Selective oestrogen receptor degraders in breast cancer: a review and perspectives

Area of Science:

• Oncology
• Endocrinology
• Pharmacology

Background:

• Estrogen receptor-positive (ER+) breast cancer comprises 70% of all breast cancer cases.
• Current treatments for metastatic ER+ breast cancer involve endocrine therapy, often combined with CDK 4/6 or mTOR inhibitors.
• Endocrine resistance remains a significant challenge in managing advanced ER+ breast cancer.

Purpose of the Study:

• To review the emerging strategies for addressing endocrine resistance in ER+ breast cancer.
• To highlight the potential of novel selective estrogen receptor degraders (SERDs) in overcoming resistance mechanisms.

Main Methods:

• Review of current literature on endocrine resistance in ER+ breast cancer.
• Analysis of molecular mechanisms of resistance, including ESR1 mutations.
• Evaluation of the role and development of SERDs, particularly novel oral agents.

Main Results:

• ESR1 mutations in the estrogen receptor ligand-binding domain are a key mechanism of endocrine resistance, often induced by aromatase inhibitors.
• Selective estrogen receptor degraders (SERDs) may retain efficacy despite ESR1 mutations.
• Novel, orally available, nonsteroidal SERDs are in clinical development and have shown promising target engagement and early clinical activity.

Conclusions:

• Orally available nonsteroidal SERDs represent a promising new therapeutic class for endocrine-resistant ER+ advanced breast cancer.
• Further clinical validation in larger patient cohorts is necessary to confirm the efficacy of these novel SERDs.