Oral selective estrogen receptor degraders (SERDs) for the treatment of hormone receptor-positive, HER2-negative breast cancer title.

INTRODUCTION

Endocrine therapy (ET) remains the backbone of treatment for hormone receptor-positive (HR+), HER2-negative breast cancer. However, resistance, frequently driven by acquired ESR1 mutations detected in up to 40% of patients progressing on first-line ET, represents a major clinical challenge. Oral selective estrogen receptor degraders (SERDs) have been developed to overcome the limitations of first-generation agents and achieve more potent ER targeting.

AREAS COVERED: This review summarizes the mechanism of action of oral SERDs compared with prior endocrine therapies and evaluates clinical evidence supporting their use across treatment settings in HR+/HER2- breast cancer. Literature was identified through systematic searches of PubMed, ClinicalTrials.gov, and major oncology congresses (ASCO, ESMO, SABCS) through early 2026.

EXPERT OPINION: Oral SERDs are reshaping the management of ESR1-mutant disease, with agents such as elacestrant and imlunestrant emerging as standard second-line options. In early-stage disease, trials such as lidERA suggest potential outcome improvements. However, primary resistance to SERD monotherapy remains substantial, highlighting the need for combination strategies. Future directions include ctDNA-guided approaches and expansion into earlier treatment settings.