The Dysregulated Pharmacology of Clinically Relevant ESR1 Mutants is Normalized by Ligand-activated WT Receptor

Abstract

The estrogen receptor (ER/ESR1) is expressed in a majority of breast cancers and drugs that inhibit ER signaling are the cornerstone of breast cancer pharmacotherapy. Currently, aromatase inhibitors are the frontline endocrine interventions of choice although their durability in metastatic disease is limited by activating point mutations within the ligand-binding domain of ESR1 that permit ligand-independent activation of the receptor. It has been suggested that the most commonly occurring ESR1 mutations would likely compromise the clinical activity of selective estrogen receptor downregulators and selective estrogen receptor modulators (SERMs) when used as second-line therapies. It was unclear, however, how these mutations, which are likely coexpressed in cells with ER WT , may impact response to ER ligands in a clinically meaningful manner. To address this issue, we dissected the molecular mechanism(s) underlying ESR1-mutant pharmacology in models relevant to metastatic disease. These studies revealed that the response of ESR1 mutations to ligands was dictated primarily by the relative coexpression of ER WT in cells. Specifically, dysregulated pharmacology was only evident in cells in which the mutants were overexpressed relative to ligand-activated ER WT ; a finding that highlights the role of allelism in determining ER-mutant pharmacology. Importantly, we demonstrated that the antagonist activity of the SERM, lasofoxifene, was not impacted by mutant status; a finding that has led to its clinical evaluation as a treatment for patients with advanced ER-positive breast cancer whose tumors harbor ESR1 mutations.

ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer

“…On the other hand, D538G produces greater metastatic potential, especially to the liver, and unlike Y537S may increase Wnt signaling [ 8 , 33 , 40 ]. In addition, resistance of ESR1-MUT to tamoxifen and fulvestrant is far less prominent in HEK-293T cells compared to breast cancer cell lines [ 4 ], and ESR1-WT expression alongside ESR1-MUT reduces resistance [ 41 ]. This theme carries into the clinical data detailed below, where ESR1-MUT alone does not clearly confer resistance to tamoxifen or fulvestrant in patients.…”

“…Novel SERMs and SERCAs have been developed and tested specifically against ESR1-MUT (Table 2 ). Lasofoxifene, a SERM initially developed for osteoporosis and in that setting found to reduce breast cancer incidence [ 45 ], remarkably was found in vitro to retain efficacy in the presence of ESR1-MUT [ 41 ]. Lasofoxifene is currently in Phase 2 trials for patients with ESR1-MUT and for patients after progression on ET and CDK4/6 inhibition (CDK4/6i) (ELAINE: NCT03781063, ELAINE-2: NCT04432454).…”

Genomic profiling using the UltraSEEK panel identifies discordancy between paired primary and breast cancer brain metastases and an association with brain metastasis-free survival

“…The identification of therapeutic strategies in breast cancers harbouring ESR1 mutants is an area of active interest. Fulvestrant has demonstrated poor clinical activity in ESR1-mutated BC [ 27 , 28 ], whereas bazedoxifene and lasofoxifene have demonstrated activity in pre-clinical models of ESR1-mutated BC [ 29 , 30 ]. The efficacy of lasofoxifene is currently being explored in the ELAINE trial (NCT03781063) in patients with ESR1-mutated BCs (Supplementary table 3).…”

Genomic Profiling Using The UltraSEEK Panel Identifies Discordancy Between Paired Primary And Breast Cancer Brain Metastases And An Association With Brain Metastasis-Free Survival

“…The identi cation of therapeutic strategies in breast cancers harbouring ESR1 mutants is an area of active interest. Fulvestrant has demonstrated poor clinical activity in ESR1-mutated BC [26,27], whereas bazedoxifene and lasofoxifene have demonstrated activity in pre-clinical models of ESR-mutated BC [28,29]. The e cacy of lasofoxifene is currently being explored in the ELAINE trial (NCT03781063) in patients with ESR1-mutated BCs (Supplementary table 4).…”