Liquid biopsy in breast cancer: Redefining precision medicine

Abstract

Breast cancer (BC) is the most frequent cancer and the leading cause of cancer-related death among women worldwide. It represents a heterogeneous group of diseases with distinct morphological, immunophenotypic, and molecular profiles, which significantly impact clinical behavior and therapeutic response. Moreover, under treatment pressure, tumor cells may undergo molecular changes and phenotypic plasticity, leading to resistance and therapeutic failure. Although tissue biopsy remains the gold standard for diagnosis and molecular characterization, it has several limitations, including invasiveness, sampling bias, and the inability to dynamically capture tumor evolution over time. Hence, a non-invasive and repeatable approach capable of real-time monitoring is increasingly needed. Liquid biopsy (LB), through the analysis of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), has emerged as a powerful tool to complement tissue biopsy. It allows for longitudinal assessment of tumor burden, detection of minimal residual disease, and identification of molecular alterations relevant to targeted therapies. Despite promising results, the integration of LB into clinical practice is still limited by methodological heterogeneity, standardization gaps, and regulatory issues. Nonetheless, LB represents a key advancement toward precision oncology and may become essential in the personalized management of BC patients. In this review, we explore the current applications, benefits, and technical limitations of LB in different BC settings. We provide a comprehensive overview of the biological and clinical significance of CTCs and ctDNA, emphasizing their diagnostic, prognostic, and predictive roles. Finally, we present an updated summary of ongoing clinical trials that incorporate LB for clinical decision-making.

Keywords: Breast cancer; Circulating tumor DNA; Circulating tumor cells; Liquid biopsy.

Fig. 1

Schematic representation of the strengths and weaknesses of tissue and liquid biopsy approaches. TME: tumor microenvironment; LoD: Limit of Detection; MRD: Minimal Residual Disease. Created with BioRender.com.

Fig. 2

Integrated clinical workflow combining tissue and liquid biopsy (LB) in breast cancer patients' management. The algorithm illustrates the role of LB across different timepoints, including baseline profiling, treatment monitoring, and minimal residual disease detection. The star symbol indicates the only LB application currently approved in clinical practice. Dashed arrows represent time-dependent steps such as MRD surveillance or late treatment adaptation. The dotted arrow suggests that, in real-world settings, a reflex test on metastatic tissue biopsy may still be required in case of inconclusive or uninformative liquid biopsy results (e.g., low ctDNA levels or non-informative profiles). pTNM/ypTNM: pathological tumor staging (pre/post-chemotherapy); RCB: residual cancer burden; MRD: minimal residual disease. Created withBioRender.com.

Fig. 3

Schematic representation of the clinical utility of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) in breast cancer, categorized by level of evidence: green indicates validated and approved applications, yellow indicates strong but still experimental evidence, and red indicates areas with insufficient clinical evidence. Created with BioRender.com.