Dr. Aleksandra Markovets, Director at AstraZeneca Oncology R&D, outlines the transformative role of circulating tumour DNA (ctDNA) in cancer drug development and patient management. ctDNA consists of DNA fragments released by tumour cells into bodily fluids and can be detected through non-invasive liquid biopsies. Its short half-life and specificity make it a valuable biomarker for real-time disease monitoring.
Markovets reviews the wide-ranging utility of ctDNA across the cancer continuum. In early-stage disease, it supports tumour detection, diagnosis, and patient stratification, while in advanced stages, it enables real-time monitoring of treatment response, disease progression, and the emergence of resistance mutations. Depending on application, different assay sensitivities and outputs are required—for example, detecting tumour tissue origin in early diagnosis or achieving very low detection limits in minimal residual disease monitoring.
One focal point of the presentation is the challenge of ctDNA variability in untreated patients. Internal AstraZeneca studies revealed unexpected decreases in ctDNA levels prior to therapy in up to 10% of cases. This variability complicates response evaluation and suggests that stricter definitions—such as complete clearance—may provide more reliable endpoints than traditional percentage drop thresholds.
Another critical issue discussed is signal contamination from clonal hematopoiesis (CHIP). Non-tumour-derived somatic mutations from blood cells can confound ctDNA results, leading to false positives and masking therapeutic effects. Markovets presents data demonstrating how filtering out CHIP signals restores meaningful ctDNA-response correlations with clinical outcomes. Mitigation strategies include sequencing germline samples, applying machine learning classifiers, and using alternative biomarkers like methylation.
AstraZeneca’s strategy is to harness ctDNA to drive earlier interventions, enhance therapy targeting, and improve decision-making across trials. With continued analytical improvements, ctDNA holds the promise of not only complementing but potentially replacing more invasive diagnostic methods in the near future.
