Dina Hamza, Mohammad Hourani* and Rawan Bdair
Background: Breast cancer is the most common cancer and the leading cause of cancer-related death in women worldwide, with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) tumors comprising approximately 70% of breast cancer. Endocrine therapy combined with cyclin dependent kinase 4 and 6 (CDK4/6) inhibitors is standard for advanced disease; however, resistance often develops, frequently driven by estrogen receptor 1 (ESR1) mutations. Emerging therapies, such as the oral selective estrogen receptor degraders (SERDs) Elacestrant, demonstrate significant benefit, particularly in ESR1-mutated tumors. We report two HR+/HER2− metastatic cases illustrating endocrine resistance and the evolving role of SERDs in management.
Case presentations: Case 1 involved a premenopausal, breast cancer gene (BRCA) wild-type woman diagnosed in 2013 with estrogen receptor–positive (ER+)/progesterone receptor positive (PR+)/HER2-negative/invasive lobular carcinoma (ILC) of the left breast, who developed bone metastases three years after initial therapy; sequential endocrine therapy with Palbociclib and Denosumab maintained disease control, and Elacestrant was initiated in 2023 to overcome emerging ESR1 mutations (Y537N, Y537S), achieving 11 months of progression free survival (PFS) until temporary interruption for spinal surgery; subsequent progression required Capecitabine and palliative radiotherapy. Case 2 involved a 46-year-old woman diagnosed in 2020 with de novo bilateral breast cancer harboring ESR1 (Y537S, D538G), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) E545K, and GATA binding protein 3 (GATA3) S427fs mutations. She was started on Goserelin, Ribociclib (CDK4/6 inhibitor), Letrozole (aromatase inhibitor), and Denosumab. Disease progression in the bone was observed in May 2024, prompting a switch to Elacestrant in June 2024. This resulted in disease control for 15 months. Subsequent progression in October 2025 was managed with Capivasertib plus Fulvestrant.
Conclusion: Carefully selected endocrine therapies can provide meaningful disease control in metastatic hormone receptor positive breast cancer, even in the presence of resistance associated mutations. Real-world evidence demonstrates that Elacestrant is effective in ER-positive, HER2-negative, ESR1 mutant disease, particularly when used earlier in the metastatic course. These findings highlight the clinical value of Elacestrant and underscore that the therapeutic potential of endocrine therapy should not be underestimated, with genomic profiling and prior treatment history guiding optimal sequencing.