Ida Viller} and Florent Mouliere and Savvas Kinalis and Schmidt, {Ane Y.} and Rohrberg, {Kristoffer Staal} and Eric Santoni-Rugiu and Nielsen, {Finn Cilius} and Ulrik Lassen and Yde, {Christina Westmose} and Olga Oestrup and Morten Mau-Sorensen",
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Ahlborn, LB, Tuxen, IV, Mouliere, F, Kinalis, S, Schmidt, AY, Rohrberg, KS, Santoni-Rugiu, E, Nielsen, FC, Lassen, U, Yde, CW, Oestrup, O & Mau-Sorensen, M 2018, 'Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors' Oncotarget, vol. 9, no. 66, pp. 32570-32579. https://doi.org/10.18632/oncotarget.25948

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, 24.08.2018, p. 32570-32579.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

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 - 2018/8/24

Y1 - 2018/8/24

N2 - Purpose: We evaluated longitudinal tracking of BRAF V600E in circulating cellfree 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 overalland 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 cellfree 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 overalland 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.

KW - BRAF inhibitor

KW - Circulating tumor DNA

KW - Early phase study

KW - Mutant allele fraction

KW - Solid cancer

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U2 - 10.18632/oncotarget.25948

DO - 10.18632/oncotarget.25948

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JO - Oncotarget

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SN - 1949-2553

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