B7-H4 Further Stratifies Patients With Endometrial Cancer Exhibiting a Nonspecific Molecular Profile

Abstract

Context.— Endometrial cancer is classified into 4 molecular subtypes: DNA polymerase epsilon ultramutated, mismatch repair deficient, p53 mutant, and nonspecific molecular profile (NSMP). Additional biomarkers are urgently needed to better characterize the NSMP subtype, the largest group with heterogeneous pathologic features and prognoses. Objective.— To investigate the expression of B7 homolog 3 (B7-H3), B7 homolog 4 (B7-H4), and V-set and immunoglobulin domain containing 3 (VSIG-3, a ligand for B7-H5) in 833 patients with endometrial cancer and determine their associations with clinicopathologic and molecular features as well as survival outcomes. Design.— Molecular classification was determined by polymerase epsilon sequencing and immunohistochemical staining for p53 and mismatch repair proteins. B7-H3, B7-H4, VSIG-3, and programmed death ligand-1 (PD-L1) were detected via immunohistochemistry. Results.— The positivity rates for B7-H3 in each of the tumor and immune cells, B7-H4 (exclusively in tumor cells), and VSIG-3 (exclusively in tumor cells) were 89.0%, 42.3%, 71.5%, and 99.8%, respectively. B7-H3 and B7-H4 positivity in tumor cells was associated with favorable pathologic features and prognosis. In contrast, B7-H3 expression in immune cells was frequent in samples with unfavorable pathologic features; those with p53-mutant subtype, PD-L1 positivity, and a high density of CD8+ T cells; and in patients with poor prognoses. Positive B7-H4 expression was a predictor of improved survival in patients with the NSMP subtype independent of tumor stage or pathologic features. Conclusions.— The NSMP subgroup of endometrial cancer can be further stratified by B7-H4 status. Incorporating B7-H4 status into the molecular classification of NSMP could improve the ability to predict disease relapse.