Estrogen receptor positive breast cancer: contemporary nuances to sequencing therapy

The treatment landscape of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer has evolved dramatically in recent years. While the combination of endocrine therapy and a cyclin-dependent kinase 4/6 inhibitor is accepted as standard first-line treatment in most settings without visceral crisis, newer therapies have challenged traditional treatment models where cytotoxic chemotherapy was previously felt to be the only second-line option at time of progression. The incorporation of next-generation sequencing has led to the identification of molecular targets for therapeutic agents, including phosphatidylinositol 3-kinase and ESR1, though similar pathways can be targeted even in the absence of a mutation, such as with use of inhibitors of mammalian target of rapamycin. Current data also supports the use of cyclin-dependent kinase inhibitors beyond progression, even prior to the patient's first introduction to chemotherapy. The abundance of therapeutic options not only delay time to cytotoxic chemotherapy and antibody-drug conjugate initiation, but has resulted in improvement in breast cancer survivorship. Many unanswered questions remain, however, as to the most efficacious way to sequence these novel agents. To assist in this decision-making, we will review the existing data on systemic therapy and propose a treatment paradigm.