ESR1 mutations in breast cancer.

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Ligand-independent ESR1 mutations are a key mechanism of resistance to aromatase inhibitors in ER-positive metastatic breast cancer.
• These ESR1 mutations can be present in primary tumors and are enriched during metastatic spread, influencing tumor progression.
• ESR1 mutations confer a distinct transcriptional profile that promotes tumor aggressiveness.

Purpose of the Study:

• To review the mechanisms of ESR1 mutation acquisition and dissemination in breast cancer.
• To discuss the current and emerging methods for tracking ESR1 mutations using liquid biopsies.
• To explore the clinical implications and therapeutic strategies for ESR1-mutated tumors.

Main Methods:

• Review of preclinical and clinical studies on ESR1 mutations in breast cancer.
• Analysis of sensitive detection methods for ESR1 mutation tracking in circulating tumor DNA (ctDNA).
• Evaluation of clinical data on treatment outcomes for patients with ESR1 mutations.

Main Results:

• ESR1 mutations are acquired during therapy and can preexist, influencing metastasis and tumor progression.
• Liquid biopsy-based mutation tracking shows potential for predicting treatment response and guiding therapy.
• Patients with ESR1 mutations benefit from fulvestrant and CDK4/6 inhibitors, but novel therapies are needed.

Conclusions:

• Understanding ESR1 mutation mechanisms is crucial for overcoming endocrine resistance.
• Standardization of ctDNA-based mutation tracking is ongoing and essential for clinical application.
• Development of potent selective ER degraders and targeted biotherapies is required for effective treatment of ESR1-mutant breast cancer.