Clinical value of liquid biopsy in FGFR2 fusion-positive cholangiocarcinoma patients during targeted therapy

Purpose: FGFR2 fusions are observed in approximately 10% to 15% of intrahepatic cholangiocarcinoma (iCCA) patients, and these individuals may benefit therapeutically from approved FGFR inhibitors (FGFRi). In this context, we aimed to assess the feasibility of detecting FGFR2 fusions in plasma and studying plasma biomarkers that may assist in managing patients through treatment with FGFRi. Experimental Design: We conducted a retrospective study in a cohort of 18 patients with iCCA and known FGFR2 fusions or rearrangements previously identified in tissue samples obtained during prior FGFRi treatment. Both tissue and synchronous plasmas were analyzed with a custom hybrid capture gene panel combined with next-generation sequencing (referred to as VHIO-iCCA panel) and further validated through comparison with results obtained from commercial vendors. Longitudinal plasma analysis during FGFRi was performed. Subsequently, we explored the correlation between plasma biomarkers, liver enzymes, tumor volume, and clinical outcomes. Results: Sixteen patients (88.9%) were positive for FGFR2 fusion events in plasma, as evidenced by the detection of circulating tumor DNA (ctDNA) from plasma samples. Remarkably, the analysis of plasma suggests that lower levels of ctDNA are linked to clinical benefits from targeted therapy and result in improved progression-free survival (PFS) and overall survival (OS). Additionally, we observe worse OS in patients exhibiting higher concentrations of cell-free DNA (cfDNA) before FGFRi treatment. Simultaneously, elevated cfDNA levels correlated with impaired liver function, indicating compromised removal of cfDNA by the liver in these patients. Finally, the identification of increased ctDNA or the emergence of resistance mutations enables the earlier detection of disease progression compared to standard radiological imaging methods. Conclusions: VHIO-iCCA demonstrated accurate detection of FGFR2 fusions in plasma. The integration of information from various plasma biomarkers holds the potential to predict clinical outcomes and identify treatment failure prior to radiological progression, offering valuable guidance for the clinical management of patients with iCCA.