Abstract Background: Metastatic breast cancer (mBC) is one of the leading causes of death among women. Mutations in estrogen receptor alpha (ERα) are acquired as the disease becomes resistant to current therapies, leading to tumor cell metastasis to distant organs. A combination of lasofoxifene (Las) and the CDK4/6 inhibitor abemaciclib has shown promising results in the ELAINE 2 trial, with significantly increased progression-free survival and good tolerability in mBC patients with activating ERα mutations who have progressed on endocrine/CDK4/6 therapy, including fulvestrant. In mouse studies, Las, as well as the Las plus palbociclib (Pal) combination, resulted in a significant reduction in primary tumor burden and metastasis compared to fulvestrant (Ful) and Ful plus Pal treatment. Methods: In this study, we used a mBC xenograft model with the ERα Y537S mutation (MCF7 ERα Y537S mutant) and GeoMx-DSP technology to investigate differences in transcriptional and protein expression levels between Las, Ful, and their combinations with Pal. We also examined differences between ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). Results: As expected, our results show that, at both the transcriptome and protein levels, treatment with Las or Ful yields many similar outcomes. The addition of Pal shifts gene and protein expression in the same direction as Pal alone. While Las, like Ful, modulates the transcription of several genes involved in tumor growth and dissemination, the differences lie mainly in the intensity or significance of these alterations across several genes or proteins that lead to differences reflected in pathway analysis. Gene pathway analysis (GSEA/GOBP) using PanCK+ tumor cell selection suggests that Las, compared to vehicle, activates more immune pathways, while Ful activates more apoptosis pathways. Transcriptome analysis suggests that Ful is more involved in metabolic pathways, whereas Las treatment is more involved in actin filament modification and RNA/DNA modification pathways. Notably, PCNA protein expression is selectively repressed by Las in IDC compared to Ful. Conclusion: Our data reveal the complexity of Las vs Ful treatment outcomes in the MCF-7 Y537S mBC explant model and provide potential insights into the molecular mechanisms underlying the differential efficacy of Las and its combination with Pal in a metastatic breast cancer model with an activating ERα mutation. Citation Format: M. Laine, D. A. Tieri, C. Zhu, I. Raman, G. Chen, B. S. Komm, G. L. Greene. Comparative transcriptomic and proteomic analysis of lasofoxifene and fulvestrant, in an ER-mutated metastatic breast cancer explant model, identifies potential molecular mechanisms underlying differential treatment efficacy abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-12-12.
Laine et al. (Tue,) studied this question.