ESR1 mutation (ligand-binding domain, usually in ctDNA)

aka ESR1 mutation, ESR1-mutated, ESR1 Y537S, ESR1 D538G, ESR1m, ESR1 mutant breast cancer, acquired ESR1 mutation

ESR1 mutations arise in the oestrogen receptor's ligand-binding domain after aromatase inhibitor treatment, letting the receptor work without oestrogen. They are usually found in a blood test and select the oral SERDs elacestrant and imlunestrant.

Mutations between codons 310 and 547 (Y537S, Y537N, D538G, E380Q and others) are acquired under aromatase inhibitors in 30 to 40 percent of metastatic HR-positive breast cancers and are best detected in plasma cell-free DNA because they are subclonal and heterogeneous. Elacestrant (Orserdu, 2023) is labelled for ER-positive HER2-negative ESR1-mutated advanced breast cancer after at least one line of endocrine therapy, as detected by an FDA-authorised test; imlunestrant (Inluriyo, 2025) for the same population; vepdegestrant was added to the Guardant360 CDx claims in 2026. Guardant360 CDx is the listed companion diagnostic for all three. Guidelines recommend repeat plasma testing at each progression because the mutation appears over time.

Part ofEstrogen receptor (ERα)· ESR1Other readoutsER status All readouts

Estrogen receptor (ERα): what it is and how drugs act on it · animated schematic, not to scale

Target · the protein and the cell it sits on
Drug · antibody, small molecule, cell or radioligand
Effect · signal, damage or kill

In plain words · The hormone switch that drives most breast cancers. Blocking or destroying it is the oldest and most effective targeted therapy.

Sequencing 2 approval thresholds

What it means for a patient

If a blood test finds an ESR1 mutation after your cancer has progressed on an aromatase inhibitor, elacestrant or imlunestrant tablets are on label as the next hormone treatment. The mutation is usually not present at diagnosis, so the blood test is repeated each time the cancer grows; a negative result now does not rule out a positive one later.

Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.

Scoring rule

An ESR1 missense mutation between codons 310 and 547 (or the listed hotspots E380, V422del, S463, L469, L536, Y537, D538) in plasma cell-free DNA or tumour tissue by sequencing.

“ESR1 missense mutations between codons 310 and 547”
FDA: List of FDA-Authorized Companion Diagnostic Devices

Thresholds used in approvals

Threshold	Drug	Cancer	Regulator	Source
ESR1-mutated, after at least one line of endocrine therapy	Elacestrant	HR-positive / HER2-negative breast cancer	FDA	label
ESR1-mutated, after at least one line of endocrine therapy	Imlunestrant	HR-positive / HER2-negative breast cancer	FDA	label

Drugs whose label names it

Elacestrant Imlunestrant

Companion diagnostics (FDA list)

Device	Maker	Indication and sample	Drug	PMA / 510(k)
Guardant360 CDx	Guardant Health	Breast Cancer - Plasma	Elacestrant	P200010/S010 (01/27/2023)
Guardant360 CDx	Guardant Health	Breast Cancer - Plasma	Imlunestrant	P200010/S021 (09/25/2025)

Tests that measure it

FoundationOne Liquid CDx Guardant360 CDx Tempus xT and xT CDx FoundationOne CDx FoundationOne Liquid CDx Guardant360 CDx

Trials that name this readout

Matched on the name and aliases of the readout in the title, setting and summary of each trial; a match is a mention, not proof the readout was an entry criterion.