Targeting Estrogen Receptor for Breast Cancer

With a lifetime risk estimated to be 1 in 8 in industrialized countries, breast cancer is the most frequent type of cancer among women worldwide and the second leading cause of cancer deaths in women. More importantly, current evidence suggests that in women aged <45 years, breast cancer is unquestionably the leading cause of cancer-related deaths. Hormonal therapy has an established role in the treatment of breast cancer. Hormonal therapy aims at preventing the stimulation of mitogenic estrogen-dependent pathways. Hormonal therapy can be performed through blocking the production of estrogens or through blocking the action of estrogens upon tumor cells. The action of estrogens upon tumor cells can be blocked through selective estrogen receptor modulators (SERMs) or through selective estrogen receptor downregulators (SERDs). Estrogen receptor mutation (ESR1 mutation) is one of the common mechanisms by which breast cancer becomes resistant to additional therapies from SERMs or aromatase inhibitors. Fulvestrant, an injectable anti-estrogen, is the SERD commonly used. Fulvestrant has no agonistic activity and causes degradation of the estrogen receptor. This agent is more active in postmenopause than premenopause and is indicated in the treatment of advanced breast cancer in case of disease progression during or after tamoxifen. Oral SERDs are being rapidly developed to replace fulvestrant with the potential of higher efficacy and lower toxicities. Novel agents such as complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and selective estrogen receptor covalent antagonists (SERCAs) are also promising therapies. This manuscript focuses on recent advances in the development of drugs targeting the estrogen receptor.