Abstract 6825: Age-stratified therapeutic strategies targeting tumor cell subclones that drive chemoresistance and immunosuppression in triple-negative breast cancer

Abstract Age is the biggest risk factor for developing most forms of cancer, including breast cancer. While over 50% of cancer cases occur in patients over 65, fewer than 25% of patients enrolled in clinical trials are in this age group. Furthermore, most preclinical models use young mice, together indicating that preclinical research and clinical trials may not appropriately reflect the age of patients most affected by cancer. Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that has high rates of recurrent, chemoresistant disease and poor outcomes. Moreover, older patients do not tolerate chemotherapy well, so alternatives are needed. We used a preclinical mouse model that reflects clinical progression with age, whereby young (∼8 week old) and aged (12-16 month old) FVB/NJ mice were orthotopically injected with syngeneic Met1 TNBC cells. Mice were treated with standard therapy consisting of chemotherapy (paclitaxel, PTX) and immunotherapy (anti-PD-L1). Relative to young mice, aged mice did not benefit from combination therapy over monotherapy, which was at least partially due to signs of immune dysregulation and CD8+ T cell exhaustion. RNA sequencing revealed that in response to PTX or combination therapy, tumors from young mice became enriched for immune and inflammatory response hallmark programs, making the young mice look transcriptionally old. Aged mice, however, did not exhibit any response to chemotherapy, - underscoring the lack of response to treatment with age and need for chemotherapy alternatives. The Met1 TNBC cells used here contain heritable, non-immunogenic, DNA barcodes through which we identified a unique subclone of tumor cells that is resistant to PTX, both in vitro and in vivo. Among minor clones comprising 15% of the tumor cells, this clone expands with age and PTX, drives an EMT-like phenotype, and displays features of immunosuppression. A drug screen using a library of FDA-approved compounds identified histone deacetylase inhibitors (HDACi) as a potent class of drugs that kill this chemo-resistant clone. Finally, we treated young and aged mice with Panobinostat, a pan-HDACi that was the top hit in the screen, in combination with anti-PDL1. This combination led to a more significant therapeutic benefit in aged mice by reducing tumor burden and significantly extending survival compared to young. We have identified age-tailored therapies that improve TNBC outcomes in both young and aged mice, without the need for chemotherapy in aged mice. Further, specific subclones of tumor cells can drive transcriptional programs impacting age-associated differences in tumor progression, but they can be therapeutically targeted. This work sets the stage for the development of age-stratified therapeutic strategies that do not rely on toxic chemotherapy to improve outcomes for TNBC patients of all ages. Citation Format: Milos Spasic, Melissa Dolan, Adrienne Marie Parsons, Beyza Koca, Dimitry Lineker, Jacobs Hawk, Hanna Starobinets, Rachel A. Freedman, Elizabeth Mittendorf, Peter van Galen, Sandra S. McAllister. Age-stratified therapeutic strategies targeting tumor cell subclones that drive chemoresistance and immunosuppression in triple-negative breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6825.