Circulating tumor DNA-based detection of molecular residual disease in isocitrate dehydrogenase-mutant cholangiocarcinoma for biomarker-guided therapy.

Cholangiocarcinoma (CCA), particularly the IDH-mutant subtype, presents major clinical challenges because it is frequently diagnosed at an advanced stage and carries a high risk of postoperative recurrence. Detecting minimal residual disease (MRD) is crucial, as it enables early identification of patients at high risk of relapse, guiding personalized adjuvant therapy to prevent recurrence and improve survival. Standard imaging modalities are unable to reliably detect microscopic MRD. In contrast, circulating tumor DNA (ctDNA) has emerged as a promising, non-invasive biomarker for MRD detection in IDH-mutant CCA, supported by the strong concordance between IDH1/2 mutations identified in tumor tissue and those found in plasma. Current first-line therapy for advanced IDH1-mutant disease includes gemcitabine plus cisplatin combined with either durvalumab or pembrolizumab. Ivosidenib is commonly used as a second-line targeted therapy. ctDNA dynamics, such as persistent postoperative or post-chemotherapy positivity or rising levels during treatment with IDH inhibitors, are associated with poorer disease-free and overall survival. Despite its promise, ctDNA-based MRD assessment faces significant biological and technical limitations, including clonal hematopoiesis, low ctDNA fractions in body fluids, high technical costs, and the absence of standardized thresholds. More prospective clinical trials are needed to validate ctDNA-guided risk stratification, support treatment decisions on adjuvant therapy escalation or de-escalation, and enable treatment adaptation in IDH-mutant CCA, ultimately advancing precision oncology beyond the capabilities of imaging alone. This review aims to evaluate the potential of ctDNA-based MRD detection to refine precision treatment strategies in IDH-mutant CCA.