ESR1 and endocrine therapy resistance: more than just mutations

Estrogen receptor (ER)-positive breast cancer accounts for 70%–80% of all diagnosed breast cancers [1]. The adoption of endocrine therapies, including ER modulators/degraders (SERMs/SERDs), which antagonize ER, and aromatase inhibitors (AIs), which suppress estrogen synthesis, as the mainstay of treatment of ER-positive breast cancer patients has resulted in substantial survival benefit for patients with early stage disease [2]. Treating ER-positive metastatic breast cancer (MBC), however, remains a significant clinical challenge, due to the development of secondary resistance to all modalities of endocrine therapy [3]. Recently, studies have identified recurrent somatic mutations within the ligand-binding domain (LBD) of ESR1 (encoding ER) in >30% of ER-positive MBC [4–8]. These mutations alter the conformation of ER and produce a constitutively active form of the protein. Mutations at residues 536–538, in particular, promote ER activity in the absence of ligand, resulting in resistance to AIs and reduced sensitivity to SERMs/SERDs [4, 5]. ESR1 fusion genes have also been reported in ER-positive MBCs; however, a detailed description of their manifestations and clinical prevalence is lacking [9]. In this issue of Annals of Oncology, Hartmaier et al. reported the identification of recurrent hyperactive ESR1 fusion genes in breast cancers resistant to endocrine therapy [10], adding to the diversity of reported ESR1 alterations.