ESR1 ligand-binding-domain mutation (D538G, Y537S/N/C, L536H, E380Q) acquired in ~30-40%...

Deterministic view of the source YAML entity. Clinical authority remains with the cited source IDs and reviewer sign-off state.

ID	`RF-BREAST-ESR1-MUT-ACTIONABLE`
Type	Red flag
Status	reviewed 2026-04-27 \| pending_clinical_signoff
Diseases	`DIS-BREAST`
Sources	`SRC-EMERALD-BIDARD-2022` `SRC-ESMO-BREAST-METASTATIC-2024` `SRC-NCCN-BREAST-2025`

Red Flag Origin

Definition	ESR1 ligand-binding-domain mutation (D538G, Y537S/N/C, L536H, E380Q) acquired in ~30-40% of HR+/HER2- metastatic breast cancers progressing on aromatase inhibitor. Predictive for elacestrant (oral SERD; EMERALD — mPFS 3.8 vs 1.9 mo in ESR1-mut subgroup) post-AI.
Clinical direction	intensify
Category	high-risk-biology
Shifts algorithm	ALGO-BREAST-HR-POS-2L

Trigger Logic

{
  "any_of": [
    {
      "finding": "esr1_mutation",
      "value": true
    },
    {
      "finding": "esr1_status",
      "value": "mutated"
    },
    {
      "finding": "esr1_lbd",
      "value": "positive"
    }
  ],
  "type": "biomarker"
}

Notes

Test on ctDNA at progression on AI ± CDK4/6i (preferred — high concordance, polyclonal mutations common in tissue). Y537S confers more aggressive biology than D538G in some series. ESR1-WT post-AI patients did not benefit from elacestrant in EMERALD — fulvestrant + capivasertib / alpelisib alternative. Other oral SERDs (camizestrant, giredestrant, imlunestrant) and PROTACs in phase-3 development.

Used By

Algorithms

ALGO-BREAST-HR-POS-2L - ALGO-BREAST-HR-POS-2L

Red flag

RF-BREAST-ESR1-Y537S-D538G-CANDIDATE - ESR1 ligand-binding-domain hotspot Y537S or D538G — the two dominant hotspots (~70% of al...