ESR1 Mutations in HR+/HER2– Breast Cancer: Optimizing Testing Strategies and Treatment Decisions in the Era of Targeted Therapy

KEY TAKEAWAYS

• ESR1 mutations represent a common mechanism of acquired resistance to endocrine therapy, particularly aromatase inhibitors, in the metastatic setting.
• Robust and timely identification of ESR1 mutations is critical for guiding therapeutic decisions, with liquid biopsy and circulating tumor DNA being the preferred method.
• Next-generation oral selective estrogen receptor degraders (SERDs) (eg, elacestrant, imlunestrant) offer a targeted therapeutic approach in second-line or later therapy for patients with hormone receptor–positive/HER2-negative advanced or metastatic breast cancer harboring ESR1 mutations following 2 or more lines of endocrine therapy.
• Oral SERDs are effective in treating ESR1-mutated tumors, yet the greatest magnitude of benefit with monotherapy is observed in patients who demonstrate greater endocrine sensitivity. However, caution should be taken when using rigid duration cutoffs for treatment selection.
• The advantages and limitations of single-agent oral SERDs, sequencing options, and combination therapies are discussed, striving for a balance of therapeutic efficacy, safety, and patient quality of life.
• When patients have ESR1 and PIK3CA co-mutations, the therapeutic index of available agents, clinical aggressiveness of the disease, and patient comorbidities should be considered; highly aggressive disease with multiple ESR1 mutations would favor a PI3K-targeted agent.