Abstract PS3-12-07: Tertiary Lymphoid Structures as Histopathologic Biomarkers in Invasive Breast Cancer: Subtype-Specific Patterns and Clinical Implications

Abstract Invasive breast cancer encompasses a range of tumor subtypes with variable immune landscapes that influence prognosis and treatment response. Tertiary lymphoid structures (TLS), organized immune aggregates resembling secondary lymphoid organs, may serve as histologic indicators of local antitumor immunity. We evaluated clinicopathologic and immune features associated with TLS presence and maturity using histology-based scoring and gene expression–based modeling. TLS and tumor-infiltrating lymphocytes (TILs) were scored on H&E-stained whole slide images (N = 842) from the Carolina Breast Cancer Study (CBCS). Associations with clinicopathologic features and progression-free survival (PFS) were assessed using multinomial logistic and Cox models. Immune expression profiles of TLS groups informed development of weighted centroid classifiers: a 10-gene TLS classifier based on Tfh genes enriched in TLS-positive tumors and B cell genes elevated in tumors with mature (mTLS) vs. only immature (iTLS), and an 18-gene TIL signature derived from remaining lymphocyte markers upregulated in TLS-positive cases. Classifiers were trained and tested on non-overlapping subsets of the CBCS cohort, then applied to the I-SPY2 neoadjuvant trial dataset to assess association with pathologic complete response (pCR). TLS were identified in 38% of tumors and varied in number and location. Subjects were assigned to one of three TLS groups: No TLS, iTLS Only, or mTLS Present (>93% of which also contained iTLS). mTLS Present tumors harbored approximately 2-fold the total TLS compared to iTLS Only and were over twice as likely to contain intratumoral TLS (54.2% vs. 26.3%). TLS presence and maturation were significantly associated with younger age (