Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study

Clin Cancer Res. 2017 Jun 1;23(11):2691-2701. doi: 10.1158/1078-0432.CCR-16-1729. Epub 2016 Dec 15.


Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC).Experimental Design: Patients received 5-azacitidine 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3, 10) on a 28-day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%).Results: There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0-19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort.Conclusions: Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. Clin Cancer Res; 23(11); 2691-701. ©2016 AACR.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Adult
  • Aged
  • Azacitidine / administration & dosage*
  • Azacitidine / adverse effects
  • Benzamides / administration & dosage*
  • Benzamides / adverse effects
  • Biomarkers, Tumor / blood
  • Combined Modality Therapy
  • Disease-Free Survival
  • Epigenesis, Genetic / genetics*
  • Estrogen Receptor alpha / genetics
  • Female
  • Humans
  • Middle Aged
  • National Cancer Institute (U.S.)
  • Neoplasm Staging
  • Pyridines / administration & dosage*
  • Pyridines / adverse effects
  • Treatment Outcome
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / pathology
  • United States


  • Benzamides
  • Biomarkers, Tumor
  • Estrogen Receptor alpha
  • Pyridines
  • entinostat
  • Azacitidine