Journal
CLINICAL CANCER RESEARCH
Volume 23, Issue 11, Pages 2691-2701Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-16-1729
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Funding
- Stand Up To Cancer Epigenetics Dream Team (Stand Up To Cancer is a program of the Entertainment Industry Foundation)
- Cancer Therapy Evaluation Program, NCI [MCR-0019-P2C, U01 CA070095, UM1CA186691]
- Specialized Program Of Research Excellence in Breast Cancer [P50 CA88843]
- Microarray Core (NIH) [P30 CA006973]
- Analytical Pharmacology Core of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (NIH) [P30 CA006973, UL1 TR 001079]
- Shared Instrument grant [1S10RR026824-01]
- Clinical Protocol and Data Management facilities [P30 CA006973, P30CA 047904]
- Bioinformatics Core [P30 CA006973]
- National Center for Advancing Translational Sciences (NCATS), a component of the NIH [UL1 TR 001079]
- NIH Roadmap for Medical Research
- Pennsylvania Department of Health
- QVC
- Fashion Footwear Association of New York (FFANY)
- Cindy Rosencrans Fund for Triple Negative Breast Cancer Research
- Lee Jeans
- Entertainment Industry Foundation
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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/m(2) (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. (C) 2016 AACR.
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