Spatial architecture of tumor-infiltrating lymphocytes adds predictive value beyond stromal TIL density for neoadjuvant response in triple-negative breast cancer.

Background: Stromal tumor-infiltrating lymphocytes (TILs) are established biomarkers in triple-negative breast cancer (TNBC), but conventional density-based assessment does not capture their spatial relationship to tumor nests. We evaluated whether an H&E-derived spatial architecture index (SAI) provides predictive information beyond stromal TIL density for pathologic complete response (pCR) after neoadjuvant therapy. Methods: This single-center retrospective cohort included 236 patients with TNBC who had evaluable pretreatment core biopsy slides and definitive surgical response assessment. The primary SAI was the equally weighted mean of standardized close interaction ratio and lymphocyte cluster index, together with reverse-coded standardized lymphocyte-tumor distance and edge enrichment. The primary multivariable analysis included 231 patients with complete clinicopathologic data. Robustness was evaluated using bootstrap optimism correction, alternative SAI constructions, treatment-regimen and propensity-score analyses, repeated nested cross-validation, and a 60-case reproducibility assessment. During internal validation, preprocessing and SAI construction were repeated within each training fold. Results: Of 236 patients, 122 (51.7%) achieved pCR. In the main multivariable model, the SAI remained associated with pCR (OR 2.79 per 1 SD, 95% CI 1.79-4.35; Conclusion: In this exploratory single-center retrospective cohort, the H&E-derived SAI provided internally validated predictive information beyond stromal TIL density for pCR. External multicenter validation, assessment of intersite technical reproducibility, and prospective calibration are required before clinical implementation.