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

Abstract

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.

Clinical Implications of ESR1 Mutations in Hormone Receptor-Positive Advanced Breast Cancer

“…These definitions, although imperfect and arbitrary, have been useful in some clinical trials to stratify patient populations (30). As noted above, ESR1 mutations are characteristically absent in primary tumors and are an unlikely mechanism of primary resistance (2, 15).…”

Tamoxifen differentially regulates miR-29b-1 and miR-29a expression depending on endocrine-sensitivity in breast cancer cells

“…These and other data implicate ERα as an important target in endocrine resistance. While still not completely understood, a variety of mechanisms play a role in endocrine resistance including increases in coactivators SRC-1 (NCOA1) and/or SRC-3 (NCOA3), activation of receptor tyrosine kinases (TRKs, e.g ., epidermal growth factor receptor (EGFR)) that crosstalk with ERα, and deregulation of apoptotic or cell survival signals [2, 10, 11]. …”

Imaging Diagnostic and Therapeutic Targets: Steroid Receptors in Breast Cancer

“…Evidence is increasing regarding the complementary role of targeted therapy of growth factor activation and cell-cycle control pathways with endocrine therapy for patients with recurrent or metastatic breast cancer and indications for this approach have been recently incorporated into clinical practice guidelines (2, 45). These include everolimus, an inhibitor of the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, in combination with exemestane, a steroidal aromatase enzyme inactivator, and palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in combination with fulvestrant or letrozole, a non-steroidal aromatase inhibitor.…”