Abstract
BackgroundGene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified.ResultsTo investigate the relationship between proliferation and immune gene signatures, we analyzed an integrated dataset of 1,954 clinically annotated breast tumor expression profiles randomized into training and test sets to allow two-way discovery and validation of gene-survival associations. Hierarchical clustering revealed a large cluster of distant metastasis-free survival-associated genes with known immunological functions that further partitioned into three distinct immune metagenes likely reflecting B cells and/or plasma cells; T cells and natural killer cells; and monocytes and/or dendritic cells. A proliferation metagene allowed stratification of cases into proliferation tertiles. The prognostic strength of these metagenes was largely restricted to tumors within the highest proliferation tertile, though intrinsic subtype-specific differences were observed in the intermediate and low proliferation tertiles. In highly proliferative tumors, high tertile immune metagene expression equated with markedly reduced risk of metastasis whereas tumors with low tertile expression of any one of the three immune metagenes were associated with poor outcome despite higher expression of the other two metagenes.ConclusionsThese findings suggest that a productive interplay among multiple immune cell types at the tumor site promotes long-term anti-metastatic immunity in a proliferation-dependent manner. The emergence of a subset of effective immune responders among highly proliferative tumors has novel prognostic ramifications.
Highlights
Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes
While the majority of variables showed moderately to highly significant associations with distant metastasis-free survival (DMFS) by univariable analysis, in the combined model, only the B cell/plasma cell (B/P) metagene, nodal status, tumor size and treatment remained significant, with greatest significance observed for the B/P metagene (P = 0.0001). These findings demonstrate that the immune gene signatures capture distinct aspects of patient prognosis with the B/P signature, in particular, imparting the most significant and additive prognostic power in highly proliferative breast cancer compared to the other immune metagenes and conventional prognostic markers
We demonstrate for the first time that a proliferation metagene reflecting tumor proliferative capacity can sharply demarcate breast cancer cases into proliferative subclasses where the prognostic attributes of immune gene signatures are differentially manifested
Summary
Gene expression signatures indicative of tumor proliferative capacity and tumor-immune cell interactions have emerged as principal biology-driven predictors of breast cancer outcomes. How these signatures relate to one another in biological and prognostic contexts remains to be clarified. We and others have observed that elevated expression levels of many genes involved in immune response pathways are associated with reduced risk of breast cancer recurrence [15,16,17,18,19] These observations support the view that cancer-leukocyte interactions in the microenvironment of established tumors may function to limit the growth and metastatic progression of breast cancer [20,21,22]. The extent to which these genes reflect different effector cell populations, or contribute to patient prognosis in the presence of other predictive biomarkers such as proliferation, remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
