Integrating ctDNA-Based ESR1 m Monitoring Into First-Line Care for ER+, HER2– Advanced Breast Cancer: A Consensus Workflow

Circulating tumor DNA (ctDNA) is an emerging tool in precision oncology that enables noninvasive tumor profiling, detection of minimal residual disease, and treatment monitoring. Furthermore, routine ctDNA analyses offer the potential to support more personalized and dynamic cancer care. In advanced breast cancer (aBC), ctDNA-based monitoring has been investigated across multiple studies as a tool for detecting emerging resistance mechanisms, predicting treatment responses and informing biomarker-guided treatment decisions. One example, investigated in the phase III PADA-1 and SERENA-6 trials, is monitoring for emergent estrogen receptor alpha mutations (ESR1m) during first-line endocrine therapy in estrogen-receptor positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) aBC. While not yet widely adopted in clinical practice, broader implementation of routine ctDNA-based monitoring for ESR1m is anticipated and will require standardized diagnostic workflows, encompassing both institutional operational processes and patient-centered scheduling pathways. Insights and recommendations were gathered from multidisciplinary experts across academic and community practices in the US regarding the feasibility, barriers, and operational requirements for implementing ESR1m monitoring during first-line treatment of aBC. Here, we present practical, experience-informed considerations, supplemented by an opinion-based consensus workflow model designed to provide clinicians with a flexible framework for implementing ctDNA-based ESR1m monitoring during first-line care for ER+, HER2- aBC.