Revisiting the estrogen receptor pathway and its role in endocrine therapy for postmenopausal women with estrogen receptor-positive metastatic breast cancer.

Endocrine therapy (ET) is the most commonly administered first-line systemic therapy for estrogen receptor-positive (ER+) metastatic breast cancer (MBC). Manipulation of hormone levels was one of the earliest ET approaches. However, treatment modalities have since evolved with the growing understanding of estrogen biosynthesis and ER biology. The current armamentarium of ET includes selective estrogen receptor modulation, aromatase inhibition, and selective estrogen receptor downregulation. However, intrinsic or acquired resistance to ET is frequently observed. Significant strides have been made in recent years in our understanding of the mechanisms of resistance to ET, and several targeted approaches including inhibitors against the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway and cyclin-dependent kinase 4/6 (CDK4/6) have shown great promise. The mTOR inhibitor, everolimus, is already in clinical use for the treatment of resistant ER+MBC. However, multiple levels of evidence indicate that ER signaling remains as an important therapeutic target even in the resistance setting, providing the rationale for sequencing multiple lines and combinations of ET. In addition, recurrent mutations in estrogen receptor 1 (ESR1), the gene that encodes the ER, have been identified in the genomic studies of metastatic ER+ breast cancer. ESR1 mutations are an important mechanism for acquired resistance, and effective ER targeting in this setting is particularly important.