ESR1 mutations in HR+/HER2− advanced breast cancer: ctDNA-guided detection and treatment sequencing

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Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer is the most common molecular subtype of advanced breast cancer (ABC). The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) has become the standard first-line treatment and has improved outcomes for many patients. However, disease progression remains nearly inevitable and reflects a heterogeneous resistance state rather than isolated CDK4/6i failure. Among resistance mechanisms, ESR1 mutations are the most clinically relevant markers of acquired endocrine resistance. They emerge under aromatase-inhibitor selection pressure, stabilize ligand-independent estrogen receptor (ER) signaling, and directly compromise estrogen-deprivation strategies while preserving ER as a therapeutic vulnerability. Circulating tumor DNA (ctDNA) testing has reframed these mutations as dynamic markers of clonal evolution, enabling detection of emerging ESR1 -mutant clones before radiographic progression and defining a window of “molecular progression” that can be acted upon. The PADA-1 trial established proof of concept for switching ET at molecular progression, and the confirmatory phase III SERENA-6 trial led to regulatory approval of the oral selective estrogen receptor degrader camizestrant for ESR1 -mutated ABC. The first proteolysis-targeting chimera ER degrader, vepdegestrant, has likewise been approved in the ESR1 -mutant setting. In this review, we focus on this ctDNA-guided “detect-and-switch” paradigm. We summarize the structural biology and clonal dynamics of ESR1 mutations, critically appraise the evidence for endocrine switching at molecular progression together with its remaining limitations. We also integrate emerging ER-targeted agents, pathway-directed combinations, and antibody-drug conjugates into an ESR1 -based treatment-sequencing framework after CDK4/6i progression.