Association Between Circulating CD107a+ Natural Killer Cells and Clinical Nodal Stage in Early Breast Cancer: An Exploratory Prospective Biomarker Cohort Study

Objectives: Minimally invasive biomarkers for risk stratification in early breast cancer are lacking. We examined whether pretreatment circulating natural killer (NK)-cell subsets, specifically CD107a+ NK cells, are associated with clinicopathological features and outcomes of early breast cancer and whether tumor transcriptomes reflect NK-cell subset levels. Materials and Methods: Circulating NK-cell subsets were quantified by flow cytometry in 94 patients with stages I–III breast cancer prior to surgery and systemic therapy (median follow-up 42.6 months; 10 relapses, 7 deaths). Associations across 12 immune subsets were corrected for multiple comparisons (Benjamini–Hochberg false-discovery rate, FDR). Matched tumor RNA-sequencing (n = 25) informed a weighted CD107a-associated tumor-expression score that was examined for an association with survival in TCGA-BRCA (n = 1096). Results: Low circulating CD107a+ NK-cell levels were associated with clinically node-positive disease (cN1–3, raw p = 0.048), increased relapse rate (p = 0.003), and death (p < 0.001). Of 96 association tests, only the CD107a+ NK-cell level and overall survival approached significance after FDR correction (q = 0.096); the clinical nodal-stage association did not survive correction (q = 0.93). Exploratory multivariable models were unstable given the few events. Immunoglobulin lambda genes, the dominant contributors to the tumor-expression score, separated survival in TCGA-BRCA (log-rank p = 0.0096), confirming a tumor signature rather than validating circulating CD107a+ NK cells as a biomarker. Conclusions: Low circulating CD107a+ NK cells were associated with, but do not yet establish, higher-risk early breast cancer. The findings of the present study are hypothesis-generating and do not confirm biomarker status of CD107a+ NK cells in early breast cancer. Prospective, adequately powered, externally validated studies are required before prognostic or therapeutic use.