Should Tumor Infiltrating Lymphocytes, Androgen Receptor, and FOXA1 Expression Predict the Clinical Outcome in Triple Negative Breast Cancer Patients?

Abstract

Tumor-infiltrating lymphocytes (TILs) are a valuable indicator of the immune microenvironment that plays the central role in new anticancer drugs. TILs have a strong prognostic role in triple negative breast cancer (TNBC). Little is known about the interaction with the androgen receptor (AR) and forkhead box A1 (FOXA1). We analyzed the relationships between TIL levels, AR, and FOXA1 expression and their clinical significance in TNBC patients. Further, we investigated their interaction with other biomarkers like programmed cell death ligand-1 (PD-L1), breast cancer type 1 susceptibility protein (BRCA1), poly (ADP-Ribose) polymerase 1 (PARP1), and Na+/H+ exchanger regulatory factor 1 (NHERF1). The expression of the proteins was evaluated by immunohistochemistry in 124 TNBC samples. TILs were performed adhering to International TILs Working Group 2014 criteria. Cox proportional hazards models were also used to identify risk factors associated with poor prognosis. Multivariate analysis identified TILs as independent prognostic factor of disease free survival (DFS; p = 0.045). A Kaplan–Meyer analysis revealed that the patients with high TILs had a better DFS compared to patients with low TILs (p = 0.037), and the phenotypes TILs−/AR+ and TILs−/FOXA1− had a worse DFS (p = 0.032, p = 0.001 respectively). AR was associated with FOXA1 expression (p = 0.007), and the tumors FOXA1+ presented low levels of TILs (p = 0.028). A poor DFS was observed for AR+/FOXA1+ tumors compared to other TNBCs (p = 0.0117). Low TILs score was associated with poor patients’ survival, and TILs level in combination with AR or FOXA1 expression affected patient’s clinical outcome. In addition, AR+/FOXA1+ phenotype identified a specific subgroup of TNBC patients with poor prognosis. These data may suggest new ways of therapeutic intervention to support current treatments.

Clinical Implications of Androgen-Positive Triple-Negative Breast Cancer

“…Recent scientific research is emerging to identify novel prognostic biomarkers for targeted analysis and therapy of TNBCs [ 55 ]. PD1 is an immune checkpoint receptor and a cardinal immunosuppression mechanism used by cancer cells to escape host immunity [ 55 ]. Its ligand, PDL1 predicted AR positivity, as AR-positive TNBC was threefold more likely to express PD-L1 on cancer cells.…”

“…FOXA1 is a key determinant of ER function and endocrine response. There is a significant association between AR and FOXA1 status [ 55 , 58 ]. In one study, co-expression of AR and FOXA1 was found in 15% of all TNBCs [ 26 ] and it was associated with shorter DFS [ 55 ].…”

NLRP3 Inflammasome From Bench to Bedside: New Perspectives for Triple Negative Breast Cancer

“…To date, there are no targeted therapies available for patients with advanced TNBC (84). This subgroup of tumors represents a very heterogeneous disease, consisting of a wide spectrum of biologically distinct subtypes with different prognosis (85). TNBC harbors a specific inflammatory microenvironment in which high levels of molecules released from activated inflammatory cells, such as pro-inflammatory cytokines, ROS, reactive nitrogen species (RNS), coexist with angiogenic factors, such as the Vascular Endothelial Growth Factor (VEGF), and with a significant amount of Tumor-Infiltrating Lymphocytes and TAMs (86).…”

New Insights into Breast and Endometrial Cancers

“…TNBC is the most immunogenic breast cancer subtype; an increasing number of PD-L1 expression levels and immune checkpoint inhibitors have been emerging as potential therapeutic options for TNBC. A previous study has provided information on the prognosis of tumor-infiltrating lymphocytes (TILs), androgen receptor (AR), and forkhead box A1 (FOXA1) in TNBC [ 14 ]. In the study, patients with low TIL scores exhibited low survival and the combination of TIL levels and AR or FOXA1 expression affected the clinical outcome [ 14 ].…”

“…A previous study has provided information on the prognosis of tumor-infiltrating lymphocytes (TILs), androgen receptor (AR), and forkhead box A1 (FOXA1) in TNBC [ 14 ]. In the study, patients with low TIL scores exhibited low survival and the combination of TIL levels and AR or FOXA1 expression affected the clinical outcome [ 14 ]. In another study, a gene expression profiling meta-analysis revealed novel gene signatures related tyrosine kinase in TNBC [ 15 ].…”