Addressing unmet need in the management of patients with ER+/HER2-, ESR1-mutated metastatic breast cancer: clinician's perspective.

Approximately 70% of breast tumors are ER+ and HER2-. First-line treatment that combines endocrine therapy (AIs, SERMs, and SERDs) with a CDK4/6 inhibitor is the treatment of choice for many patients with ER+/HER2- metastatic breast cancer. However, ESR1 mutations develop in up to 40% of patients-more than 90% of these in response to therapy. The presence of ESR1 mutations is associated with a worse prognosis, including faster progression and poorer survival, underscoring the need for routine testing and the urgency of developing novel therapies that address ESR1-mutated breast cancer. For more than 20 years, fulvestrant (given as an intramuscular injection) was the only SERD approved by the US Food and Drug Administration for the treatment of ER+/HER2- metastatic breast cancer, and a standard second-line therapy following progression on an AI. This review discusses (1) the importance of routine testing for ESR1 mutations after disease recurrence or progression and the role of liquid biopsy in this regard; (2) elacestrant, a novel oral SERD approved in 2023 for the treatment of postmenopausal women and adult men with ER+/HER2-, ESR1-mutated advanced or metastatic breast cancer with disease progression following 1 or more lines of endocrine therapy (unlike other SERDs, elacestrant is not associated with cardiac or ocular toxicity); and (3) new agents in development, including SERDs and innovative molecules targeting the ER-PROTACs, SERCAs, and CERANs-currently being tested in early-phase trials in combination with targeted agents, including CDK4/6 inhibitors.