Navigating first- and second-line treatment options in hormone receptor-positive HER2-negative advanced breast cancer

Outcomes for patients with hormone receptor-positive HER2-negative (HR+ HER2-) advanced breast cancer (ABC) have improved considerably in recent years and CDK4/6 inhibitors are the preferred first-line therapy for most patients. Newer therapeutic classes include PI3K/AKT inhibitors, oral selective estrogen receptor degraders, proteolysis-targeting chimeras, PARP inhibitors, and antibody-drug conjugates. The development and regulatory approval of these new therapies to treat HR+ HER2- breast cancer raises the question of how to use and sequence this fast-growing armamentarium to maximize benefit for individual patients. Disease progression and resistance mechanisms emerging on treatment (therapeutic pressure) add further complexity by inducing molecular alterations; thus, a clear understanding of the mechanisms behind resistance to both endocrine and CDK4/6 inhibitor therapies and their implications for subsequent treatment is critical. In principle, the most effective and tolerable drugs should be used first with the goals of delaying chemotherapy and offering patients the best quality and duration of life. This review aims to explain the evolving treatment landscape for HR+ HER2- ABC and provides the scientific background for developing future treatment algorithms driven by preclinical and clinical results.