Abstract 416: Spatial transcriptomic analysis of breast cancer patients with early and late progression of disease after endocrine and CDK4/6 treatments: deconvoluting the tumor microenvironment

Abstract Background: Cyclin-dependent kinase inhibitors, CDK4/6i, have been one of the most significant practice-changing advancements for the estrogen receptor positive (ER+) breast cancer therapy in the recent decade. However, no molecular biomarkers are successful in predicting sensitivity/resistance to CDK4/6 inhibitors in clinical trials. It is believed that the heterogeneity of the tumor microenvironment (TME) plays a key role in resistance and metastasis. Deconvolution of TME in CDK4/6 treated samples may provide novel tumor-specific strategies to overcome resistance and reduce mortality in ER+ breast cancer. Methods: Samples of primary tumors from patients treated for metastatic ER+ breast cancer with CDK4/6 inhibitors were identified from the database of Emory University hospital. Archival FFPE sections were analyzed using 10X CytAssist-enabled Visium Spatial transcriptomics using the UAB Flow Cytometry and Single Cell Core Facility. IRIS and cell type deconvolution analyses were performed to identify TME parameters (immune markers and cell types) associated with time to progression on CDK4/6i. Results: The analysis was performed on 10 patients who were all treated with Palbociclib and endocrine therapy. The early time to progression (<6 months; n=6) exhibited differential cellular phenotypes (Tumor, Stroma, and Immune Cells) in comparison to late time of progression (>30 months; n=4). The study revealed that both B cells, and CD4+ and CD8+ T cells, are present in significantly higher proportions in the progression of the <6 months group, suggesting a role for immune-related mechanisms in the development of resistance. In addition to lymphocytes, cancer-associated fibroblasts (CAFs) were more prominent in early progression cases suggesting the involvement of tumor microenvironment. Additional confirmatory analyses are on-going. Conclusion: Deconvolution of the TME using spatial transcriptomics will be a powerful tool for understanding the tumor heterogeneity. Better understanding of the cellular interactions could provide novel strategies to prevent CDK4/6 inhibitor resistance. Citation Format: Sunil S. Badve,Shihan Liu,Madhubanti Basu,Chiao-Wang Sun,Shanrun Liu,Jian Hu,Yesim Gokmen-Polar. Spatial transcriptomic analysis of breast cancer patients with early and late progression of disease after endocrine and CDK4/6 treatments: deconvoluting the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 416.