Clinical Utility and Prognostic Implications of Circulating Cell-Free DNA in Biliary Tract Cancer Journal Article
| Authors: | Cowzer, D.; Darmofal, M.; Seier, K.; Thummalapalli, R.; Walch, H.; El Dika, I.; Khalil, D. N.; Park, W.; Dhyani, A.; Yaqubie, A.; Shin, P.; Gholami, S.; Erinjeri, J.; Wei, A. C.; Yeh, R. Y.; Do, R. K.; Basturk, O.; Shia, J.; Cercek, A.; Schram, A.; Chatila, W. K.; Schultz, N.; O'Reilly, E. M.; Gonen, M.; Berger, M. F.; Solit, D. B.; Abou-Alfa, G. K.; Jarnagin, W.; Harding, J. J. |
| Article Title: | Clinical Utility and Prognostic Implications of Circulating Cell-Free DNA in Biliary Tract Cancer |
| Abstract: | <p>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-na & iuml;ve 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.</p> |
| Keywords: | cholangiocarcinoma; multicenter; open-label |
| Journal Title: | JCO Precision Oncology |
| Volume: | 9 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2025-09-01 |
| Language: | English |
| ACCESSION: | WOS:001572200300001 |
| DOI: | 10.1200/po-25-00355 |
| PROVIDER: | wos |
| Notes: | Article -- e2500355 -- Source: Wos |
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