Therapeutic yield of extensive molecular profiling in cholangiocarcinoma: a retrospective single-center study

Introduction Current available systemic therapies for advanced cholangiocarcinoma (CCA) are of limited effectiveness and prognosis is poor. Recently, introduction of next-generation sequencing (NGS) technologies led to a better understanding of the genetic pathophysiology and, consequently, identification of molecular alterations for targeted treatment. Aim To determine the proportion of actionable alterations using extensive molecular profiling in a routine diagnostic setting and to study the effect of targeted treatment on disease control. Methods Results of extensive molecular testing by either FoundationOne NGS or an in-house developed 96 cancer gene panel were retrospectively collected from patients with locally advanced or metastatic CCA diagnosed between 01/12/2018 and 01/08/2021 in a single center. Gene variants were classified according to ESCAT and correlated with efficacy endpoints. Results Of 125 patients included, 65 patients had an intrahepatic CCA (iCCA). FGFR2 fusions and IDH1/BAP1 mutations were more frequent in iCCA, while KRAS and SMAD4 mutations were predominant in extrahepatic CCA (eCCA). Targetable alterations (ESCAT tiers I–IV) were identified in 73,6% of patients. Overall survival was significantly better for higher tiers regardless of treatment. Thirteen patients (10.4%) received targeted treatment based on molecular profiling, with a median progression-free survival (PFS) of 7.3 months. Conclusions Extensive molecular characterization led to the identification of targetable and potentially targetable alterations in a significant proportion of patients with locally advanced or metastatic CCA. We confirmed the association between higher ESCAT tier and benefit of a targeted treatment. Molecular analysis should therefore be considered in all patients fit enough for systemic treatment.