ESR1 Mutations in Breast Cancer

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Breast cancer
ESR1m

ESR1m

Jump to:

Role of ESR1
Prevalence
Testing Recommendations
ctDNA-Mediated Testing to Detect ESR1m
Sponsored Testing
Considerations for Your Practice
Helpful Resources

Role of ESR1

ESR1 is the gene encoding estrogen receptor alpha (ERα), a key driver of hormone-dependent cancers¹

This is particularly evident in estrogen receptor-positive (ER+) breast cancer, including HR+/HER2-, where ESR1 promotes tumor growth.

ESR1 mutations may promote breast cancer tumor growth through estrogen-mediated transcriptional regulation³

Acquired resistance

ESR1m is an acquired mutation that evolves frequently through resistance to endocrine therapy (ET).^4-7

Proactive identification and ESR1m interpretation

Identify ESR1m as quickly as possible, as these mutations may lead to disease progression and poorer patient outcomes.⁴

ctDNA, circulating tumor DNA; ESR1m, estrogen receptor 1 mutation; HR+, hormone receptor-positive; HER2-, human epidermal growth factor receptor-negative.

ESR1 Mutation Prevalence: ESR1 Mutations Are Not Commonly Present at Diagnosis of Metastatic Breast Cancer (mBC) in Patients Who Are Endocrine Therapy (ET) Naive^3-8

~6%

of patients who are ET naive carry an ESR1 mutation, which is detected when tested at mBC diagnosis^3,8

Exposure to aromatase inhibitors (AIs) during 1L treatment leads to the emergence of endocrine resistance^8,9

Among patients who typically receive AIs in the metastatic setting

nearly

40%

acquire ESR1 mutations^4,9

1L, first-line.

Testing Recommendations for ESR1m^7,9-14

ESR1 mutations may signal development of endocrine resistance⁹

Early and routine testing for ESR1m in addition to ESR1m analysis provides a pivotal opportunity to impact patient outcomes in breast cancer because its emergence precedes radiographic or clinical evidence of disease progression.⁷

Who to test:

Patients with HR+/HER2- mBC on ET^1,10,14

How to test:

NGS, PCR^10,14

When to test:

Early and repeatedly: Establish a cadence for repeat testing^4,7

ESR1m detection is highest between months 6-30 on ET.¹⁵

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) recommend evaluating ESR1m status through NGS or PCR^10,14

NCCN Guidelines^® recommend testing ESR1m through NGS or PCR (blood samples preferred).^10,14

ctDNA is a validated method for identifying ESR1m.^11-14

ESR1m ctDNA Testing Options Overview^16-38

Laboratory	Assay name/platform	Technology	FDA-approved test
Guardant Health	Guardant360^® CDx	NGS (Large panel CGP)
Foundation Medicine	FoundationOne^® Liquid CDx	NGS (Large panel CGP)
Thermo Fisher Scientific	Oncomine^TM Precision Assay	NGS (Small panel CGP)
Caris Life Sciences	Caris Assure^®	NGS (Large panel CGP)	RUO
Labcorp	Labcorp Plasma Complete Portfolio	NGS (Large panel CGP)	RUO
NeoGenomics	NEO PanTracer LBx Assay	NGS (Large panel CGP)	RUO
Roche	AVENIO ctDNA Expanded Kit V2	NGS (Large panel CGP)	RUO
Thermo Fisher Scientific	Oncomine^TM Pan-Cancer Cell-Free Assay	NGS (Large panel CGP)	RUO
Tempus	Tempus^® xF+ Liquid Biopsy Assay	NGS (Large panel CGP)	RUO
BostonGene	BostonGene Liquid Biopsy	NGS (Large panel CGP)	RUO
CSI/Fulgent	Lumera^® Liquid Biopsy	NGS (Large panel)	RUO
Pillar Biosciences	OncoReveal^TM Essential LBx	NGS (Small panel)	RUO
BillionToOne	Northstar Select^®	NGS (Small panel)	RUO
APIS Assay Technologies	ESR1 Mutations qPCR Kit	qPCR	RUO
Biotechne/Asuragen	Quantidex^® qPCR ESR1 exoMutation Kit	qPCR	RUO
Thermo Fisher Scientific	Oncomine^TM Breast cfDNA Assay	qPCR/dPCR	RUO
Bio-Rad Laboratories	ddPLEX ESR1 Mutation Detection Kit	dPCR	RUO
QIAGEN	IDNAPTEX ESR1 (Primers and Probes Set for ESR1 Mutation Detection)	dPCR	RUO
Stilla Technologies	Stilla ESR1 (17 mutations) Crystal Digital PCR^® Assay	dPCR	RUO
APIS Assay Technologies	APIS ESR1 dPCR Kit	dPCR	RUO
Biodesix	ddPLEX ESR1 Mutation Detection Kit	dPCR	RUO

CDx, companion diagnostic; CGP, comprehensive genomic profiling; ctDNA, circulating tumor DNA; ddPCR, droplet digital polymerase chain reaction; dPCR, digital polymerase chain reaction; FDA, US Food and Drug Administration; LBx, liquid biopsy; NGS, next generation sequencing; qPCR, quantitative polymerase chain reaction; RUO, research use only; VAF, variant allelle frequency.

