JCO precision oncology · 2025
Clinical Utility and Prognostic Implications of Circulating Cell-Free DNA in Biliary Tract Cancer.
СтатьяНазвание и аннотация: Перевод в очереди
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Cowzer Darren, Darmofal Madison, Seier Kenneth, Thummalapalli Rohit, Walch Henry, El Dika Imane, Khalil Danny N, Park Wungki, Dhyani Aruj, Yaqubie Amin, Shin Paul, Gholami Sepideh, Erinjeri Joseph, Wei Alice C, Yeh Randy, Do Richard K, Basturk Olca, Shia Jinru, Cercek Andrea, Schram Alison, Chatila Walid K, Schultz Nikolaus, O'Reilly Eileen M, Gonen Mithat, Berger Michael F, Solit David B, Abou-Alfa Ghassan K, Jarnagin William, Harding James J
Аннотация
PURPOSE: An estimated 25% of patients with biliary tract cancer (BTC) do not undergo genotyping, representing a missed opportunity for therapeutic targeting.
METHODS: Cell-free DNA (cfDNA) and matched tumor sample from patients with BTC were analyzed using targeted next-generation sequencing (NGS) assay and compared. We sought to define the molecular profile of cancer-derived cfDNA, frequency of OncoKB level 1/2 alterations, plasma:tumor genotype concordance, the prognostic impact of cfDNA, and clonal evolution after targeted therapy progression.
RESULTS: cfDNA-based genotyping was performed on 297 blood samples from 170 patients with BTC. The most frequently altered genes were TP53 (29%), FGFR2 (16%), ARID1A (13%), CDKN2A (11%), and KRAS (11%); 25% of patients had OncoKB level 1/2 alterations and 36.2% of potentially actionable alterations were detected in plasma alone. The cfDNA:tissue concordance accuracy was high (96% IDH1, 98% BRAF, 92% KRAS mutations, 99% ERBB2 amplifications, and 96% FGFR2 fusions). Detectable tumor-derived cfDNA after resection did not predict recurrence. In treatment-naïve metastatic BTC, high variant allele fraction was associated with worse progression-free survival and overall survival. RAS alterations not detected in samples before treatment were identified at progression in 24% of patients who received BRAF-, FGFR-, or HER2-directed therapy, identifying RAS alterations as a convergent mechanism of targeted therapy resistance.
CONCLUSION: Molecular profiling of cfDNA from patients with BTC identified OncoKB level 1/2 gene alterations and putative genomic resistance mechanisms to targeted therapy. Concordance analysis suggests that cfDNA-based NGS is complementary to that of tissue-based sequencing in the identification of potentially actionable alterations.
METHODS: Cell-free DNA (cfDNA) and matched tumor sample from patients with BTC were analyzed using targeted next-generation sequencing (NGS) assay and compared. We sought to define the molecular profile of cancer-derived cfDNA, frequency of OncoKB level 1/2 alterations, plasma:tumor genotype concordance, the prognostic impact of cfDNA, and clonal evolution after targeted therapy progression.
RESULTS: cfDNA-based genotyping was performed on 297 blood samples from 170 patients with BTC. The most frequently altered genes were TP53 (29%), FGFR2 (16%), ARID1A (13%), CDKN2A (11%), and KRAS (11%); 25% of patients had OncoKB level 1/2 alterations and 36.2% of potentially actionable alterations were detected in plasma alone. The cfDNA:tissue concordance accuracy was high (96% IDH1, 98% BRAF, 92% KRAS mutations, 99% ERBB2 amplifications, and 96% FGFR2 fusions). Detectable tumor-derived cfDNA after resection did not predict recurrence. In treatment-naïve metastatic BTC, high variant allele fraction was associated with worse progression-free survival and overall survival. RAS alterations not detected in samples before treatment were identified at progression in 24% of patients who received BRAF-, FGFR-, or HER2-directed therapy, identifying RAS alterations as a convergent mechanism of targeted therapy resistance.
CONCLUSION: Molecular profiling of cfDNA from patients with BTC identified OncoKB level 1/2 gene alterations and putative genomic resistance mechanisms to targeted therapy. Concordance analysis suggests that cfDNA-based NGS is complementary to that of tissue-based sequencing in the identification of potentially actionable alterations.