Monitoring tumor specific mutations in plasma during systemic treatment of biliary tract cancer.

Abstract

318 Background: We have previously reported a rate of 23% RAS/RAF mutations in plasma from patients with KRAS exon 2 and 3 wild-type, non-resectable biliary tract tumors. We wanted to explore the changes in circulating tumor specific DNA (ctDNA) during systemic chemotherapy in these patients. Methods: Patients with non-resectable biliary tract cancer treated within a phase II trial were included if they had KRAS exon 2 and 3 wild-type tumor tissue, had quantifiable levels of tumor specific DNA in plasma and progressive disease on imaging. They received gemcitabine, oxaliplatin and capecitabine with either bevacizumab or panitumumab. Treatment continued for up to six months until progression. Blood sampling and evaluation according to RECIST 1.1 were done every 12 weeks. Droplet Digital PCR was performed on DNA isolated from 4 ml plasma. A pre-amplification step was done and adequate positive and negative controls were included. The extended RAS and BRAF mutation analysis covered 20 mutations in KRAS exons 3/4, NRAS exon 2/3, PIK3CA and BRAF V600E. The percentage of tumor specific DNA relative to total DNA was reported. Results: The inclusion criteria were met by 13 patients, 10 women and three men. The typical pattern was seen in eight cases, where the percentage of tumor specific DNA dropped at least half during therapy and rose at least two-fold at progression. In three patients, a baseline sample was not available or there was not an initial drop, but the ctDNA rose at progression. One patient had an initial drop, but not a rise a progression based on imaging. The last patient progressed rapidly. Conclusions: This exploratory analysis pointed toward changes in percentage of tumor specific mutations in plasma as a marker of effect and progression. Dynamics of liquid biopsies is a promising tool in monitoring biliary tract cancer patients during systemic therapy. Clinical trial information: NCT01206049.