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Next-Generation Sequencing of Circulating Tumor DNA for Precision Medicine in Patients with Advanced Biliary Tract
Laura Visa1,2,3, Jordi Badia-Ramentol2, Maria Concepción Fernández4
1Medical Oncology Department, Hospital del Mar, Barcelona, Spain.
Purpose:
Next-generation sequencing (NGS) tissue testing is recommended in advanced biliary tract cancers (aBTC) due to the increasing approval of targeted therapies. However, tissue NGS is frequently limited by poor access and insufficient tumor material. We exploited circulating tumor DNA (ctDNA) as an alternative for molecular profiling in aBTC.
Experimental Design:
We retrospectively analyzed 10,937 patients with aBTC to characterize the molecular landscape and assess the clinical validity of ctDNA profiling. In a second retrospective cohort of 126 patients from nine Spanish referral centers with available clinical and tumor tissue annotations, paired tissue and ctDNA NGS testing and turnaround time (TAT) were evaluated. Blood samples were analyzed using a comprehensive ctDNA NGS assay (Guardant Health). Genomic alterations (GA) were classified according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT).
Results:
In the global cohort, ctDNA NGS revealed a molecular landscape comparable with tissue-based sequencing, including detection rates of ESCAT actionable GA. Higher ctDNA burden was associated with worse overall survival [27.7 months (95% confidence interval [CI], 24.1-33.8) in undetectable ctDNA, 18.5 months (95% CI, 16.7-20.2) in low ctDNA burden, and 13.6 months (95% CI, 12.5-15) in high ctDNA burden; log-rank P < 0.0001]. In the independent cohort, ctDNA NGS was available in 90% of patients versus 50% for tissue NGS. Overall concordance for ESCAT GA was 83%, including 80% for FGFR2 fusions. Median TAT was shorter for ctDNA than for tissue (8 vs. 27 days). Survival seemed longer in the small subset receiving ESCAT-matched therapy.
Conclusions:
In this retrospective analysis, ctDNA represents a practical alternative to tumor tissue for NGS-based biomarker testing in aBTC, offering improved access and faster results. See related commentary by Au and Tie, p. 4221.
Insights
Liquid biopsy using cell-free DNA (ctDNA) next-generation sequencing (NGS) is a practical alternative to tissue testing for advanced biliary tract cancers (aBTC). ctDNA profiling offers improved access and faster results for molecular characterization in aBTC patients.
Area of Science:
- Oncology
- Molecular Diagnostics
- Genomics
Background:
- Next-generation sequencing (NGS) of tumor tissue is recommended for advanced biliary tract cancers (aBTC) to identify actionable genomic alterations (GA) for targeted therapies.
- Tissue NGS is often limited by inadequate tumor samples and difficult tumor access in aBTC.
- Cell-free DNA (ctDNA) profiling presents a potential alternative for molecular characterization in aBTC.
Purpose of the Study:
- To evaluate the utility of ctDNA next-generation sequencing (NGS) as a surrogate for tissue NGS in advanced biliary tract cancers (aBTC).
- To characterize the molecular landscape of aBTC using ctDNA.
- To assess the clinical validity, concordance, and turnaround time (TAT) of ctDNA profiling compared to tissue NGS.
Main Methods:
- Retrospective analysis of 10,937 aBTC patients for molecular landscape characterization using ctDNA.
- Evaluation of paired tissue and ctDNA NGS testing, including turnaround time (TAT), in a separate cohort of 126 aBTC patients from nine Spanish centers.
- Genomic alterations (GA) classified according to the European Society for Clinical Oncology (ESCAT) criteria.
Main Results:
- ctDNA-NGS revealed a molecular landscape comparable to tissue sequencing, with similar detection rates for ESCAT-actionable GAs.
- Higher ctDNA burden was significantly associated with worse overall survival (log-rank p<0.0001).
- ctDNA-NGS testing was feasible in 90% of patients versus 50% for tissue NGS, with 83% overall concordance for ESCAT GAs and a shorter median TAT (8 vs. 27 days).
Conclusions:
- ctDNA represents a practical and accessible alternative to tumor tissue for NGS-based biomarker testing in aBTC.
- ctDNA profiling provides faster results and comparable molecular information to tissue-based testing.
- This approach may facilitate timely treatment decisions and improve outcomes for aBTC patients.
