CfDNA Alterations in 1671 Patients with Advanced BTC: A Clinical Landscape

The following is the summary of  “Clinical landscape of cell-free DNA alterations in 1671 patients with advanced biliary tract cancer” published in the December 2022 issue of Oncology by Berchuck, et al.


Targeted medicines have revolutionized clinical care of advanced biliary tract cancer (BTC). In contrast to conventional tissue analysis, which has its own set of limitations when it comes to cancer genomic profiling, cell-free DNA (cfDNA) analysis has a lot going for it. Therefore, researchers analyzed cfDNA as a means of gaining unique insights into the biology of BTC tumors and informing therapeutic therapy of patients with advanced disease. Guardant360 generated next-generation sequencing data from 2068 cfDNA samples from 1671 patients with advanced BTC. 

To evaluate intra-patient cfDNA-tumor concordance and the correlation of cfDNA variable allele fraction (VAF) with clinical outcomes, researchers performed clinical annotation on a subgroup drawn from several different institutions (n=225). cfDNA showed genetic abnormalities in 84% of individuals, with 44% showing alterations that might be treated. In addition, the clonal nature of most cases confirmed the early driver status of targetable changes such Fibroblast growth factor receptor 2 (FGFR2) fusions, isocitrate dehydrogenase 1 (IDH1) mutations, and BRAF V600E in BTC. IDH1 (87%), BRAF V600E (100%), and FGFR2 fusions (18%) all had high concordance between cfDNA and tissue for mutation identification. Mutation of the cysteine residue (FGFR2 C492F) to which covalent FGFR inhibitors bind was one of the novel possible causes of resistance to targeted therapy discovered by cfDNA analysis. 

A high cfDNA VAF worsened the results of chemotherapy and targeted therapy before treatment. Finally, researchers reveal the prevalence of interesting targets in advanced BTC, such as KRAS G12C (1%), KRAS G12D (5%), PIK3CA mutations (68%), and ERBB2 amplifications (4.9%), that are now under research in other advanced solid tumors. These results from the broadest and most thorough research of cfDNA from patients with advanced BTC to yet demonstrate the value of cfDNA analysis in the current therapy of this disease. These findings have important implications for drug development efforts to minimize mortality among BTC patients by elucidating oncogenic drivers and mechanisms of treatment resistance.

Source: sciencedirect.com/science/article/pii/S0923753422041412

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