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Therapeutic yield of extensive molecular profiling in cholangiocarcinoma: a retrospective single-center study
Justine Vancanneyt1, Bie Wilmsen2, Caroline Luyten2
1Department of Gastroenterology, University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium. justine.vancanneyt@gmail.com.
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.
Insights
Extensive molecular profiling identified actionable alterations in 73.6% of advanced cholangiocarcinoma (CCA) patients. Targeted treatments showed improved progression-free survival, supporting molecular analysis for personalized therapy in CCA.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Advanced cholangiocarcinoma (CCA) has limited treatment options and poor prognosis.
- Next-generation sequencing (NGS) has improved understanding of CCA's genetic landscape.
- Identification of molecular alterations enables targeted treatment strategies.
Purpose of the Study:
- To determine the frequency of actionable molecular alterations in advanced CCA using comprehensive profiling.
- To evaluate the impact of targeted therapies on disease control in CCA patients.
- To correlate molecular findings with treatment efficacy and patient outcomes.
Main Methods:
- Retrospective analysis of extensive molecular testing (NGS or gene panels) in locally advanced/metastatic CCA patients.
- Classification of gene variants using the ESCAT system.
- Correlation of identified alterations with clinical efficacy endpoints.
Main Results:
- Actionable alterations (ESCAT tiers I-IV) were found in 73.6% of 125 CCA patients.
- FGFR2 fusions and IDH1/BAP1 mutations were more common in intrahepatic CCA (iCCA), KRAS/SMAD4 in extrahepatic CCA (eCCA).
- Patients receiving targeted therapy (10.4%) had a median progression-free survival (PFS) of 7.3 months.
Conclusions:
- Extensive molecular characterization identifies targetable alterations in a significant proportion of advanced CCA.
- Higher ESCAT tiers correlate with improved outcomes, supporting targeted treatment benefits.
- Molecular analysis is recommended for advanced CCA patients eligible for systemic therapy.
