Immune response indicated by clinically enlarged but pathologically negative regional lymph nodes predicts favorable survival in triple negative breast cancer

"The significance of breast cancer patients with clinically positive but pathologically negative regional lymph nodes remains elusive. Herein, we seek to investigate the clinicopathological features, the breast cancer-specific survival (BCSS)as well as the transcriptomics of breast cancer patients carrying enlarged non-tumor infiltrated lymph nodes. A total of 692 female patients with T1-2, cN0-N1pN0 infiltrating ductal carcinoma from the current Surveillance, Epidemiology, and End Results database were identified. We first investigated the relationship between the clinicopathological variables and clinically lymph node (cN) status. Next, we assessed the impact of cN status on BCSS in the whole cohort and subgroups after stratified by hormone receptor (HR) and HER-2 status. Finally, we performed RNA sequencing of 12 paired enlarged and small lymph nodes to investigate the immunogenomic portrait and molecular characteristics of enlarged non-tumor infiltrating lymph nodes compared to small lymph nodes.The cN1pN0 status was more frequent in patients with younger age, larger tumor size, higher grade, more chemotherapy and triple negative status than the cN0pN0 status. There was no prognostic relevance of cN status on BCSS in the whole (P=0.639), luminal-like (HR+, any HER-2 status) (P=0.081) and HER-2 enriched (HR-, HER-2+) (P=0.504) patients. However, cN1pN0 cases had improved survival in triple negative (HR- and HER-2-) breast cancer (TNBC) (P=0.001). Multivariable analysis showed that cN1pN0 was still a favorable prognostic factor for TNBC patients after adjustment by some confounding factors (P=0.004, hazard ratio = 0.148, Confidence interval: 0.040-0.546). Transcriptome analysis showed that increased immune activation signaling and immune cell abundance was observed in enlarged negative lymph nodes compared to small lymph nodes. Our data implicated that immune activation was the mechanism for patients with clinically enlarged but pathologically confirmed negative regional lymph nodes, which brings favorable outcomes in TNBC subtype."