CDx, companion diagnostic; cfDNA, cell-free DNA; CGP, comprehensive genomic profiling; ctDNA, circulating tumor DNA; dPCR, digital polymerase chain reaction; ESR1, estrogen receptor 1; ESR1m, estrogen receptor 1 mutation; ET, endocrine therapy; FDA, US Food and Drug Administration; HR+, hormone receptor-positive; HER2, human epidermal growth factor receptor 2; LBx, liquid biopsy; mBC, metastatic breast cancer; NCCN, National Comprehensive Cancer Network; NGS, next-generation sequencing; PCR, polymerase chain reaction; qPCR, quantitative polymerase chain reaction; RUO, research use only.

Utilizing ctDNA-Mediated Testing to Detect ESR1m¹¹

ctDNA-mediated testing with liquid biopsy (blood samples) identifies tumor-specific genomic alterations in patients with metastatic breast cancer
NGS panel tests should be performed on blood samples
At present, FDA-approved companion diagnostic tests for ESR1 mutations are available for plasma specimens only^39,40
While ESR1 alterations may be identified through tissue-based genomic profiling, tissue assays are not FDA approved for ESR1 mutation detection and may not reflect acquired or heterogeneous resistance mechanisms^39,40

NCCN Guidelines do not recommend testing with primary archived tissue given the acquired nature of ESR1m.¹⁰

Benefits of ctDNA assays to detect mutations¹¹

Less invasive
Analytically validated
Assesses multiple tumor locations in breast cancer

ctDNA testing options overview^{26,30,34,41,42}

Method	Turnaround time	Results	Potential impact
NGS	7-14 days	Comprehensive genomic data	More informed decision-making
PCR	1 day	Efficient ESR1 results only (single-gene test)	Faster decision-making

Detailed PCR testing overview⁴³

PCR method	Detection timing	Quantification type	Assay type
qPCR	Real time	Relative	Quantitative with standard curves
dPCR	End point	Absolute	Qualitative
ddPCR	End point	Absolute	Qualitative

When determining which method is appropriate for your patient and practice, consider the functional differences between timing, cost, and reporting characteristics.

ctDNA, circulating tumor DNA, ddPCR, digital polymerase chain reaction; dPCR, droplet digital PCR; ESR1, estrogen receptor 1; ESR1m, estrogen receptor 1 mutation; FDA, US Food and Drug Administration; NGS, next-generation sequencing; PCR, polymerase chain reaction; qPCR, quantitative polymerase chain reaction.

ESR1m Sponsored Testing Program

Only test-eligible patients meet the criteria for the sponsored testing program; please review eligibility before ordering.

HCP attests that:

The patient has histologically confirmed HR‑positive, HER2‑negative locally advanced breast cancer and is on first‑line endocrine treatment
The patient is on CDK4/6 and aromatase inhibitor (AI) therapy with no evidence of progression
Testing of the patient’s sample is consistent with the Guardant Assay CDx label
The patient’s insurance does not cover repeat NGS testing prior to radiological progression
This test will be used for ESR1 monitoring
The ESR1 test is clinically appropriate and medically necessary for the patient

To order an ESR1 Sponsored Test, visit the Guardant website at:
https://www.ghsponsoredtesting.com/Ordering

NOTE: Even if you typically order Guardant Health test(s) through your EMR, ESR1 Sponsored Testing Program orders must be submitted by following the website link.

Have questions?

Call the Guardant360® CDx Helpline at 855-698-8887.

Terms and Conditions

The ESR1 Sponsored Testing Program covers only the cost of the test. The Program does not cover any additional services associated with the patient’s treatment, including the cost of blood collection. No patients, providers, or payers, including government payers, are billed for the Program. Providers may not seek reimbursement from the patient or third‑party payer (including commercial health plans and government health care programs) for Guardant360® CDx or other services provided in connection with the Program. AstraZeneca does not receive patient or provider identifiable information in connection with the Program. AstraZeneca retains the right to amend or rescind the Program at any time. While AstraZeneca provides financial support for the Program, tests and services are performed by Guardant Health. AstraZeneca assumes no liability and provides no warranties for the testing services provided by Guardant Health. The Program is available only in the United States in the 50 states and the District of Columbia.

