The rise of selective estrogen receptor modulators (SERMs) in breast cancer therapy: a promising horizon

Area of Science:

• Oncology
• Endocrinology
• Pharmacology

Background:

• Breast cancer remains a leading cause of cancer death globally, with most cases being estrogen receptor-positive (ER+).
• Selective Estrogen Receptor Modulators (SERMs) are a cornerstone of endocrine therapy for ER+ breast cancer, acting via estrogen receptor modulation.
• Understanding SERM mechanisms, successes, and failures is crucial for advancing breast cancer treatment.

Purpose of the Study:

• To critically evaluate the pharmacologic development, thermodynamics, and clinical effectiveness of SERMs.
• To analyze approved, investigational, and discontinued SERMs to understand their structural basis for success and failure.
• To explore molecular drivers of SERM resistance and inform future therapeutic strategies.

Main Methods:

• Systematic analysis of approved SERMs (e.g., tamoxifen, raloxifene) and investigational drugs (e.g., endoxifen).
• Review of historical SERM compounds to identify structural-activity relationships.
• Exploration of molecular mechanisms underlying SERM resistance, including ESR1 mutations and epigenetic changes.

Main Results:

• Early-generation SERMs exhibit limitations including paradoxical partial agonism, thromboembolic risks, and acquired resistance.
• Specific structural features correlate with clinical success and failure of SERMs.
• Molecular drivers such as ESR1 mutations and growth factor cross-talk contribute significantly to SERM resistance.

Conclusions:

• The limitations of current SERMs necessitate a paradigm shift in endocrine therapy for ER+ breast cancer.
• Complete Estrogen Receptor Antagonists (CERANs) and oral Selective Estrogen Receptor Degraders (SERDs) represent the next generation of precision oncology treatments.
• This review provides critical insights into the future of endocrine therapy, emphasizing targeted approaches for improved patient outcomes.