Background: Immunotherapy is a rapidly evolving treatment option in breast cancer (BC); However, the BC immune microenvironment is understudied in Black and younger (<50 years) patients. Methods: We used histological and RNA-based immunoprofiling methods to characterize the BC immune landscape in 1,952 tumors from the Carolina Breast Cancer Study, a population-based study that oversampled Black (n=1,030) and young women (n=1,039). We evaluated immune response leveraging markers for 10 immune cell populations, compared profiles to those in the Cancer Genome Atlas Project [n=1095 tumors, Black (n=183), and young women (n=295)], and evaluated in association with clinical and demographic variables, including recurrence. Results: Consensus clustering identified three immune clusters in CBCS [adaptive-enriched, innate-enriched, or immune-quiet] that varied in frequency by race, age, tumor grade and subtype; however, only two clusters were identified in TCGA, which were predominantly comprised of adaptive-enriched and innate-enriched tumors. In CBCS, the strongest adaptive immune response was observed for basal-like, HER2+, TNBC, and high-grade tumors. Younger patients had higher proportions of adaptive-enriched tumors, particularly among estrogen receptor (ER)-negative cases. Black patients had higher frequencies of both adaptive-enriched and innate-enriched tumors. Immune clusters were associated with recurrence among ER-negative tumors, with adaptive-enriched showing the best and innate-enriched showing the poorest 5-year recurrence-free survival. Conclusions: These data suggest that immune microenvironments are intricately related to race, age, tumor subtype, and grade. Impact: Given higher mortality among Black and young women, more defined immune classification using cell-type specific panels could help explain higher recurrence and ultimately lead to targetable interventions.

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