ctDNA in Genetic Profiling and Clinical Outcomes of Advanced Biliary Tract Cancer

Role of Circulating Tumor DNA (ctDNA) in Genetic Profiling and Clinical Outcomes for Advanced Biliary Tract Cancer (BTC) Patients - Prospective, Observational, Epidemiology Study

This prospective, multicenter, observational study aims to evaluate the role of circulating tumor DNA (ctDNA) in advanced or metastatic biliary tract cancer (BTC) patients in Korea. Tissue-based genomic profiling is often limited due to the anatomical challenges of tumor biopsy and insufficient DNA quality. ctDNA analysis offers a minimally invasive alternative for identifying actionable genetic alterations, including Fibroblast Growth Factor Receptor 2 (FGFR2) fusions, Isocitrate Dehydrogenase 1 (IDH1) mutations, and Human Epidermal Growth Factor Receptor 2 (HER2) amplifications. The study will recruit 100 patients across 11 institutions and assess the concordance between ctDNA and tissue genomic profiling, as well as the clinical relevance of ctDNA in predicting treatment outcomes and prognosis.

Biliary tract cancer (BTC) is a heterogeneous and aggressive malignancy with poor prognosis, especially in advanced or metastatic stages where surgical resection is not feasible. The current standard first-line therapy with gemcitabine and cisplatin provides limited survival benefit, with median overall survival around 11-12 months. Targeted therapies, such as FGFR inhibitors for FGFR2 fusions and IDH1 inhibitors, as well as immune checkpoint inhibitors, have improved outcomes in subsets of patients. However, tumor tissue acquisition remains challenging in BTC, limiting the ability to perform comprehensive genomic profiling.

Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for molecular profiling, treatment monitoring, and prognosis assessment. Prior studies demonstrated acceptable concordance between ctDNA-based and tissue-based next-generation sequencing, particularly for FGFR2 fusions, and highlighted the potential of ctDNA in identifying additional genomic alterations not detected in tissue samples.

This prospective study will enroll 100 Korean patients with advanced or metastatic BTC from 11 hospitals. Approximately two-thirds of patients will provide blood samples prior to first-line systemic therapy, while one-third will provide samples before subsequent therapy. Additional blood draws will be performed at progression in patients harboring FGFR2 fusion, IDH1 mutation, or HER2 amplification. Collected samples will be analyzed by a central laboratory (SCL Healthcare, a precision medicine service provider specializing in biomarker-based diagnostics).

The primary objective is to evaluate the frequency of actionable genomic alterations, especially FGFR2 fusions, detected by ctDNA in advanced BTC patients. Secondary objectives include:

• Assessing the concordance between ctDNA and tissue genomic profiling
• Evaluating the proportion of patients who received targeted therapy based on ctDNA results (e.g., pemigatinib [Pemazyre®])
• Exploring associations between ctDNA maximum variant allele frequency (max VAF) and survival outcomes
• Identifying potential resistance mechanisms and clonal evolution during targeted therapy

This study is expected to provide robust evidence for the clinical utility of ctDNA in BTC and contribute to the establishment of precision medicine approaches, potentially supporting future guideline development and regulatory approval of ctDNA assays in Korea and globally.

Inclusion Criteria:

• Histologically confirmed advanced or metastatic biliary tract cancer (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder carcinoma)

• Patients meeting one of the following conditions:

  • Prior to initiation of first-line systemic therapy
  • Patients who previously received systemic therapy and are able to provide a blood sample prior to initiation of subsequent therapy

• Age ≥ 19 years at the time of enrollment

• Willingness and ability to provide blood samples for ctDNA analysis

Exclusion Criteria:

• Refusal to provide blood samples for ctDNA testing
• Inability to provide written informed consent