Abstract
Immune response and immunotherapy play important roles in triple-negative breast cancer (TNBC). However, it is difficult to judge whether cancer is “immune-inactivated” or “immune-activated” by the carcinoma itself. The immune reaction of the microenvironment or the host to the tumor might be more informative. We assumed that clinically enlarged but pathologically negative regional lymph nodes served as an indicator for early immune response to tumors. First, we identified women with pN0 breast cancer disease from the current Surveillance, Epidemiology, and End Results database, and we compared the cN1 patients of breast cancer-specific survival (BCSS) with cN0 patients. Then, we extracted total RNA from 36 paired large (defined as minimum diameter more than 15 mm in size) and small lymph nodes (defined as maximum diameter less than 5 mm in size) from 12 TNBC, 12 HER2-enriched, and 12 luminal-like patients and performed RNA sequencing to explore the gene expression and cellular landscape of large nodes compared to small ones. Among 692 women with pathologically confirmed node-negative disease, cN1 patients unexpectedly had a better BCSS compared with cN0 in TNBC (adjusted hazard ratio 0.148, 95% CI, 0.040–0.546, P = 0.004) but not in other subtypes. Further transcriptome sequencing of 12 paired enlarged and small negative nodes from TNBC patients revealed that increased immune activation signaling (e.g., interferon-gamma response pathways) and abundant immune cells (activated dendritic cells, CD4+ and CD8+ T-cells) were more frequently observed in enlarged nodes. Our data implied that early immune activation in regional lymph nodes in TNBC might affect survival.
Highlights
MATERIALS AND METHODSAmong females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer for incidence, and vice versa for mortality [1]
Considering its heterogeneous biological nature, breast cancer can be clinically stratified into three main subtypes: luminal-like, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative breast cancer (TNBC), according to the status of three critical receptors: estrogen receptor (ER), progestogen receptor (PR), and HER2 [2]
Considering that regional lymph nodes are parts of the host’s immune system, we hypothesized that clinically enlarged but pathologically negative regional lymph nodes might serve as an indicator for early systemic immune response to tumor and that immune activation probably resulted in an improved survival outcome of breast cancer patients
Summary
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer for incidence, and vice versa for mortality [1]. Considering that regional lymph nodes are parts of the host’s immune system, we hypothesized that clinically enlarged but pathologically negative regional lymph nodes might serve as an indicator for early systemic immune response to tumor and that immune activation probably resulted in an improved survival outcome of breast cancer patients To test this hypothesis, we conducted the present study. Because of the absence of data on HER2 status of patients diagnosed before 2010, we identified eligible patients according to the following criteria: diagnosed between 2010 and 2015, female, aged between 18 and 70 years, breast cancer as the first cancer diagnosis, microscopically confirmed infiltrating ductal carcinoma, unilateral, pT1-T2, cN0-N1, surgery performed, and regional lymph node examined to be pathologically negative (pN0). Statistical significance was determined with two-sided P < 0.05
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