Abstract PS5-03-25: Bexmet trial for metastatix tnbc patients

Abstract The ability to precisely manipulate cancer cell states represents a promising approach to enhance therapeutic response. Our previous work demonstrated that retinoids can reduce tumorigenicity in triple-negative breast cancer (TNBC) models by shifting cells from a mesenchymal to an epithelial state, thereby sensitizing resistant TNBC cells to standard-of-care treatments. Here, we designed a Phase I trial, BEXMET, to investigate whether bexarotene, a retinoid X receptor agonist, can induce epithelial cell state changes and increase sensitivity to capecitabine in patients with metastatic TNBC. This cohort included 12 patients who received bexarotene during a two-week lead-in period, followed by repeated treatment cycles consisting of two weeks of oral capecitabine and one week of bexarotene. Tumor biopsies were collected at four time points: pre-treatment, post-bexarotene lead-in, post-capecitabine (cycle 1), and at disease progression (if applicable). RNA-Seq and multiplex immunohistochemistry were performed on all biopsies. Our results show that bexarotene induced a mesenchymal-to-epithelial transition (MET) in 3 of 9 patients, as indicated by transcriptional and histological markers. These bexarotene responders demonstrated increased sensitivity to capecitabine, evidenced by enrichment of cell death-related gene expression following treatment. Notably, the MET responders exhibited reduced immune cell infiltration and a more epithelial-like phenotype after two weeks of bexarotene treatment. At baseline, these responders tended to have a more mesenchymal and immune-infiltrated tumor profile, suggesting potential predictive biomarkers for response. In conclusion, this study provides early clinical evidence that pharmacologic induction of cell state changes can enhance the efficacy of existing chemotherapies in metastatic TNBC. Targeting cell plasticity may offer a cost-effective and accessible therapeutic strategy for this aggressive breast cancer subtype. Citation Format: Y. ZHANG, E. Pathak, C. Koh, J. Lidster, J. Yeong, E. Lim, W. Tam. Bexmet trial for metastatix tnbc patients [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 PS5-03-25.