Are We Ready to Use ESR1 Mutations in Clinical Practice?

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Recurrent ligand-binding domain ESR1 mutations are a key mechanism of endocrine resistance in estrogen receptor-positive (ER+) metastatic breast cancer.
• These ESR1 mutations emerge under endocrine treatment pressure and are uncommon in treatment-naïve ER+ breast cancers.
• Preclinical data indicate ESR1 mutations confer ligand-independent activity, leading to resistance against aromatase inhibitors, tamoxifen, and fulvestrant.

Purpose of the Study:

• To review the prognostic and predictive significance of ESR1 mutations in ER+ metastatic breast cancer.
• To highlight the need for larger datasets and prospective studies to validate existing findings.
• To identify knowledge gaps regarding treatment responses and optimal therapeutic strategies for patients with ESR1 mutations.

Main Methods:

• Retrospective analysis of ESR1 mutations in baseline plasma circulating tumor DNA from clinical trials.
• Review of preclinical studies investigating the functional impact of ESR1 mutations.
• Literature review to identify current understanding and future research needs.

Main Results:

• Retrospective analyses suggest ESR1 mutations are associated with poorer overall survival.
• ESR1 mutations appear predictive of resistance to aromatase inhibitors in metastatic settings.
• Current data are primarily from retrospective analyses, necessitating further validation.

Conclusions:

• ESR1 mutations represent a significant challenge in managing ER+ metastatic breast cancer, contributing to endocrine resistance.
• Prospective studies are crucial to confirm the prognostic and predictive value of ESR1 mutations.
• Further research is required to elucidate treatment responses and develop effective combination therapies for patients harboring ESR1 mutations.