CDK4/6, cyclin-dependent kinase 4/6; CDx, companion diagnostic; EMR, electronic medical records; ESR1, estrogen receptor 1; ESR1m, estrogen receptor 1 mutation.

Considerations for Your Practice

Collaboration between pathologists, medical oncologists, or tumor boards on ESR1m testing may help improve patient care.^7,44

Integrating ctDNA-mediated repeat ESR1m testing into pathology workflows may help to identify the emergence of endocrine resistance, a valuable insight for your care team¹⁰
Evaluating your lab’s capacity for ctDNA-mediated ESR1m testing, especially as demand increases with guideline-based adoption of liquid biopsy testing, enables preparedness
Providing evidence-based guidance on ESR1m testing for treatment decisions^10,14
Choosing a digital form of ordering vs manual forms improves your ordering experience

View educational resources that can help facilitate testing conversations between you and your patients with breast cancer in the Resource Library.

ctDNA, circulating tumor DNA; ESR1m, estrogen receptor 1 mutation.

Helpful Resources

Check out these featured resources on ESR1m biomarker testing in metastatic breast cancer.

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Xia S, Lin Q. Estrogen receptor bio-activities determine clinical endocrine treatment options in estrogen receptor-positive breast cancer. Technol Cancer Res Treat. 2022;21:15330338221090351. doi:10.1177/15330338221090351
Clatot F, Perdrix A, Beaussire L, et al. Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer. Breast Cancer Res. 2020;22(1):56. doi:10.1186/s13058-020-01290-x
Grinshpun A, Chen V, Sandusky ZM, Fanning SW, Jeselsohn R. ESR1 activating mutations: from structure to clinical application. Biochim Biophys Acta Rev Cancer. 2023;1878(1):188830. doi:10.1016/j.bbcan.2022.188830
Allouchery V, Beaussire L, Perdrix A, et al. Circulating ESR1 mutations at the end of aromatase inhibitor adjuvant treatment and after relapse in breast cancer patients. Breast Cancer Res. 2018;20(1):40. doi:10.1186/s13058-018-0968-0
Beije N, Sieuwerts AM, Kraan J, et al. Estrogen receptor mutations and splice variants determined in liquid biopsies from metastatic breast cancer patients. Mol Oncol. 2018;12(1):48-57. doi:10.1002/1878-0261.12147
Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol. 2016;2(10):1310-1315. doi:10.1001/jamaoncol.2016.1279
Fribbens C, Garcia Murillas I, Beaney M, et al. Tracking evolution of aromatase inhibitor resistance with circulating tumour DNA analysis in metastatic breast cancer. Ann Oncol. 2018;29(1):145-153. doi:10.1093/annonc/mdx483
Bhave MA, Quintanilha JCF, Tukachinsky H, et al. Comprehensive genomic profiling of ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(−) metastatic breast cancer: prevalence along treatment course and predictive value for endocrine therapy resistance in real‑world practice. Breast Cancer Res Treat. 2024;207(3):599-609. doi:10.1007/s10549-024-07376-w
Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. doi:10.1186/s13058-021-01462-3
Gradishar WJ, Moran MS, Abraham J, et al. NCCN Guidelines^® insights: breast cancer, version 4.2023. J Natl Compr Canc Netw. 2023;21(6):594-608. doi:10.6004/jnccn.2023.0031
Pascual J, Attard G, Bidard FC, et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2022;33(8):750-768. doi:10.1016/j.annonc.2022.05.520
Shaw J, Page K, Ambasger B, et al. Serial postoperative ctDNA monitoring of breast cancer recurrence. Abstract 562. J Clin Oncol. 2022;40(suppl 16):562. doi:10.1200/JCO.2022.40.16_suppl.562
Gawel SH, Jackson L, Jeanblanc N, Davis GJ. Current and future opportunities for liquid biopsy of circulating biomarkers to aid in early cancer detection. J Cancer Metastasis Treat. 2022;8(5):26. doi:10.20517/2394-4722.2022.13
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Breast Cancer V.4.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed June 15, 2026. To view the most recent and complete version of the guideline, go online NCCN.org
Dawood S. Implementing SERENA6 in the clinic in the UAE: critical thinking of a community oncologist. ESMO Open. 2025;10(11):105849. doi:10.1016/j.esmoop.2025.105849
