Molecular Biological Features of Nottingham Histological Grade 3 Breast Cancers

Introduction: Cancer biology dominates the behavior and prognosis of a tumor. Although Nottingham histological grade is a subjective pathological determination, it has been accepted as a surrogate model for cancer biology. As such, histologic grade was incorporated into the latest 8th edition of the American Joint Committee on Cancer breast cancer staging system. In this study, we hypothesized that grade 3 breast cancers demonstrate aggressive molecular biological profiles, reflecting worse biology and possible underlying immunogenicity. Methods: Transcriptomic and clinical data were obtained from the Molecular Taxonomy of Breast Cancer International Consortium, and the findings were validated by The Cancer Genome Atlas breast cancer cohort and GSE25066. Results: Overall, 2876 patients were analyzed in this study. Grade 3 tumors were more common in estrogen receptor (ER)-negative, advanced-stage patients, and were associated with human epidermal growth factor receptor 2 and basal subtypes by the PAM50 classifier, as well as with increased MKI67 expression (all p <0.001). Disease-free survival was significantly worse in grade 3 tumors (all cohorts). Gene set enrichment analysis demonstrated that grade 3 tumors were significantly enriched with not only cell proliferation and cell cycle-related gene sets but also immune activity-related gene sets. CIBERSORT confirmed that grade 3 tumors were infiltrated with macrophage M1, follicular helper T cells, and activated natural killer cells (all p <0.001). Furthermore, grade 3 tumors were associated with more diverse T cell receptors (p =0.001) and increased cytolytic activity (p <0.001). Lastly, major T-cell exhaustion markers were significantly elevated in grade 3 breast cancers (p <0.001). Conclusion: Grade 3 breast cancers demonstrated aggressive transcriptomic features with enhanced immunogenicity and elevated T-cell exhaustion markers.