Circulating tumor DNA in early breast cancer: Evidence, challenges, next steps

Circulating tumor DNA (ctDNA) is a tumor-derived, circulating bioanalyte that can be detected in blood using minimally invasive, blood-based biomarker procedures and has prognostic value in early breast cancer. Quantitative features of ctDNA, including baseline detectability and levels, have shown prognostic potential in early breast cancer by reflecting tumor burden and biologic aggressiveness, thereby supporting risk stratification. Post-treatment ctDNA detection may identify minimal residual disease and can precede radiologic or symptomatic recurrence by several months to years. Nevertheless, ctDNA has not yet been adopted in routine clinical practice in early breast cancer, partly because of biologic constraints, including low and heterogeneous tumor DNA shedding, as well as pre-analytical and analytical variability that can affect testing sensitivity. Ongoing efforts are focused on methodological standardization and clarification of the clinically actionable context. This narrative review examines the challenges in applying ctDNA to early breast cancer, spanning patient selection, sampling logistics, specimen handling, assay performance, and sources of assay failure. The authors outline determinants of ctDNA measurement that restrict the proportion of evaluable patients and limit translation to clinical practice and then summarize evidence supporting ctDNA for early response monitoring during neoadjuvant therapy, postoperative minimal residual disease detection, and longitudinal molecular surveillance. Finally, ctDNA-guided therapeutic interception strategies and emerging multimodal cell-free DNA approaches are discussed.