Noninvasive biomarkers in thymic epithelial tumors: a systematic review of cfDNA/ctDNA detection, molecular profiling, and organoid-based monitoring

Background: Thymic epithelial tumors (TETs), including thymomas and thymic carcinomas, are rare malignancies with limited treatment options and no established biomarkers for surveillance. Circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) provide a non-invasive method for understanding tumor biology, detecting minimal residual disease (MRD), and possibly identifying recurrence. While this approach has added to the management of other solid tumors, its role in TETs remains poorly defined. The objective of this review was to evaluate the feasibility, molecular insights, and clinical utility of cfDNA and ctDNA for diagnosis, molecular profiling, and recurrence monitoring in TETs. Methods: This systematic review summarizes the current evidence on cfDNA and ctDNA in TETs. Studies were identifies through systematic searches of PubMed, Embase, Web of Science, MEDLINE, Cochrane Library, and American Society of Clinical Oncology (ASCO) meeting abstracts from inception through July 2025. Eligible studies reported cfDNA or ctDNA analysis in patients with histologically confirmed thymoma or thymic carcinoma, and excluded reviews, commentaries, abstracts without full text, and non-blood based liquid biopsy studies. Data extraction included patient characteristics, assay platforms, mutational findings, and clinical applications. Data were synthesized narratively due to methodological heterogeneity. No formal risk of bias assessment was performed because of the small number of included studies. Results: , and other variants. Liquid biopsy enabled genomic profiling at diagnosis and dynamic monitoring during treatment. Notably, several studies have suggested that disease recurrence may be detectable through liquid biopsy prior to the appearance of radiographic changes on conventional imaging. Despite these promising observations, evidence remains limited by small sample size, variability in assay methods, and short follow up duration. Conclusions: Liquid biopsy approaches based on cfDNA and ctDNA have shown applicability in TETs and provide clinically relevant molecular information in settings where tissue-based analysis is limited. Tumor informed ctDNA strategies show particular promise for postoperative monitoring and longitudinal disease assessment, whereas broader clinical adoption remains investigational. Further prospective, multicenter studies are needed to establish standardized workflows and clarify the role of liquid biopsy across diagnostic, therapeutic, and surveillance contexts in TETs.