Clinical Utility and Prognostic Implications of Circulating Cell-Free DNA in Biliary Tract Cancer.

Abstract

An estimated 25% of patients with biliary tract cancer (BTC) do not undergo genotyping, representing a missed opportunity for therapeutic targeting. Cell-free DNA (cfDNA) and matched tumor sample from patients with BTC were analyzed using targeted next-generation sequencing (NGS) assay and compared. We sought to define the molecular profile of cancer-derived cfDNA, frequency of OncoKB level 1/2 alterations, plasma:tumor genotype concordance, the prognostic impact of cfDNA, and clonal evolution after targeted therapy progression. cfDNA-based genotyping was performed on 297 blood samples from 170 patients with BTC. The most frequently altered genes were <i>TP53</i> (29%), <i>FGFR2</i> (16%), <i>ARID1A</i> (13%), <i>CDKN2A</i> (11%), and <i>KRAS</i> (11%); 25% of patients had OncoKB level 1/2 alterations and 36.2% of potentially actionable alterations were detected in plasma alone. The cfDNA:tissue concordance accuracy was high (96% <i>IDH1</i>, 98% <i>BRAF</i>, 92% <i>KRAS</i> mutations, 99% <i>ERBB2</i> amplifications, and 96% <i>FGFR2</i> fusions). Detectable tumor-derived cfDNA after resection did not predict recurrence. In treatment-naïve metastatic BTC, high variant allele fraction was associated with worse progression-free survival and overall survival. <i>RAS</i> alterations not detected in samples before treatment were identified at progression in 24% of patients who received BRAF-, FGFR-, or HER2-directed therapy, identifying <i>RAS</i> alterations as a convergent mechanism of targeted therapy resistance. Molecular profiling of cfDNA from patients with BTC identified OncoKB level 1/2 gene alterations and putative genomic resistance mechanisms to targeted therapy. Concordance analysis suggests that cfDNA-based NGS is complementary to that of tissue-based sequencing in the identification of potentially actionable alterations.