Abstract P6-05-05: Gene expression signatures of effector immune cell abundance are significantly associated with pathologic breast tumor response in the neoadjuvant setting

Abstract

Abstract Background Neoadjuvant chemotherapy for early breast cancer leads to significant clinical response rates of 70-90%, with only 10-20% complete pathologic responses (pCR). The biological and clinical factors that determine the degree of pCR are incompletely understood and most investigated are drug choice, proliferation index, intrinsic subtypes and host-therapy interactions. Mounting evidence indicates that the patient's immune system contributes to tumor regression and can be modulated by therapies. Investigations using immunohistochemical approaches confirmed that immune cell infiltrate on pre-treatment or post-treatment tumor biopsies are associated with greater frequency of pCR. 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 suggesting a strong link between infiltrating immune cell abundance and anti-tumor immunogenicity. More recently, we and others have shown that the relative abundance of TIL 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 separate immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. These metagenes, referred as 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 the distant metastasis-free survival of patients with highly proliferative cancer of the Basal-like, HER2-Enriched and Luminal B subtypes, in particular. Aim Given 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 the pre-chemotherapy immune gene signatures would be significantly predictive of tumor responses. Methods In a multi-institutional, meta-cohort analysis of 701 breast tumor patients receiving neoadjuvant chemotherapy, gene expression profiles of tumor biopsies were investigated to determine the relationships between immune metagenes, tumor proliferative capacity, and molecular breast tumor subtypes. Results We used multiple logistic regression to investigate the predictive value of the immune signatures. In a univariate analysis the B/P, T/NK and M/D immune metagenes were statistically significantly associated with excellent pathologic response as defined by residual cancer burden scores ((B/P (odds ratio (95% CI) 1.6 (1.3, 1.9), T/NK 1.6 (1.2, 2.0), M/D 1.7 (1.3, 2.1)). In multivariate analysis, B/P and M/D metagenes remained significant after adjustment for intrinsic subtype and proliferation (B/P 1.25 (1.01, 1.54), M/D 1.4 (1.03, 1.90). Conclusions Gene expression signatures of infiltrating immune cells carry both prognostic and therapy-predictive value. Furthermore, our work highlights a less described role for myeloid derived antigen presenting cells that could explain the variability of pathologic response to neoadjuvant chemotherapy. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-05.