The abundance and functional orientation of tumor-infiltrating lymphocytes in breast cancer is associated with distant metastasis-free survival, yet how this association is influenced by tumor phenotypic heterogeneity is poorly understood. Here, a bioinformatics approach defined tumor biological attributes that influence this association, and delineated tumor subtypes that may differ in their ability to sustain durable antitumor immune responses. A large database of breast tumor expression profiles and associated clinical data was compiled, from which the ability of phenotypic markers to significantly influence the prognostic performance of a classification model that incorporates immune cell-specific gene signatures was ascertained. Markers of cell proliferation and intrinsic molecular subtype reproducibly distinguished two breast cancer subtypes that we refer to as immune benefit-enabled (IBE) and immune benefit-disabled (IBD). The IBE tumors, comprised mostly of highly proliferative tumors of the basal-like, HER2-enriched, and luminal B subtypes, could be stratified by the immune classifier into significantly different prognostic groups, while IBD tumors could not, indicating the potential for productive engagement of metastasis-protective immunity in IBE tumors, but not IBD tumors. The prognostic stratification in IBE was independent of conventional variables. Gene network analysis predicted the activation of tumor necrosis factor-α/interferon-γ signaling pathways in IBE tumors and the activation of the transforming growth factor-β pathway in IBD tumors. This supports a model in which breast tumors can be distinguished on the basis of their potential for metastasis-protective immune responsiveness. Whether IBE and IBD represent clinically-relevant contexts for evaluating sensitivity to immunotherapeutic agents warrants further investigation.
- Received June 17, 2015.
- Revision received December 23, 2015.
- Accepted February 16, 2016.
- Copyright ©2016, American Association for Cancer Research.