Sequencing CDK4/6 Inhibitors, Oral SERDs, and ADCs in HR Positive Breast Cancer

This segment synthesizes panel guidance on sequencing available endocrine and targeted modalities alongside antibody drug conjugates in HR positive HER2 negative disease. Panelists recommend CDK4/6 inhibition plus endocrine therapy as first line in the metastatic setting when clinically appropriate, and emphasize routine molecular profiling at diagnosis and at progression to identify targetable alterations such as PIK3CA and ESR1. Circulating tumor DNA testing is underscored as a repeatable tool to guide transitions. For ESR1 mutated tumors after prior endocrine plus CDK4/6 exposure, oral SERDs are positioned as biomarker directed second line options. ADCs and cytotoxic approaches are generally reserved for patients who are endocrine refractory or have rapidly progressive visceral disease, given their different toxicity spectra and impact on quality of life. The panel emphasizes tailoring sequences to prior response durability, comorbidity, and patient goals while prioritizing therapies that maximize disease control with the least impact on daily function.