Increased intratumor heterogeneity, angiogenesis and epithelial to mesenchymal transition pathways in metaplastic breast cancer

Metaplastic breast cancer (MBC) constitutes a rare but unique histologic entity with poor prognosis. We hypothesized that MBC possesses unique genetic profile and tumor immune microenvironment. MBC cases were identified from a total of 10827 breast cancer entries in the Cancer Genome Atlas Data Set (TCGA) and the AACRGENIE (Genomics Evidence Neoplasia Information Exchange) cohorts. Tumor infiltrated immune cells were estimated by xCell. Baseline clinical characteristics were compared, and gene set enrichment analysis (GSEA) was performed. MBC comprised 0.66% of the cohorts (1.2% of TCGA and 0.6% of GENIE). MBC cases were predominantly triple-negative (TNBC) (8 (61.5%) vs 151 (14.4%), P<0.001), and high Nottingham histological grade (8 (61.5%) vs 222 (21.1%), P=0.02) compared to non-MBC in the TCGA cohort. Increased infiltration of M1 macrophages (P=0.012), dendritic cells (P<0.001) and eosinophils (P=0.036) was noted in the MBC cohort however there was no difference in cytolytic activity (P=0.806), CD4 memory (P=0.297) or CD8 T-cells (P=0.864). Tumor mutation burden was lower in the MBC compared to the non-MBC, median: 0.4 vs 1.6/Mb in the TCGA-TNBC cohort (P=0.67) and 3.0 vs 4.0/Mb (P=0.1) in the GENIE-cohort. MBC had increased intratumor heterogeneity (P<0.001), macrophage regulation (P=0.008) and TGF-beta response (P<0.001). Disease-specific survival was decreased in MBC (P=0.018). Angiogenesis and epithelial-to-mesenchymal transition pathways were enriched in triple-negative MBC by GSEA (P=0.004 and P<0.001, respectively). Our results suggest that high intratumor heterogeneity, enriched angiogenesis and EMT pathway expression represent possible mechanisms leading to worse disease-specific survival found in metaplastic breast cancer.