title: Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study.
abstract: 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.
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Roisin M
authors.initials: RM
authors.lastname: Connolly
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Huili
authors.initials: H
authors.lastname: Li
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Jankowitz
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Stacie C
authors.initials: SC
authors.lastname: Jeter
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Shannon A
authors.initials: SA
authors.lastname: Slater
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Penny
authors.initials: P
authors.lastname: Powers
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Wolff
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: John H
authors.initials: JH
authors.lastname: Fetting
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Adam
authors.initials: A
authors.lastname: Brufsky
authors.affiliation: Cancer Therapy Evaluation Program (CTEP), NCI, Bethesda, Maryland.
authors.forename: Richard
authors.initials: R
authors.lastname: Piekarz
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
authors.affiliation: Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.affiliation: Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.affiliation: University of Southern California, Los Angeles, California.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Leslie
authors.initials: L
authors.lastname: Cope
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: City of Hope, Duarte, California.
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.affiliation: University of Southern California, Los Angeles, California.
authors.forename: Agustin A
authors.initials: AA
authors.lastname: Garcia
authors.affiliation: Van Andel Research Institute, Grand Rapids, Michigan.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Zahnow
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland. vstearn1@jhmi.edu.
authors.forename: Vered
authors.initials: V
authors.lastname: Stearns
mesh_terms: D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000097:blood; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D054547:National Cancer Institute (U.S.); D009367:Neoplasm Staging; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014481:United States
chemical_list: D001549:Benzamides; D014408:Biomarkers, Tumor; D047628:Estrogen Receptor alpha; D011725:Pyridines; C118739:entinostat; D001374:Azacitidine