Abstract P5-12-02: Intratumor heterogeneity, angiogenesis and epithelial to mesenchymal transition are enhanced in metaplastic breast cancer
Authors: Masanori Oshi, Konstantinos Chouliaras, Mariko Asaoka, Rongrong Wu, Akimitsu Yamada, Thaer Khoury, Itaru Endo, Takashi Ishikawa, Kazuaki Takabe
Journal: Cancer Research (2022)

Abstract 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 AACR-GENIE (Genomics Evidence Neoplasia Information Exchange) cohorts. Tumor infiltrated immune cells were estimated by xCell algorithm. Baseline clinical characteristics were compared, and gene set enrichment analysis (GSEA) was performed. MBC formed 0.66% of all breast cancer cohorts (13/1064 (1.2%) of TCGA and 59/9763 (0.6%) of GENIE). MBC cases were predominantly triple-negative (TNBC) (8 (61.5%) vs 151 (14.4%), p &amp;lt; 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. Node positive disease was noted in 2 (15.4%) metaplastic cases vs. 538 (51.2%) non-metaplastic cases (p = 0.01). In the tumor immune microenvironment, increased infiltration of M1 macrophages (p = 0.012), dendritic cells (p &amp;lt; 0.001) and eosinophils (p = 0.036) was noted in the MBC cohort however there was no difference in infiltration of CD4+ memory (p = 0.297) and CD8+ T-cells (p = 0.864) nor in cytolytic activity (p = 0.806). MBC was also significantly associated with high leucocyte fraction (p = 0.004), Transforming growth factor (TGF)-β response (p &amp;lt; 0.001), and macrophage regulation (p = 0.008), based on scoring by Thorsson et al, compared to non-MBC in the TCGA cohort. 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 = 0.100) in the GENIE cohort. Furthermore, MBC had increased intratumor heterogeneity (p &amp;lt; 0.001) in the TCGA cohort. Disease-specific survival was worse in MBC (p = 0.018) compared to non-MBC. When we compared the biological function between triple-negative MBC and TNBC, angiogenesis and epithelial-to-mesenchymal transition (EMT) pathways were enriched in triple-negative MBC by GSEA (Normalized Enrichment Score (NES) = 1.81, False discovery rate (FDR) = 0.14, p = 0.004 and NES = 1.88, FDR = 0.017, p &amp;lt; 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, and these factors highlight potential mechanisms rendering MBC resistant to chemotherapy and provide insight into its tumor microenvironment. Citation Format: Masanori Oshi, Konstantinos Chouliaras, Mariko Asaoka, Rongrong Wu, Akimitsu Yamada, Thaer Khoury, Itaru Endo, Takashi Ishikawa, Kazuaki Takabe. Intratumor heterogeneity, angiogenesis and epithelial to mesenchymal transition are enhanced in metaplastic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-12-02.