Implementing liquid biopsy in HR+/HER2- metastatic breast cancer: challenges and opportunities.

Liquid biopsy (LB) is rapidly transforming the management of hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). In this review, we discuss the most recent findings on circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), exploring their roles across the treatment continuum, from treatment selection to resistance monitoring. ctDNA-based detection of actionable mutations - including ESR1 and PIK3CA - achieved regulatory validation as a primary predictive biomarker for treatment selection, supporting the approval of novel endocrine agents and targeted therapies in HR+/HER2- mBC. Serial ctDNA monitoring demonstrated the ability to intercept emerging resistance mechanisms ahead of radiological progression, opening a window for preemptive therapeutic adaptation. CTCs enumeration maintains robust independent prognostic value, with emerging evidence supporting its role in guiding treatment escalation and de-escalation decisions. Integrated multiparametric LB approaches combining CTCs and ctDNA are crucial to improve prognostic accuracy and clinical decision-making. LB is progressively shifting from a research tool to a clinical decision-making instrument in HR+/HER2- mBC. Prospective interventional trials, methodological standardization, and integrated strategies are needed to fully translate its potential into improved patient outcomes.