Development of an Immune-Related Prognostic Signature in Breast Cancer

BACKGROUND: Although increased early detection, diagnosis and treatment have improved the outcome of breast cancer patients, prognosis estimation still poses challenges due to the disease heterogeneity. Accumulating data indicated an evident correlation between tumor immune microenvironment and clinical outcomes. OBJECTIVE: To construct an immune-related signature that can estimate disease prognosis and patient survival in breast cancer. METHODS: Gene expression profiles and clinical data of breast cancer patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, which were further divided into a training set (n = 499), a testing set (n = 234) and a Meta-validation set (n = 519). In the training set, immune-related genes were recognized using combination of gene expression data and ESTIMATE algorithm-derived immune scores. An immune-related prognostic signature was generated with LASSO Cox regression analysis. The prognostic value of the signature was validated in the testing set and the Meta-validation set. RESULTS: A total of 991 immune-related genes were identified. Twelve genes with non-zero coefficients in LASSO analysis were used to construct an immune-related prognostic signature. The 12-gene signature significantly stratified patients into high and low immune risk groups in terms of overall survival independent of clinical and pathologic factors. The signature also significantly stratified overall survival in clinical defined groups, including stage I/II disease. Several biological processes, such as immune response, were enriched among genes in the immune-related signature. The percentage of M(2) macrophage infiltration was significantly different between low and high immune risk groups. Time-dependent ROC curves indicated good performance of our signature in predicting the 1-, 3- and 5-year overall survival for patients from the full TCGA cohort. Furthermore, the composite signature derived by integrating immune-related signature with clinical factors, provided a more accurate estimation of survival relative to molecular signature alone. CONCLUSION: We developed a 12-gene prognostic signature, providing novel insights into the identification of breast cancer with a high risk of death and assessment of the possibility of immunotherapy incorporation in personalized breast cancer management.