Introduction. Breast cancer progression is driven by genomic instability and clonal evolution, processes that contribute to tumor heterogeneity, therapeutic resistance, and disease recurrence. Conventional tissue biopsies provide limited information on tumor dynamics because they represent only a single spatial and temporal snapshot of the disease. Circulating tumor DNA (ctDNA), a tumor-derived fraction of cell-free DNA released into the bloodstream, has emerged as a promising non-invasive biomarker capable of capturing tumor genomic alterations in real time. ctDNA analysis may therefore provide insight into tumor evolution and molecular heterogeneity during treatment and disease progression. This investigation aimed to evaluate the role of ctDNA in detecting genomic instability and clonal evolution in breast cancer.
Methods. A systematic review was conducted according to PRISMA 2020 guidelines. Original research articles investigating ctDNA in breast cancer and reporting genomic alterations or clonal dynamics were included, while reviews, editorials, case reports, and studies not involving ctDNA analysis were excluded. A search was performed for studies using the following keywords: circulating tumor DNA, ctDNA, liquid biopsy, breast cancer, genomic instability, and clonal evolution.
Results. In total, 124 records were collected, of which 45 articles were selected for full-text evaluation. Following application of the eligibility criteria, 25 studies published between 2014-2026 were included in the final analysis. ctDNA analysis revealed somatic mutations, copy number alterations, and resistance-associated variants, reflecting tumor heterogeneity and genomic instability. Longitudinal ctDNA monitoring frequently detected emerging resistance mutations prior to clinical progression and was associated with tumor burden and treatment response. In early breast cancer, ctDNA detection predicted molecular relapse before clinical or radiological recurrence.
Conclusions. ctDNA is a promising non-invasive biomarker for detecting genomic instability and monitoring clonal evolution in breast cancer. These findings highlight ctDNA as a powerful tool for capturing tumor dynamics and supporting precision oncology strategies.
