Second-Line Strategies to Overcome Resistance to Oestrogen Therapy in Patients with ER+/HER2- Metastatic Breast Cancer: A Year in Review

Despite advances in first-line endocrine therapy (ET) plus cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) in oestrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+/HER2-) metastatic breast cancer (mBC), disease progression often occurs. When this happens, most patients remain eligible for ET with or without targeted therapies, while those with visceral crisis or primary endocrine resistance (progression after <6 months of ET plus CDK4/6i) should be treated with cytotoxic regimens (chemotherapy or antibody–drug conjugates). This review discusses the latest advancements in overcoming resistance to first-line ET in ER+/HER2− metastatic breast cancer that emerged during 2024 from the American Society of Clinical Oncology (ASCO) Annual Meeting in May and June, the European Society for Medical Oncology (ESMO) Congress in September, and the San Antonio Breast Cancer Symposium in December. The article highlights the crucial role of biomarker-driven strategies to address the emergence of ESR1 mutations and the presence of intrinsic PI3K/AKT/mTOR pathway alterations. Elacestrant is the only oral selective oestrogen receptor degrader (SERD) approved for ESR1-mutated mBC, having demonstrated a hazard ratio (HR) of 0.55 (95% CI: 0.39–0.77) versus standard of care (SOC) in patients with ESR1-mutated tumours in the EMERALD study. An exploratory subgroup analysis of patients with longer prior ET plus CDK4/6i exposure (at least 12 months) demonstrated a median progression-free survival (PFS) of 8.6 months versus 1.9 months with SOC (HR: 0.41; 95% CI: 0.26–0.63), and 5.5 months in patients with co-existing PIK3CA mutations. These findings were supported by real-world studies, which showed a median PFS of 8–9 months with second- and third-line elacestrant, and 5.2 months in patients with co-existing ESR1 and PIK3CA mutations. Additionally, CAPItello-291 demonstrated a 5.5-month median PFS with capivasertib plus fulvestrant in PIK3CA/AKT1/PTEN-altered mBC in patients previously treated with CDK4/6i. Biomarker-driven treatment selection is now critical, emphasising the need for ESR1 mutation testing after each progression.