Circulating Tumor DNA-Guided Molecular Interception of Endocrine Resistance in Breast Cancer

Aromatase inhibitor therapy combined with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor is a standard first-line treatment for hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Estrogen receptor 1 (ESR1) mutations commonly emerge under this selective pressure and mediate acquired endocrine resistance. Serial plasma circulating tumor DNA (ctDNA) testing can identify an emerging ESR1-mutant clone before clinical or radiographic progression, creating a potential window for molecular interception. In this review, molecular interception denotes a treatment change prompted by a newly emerging, analytically credible, and actionable resistance alteration while disease remains clinically and radiographically controlled. We review ESR1 clonal evolution, assay selection, preanalytical quality control, confirmation of low-frequency variants, randomized evidence, and practical limits. PADA-1 provided proof of concept. SERENA-6 subsequently showed that, in a defined population receiving first-line aromatase inhibitor plus a CDK4/6 inhibitor, replacing the aromatase inhibitor with camizestrant while continuing the same CDK4/6 inhibitor prolonged progression-free survival. Longer follow-up also showed improvement in second progression-free survival. These findings support the biological and clinical feasibility of ctDNA-guided early switching, but they do not establish superiority over using the same agent after radiographic progression; overall survival data remain immature. Clinical decisions should therefore incorporate assay performance, confirmation that the mutation is truly emergent, exclusion of synchronous progression and dominant non-ESR1 resistance, treatment safety and availability, and patient preference. The evidence remains closely tied to the studied assay, drug combinations, duration of first-line disease control, and absence of visceral crisis; extrapolation beyond these conditions is not justified. Testing every 2–3 months reflects the trial design rather than a universal monitoring standard. Regulatory status also differs across regions. Treatment should follow a locally approved indication or an appropriately governed prospective study and should not be triggered by an isolated positive ctDNA result. Wider use in China will require standardized testing, direct early-versus-late sequencing comparisons, mature survival data, real-world validation, and health-economic evaluation.