National clinical study

Value of ctDNA for Precision Medicine in Treatment-Refractory Biliary Tract Cancer

Cholangiocarcinoma (CCA) is rare in the Western world, with approximately 250 new cases annually in Denmark. Recurrence after surgery is common, and for inoperable or metastatic CCA, prognosis remains poor, with a median survival under one year. First-line palliative treatment extends survival by only a few months, and second-line chemotherapy off ers limited additional benefi t. There is an urgent need to identify new treatment targets and establish predictive and prognostic markers.

The project received funding in 2024.

Abstract

Cholangiocarcinoma (CCA) is rare in the Western world, with approximately 250 new cases annually in Denmark. Recurrence after surgery is common, and for inoperable or metastatic CCA, prognosis remains poor, with a median survival under one year. First-line palliative treatment extends survival by only a few months, and second-line chemotherapy offers limited additional benefit. There is an urgent need to identify new treatment targets and establish predictive and prognostic markers.

The molecular landscape of CCA is highly heterogeneous, with potentially actionable oncogenic alterations identified in some patients. Targeted treatments have demonstrated survival benefits in these cases, and molecular analysis is recommended for patients with advanced disease eligible for systemic treatment. Tumor tissue analysis is standard for identifying candidates for targeted therapy but may not provide a comprehensive view of a tumor’s genetic heterogeneity or clonal evolution. Additionally, repeated biopsies are invasive, costly, and carry procedural risks. However, clinical evidence supporting ctDNA use in CCA patients is limited compared to other cancer types, emphasizing the need for further research.

Retrospective studies in small patient samples have demonstrated that oncogenic alterations in cfDNA and ctDNA are detectable in CCA patients using smaller panels. The correlation between tissue based and blood based genomic profiling has only been dealt with in very studies using small or in intermediate size panels demonstrating good correlation between blood and tissue based genomic profi ling in Asian patients. However, similar data are lacking in non-Asian cohorts, which limits applicability due to known regional diff erences in CCA biology.

Comprehensive genomic profiling is costly, and it’s crucial that the most relevant patients are selected for this analysis. In this study, we wish to address a more cost-effective approach to prediction medicine by evaluating if it is possible to i) select those patients who are most likely to benefit from comprehensive genomic profiling based upon prognostic markers and amount of cfDNA and ii) to replace tissue based comprehensive genomic profiling with blood based profi ling for treatment selection.

Patient samples from two clinical cohorts, The OPRA Trial and The CHOCA trial, will be analyzed both quantitively and qualitatively. Initially, samples will be evaluated with respect to ctDNA levels using quantitative methods (ddPCR analysis of specific DNA methylation patterns (HOXA9) and total cfDNA Quantification by direct fl uorescent assay (DFA)), thus identifying patient samples for further comprehensive genomic profiling. These patient samples will be analyzed qualitatively using TSO500 ctDNA analyses for identifying clinically relevant genomic findings. Results from blood based genomic profiling will ultimately be correlated to tissue based comprehensive genomic profiling performed in the OPRA Trial (WGS/WES and RNA sequencing), and correlated to clinical outcome data (number of potentially targetable variants, number of patients allocated to treatment based upon comprehensive genomic profiling, and OS).

The study is a collaboration between The Department of Clinical Oncology and The Department of Molecular Medicine, Aarhus University Hospital, as well as with Department of Biochemistry, Vejle Hospital and Department of Oncology, Herlev Sygehus and will ultimately also involve a collaboration with The Phase 1 Unit, RH.

The limited data on ctDNA’s role in CCA, combined with precision medicine's potential, have driven the formation of a national collaboration for ctDNA studies in CCA. This project aims at improving selection of CCA patients for comprehensive genomic profiling using ctDNA, thus improving precision medicine for this group of hard to treat patients. The study will be the foundation for at least one PhD study evaluating ctDNA in CC, supported by seed funding from the ctDNA research center for future larger funding applications. The results will contribute to a greater understanding of ctDNA in CCA research.

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