ctDNA Liquid Biopsy Shows Promise with New Clinical Evidence and Nanotechnology Advances

Circulating tumour DNA (ctDNA) is emerging as a transformative biomarker for non-invasive cancer management, with new clinical trial results supporting its use to guide therapy and ongoing nanotechnology innovations poised to improve detection sensitivity. The phase III IMvigor011 trial has provided one of the most robust datasets supporting ctDNA-guided treatment, demonstrating significantly longer disease-free survival and overall survival in bladder cancer patients.

The IMvigor011 trial utilised ctDNA-based detection of molecular residual disease (MRD) to identify patients at high risk for recurrence after cystectomy for bladder cancer, despite no radiographic evidence of disease, and to guide subsequent adjuvant therapy with atezolizumab. The strategy resulted in significantly longer disease-free survival and overall survival compared with patients who tested ctDNA-positive but received placebo.

However, challenges remain in validating liquid biopsy platforms and standardising protocols for routine clinical implementation. Tumour-derived DNA fragments exist in tiny quantities within a background of non-tumour cell-free DNA (cfDNA), with the variant allele frequency of ctDNA in cfDNA typically ranging from approximately 0.1–10%. This presents a particular issue in patients with early-stage disease or those with low-shedding tumours, as ctDNA levels may fall below the limits of detection even for the most sensitive assays, potentially resulting in false negative results. Widespread clinical adoption of ctDNA is also restricted by limited standardised guidance on how to practically apply the test results.

Several initiatives are underway to address standardisation gaps. The Japanese Society of Clinical Oncology has published a position paper with recommendations on the appropriate clinical use of MRD testing across solid tumours. In Europe, a large-scale French Delphi consensus has produced technical recommendations to standardise ctDNA analysis, where routine use of ctDNA testing for MRD is not currently recommended after treatment with curative intent.

Looking ahead, ctDNA testing is expected to revolutionise cancer management through the discovery of actionable mutations. In breast cancer, a phase III study demonstrated that patients with mutated ESR1 who were switched from an aromatase inhibitor to the selective oestrogen receptor degrader camizestrant experienced a 56% reduction in the risk of disease progression or death compared with patients who continued the aromatase inhibitor. In gynaecological oncology, ctDNA holds transformative potential, enabling non-invasive molecular classification, early detection of recurrence and personalised treatment decisions.

Technological advances are also advancing the field. A recent review in the International Journal of Nanomedicine highlighted how nanotechnology-assisted strategies are accelerating progress in ctDNA detection, including surface-engineered nanomaterials for selective enrichment, nano-enabled signal amplification modalities, and integrated platforms such as CRISPR-based detection, microfluidics and nanopore technologies. The review also noted the increasing incorporation of artificial intelligence in nanostructure characterisation, aptamer and probe design, multi-omics data integration, and algorithm development is reshaping the landscape of nano-assisted liquid biopsy. These innovations are critical for advancing the clinical applicability of ctDNA-based liquid biopsy, particularly for personalised medicine.

Current priorities for the field include harmonising assay standards, building prospective interventional evidence specific to different tumour types, and learning to interpret ctDNA results with appropriate clinical nuance. Interventional trials are required to determine whether ctDNA-guided treatment modifications can have a positive impact on patient outcomes.