Abstract
Breast cancer is one of the most commonly diagnosed cancers worldwide and is a significant contributor to the global cancer burden. It is a clinically heterogeneous disease and reliable tools are needed to support treatment decisions, including patient risk, prediction of therapeutic response and monitoring patients throughout their cancer journey. DNA methylation alterations are an early occurring, highly pervasive and stable modification during tumorigenesis, making DNA methylation an attractive target for the development of biomarkers. In this review, we first provide an overview of DNA methylation and explore its role in cancer, with an emphasis on breast cancer. We then focus on the potential use of tissue- and blood-based DNA methylation biomarkers to inform clinical decision-making in breast cancer paradigms: diagnosis; disease sub-typing; prediction of therapy response to neoadjuvant chemotherapy, endocrine therapy and immunotherapy; prognosis; and the tumor microenvironment. We highlight the significant progress achieved over recent decades in the development of DNA methylation-based biomarkers for breast cancer care. We end by discussing how the integration of advanced research methodologies and bioinformatic tools, and their incorporation into liquid biopsy platforms and ctDNA assays, offer promising opportunities for these biomarkers to be widely adopted in clinical practice.