title: The interplay of epigenetic therapy and immunity in locally recurrent or metastatic estrogen receptor-positive breast cancer: Correlative analysis of ENCORE 301, a randomized, placebo-controlled phase II trial of exemestane with or without entinostat.
abstract: Entinostat, a class I-selective histone deacetylase inhibitor, has shown promising activity in ENCORE 301, a randomized, placebo-controlled, phase II trial of exemestane with or without entinostat in women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor. ENCORE 301 showed an 8.3-mo improvement in median overall survival among patients who received entinostat. We investigated the impact of entinostat on immune subsets with CD40, HLA-DR, and immune checkpoint receptor expression analyses in 34 patient blood samples from ENCORE 301. We found that entinostat significantly decreased granulocytic and monocytic MDSCs at cycle 1 day 15. MDSC CD40 was significantly downregulated by entinostat. A significant increase in HLA-DR expression on CD14+monocytes by entinostat was observed. Entinostat did not impact T-cell subsets or T-cell immune checkpoint receptor expression. Our findings suggest that a significant interplay between this epigenetic regimen and host immune homeostatic mechanisms may impact therapeutic outcome.
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.
authors.forename: Sunmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.
authors.forename: Saori
authors.initials: S
authors.lastname: Tomita
authors.affiliation: Mayo Clinic , Jacksonville, FL, USA.
authors.forename: Saranya
authors.initials: S
authors.lastname: Chumsri
authors.affiliation: Syndax Pharmaceuticals Inc. , Waltham, MA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Cruickshank
authors.affiliation: Syndax Pharmaceuticals Inc. , Waltham, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Ordentlich
authors.affiliation: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
keywords: Breast cancer; HLA-DR; entinostat; exemestane; histone deacetylase inhibitors; immune checkpoint receptor; immune subsets; monocyte; myeloid-derived suppressor cell; regulatory T cell