Peripheral T-cell receptor beta repertoire in breast cancer: Implications for prognosis and therapy-associated immune repertoire dynamics

Purpose: Sequencing of the T-cell receptor (TCR) repertoire provides insight into host immune status and can serve as a biomarker of therapeutic response. This study aimed to comprehensively evaluate the relationships between peripheral TCR repertoire characteristics, clinicopathological parameters, survival outcomes, and treatment regimens in breast cancer. Experimental Design: Peripheral blood from patients with early- or late-stage breast cancer was analyzed using the Oncomine™ TCR Beta-LR Assay, and matched tumor tissues were profiled with the Oncomine™ Comprehensive Assay v3. Patients were classified into three groups: (1) first-line surgery followed by adjuvant therapy, (2) neoadjuvant chemotherapy (NACT) followed by surgery, and (3) de novo or recurrent Stage IV disease. TCR diversity metrics including clonality, convergence, richness, and Shannon diversity were correlated with clinicopathologic features, genomic alterations, and overall survival using Pearson correlation, Kaplan-Meier, and Cox regression analyses. Results: Among 856 enrolled patients, baseline TCR clonality was inversely correlated with both richness and Shannon diversity, while convergence showed a modest positive association with clonality. Higher clonality correlated weakly but significantly with patient age and tumor stage. Elevated baseline clonality was associated with poorer overall survival and remained an independent prognostic factor in multivariate Cox analysis. Patients harboring ARID1A mutations exhibited reduced TCR richness and lower Shannon diversity compared with wild-type counterparts. Treatment-specific analysis revealed that adjuvant chemotherapy, particularly taxane- or anthracycline-taxane-based regimens, induced peripheral T-cell clonal expansion and loss of diversity, with trastuzumab-associated changes confined to HER2-enriched but not luminal B2 subtypes. Similarly, NACT, especially anthracycline-taxane or platinum-containing regimens, promoted clonal expansion and reduced diversity, with HER2-targeted effects again restricted to HER2-enriched tumors. Conclusion: Peripheral TCR clonality serves as an independent prognostic biomarker in Stage IV breast cancer. HER2-targeted therapies and specific chemotherapy regimens modulate immune repertoire dynamics in a subtype-dependent manner. These findings highlight that treatment type significantly influences TCR diversity and underscore the potential of integrating repertoire profiling with genomic and clinical data to guide personalized therapy in breast cancer.