Abstract PS3-12-01: T-cell receptor (TCR) Repertoire Differences Between Stage III Inflammatory Breast Cancer (IBC) and Matched Non-IBC Controls

Abstract Background: Inflammatory breast cancer (IBC) is a rare and aggressive subtype of breast cancer characterized by a distinct clinical presentation and poor prognosis. Despite multiple studies aimed at understanding the biological drivers of its aggressive behavior, the underlying mechanisms remain elusive. Emerging evidence suggests that the host immune system may play a role in the unique clinical course of IBC. Prior research has demonstrated that peripheral blood T-cell receptor (TCR) clonotype diversity declines with age, and it is associated with cancer risk and disease progression. However, the peripheral blood TCR clonotype repertoire has not been studied in IBC. Methods: We conducted a matched-cohort study using baseline peripheral blood samples from treatment-naïve patients. Stage III cases and controls were matched 1:1 by age such that the ages of each case-control pair were within 5 years of each other. The controls were identified from our institutional annotated datasets (COQD, EMBRACE). RNA was extracted from whole blood and subjected to TCR sequencing to characterize the clonotype repertoire. TCR diversity was quantified using established metrics, including Shannon entropy, Richness, and clonality indices. We compared the frequencies and uniqueness of CDR3 sequences between IBC and non-IBC patients. We also clustered all CDR3 (alpha or beta) sequences from patients using Geometric Isometry-based TCR AligNment Algorithm (GIANA) tool to evaluate CDR3 cluster differences between the two groups. Results: 41 patients with stage III IBC and age-matched 41 patients with stage III non-IBC were included (n = 82). The age ranged from 26 to 87 in the groups. A trend toward increased TCRα clonotype diversity was observed in non-IBC compared to IBC samples. This was evidenced by higher Shannon entropy and Richness scores in non-IBC samples, reflecting a more diverse and heterogeneous T-cell receptor repertoire. Conversely, IBC samples exhibited lower diversity, as indicated by higher Shannon and Simpson clonality values, consistent with a more oligoclonal T-cell population. The ratio of unique CDR3a sequences in individual patients was significantly higher in the non-IBC group (Mann-Whitney U test, p=0.036). Non-IBC samples also had more unique CDR3 clusters than IBC samples, indicating greater T-cell repertoire heterogeneity. TCR diversity was not significantly associated with overall survival in either group, however, the number of events was low. Conclusions: In this study, we evaluated TCR clonotype diversity in patients with stage III IBC and non-IBC. Our findings suggest that IBC is associated with a less diverse TCR repertoire, which may reflect a more restricted or less effective anti-tumor immune response. These results warrant further investigation to determine the clinical relevance and potential therapeutic implications of TCR characteristics in IBC. Citation Format: I. Schlam, X. Cai, N. U. Lin, C. Stever, A. Giordano, J. Rosenbluth, C. C. Block, C. Graser, F. Nakhlis, G. Kirkner, A. Martin, F. Michor, S. T. Schumer, E. Rotella, M. Moore, H. Heiling, C. Snow, A. Patel, S. M. Tolaney, K. Polyak, F. Lynce. T-cell receptor (TCR) Repertoire Differences Between Stage III Inflammatory Breast Cancer (IBC) and Matched Non-IBC Controls 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 PS3-12-01.