Immunogenicity and transcriptomic biology in Nottingham histologic grade 3 breast cancer.

Abstract

e12563 Background: Cancer biology dictates disease progression and prognosis of a tumor. Histological grade has been used as a proxy of tumor biology in various cancer types, although it depends on morphological analysis of the tissue. As such, Nottingham histological grade is recently incorporated into the 8th edition of the AJCC Breast Cancer Staging. Herein, we hypothesized that Nottingham histological Grade3 breast cancer (BC) demonstrate strong immunogenicity in response to aggressive phenotypes, reflecting worse clinical outcomes. Methods: Clinicopathological data and transcriptomes were obtained from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA) Invasive breast carcinoma (BRCA) cohort, and GSE25066. While METABRIC was used as a training cohort, the other two cohorts served as validation cohorts. As TCGA did not contain pathological information, Nottingham histological grade was manually collected through the Text Information Extraction Systems (TIES). Results: 2876 patients were analyzed in this study. Grade1 tumors were 274 patients (9.5%), Grade2 tumors 1185 patients (41.2%), and Grade3 tumors 1417 patients (49.3%). Grade3 tumors were common in patients with Estrogen receptor (ER) negative (p < 0.001), with Her2 and Basal molecular subtypes by the PAM50 classifier (p < 0.001), and associated with increased MKI-67 expression (p < 0.001). Disease-free survival (DFS) was significantly worse in Grade3 tumors in all cohorts. Gene set enrichment analysis (GSEA) demonstrated that Grade3 tumors significantly enriched immune activity related gene sets as well as cell proliferation and cell cycle related gene sets. CIBERSORT also demonstrated that Grade3 BCs were infiltrated with anti-cancer macrophage M1, follicular helper T cells, and activated NK cells (all p < 0.001). Furthermore, Grade3 tumors were associated with more diverse T cell receptor (p = 0.001) and increased cytolytic activity (p < 0.001). Lastly, T cell exhaustion markers, including PD-L1, PD-1, and CTLA4, were significantly elevated in Grade3 BCs (all p < 0.001) as a negative feedback loop. Conclusions: Grade3 BCs demonstrated enhanced immunogenicity as well as aggressive transcriptomic features.