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Updated: Aug 18, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Clinical Implications and Treatment Strategies for ESR1 Fusions in Hormone Receptor-Positive Metastatic Breast
Jamie O Brett1, Lauren L Ritterhouse2,3, Erik T Newman3,4
1Massachusetts General Hospital Department of Medicine, Harvard Medical School, Boston, MA, USA.
Abstract:
In hormone receptor-positive metastatic breast cancer (HR+ MBC), endocrine resistance is commonly due to genetic alterations of ESR1, the gene encoding estrogen receptor alpha (ERα). While ESR1 point mutations (ESR1-MUT) cause acquired resistance to aromatase inhibition (AI) through constitutive activation, far less is known about the molecular functions and clinical consequences of ESR1 fusions (ESR1-FUS). This case series discusses 4 patients with HR+ MBC with ESR1-FUS in the context of the existing ESR1-FUS literature. We consider therapeutic strategies and raise the hypothesis that CDK4/6 inhibition (CDK4/6i) may be effective against ESR1-FUS with functional ligand-binding domain swaps. These cases highlight the importance of screening for ESR1-FUS in patients with HR+ MBC while continuing investigation of precision treatments for these genomic rearrangements.
Insights
Genetic alterations in ESR1 cause endocrine resistance in metastatic breast cancer. This case series explores ESR1 fusions (ESR1-FUS) and suggests CDK4/6 inhibition may be an effective treatment strategy for these genomic rearrangements.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Endocrine resistance in hormone receptor-positive metastatic breast cancer (HR+ MBC) is often linked to ESR1 genetic alterations.
- While ESR1 point mutations (ESR1-MUT) are known to cause resistance to aromatase inhibitors (AI), the role of ESR1 fusions (ESR1-FUS) is less understood.
Purpose of the Study:
- To investigate the molecular functions and clinical implications of ESR1 fusions (ESR1-FUS) in HR+ MBC.
- To explore potential therapeutic strategies for patients with ESR1-FUS.
Main Methods:
- Case series analysis of 4 patients with HR+ MBC and ESR1-FUS.
- Review of existing literature on ESR1-FUS.
Main Results:
- Identified 4 cases of HR+ MBC with ESR1-FUS.
- Hypothesized that CDK4/6 inhibition (CDK4/6i) may be effective against ESR1-FUS, particularly those with functional ligand-binding domain swaps.
Conclusions:
- Highlights the clinical significance of screening for ESR1-FUS in HR+ MBC patients.
- Emphasizes the need for continued research into precision treatments for ESR1 genomic rearrangements.
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