ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer

Abstract

Over the past 18 months, recurrent activating mutations within the oestrogen receptor α (ER) LBD have been detected in 15–20% of patients with metastatic ER-positive endocrine-resistant breast cancer The ER LBD mutations confer constitutive ligand-independent activity and are relatively resistant to tamoxifen and fulvestrant treatment These mutations in the gene encoding the ER, ESR1, are detected mainly in metastatic tumours, implicating the clonal selection of these mutations as the mechanism of resistance to therapy Structural studies have shown that the ER LBD mutations lead to ligand-independent stabilization of the LBD in the agonistic conformation To study the clonal evolution and discern the full genetic complexity and clinical significance of the ESR1 mutations, new sensitive sequencing technologies will need to be applied Potential strategies to overcome ER-related endocrine resistance include high-dose fulvestrant and tamoxifen, inhibitors of ER co-activator proteins, novel SERDs and SERMs, and other agents targeting the ER signalling axis