Guardant Health. Technical information. Accessed May 15, 2026. https://www.guardantcomplete.com/assets/pdf/Guardant360-CDx-Technical-Information-US.pdf
Foundation Medicine. FoundationOne^®Liquid CDx: Technical specifications. Accessed May 15, 2026. https://www.foundationmedicine.com/sites/default/files/media/documents/2023-10/F1LCDx_Technical_Specs_072021-2.pdf
Foundation Medicine. Our Proven Portfolio. That’s Our Foundation. Accessed May 15, 2026. https://www.foundationmedicine.com/portfolio
ThermoFisher. Oncomine Precision Assay on the Genexus System. Accessed May 15, 2026. https://www.thermofisher.com/us/en/home/clinical/preclinical-companion-diagnostic-development/oncomine-oncology/oncomine-precision-assay.html
Caris Life Sciences. Caris Assure: Technical Specifications. Accessed May 15, 2026. https://d35ibn74wp9llh.cloudfront.net/000d31fd-e04b-4936-be1c-11acbe19e1ec/f55d2c47-6ce2-4429-ac40-14e89e5e7b10/f55d2c47-6ce2-4429-ac40-14e89e5e7b10_source__v.pdf
Labcorp. Labcorp Plasma Complete. Accessed May 15, 2026. https://oncology.labcorp.com/sites/default/files/2025-01/683903_DX_BRO_PlasmaComplete_FINAL-0125%20%281%29.pdf
NeoGenomics. PanTracer TSO 500 for Pharma Partners. Accessed May 15, 2026. https://www.neogenomics.com/PanTracer-LDT/
Pipinikas C, Patel KB, Vyas H, et al. Analytical validation and clinical performance of a plasma-based CGP assay, NEO | PanTracer LBx. J Clin Oncol. 2025;43(16_suppl):e15047. doi:10.1200/JCO.2025.43.16_suppl.e15047
Roche. AVENIO ctDNA Expanded Kit V2. Accessed May 15, 2026. https://sequencing.roche.com/us/en/products/group/avenio-ctdna-expanded-kits.html#productInfo
ThermoFisher. Oncomine^™ Breast cfDNA Assay v2. Accessed May 15, 2026. https://www.thermofisher.com/order/catalog/product/A31183
Tempus. Tempus xF/xF+ liquid biopsy. Accessed May 15, 2026. https://www.tempus.com/oncology/genomic-profiling/xf/
BostonGene Corporation. Biologically grounded AI for drug development and precision clinical decision-making. Accessed May 15, 2026. https://www.bostongene.com
Fulgent Oncology. Lumera^® Liquid Biopsy: ctDNA Detection by Liquid Biopsy. Accessed May 15, 2026. https://fulgentoncology.com/lumera-liquid-biopsy
Pillar Biosciences. Essential LBx Panel. Accessed May 15, 2026. https://www.pillarbiosci.com/wp-content/uploads/2024/09/MK-0050-oncoReveal-Essential-LBx-5.2024_v1.3.pdf
Bower XS, Wignall J, Varga MG, et al. Validation of a liquid biopsy assay with increased sensitivity for clinical comprehensive genomic profiling. J Liq Biopsy. 2025;9:100322. doi:10.1016/j.jlb.2025.100322
APIS Assay Technologies. APIS ESR1 qPCR Kit. Accessed May 15, 2026. https://static1.squarespace.com/static/5e8c8b846bab995ffb19007a/t/6839cfc32132492fa710cc80/1748619204140/APIS+ESR1+qPCR+Kit+Flyer.pdf
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Stilla Technologies. ESR1 (17 Mutations) Crystal Digital PCR^® Assay. Accessed May 15, 2026. https://go.stillatechnologies.com/assay/esr1-17-mutations-crystal-digital-pcr-r-assay
APIS Assay Technologies. APIS ESR1 dPCR Kit. Accessed May 15, 2026. https://www.apisassay.com/apis-esr1-dpcr-kit
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Guerini-Rocco E, Venetis K, Cursano G, et al. Standardized molecular pathology workflow for ctDNA-based ESR1 testing in HR+/HER2- metastatic breast cancer. Crit Rev Oncol Hematol. 2024;201:104427. doi:10.1016/j.critrevonc.2024.104427

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Role of ESR1

Acquired resistance

Proactive identification and ESR1m interpretation

ESR1 Mutation Prevalence: ESR1 Mutations Are Not Commonly Present at Diagnosis of Metastatic Breast Cancer (mBC) in Patients Who Are Endocrine Therapy (ET) Naive3-8

Testing Recommendations for ESR1m7,9-14

Footnotes

Utilizing ctDNA-Mediated Testing to Detect ESR1m11

ESR1m Sponsored Testing Program

Considerations for Your Practice

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ESR1 Mutation Prevalence: ESR1 Mutations Are Not Commonly Present at Diagnosis of Metastatic Breast Cancer (mBC) in Patients Who Are Endocrine Therapy (ET) Naive^3-8

Testing Recommendations for ESR1m^7,9-14

Utilizing ctDNA-Mediated Testing to Detect ESR1m¹¹