From:  ESR1 mutations in ER-positive breast cancer: from endocrine resistance to ctDNA-guided therapeutic interception

 Common ESR1 mutations in metastatic ER+ breast cancer and their functional implications.

ESR1 mutationFrequencyLocationFunctional consequenceClinical impactReferences
E380QLess common (1.1–10% of ESR1 mutations)LBD (outside helix 12)Ligand-independent activity; estradiol hypersensitivity; increased DNA bindingEndocrine resistance may be associated with a higher tumor mutational burden, distinct from H11-12 mutations[31, 33–35]
D538GMost common in tissue (38–45%); variable in ctDNAHelix 12, LBDConstitutive ER activation; retains enhanced estrogen responsiveness; altered chromatin bindingReduced AI efficacy; retained SERD sensitivity; associated with shorter PFS on exemestane monotherapy (2.69 vs. 3.94 months); may drive CDK4/6i resistance[17, 30, 39–42]
Y537SSecond most common in tissue (25–42%); variable in ctDNAHelix 12, LBDConstitutive ER activation; complete ligand independence; higher coactivator affinity than D538GReduced AI efficacy; retained SERD sensitivity; associated with worse OS (19.98 months) than D538G (25.99 months); may drive CDK4/6i resistance[17, 30, 39–43]
Y537N and Y537CCommon (Y537N ~10%; Y537C ~3–10%)Helix 12, LBDConstitutive ER activation; ligand-independent growthSimilar to Y537S; differential drug sensitivities across anti-estrogen classes[33, 38]
Multiple/Polyclonal26–36% of ESR1-mutant casesVariousCompound resistance mechanisms; clonal heterogeneityComplex treatment selection may require combination approaches; variable prognosis depending on specific mutations present[17, 34, 38]
Both Y537S + D538G~D538G (21.1%) and Y537S (13.3%) of ESR1-mutant casesHelix 12, LBDDual constitutive activation pathwaysReported in a single cohort analysis to have poor outcomes (median OS 15.15 months); requires independent validation; may reflect higher overall ctDNA burden rather than specific mutational combination[42]
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AI: aromatase inhibitor; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; ctDNA: circulating tumor DNA; ER+: estrogen receptor-positive; LBD: ligand-binding domain; OS: overall survival; PFS: progression-free survival; SERD: selective estrogen receptor degrader.