Biomarker Testing and Treatment Selection in HR+/HER2− mBC

The panel discusses the role of biomarker testing in guiding treatment selection for patients with hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2− mBC) at progression. Dr. Mayer explains the complementary roles of liquid biopsy using circulating tumor DNA (ctDNA) and tissue-based testing, emphasizing assessment for actionable PI3K pathway and ESR1 alterations. She describes using comprehensive genomic profiling at diagnosis and repeating ctDNA testing at progression because ESR1 mutations can emerge during treatment with an aromatase inhibitor. Tissue biopsy may provide additional information through immunohistochemical reassessment of ER, PR, and HER2 status, particularly when biomarker status may have changed or when disease demonstrates a discordant response. Dr. Mayer then provides a broad framework for second-line treatment selection based on biomarker status. For patients with ESR1 alterations, oral selective estrogen receptor degraders or other novel endocrine therapies may be considered. For PI3K pathway alterations, pathway-directed therapy is an important consideration. Patients without actionable biomarkers may be candidates for continued CDK4/6 inhibition with a different agent, mTOR-directed therapy, or emerging pan-pathway inhibition strategies.