An emerging generation of endocrine therapies in breast cancer: a clinical perspective

Abstract

Anti-estrogen therapy is a key component of the treatment of both early and advanced-stage hormone receptor (HR)-positive breast cancer. This review discusses the recent emergence of several anti-estrogen therapies, some of which were designed to overcome common mechanisms of endocrine resistance. The new generation of drugs includes selective estrogen receptor modulators (SERMs), orally administered selective estrogen receptor degraders (SERDs), as well as more unique agents such as complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeric (PROTACs), and selective estrogen receptor covalent antagonists (SERCAs). These drugs are at various stages of development and are being evaluated in both early and metastatic settings. We discuss the efficacy, toxicity profile, and completed and ongoing clinical trials for each drug and highlight key differences in their activity and study population that have ultimately influenced their advancement.

Fig. 1. Mechanisms of action of various classes of anti-estrogen therapies.

The binding of estrogen to the ligand-binding domain of ER induces an activating conformational change enabling its dimerization and intranuclear localization. Activated ER can interact with estrogen-responsive elements (EREs), allowing for gene transcription, which leads to cell survival and proliferation. Aromatase inhibitors (AIs). AIs, block estrogen production by inhibiting aromatase, which converts androgens to estrogens. Selective estrogen receptor modulators (SERMs). SERMs competitively inhibit the binding of estrogen to ER. SERM-bound ER dimers interact with chromatin at EREs of the DNA. In the breast, they are associated with co-repressors (CoR) which inhibit ER transcriptional activity, but in other organ tissues such as bone and endometrium, they are associated with co-activators (CoA), allowing for gene transcription. Selective estrogen receptor downregulators (SERDs). SERDs are pure ER antagonists. The SERD–ER complex is unable to translocate to the nucleus or undergo an open chromatin conformation that would allow transcription of ER-regulated genes. The SERD-ER complex subsequently undergoes proteosomal degradation. Proteolysis targeting chimerics (PROTACs): PROTACs are bifunctional molecules that consist of a ligand that binds to a target protein (ER) and another ligand that binds to the E3 ubiquitin ligase. The interaction results in ubiquitination and degradation of the target protein through the ubiquitin-proteasome complex. Complete estrogen receptor antagonists (CERANs). CERANs block both transcriptional activation domains (AF1 and AF2) of ER by recruiting nuclear receptor corepressors (N-CoR) to inactivate AF1 and directly inhibit AF2. Selective estrogen receptor covalent antagonists (SERCAs). SERCAs covalently bind to a cysteine residue (C530) on ER, resulting in ER inactivation and inhibition of gene transcription.