Ki67 Gene Expression is Associated with Immune Cell Infiltration and Neoadjuvant Chemotherapy Response in ER+/HER2− Breast Cancer

BACKGROUND: Ki67 is one of the most widely used markers of cell proliferation. However, current measurements using immunohistochemistry (IHC) are limited by interobserver variability and lack of standardized cutoffs. To address this, we investigated the association of Ki67 gene (MKI67) expression with biological features and treatment response in estrogen receptor-positive (ER+) breast cancer (BC), the most common subtype. PATIENTS AND METHODS: We analyzed 5036 patients with ER+/HER2- BC across 11 independent cohorts with tumor transcriptomes and clinical data. Patients with MKI67 expression in the top 20% were defined as the high-expression group on the basis of prior IHC-based thresholds. RESULTS: MKI67 expression correlated with Nottingham histologic grade and proliferation score, and consistently enriched all the hallmark cell proliferation-related gene sets across TCGA, METABRIC, and SCAN-B cohorts. High MKI67 expression trended toward worse survival but achieved statistical significance only in the METABRIC cohort. MKI67 high ER+/HER2- BC was associated with increased mutation rates, fraction altered, homologous recombination deficiency and intratumoral genomic heterogeneity. MKI67 expression was associated with infiltration of Th1 and Th2 cells as well as M1 and M2 macrophages across three cohorts. Conversely, MKI67 low ER+/HER2- BC was enriched for Hypoxia, Coagulation, Epithelial-to-Mesenchymal Transition, NOTCH, Hedgehog, TGF-beta, and KRAS-signaling gene sets. MKI67 high ER+/HER2- BC was associated with a higher pathological complete response (pCR) rate in four of the eight neoadjuvant chemotherapy cohorts. CONCLUSIONS: High MKI67 expression identifies highly proliferative tumors that are associated with genomic instability and immune activity and is associated with higher pCR rates following neoadjuvant chemotherapy in ER+/HER2- BC.