The Diversity of Liquid Biopsies and Their Potential in Breast Cancer Management

Simple Summary In breast cancer patients, a blood sample contains components from tumor origin as well as those influenced by the tumor disease. Blood samples are being discussed as an early detection method and, under therapy, blood analysis was shown to have the potential of adapting therapy or to detect remaining breast cancer cells to forecast a recurrence. It is clear that blood components can forecast patients' outcomes; however, blood samples for risk estimation are not used in clinical routine. In a subgroup of breast cancer patients, the detection of mutations in a specific gene using cell-free DNA from blood might be suitable for therapy monitoring. In this context, analysis of ESR1 and PIK3CA mutation detection in cfDNA has already been recommended to select targeted therapies. However, the usage of blood for therapy management still has challenges, like a lack of preanalytical and analytic standards and difficulties in proving the clinical utility.Abstract Analyzing blood as a so-called liquid biopsy in breast cancer (BC) patients has the potential to adapt therapy management. Circulating tumor cells (CTCs), extracellular vesicles (EVs), cell-free DNA (cfDNA) and other blood components mirror the tumoral heterogeneity and could support a range of clinical decisions. Multi-cancer early detection tests utilizing blood are advancing but are not part of any clinical routine yet. Liquid biopsy analysis in the course of neoadjuvant therapy has potential for therapy (de)escalation.Minimal residual disease detection via serial cfDNA analysis is currently on its way. The prognostic value of blood analytes in early and metastatic BC is undisputable, but the value of these prognostic biomarkers for clinical management is controversial. An interventional trial confirmed a significant outcome benefit when therapy was changed in case of newly emerging cfDNA mutations under treatment and thus showed the clinical utility of cfDNA analysis for therapy monitoring. The analysis of PIK3CA or ESR1 variants in plasma of metastatic BC patients to prescribe targeted therapy with alpesilib or elacestrant has already arrived in clinical practice with FDA-approved tests available and is recommended by ASCO. The translation of more liquid biopsy applications into clinical practice is still pending due to a lack of knowledge of the analytes' biology, lack of standards and difficulties in proving clinical utility.