Circulating tumor DNA as a marker of treatment response in BRAF V600E mutated non-melanoma solid tumors
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Lise Barlebo Ahlborn1,2, Ida Viller Tuxen1, Florent Mouliere3, Savvas Kinalis2, Ane Y. Schmidt2, Kristoffer Staal Rohrberg1, Eric Santoni-Rugiu4, Finn Cilius Nielsen2, Ulrik Lassen1, Christina Westmose Yde2, Olga Oestrup2 and Morten Mau-Sorensen1
1The Phase I Unit, Department of Oncology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark
2Center for Genomic Medicine, Rigshospitalet, Copenhagen University, Copenhagen, Denmark
3Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
4Department of Pathology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark
Lise Barlebo Ahlborn, email: firstname.lastname@example.org
Keywords: BRAF inhibitor; circulating tumor DNA; mutant allele fraction; early phase study; solid cancer
Received: June 04, 2018 Accepted: July 29, 2018 Published: August 24, 2018
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.
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