Dynamic circulating tumor DNA profiling of ESR1 mutations in HR+/HER2− advanced breast cancer: from prognostic biomarker to clinical decision-making – a comprehensive review

BACKGROUND: The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is the standard first-line regimen for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). Resistance remains a challenge, with estrogen receptor 1 gene (ESR1) mutations serving as a central mechanism. Liquid biopsy enables non-invasive monitoring via circulating tumor DNA (ctDNA), with ESR1 mutations increasingly recognized as dynamic molecular events rather than static markers. OBJECTIVE: This comprehensive review evaluates the prognostic and predictive value of baseline and on-treatment ctDNA ESR1 mutations in HR+/HER2- advanced breast cancer patients receiving CDK4/6i and ET, and explores their evolution into dynamic intervention nodes for precision decision-making. METHODS: Following PRISMA guidelines, we searched major databases and conference proceedings up to February 2026. Studies reporting ctDNA ESR1 mutations and clinical outcomes in CDK4/6i plus ET-treated patients were included. Due to substantial clinical and methodological heterogeneity, a quantitative meta-analysis was not feasible; instead, a narrative synthesis was performed. RESULTS: Nine high-quality studies met eligibility criteria. Key findings: (1) Baseline ESR1 mutations, particularly Y537S, are adverse prognostic factors; high ctDNA tumor fraction (≥10%) identifies patients deriving greater benefit from first-line CDK4/6i (PFS2 HR 0.58). (2) ctDNA clearance by cycle 2 day 1 predicts prolonged PFS (HR = 0.44). (3) Pre-emptive switching to camizestrant upon ctDNA-detected ESR1 mutations reduced progression risk by 56% (HR = 0.44, P<0.0001) in the SERENA-6 trial. CONCLUSIONS: Baseline ctDNA ESR1 mutations define a more aggressive disease subtype and have evolved from molecular drivers to actionable clinical decision nodes. However, routine clinical adoption requires prospective validation, harmonized testing standards, and consensus on monitoring protocols. This review provides a comprehensive evidence-graded framework to guide future research and clinical implementation.