Dual roles for immune metagenes in breast cancer prognosis and therapy prediction.

Angela Alistar,Srikanth Nagalla,Lance D Miller,Jeff W Chou,Michael A Black,Ralph D’Agostino

doi:10.1186/s13073-014-0080-8

Abstract

BackgroundNeoadjuvant chemotherapy for breast cancer leads to considerable variability in clinical responses, with only 10 to 20% of cases achieving complete pathologic responses (pCR). Biological and clinical factors that determine the extent of pCR are incompletely understood. Mounting evidence indicates that the patient’s immune system contributes to tumor regression and can be modulated by therapies. The cell types most frequently observed with this association are effector tumor infiltrating lymphocytes (TILs), such as cytotoxic T cells, natural killer cells and B cells. We and others have shown that the relative abundance of TILs in breast cancer can be quantified by intratumoral transcript levels of coordinately expressed, immune cell-specific genes. Through expression microarray analysis, we recently discovered three immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. The B/P (B cell/plasma cell), T/NK (T cell/natural killer cell) and M/D (monocyte/dendritic cell) immune metagenes were significantly associated with distant metastasis-free survival of patients with highly proliferative cancer of the basal-like, HER2-enriched and luminal B intrinsic subtypes.MethodsGiven the histopathological evidence that TIL abundance is predictive of neoadjuvant treatment efficacy, we evaluated the therapy-predictive potential of the prognostic immune metagenes. We hypothesized that pre-chemotherapy immune gene signatures would be significantly predictive of tumor response. In a multi-institutional, meta-cohort analysis of 701 breast cancer patients receiving neoadjuvant chemotherapy, gene expression profiles of tumor biopsies were investigated by logistic regression to determine the existence of therapy-predictive interactions between the immune metagenes, tumor proliferative capacity, and intrinsic subtypes.ResultsBy univariate analysis, the B/P, T/NK and M/D metagenes were all significantly and positively associated with favorable pathologic responses. In multivariate analyses, proliferative capacity and intrinsic subtype altered the significance of the immune metagenes in different ways, with the M/D and B/P metagenes achieving the greatest overall significance after adjustment for other variables.ConclusionsGene expression signatures of infiltrating immune cells carry both prognostic and therapy-predictive value that is impacted by tumor proliferative capacity and intrinsic subtype. Anti-tumor functions of plasma B cells and myeloid-derived antigen-presenting cells may explain more variability in pathologic response to neoadjuvant chemotherapy than previously recognized.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-014-0080-8) contains supplementary material, which is available to authorized users.

Highlights

Neoadjuvant chemotherapy for breast cancer leads to considerable variability in clinical responses, with only 10 to 20% of cases achieving complete pathologic responses
Neoadjuvant chemotherapy can lead to significant clinical response rates of 60 to 80%, only 10 to 20% of patients will exhibit a complete pathologic response [2,6]. pathologic responses (pCR) is typically defined as tumor regression marked by the absence of detectable residual disease in the breast and lymph nodes at surgery
Through gene ontology enrichment analysis and demonstration of immune cell type-specific expression patterns, we provided evidence that these immune metagenes reflect tumor-infiltrating populations of: 1) B cells/plasma B cells (B/P) marked by the high expression of IgG antibody isotype-related genes; 2) a T cell/natural killer cell-specific population (T/NK) likely reflecting a predominantly Th1-type functional orientation; and 3) a monocyte/dendritic cell population (M/D) marked by the expression of myeloid specific markers and a host of major histocompatibility complex (MHC) class II antigen-presenting molecules

Summary

Introduction

Neoadjuvant chemotherapy for breast cancer leads to considerable variability in clinical responses, with only 10 to 20% of cases achieving complete pathologic responses (pCR). We and others have shown that the relative abundance of TILs in breast cancer can be quantified by intratumoral transcript levels of coordinately expressed, immune cell-specific genes. The B/P (B cell/plasma cell), T/NK (T cell/natural killer cell) and M/D (monocyte/dendritic cell) immune metagenes were significantly associated with distant metastasis-free survival of patients with highly proliferative cancer of the basal-like, HER2-enriched and luminal B intrinsic subtypes. Neoadjuvant chemotherapy can lead to significant clinical response rates of 60 to 80%, only 10 to 20% of patients will exhibit a complete pathologic response (pCR) [2,6]. PCR is typically defined as tumor regression marked by the absence of detectable residual disease in the breast and lymph nodes at surgery. Measurement of residual cancer burden (RCB) provides a categorical index for tumor responsiveness to neoadjuvant treatment based on size and cellularity of the primary tumor and number and size of involved lymph nodes [9]

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Results

Conclusion