ESR1

  • Estrogen receptor 1 (ESR1); encodes estrogen receptor alpha (ERα)
  • Gene Location: Chromosome 6 (6q25.1)

Biology

  • ESR1 encodes ERα, a ligand-activated nuclear hormone receptor that is a principal driver of cell growth, survival, and proliferation in estrogen receptor (ER)-positive breast cancer.1
  • Under normal conditions, estrogen (estradiol) binds ERα, prompting receptor dimerization and recruitment of transcriptional coactivators that activate estrogen-responsive genes promoting tumor cell proliferation.1
  • Endocrine therapies interrupt this axis by modulating the receptor (selective estrogen receptor modulators, SERMs), degrading it (selective estrogen receptor degraders, SERDs), or depriving it of estrogen (aromatase inhibitors, AIs).
  • Hotspot mutations in the ligand-binding domain confer constitutive, ligand-independent ERα activity, driving resistance to standard endocrine therapy. Y537S in particular is associated with the highest degree of endocrine resistance.2,3

Etiology and Epidemiology

  • ESR1 mutations are rare in treatment-naive primary tumors and emerge under the selective pressure of prolonged endocrine therapy, most notably aromatase inhibitors, as an acquired mechanism of resistance.1
  • Activating ESR1 mutations are present in up to approximately 40% of ER-positive/HER2-negative advanced or metastatic breast cancers previously treated with endocrine therapy.4
  • The hotspot ligand-binding domain mutations Y537S and D538G together account for the majority of ESR1 mutations identified in breast cancer.2
  • ESR1 mutations are typically subclonal and polyclonal, and their prevalence rises with successive lines of endocrine therapy.1,4

Testing

When to Test:

  • Testing for ESR1 mutations is recommended at disease recurrence or progression on endocrine therapy in HR-positive/HER2-negative disease, rather than at initial diagnosis, because these mutations are typically acquired.5
  • Because ESR1 mutations are subclonal and acquired, retesting at each progression is advised to capture newly emergent alterations.5

Testing Methodologies:

  • Circulating tumor DNA (ctDNA) liquid biopsy is the preferred and most sensitive approach given the temporal and spatial heterogeneity of ESR1 mutations; tissue-based next-generation sequencing (NGS) is an acceptable alternative.5
  • Guardant360 CDx is the companion diagnostic used to identify ESR1 mutations for both agents, performed on a plasma specimen (ctDNA). Note the labels differ in wording: ORSERDU directs selection using an FDA-approved test, while VEPPANU specifies an FDA-authorized test. Reproduce each verbatim rather than harmonizing them.6,7

Guideline Recommendations

  • ASCO recommends ESR1 mutation testing, with blood-based ctDNA preferred over tissue, at recurrence or progression on endocrine therapy in HR-positive/HER2-negative metastatic breast cancer.5
  • NCCN includes ESR1 mutation testing in ER-positive/HER2-negative advanced or metastatic disease, performed on blood-based ctDNA at progression on endocrine therapy.8

Targeted Therapy

Approved Agents

  • Two oral agents are FDA-approved specifically for ESR1-mutated, ER-positive/HER2-negative advanced or metastatic breast cancer: elacestrant (Orserdu) and vepdegestrant (Veppanu).
  • On January 27, 2023, the US Food and Drug Administration approved elacestrant, the first oral SERD in this setting, based on the phase 3 EMERALD trial (NCT03778931), which demonstrated improved progression-free survival versus standard-of-care endocrine monotherapy in patients with ESR1-mutated tumors.6,9
  • On May 1, 2026, the FDA approved vepdegestrant based on the phase 3 VERITAC-2 trial (NCT05654623). Vepdegestrant is the first PROTAC protein degrader approved for any indication. Guardant360 CDx was approved concurrently as a companion diagnostic.7,10
  • In VERITAC-2, progression-free survival was assessed both in patients whose tumors carried an ESR1 mutation and in the overall population; a statistically significant benefit was demonstrated only in the ESR1-mutated population, which is the basis for the biomarker-restricted indication. Overall survival was immature at the time of the analysis.7,10

Elacestrant (Orserdu)

  • FDA-Approved Indication:
    • Postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.6
  • Mechanism of Action:
    • Elacestrant is an oral selective estrogen receptor degrader (SERD) that binds ERα and promotes its degradation.6
    • Degradation of ERα inhibits estrogen-dependent signaling and tumor cell proliferation, including in cells harboring ESR1 ligand-binding domain mutations.6

Drug Information:

Learn more about Elacestrant ›

Patient Resources:

https://www.orserdu.com/

Vepdegestrant (Veppanu)

  • FDA-Approved Indication:
    • Adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 (ESR1)-mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy.7
  • Mechanism of Action:
    • Vepdegestrant is a heterobifunctional protein degrader (PROTAC): a small molecule comprising an estrogen receptor binding domain joined by a linker to an E3 ligase binding domain.7
    • It binds ER and the E3 ligase cereblon (CRBN), triggering CRBN-mediated polyubiquitination and proteasomal degradation of ER, reducing ER protein levels in breast cancer cells.7
    • Vepdegestrant induces degradation of both wild-type and mutant ER and has demonstrated antitumor activity in wild-type and ESR1-mutant breast cancer models.7

Drug Information:

Learn more about Vepdegestrant ›

Patient Resources:

https://www.veppanu.com/

References

1. Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations as a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12(10):573-583. doi:10.1038/nrclinonc.2015.117

2. Toy W, Shen Y, Won H, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45(12):1439-1445. doi:10.1038/ng.2822

3. Fanning SW, Mayne CG, Dharmarajan V, et al. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. eLife. 2016;5:e12792. doi:10.7554/eLife.12792

4. 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

5. Burstein HJ, DeMichele A, Somerfield MR, et al. Testing for ESR1 mutations to guide therapy for hormone receptor-positive, HER2-negative metastatic breast cancer: ASCO guideline rapid recommendation update. J Clin Oncol. [confirm volume, year, and pagination]

6. ORSERDU (elacestrant). Prescribing information. Stemline Therapeutics, Inc, a Menarini Group Company; 2023. Accessed July 2026.

7. VEPPANU (vepdegestrant). Prescribing information. Rigel Pharmaceuticals, Inc; revised 6/2026. Accessed July 2026. https://veppanu.com/downloads/pdf/VEPPANU-Full-Prescribing-Information.pdf

8. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed July 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.

9. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. doi:10.1200/JCO.22.00338

10. US Food and Drug Administration. FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. May 1, 2026. Accessed July 2026.