Abstract 5393: BRAF mutant allele fraction in circulating tumor DNA as marker of treatment response in BRAF mutated non malignant melanoma cancers identified in the Copenhagen Prospective Personalized Oncology study
Authors: Ahlborn Lise Barlebo , Tuxen Ida Viller , Oestrup Olga , Schmidt Ane Yde , Håkansson Cecilia Brunhoff , Nielsen Finn Celius , Lassen Ulrik , Yde Christina Westmose , Mau-Sorensen Morten 
Published: July 2017

Abstract
Background: BRAF inhibitors have been approved in BRAF mutated malignant melanoma. However, in other BRAF mutated cancers, the effect of BRAF inhibition has been studied less extensively. BRAF mutated non-melanoma cancer patients (pts) were identified in a prospective genomic profiling study. The effect of targeted treatment was assessed by BRAF mutant allele fraction (AF) in circulating tumor DNA (ctDNA) and radiological response.
Methods: Pts had tumor biopsies performed at enrolment and, if feasible, on or after treatment. Biopsies were subjected to whole exome sequencing, RNA sequencing and SNP array. Blood samples for ctDNA analysis were collected at baseline and longitudinally during treatment. Mutant BRAF fragments were quantified using droplet digital PCR (ddPCR) or by targeted next generation sequencing (NGS). Radiological response was evaluated according to RECIST 1.1.
Results: Twenty-two BRAF mutated non-melanoma cancer pts (lung n=2, colorectal n=14, bile duct n=4, prostate n=1, pancreas n=1) were identified out of a total of 405 (5 %) pts enrolled in the Copenhagen Prospective Personalized Oncology (CoPPO) study. In all tumors we identified the BRAF V600E mutation except in one prostate cancer pt (BRAF K601E). Fifteen pts were treated with dabrafenib/trametinib (lung, bile duct), vemurafenib/panitumumab +/- irinotecan (colorectal) or vemurafenib (pancreas, prostate). Two pts were non-evaluable because one patient requested early termination and one has pending tumor evaluation. All pts had tumor reduction, except one patient with colon cancer. Six out of 13 (46%) pts achieved partial response (lung n=2, bile duct n=1, colorectal n= 3) and 7/13 (44%) had stable disease (prostate n=1, bile duct n=1, colorectal n= 5) as best response according to RECIST 1.1. Median progression-free survival was 20 weeks. Eighteen pts analysed by ddPCR or NGS at baseline had detectable mutant BRAF in the plasma obtained before initiation of therapy. Eight of the 18 pts had ctDNA assessed during treatment and all presented with a reduction in mutant BRAF AF corresponding to a reduction in tumor volume. Moreover, in 5/8 pts, time of best radiological response coincided with the lowest detectable BRAF mutant AF. Analysis of on- and post treatment biopsies and matched ctDNA samples are pending to identify putative mechanisms of resistance and will be reported at the meeting.
Conclusion: Targeted therapy seems active in BRAF mutated non-melanoma cancer pts and treatment response is evaluable by monitoring mutant BRAF in ctDNA during therapy.
Citation Format: Lise Barlebo Ahlborn, Ida Viller Tuxen, Olga Oestrup, Ane Yde Schmidt, Cecilia Brunhoff Håkansson, Finn Celius Nielsen, Ulrik Lassen, Christina Westmose Yde, Morten Mau-Sorensen. BRAF mutant allele fraction in circulating tumor DNA as marker of treatment response in BRAF mutated non malignant melanoma cancers identified in the Copenhagen Prospective Personalized Oncology study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5393. doi:10.1158/1538-7445.AM2017-5393