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Tumor-infiltrating lymphocytes (TILs) and ectopic lymphoid formations known as tertiary lymphoid structures (TLS) are prognostically significant in triple-negative breast cancer (TNBC). However, there is a paucity of data on this matter in hormone receptor-positive (HR+) breast cancer and whether these immunological parameters are impacted by preoperative radiation therapy (RT). The purpose of this work is to assess the relationship between residual cancer burden (RCB) and TILs/TLS in HR+ early-stage breast cancer following preoperative radiation therapy. During 2019-2020, patients with cT0-T2, N0, M0 breast cancer were enrolled in a clinical trial (MC1732) in which they received hypofractionated whole-breast RT in 25 Gy in 5 fractions 4-8 weeks prior to breast-conserving surgery (BCS). RCB (determined per MD Anderson calculator), estimated % cellularity, TILs, and TLS were assessed in the surgical tissues. Low TIL was defined as < 10%, intermediate TIL as 11-49%, and high TIL as > 50%. The relationships between RCB class, numerical RCB values, and immunological parameters were explored using Kruskal-Wallace/Wilcoxon Rank Sum Test, linear regression, and Kendall's tau correlations. TILs and TLS were log-transformed to overcome extreme distributions. Lastly, a predictive model for pathologic outcomes was developed using backward elimination. Among the 22 patients analyzed for RCB, all were ER/PR positive. One patient was HER2 positive, and 13/22 had Grade 1 disease. Pathologic complete response (pCR) was noted in 18%, RCB-I in 60%, and RCB-II in 22%. In post-treatment samples, low, intermediate, and high TIL were found in 77%, 18%, and 5% of patients, respectively. Approximately 36% of patients had at least one TLS present after radiation. Kruskal-Wallace/Wilcoxon Rank Sum Test indicated a significant association between RCB class and % TILs and TLS (p = 0.010 and 0.003, respectively.) Kendall's tau correlation indicated a statistically significant positive correlation between RCB values and % TILs (p = 0.02) and TLS (p = 0.001). Linear regression revealed that for every one-unit increase in RCB value, there was a statistically significant 4.3 unit increase in the % TILs (p <0.001), and a 2.48 unit increase in TLS (p <0.001). Finally, per the backward selection model, the number of TLS was associated with increased % cellularity at the time of surgery. Our data suggest that increases in TILs and TLS following preoperative radiation are associated with increased residual disease in HR+ early-stage breast cancer. Given the fact that there are multiple types of potential immune infiltrates, further work is needed to elucidate the mechanisms behind these findings and specific types of immune infiltration. [ABSTRACT FROM AUTHOR]