An assessment of prognostic immunity markers in breast cancer

Abstract

Tumor-infiltrating lymphocytes (TIL) and immunity gene signatures have been reported to be significantly prognostic in breast cancer but have not yet been applied for calculation of risk of recurrence in clinical assays. A compact set of 17 immunity genes was derived herein from an Affymetrix-derived gene expression dataset including 1951 patients (AFFY1951). The 17 immunity genes demonstrated significant prognostic stratification of estrogen receptor (ER)-negative breast cancer patients with high proliferation gene expression. Further analysis of blood and breast cancer single-cell RNA-seq datasets revealed that the 17 immunity genes were derived from TIL that were inactive in the blood and became active in tumor tissue. Expression of the 17 immunity genes was significantly (p < 2.2E-16, n = 91) correlated with TILs percentage on H&E in triple negative breast cancer. To demonstrate the impact of tumor immunity genes on prognosis, we built a Cox model to incorporate breast cancer subtypes, proliferation score and immunity score (72 gene panel) with significant prediction of outcomes (p < 0.0001, n = 1951). The 72 gene panel and its risk evaluation model were validated in two other published gene expression datasets including Illumina beads array data METABRIC (p < 0.0001, n = 1997) and whole transcriptomic mRNA-seq data TCGA (p = 0.00019, n = 996) and in our own targeted RNA-seq data TARGETSEQ (p < 0.0001, n = 303). Further examination of the 72 gene panel in single cell RNA-seq of tumors demonstrated tumor heterogeneity with more than two subtypes observed in each tumor. In conclusion, immunity gene expression was an important parameter for prognosis and should be incorporated into current multi-gene assays to improve assessment of risk of distant metastasis in breast cancer.

Prognostic nomogram based on immune scores for breast cancer patients

“…Importantly, we found that patients with higher immune scores tended to be ER, PR, and HER2 negative. It implied that subjects might be less responsive to treatments with antiestrogen and anti‐HER2 therapy, while they may benefit from immunotherapies to further improve survival . Generally speaking, patients with ER or PR positive and HER2 negative status had better prognosis than those with ER or PR negative and HER2 positive status, respectively, which was consistent with our results from univariate analyses.…”

“…It implied that subjects might be less responsive to treatments with antiestrogen and anti-HER2 therapy, while they may benefit from immunotherapies to further improve survival. 15,25,26 Generally speaking, patients with ER or PR positive and HER2 negative status had better prognosis than those with ER or PR negative and HER2 positive status, respectively, which was consistent with our results from univariate analyses. However, in multivariate analyses, no statistical associations between ER/PR/HER2 status and prognosis were obtained, and the possible reasons are listed as followings.…”

“…The contribution of immune cells to breast cancer has been well recognized, and immunity gene signature is considered as a biomarker for immunotherapy responses . In addition, previous studies have shown that immunology gene signature significantly correlated with prognosis of breast cancer . A study found that immunity gene expression should be incorporated into the current multi‐gene assays to improve assessment of prognosis of breast cancer patients.…”

“…However, none of these has been sufficiently informative for guidance in clinical practice. Notably, the effectiveness of adopting targeted therapy depending on immune scores, still remains a major clinical issue, although gene expression profiling has significantly improved the level of comprehensive and individual treatment of breast cancer patients …”

“…Notably, the effectiveness of adopting targeted therapy depending on immune scores, still remains a major clinical issue, 13 although gene expression profiling has significantly improved the level of comprehensive and individual treatment of breast cancer patients. 14,15 To the best of our knowledge, there are limited studies that focus on the relationship between immune scores and breast cancer prognosis. We sought to evaluate the association of immune scores with prognosis and built a clinical nomogram for predicting survival of patients with breast cancer.…”