The conflicting prognostic role of the stroma-ratio in breast cancer molecular subtypes.

Abstract

The tumor microenvironment plays a key role in tumor progression. The proportion of the stroma to tumor cells (stroma-tumor ratio (STR)) has a variable prognostic significance in breast cancer (BC) molecular classes. In this study, we evaluated the mechanisms of stroma formation and composition in different molecular subtypes which could explain the different prognostic values. This study interrogated two large well-characterized BC cohorts. Firstly, an in-house BC cohort (n=822) encompassing all BC molecular subtypes from the Nottingham series was used. In each subtype, stromal assessment was carried out and tumors were assigned to two groups: high and low STR, and further correlation with tumor characteristics and patient outcomes was investigated. The contribution of tumor-infiltrating lymphocytes (TILs) to the stroma has also been studied. Secondly, the public domain dataset (The Cancer Genome Atlas data (TCGA), n=978) was used as a validation cohort and for differential gene expression (DGE) analysis. DGE was performed to identify a set of genes associated with high STR in the three main molecular subtypes. High STR was associated with favorable patient outcomes in the whole cohort and in the luminal subtype, whereas high STR showed an association with poor outcome in TNBC. No association with outcome was found in the HER2 enriched BC. DGE analysis identified various pathways in luminal and TNBC subtypes, with immune upregulation and hypoxia pathways enriched in TNBC, and pathways related to fibrosis and stromal remodeling enriched in the luminal group instead. Low STR accompanied by high TILs was shown to carry the most favorable prognosis in TNBC. In line with the DGE results, TILs played a major prognostic role in the stroma of TNBC, but not in the luminal or HER2-enriched subtypes. The underlying molecular mechanisms and composition of the stroma in BC are variable in the molecular subtypes and explain the difference in its prognostic significance.