Abstract 646: The amount of NRF2 expression in bulk tumors involves immune cells as well as cancer cells, which is associated with better prognosis in ER-positive/HER2-negative breast cancer
Authors: Oshi Masanori , Le Lan , Angarita Fernando A. , Tokumaru Yoshihisa , Yan Li , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki 
Published: July 2021

Abstract
Prior publications have described the role of nuclear factor erythroid 2-related factor 2 (NRF2) in cancer progression. These findings lead to the question of whether NRF2 should be targeted in anticancer therapy. NRF2 is commonly known as a tumor suppressor because it protects cells from oxidative insults and is thus anti-carcinogenic. However, elevated NRF2 levels in cancer cells can enhance growth and develop chemotherapy resistance by creating a redox environment, thus correlate with poor prognosis in multiple cancer types. The clinical relevance of NRF2 expression in breast cancer remains unclear because of limited data on NRF2 activation. We hypothesized that cancer cells and immune cells in the tumor microenvironment contribute to the expression of NRF2 in a bulk tumor and that infiltration of immune cells may contribute to survival outcomes in breast cancer patients. We studied the clinical relevance of NRF2 expression by conducting in silico analyses in 5,443 breast cancer patients from several large patient cohorts. We found that high NRF2 expression was significantly associated with better disease-free survival, disease-specific survival, and overall survival (OS) in ER-positive/HER2-negative (p = 0.039, 0.011, and &lt; 0.001, respectively in METABRIC cohort, and OS: p = 0.028 in GSE96058 cohort), but not in other subtypes. High NRF2 expression was associated with low pathological grade (p = 0.041 and p &lt; 0.001) in ER-positive/HER2-negative and TNBC subtypes (p = 0.047 and p &lt; 0.001) but not with AJCC cancer staging in both cohorts. High NRF2 expression in ER-positive/HER2-negative breast cancer significantly enriched inflammation- and immune-related gene sets as well as pro-cancerous gene sets by GSEA in both cohorts. NRF2 expression was elevated in cancer cells as well as T cells, myeloid cells, and stromal cells (p = 0.009). High NRF2 expression in ER-positive/HER2-negative breast cancer was associated with a low fraction of Th1 cells. Immune cytolytic activity score was elevated in high NRF2 expression tumors. NRF2 expression levels correlated with an area under the curve of several drug responses, including Paclitaxel, 5-FU, Tamoxifen, and Fulvestrant. However, there was no association between NRF2 expression and pCR rate after neoadjuvant chemotherapy in two cohorts. Finally, high NRF2 expression in ER-positive/HER2-negative breast cancer was associated with high expression of immune checkpoint molecules. We found that immune cells and tumor cells express high levels of NRF2 in the tumor microenvironment. High NRF2 expression levels enriched inflammation and immune-related gene sets and were associated with enhanced tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer. These results may explain why high NRF2 expression was associated with better survival outcomes in this subtype.
Citation Format: Masanori Oshi, Lan Le, Fernando A. Angarita, Yoshihisa Tokumaru, Li Yan, Ryusei Matsuyama, Itaru Endo, Kazuaki Takabe. The amount of NRF2 expression in bulk tumors involves immune cells as well as cancer cells, which is associated with better prognosis in ER-positive/HER2-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 646.