Next-Generation ERα Inhibitors for Endocrine-Resistant ER+ Breast Cancer.

One in eight women will be diagnosed with breast cancer in their lifetime. Because estrogen receptor-α (ERα) is expressed in ~70% of patients, therapeutic intervention by ERα-targeted endocrine therapies remains the leading strategy to prevent progression and/or metastasis in the adjuvant setting. However, the efficacy of these therapies will be diminished by the development of acquired resistance after prolonged treatment regimens. In preclinical models of endocrine-resistant metastatic breast cancers that retain ERα expression, antiestrogens with improved efficacy and potency can overcome resistance to shrink tumors and prevent metastasis. In particular, selective ER degraders or downregulators, which both antagonize ERα actions and induce its degradation, have demonstrated substantial antitumor efficacy in this setting. In the present review, we have discussed the mechanisms of acquired endocrine resistance in luminal breast cancers and the strategies used by next-generation endocrine therapies to antagonize ERα.