Dual Biomarkers and Treatment Sequencing in HR+/HER2− mBC

The panel explores treatment selection for patients with hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2− mBC) harboring both ESR1 and PI3K pathway alterations, emphasizing the need to individualize therapy according to disease biology, pace, symptoms, and treatment tolerability. Dr. Erica Mayer notes that a future goal would be to combine ESR1-directed endocrine therapy with PI3K pathway inhibition, although current treatment decisions generally require prioritizing one pathway. For patients with favorable performance status and a strong preference to minimize toxicity, an ESR1-directed approach may be appropriate, whereas patients with more symptomatic or rapidly progressing disease may benefit from greater emphasis on PI3K pathway inhibition. The discussion then turns to antibody-drug conjugates (ADCs) and chemotherapy, with Dr. Mayer describing ADCs as highly targeted forms of chemotherapy and highlighting their growing role in HR+/HER2− mBC. She emphasizes that the transition from endocrine therapy to ADCs or chemotherapy should consider endocrine sensitivity, disease burden, need for rapid response, and patient readiness. The panel also identifies ADC sequencing after prior ADC exposure as an important evolving clinical question.