Effect of (Z)-endoxifen on estrogen receptor signaling inhibition across clinically relevant <i>ESR1</i> mutations.

Abstract

e15155 Background: Activating mutations in the estrogen receptor alpha gene (ESR1) are a key mechanism of resistance to endocrine therapy in estrogen receptor–positive (ER+) breast cancer and represent an important unmet clinical need. While selective estrogen receptor degraders (SERDs) are under development for ESR1-mutant disease, the activity of (Z)-endoxifen, the active metabolite of tamoxifen, across clinically relevant ESR1 mutations has not been fully characterized. We evaluated ER signaling inhibition by (Z)-endoxifen in comparison with oral SERDs at clinically relevant concentrations. Methods: ER transcriptional activity was measured in human ER+ breast cancer cells using clinically relevant concentrations of (Z)-endoxifen (746–20 nM), elacestrant (224–56 nM), and imlunestrant (269–67.25 nM). ER signaling was quantified and expressed as percent activity relative to untreated control. Studies were conducted in ESR1 wild-type (WT) and mutant backgrounds, including Y537N, Y537S, and D538G as well as parental MCF7 cells. Results: In parental MCF-7 cells, endoxifen produced dose-dependent and statistically significant inhibition of ER signaling at all clinically relevant concentrations, reducing ER activity to 16–26% of control ( p &lt; 0.001). Elacestrant and imlunestrant also significantly suppressed ER signaling in MCF-7 cells, achieving residual activity of approximately 13–14% and 10–11%, respectively ( p &lt; 0.001). In ESR1-WT cells, all agents suppressed ER signaling to &lt; 5% of control ( p &lt; 0.001). In contrast, ESR1-mutant models demonstrated differential sensitivity. Endoxifen maintained statistically significant ER inhibition across Y537N, Y537S, and D538G mutations ( p &lt; 0.01), whereas SERDs showed reduced efficacy in mutant settings, most notably in the D538G background, where residual ER signaling remained substantially higher despite treatment ( p &lt; 0.05). Among ESR1 mutations, D538G exhibited the greatest resistance, while Y537N remained the most sensitive across therapies. Conclusions: At clinically relevant concentrations, (Z)-endoxifen demonstrates robust and consistent inhibition of ER signaling across key ESR1 mutations, including those associated with resistance to current endocrine therapies. These data support (Z)-endoxifen as a promising therapeutic approach in ESR1-mutant ER+ breast cancer and highlight its potential clinical relevance in a patient population with limited treatment options.