Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Next-Generation Sequencing of Circulating Tumor DNA for Precision Medicine in Patients with Advanced Biliary Tract Cancers.
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Visa Laura, Badia-Ramentol Jordi, Fernández Maria Concepción, Saurí Tamara, Macías Ismael, Zhang Nicole, Adeva Jorge, Zumstein Lucrezia, Peinado Paloma, Ponz-Sarvisé Mariano, Ceniceros Lucia, Fabregat-Franco Carles, Caramés Cristina, Lopez Ana M, Salinas Pedro, Monzonís Xavier, Masfarré Laura, Sibilio Annarita, Riva François, Cubillo Antonio, Faull Iris, Macarulla Teresa, Iglesias Mar, Bellosillo Beatriz, Montagut Clara
Аннотация
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.
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.