Spatially distinct cellular and molecular landscapes define prognosis in triple negative breast cancer [2]

Triple-negative breast cancer is a prevalent breast cancer subtype with the lowest 5-year survival. Several factors contribute to its treatment response, but the inherent molecular and cellular tumor heterogeneity are increasingly acknowledged as crucial determinants. Here we report on the spatial and molecular heterogeneity underlying a retrospective, treatment-naïve group of women with differential prognoses (17 with >15 years survival- good prognosis (GPx) and 15 with <3 years survival-poor prognosis (PPx)) profiled using GeoMX® DSP. Analyses revealed that the state of epithelia and its microenvironment (TME) are transcriptionally distinct between the two groups. Invasive epithelia in GPx shows a significant increase in immune transcripts, with the TME exhibiting increased immune cell presence (via IF). PPx epithelia, in contrast, are more metabolically and translationally active, with the TME being more mesenchymal/fibrotic. Notably, pre-cancerous epithelia in PPx display a prescience of aggressiveness, as evidenced by increased EMT-signaling. We identify distinct epithelial gene signatures for PPx and GPx, that can, with high accuracy, classify samples at the time of diagnosis and are likely to inform therapy. Overall design: GeoMx human whole transcriptome atlas was performed on ROIs that were selected from 32 FFPE sections from good prognosis (GPx) and poor prognosis (PPx) triple negative breast cancer samples.