Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat: A phase II national cancer institute/stand up to cancer study

Roisin Connolly, Huili Li, Rachel C. Jankowitz, Zhe Zhang, Michelle Rudek-Renaut, Stacie C. Jeter, Shannon A. Slater, Penny Powers, Antonio C Wolff, John H Fetting, Adam Brufsky, Richard Piekarz, Nita Ahuja, Peter W. Laird, Hui Shen, Daniel J. Weisenberger, Leslie Cope, James G. Herman, George Somlo, Agustin A. Garcia & 5 others Peter A. Jones, Stephen B Baylin, Nancy E. Davidson, Cynthia Zahnow, Vered Stearns

Research output: Contribution to journalArticle

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 twostage 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.

LanguageEnglish (US)
Pages2691-2701
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number11
DOIs
StatePublished - Jun 1 2017

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Azacitidine
National Cancer Institute (U.S.)
Epigenomics
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms
Hormones
Estrogen Receptors
Therapeutics
Histone Deacetylase Inhibitors
Methyltransferases
entinostat
Research Design
Up-Regulation
Down-Regulation
Biopsy
DNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat : A phase II national cancer institute/stand up to cancer study. / Connolly, Roisin; Li, Huili; Jankowitz, Rachel C.; Zhang, Zhe; Rudek-Renaut, Michelle; Jeter, Stacie C.; Slater, Shannon A.; Powers, Penny; Wolff, Antonio C; Fetting, John H; Brufsky, Adam; Piekarz, Richard; Ahuja, Nita; Laird, Peter W.; Shen, Hui; Weisenberger, Daniel J.; Cope, Leslie; Herman, James G.; Somlo, George; Garcia, Agustin A.; Jones, Peter A.; Baylin, Stephen B; Davidson, Nancy E.; Zahnow, Cynthia; Stearns, Vered.

In: Clinical Cancer Research, Vol. 23, No. 11, 01.06.2017, p. 2691-2701.

Research output: Contribution to journalArticle

Connolly, R, Li, H, Jankowitz, RC, Zhang, Z, Rudek-Renaut, M, Jeter, SC, Slater, SA, Powers, P, Wolff, AC, Fetting, JH, Brufsky, A, Piekarz, R, Ahuja, N, Laird, PW, Shen, H, Weisenberger, DJ, Cope, L, Herman, JG, Somlo, G, Garcia, AA, Jones, PA, Baylin, SB, Davidson, NE, Zahnow, C & Stearns, V 2017, 'Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat: A phase II national cancer institute/stand up to cancer study', Clinical Cancer Research, vol. 23, no. 11, pp. 2691-2701. https://doi.org/10.1158/1078-0432.CCR-16-1729
Connolly, Roisin ; Li, Huili ; Jankowitz, Rachel C. ; Zhang, Zhe ; Rudek-Renaut, Michelle ; Jeter, Stacie C. ; Slater, Shannon A. ; Powers, Penny ; Wolff, Antonio C ; Fetting, John H ; Brufsky, Adam ; Piekarz, Richard ; Ahuja, Nita ; Laird, Peter W. ; Shen, Hui ; Weisenberger, Daniel J. ; Cope, Leslie ; Herman, James G. ; Somlo, George ; Garcia, Agustin A. ; Jones, Peter A. ; Baylin, Stephen B ; Davidson, Nancy E. ; Zahnow, Cynthia ; Stearns, Vered. / Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat : A phase II national cancer institute/stand up to cancer study. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 11. pp. 2691-2701.
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T2 - Clinical Cancer Research

AU - Connolly, Roisin

AU - Li, Huili

AU - Jankowitz, Rachel C.

AU - Zhang, Zhe

AU - Rudek-Renaut, Michelle

AU - Jeter, Stacie C.

AU - Slater, Shannon A.

AU - Powers, Penny

AU - Wolff, Antonio C

AU - Fetting, John H

AU - Brufsky, Adam

AU - Piekarz, Richard

AU - Ahuja, Nita

AU - Laird, Peter W.

AU - Shen, Hui

AU - Weisenberger, Daniel J.

AU - Cope, Leslie

AU - Herman, James G.

AU - Somlo, George

AU - Garcia, Agustin A.

AU - Jones, Peter A.

AU - Baylin, Stephen B

AU - Davidson, Nancy E.

AU - Zahnow, Cynthia

AU - Stearns, Vered

PY - 2017/6/1

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N2 - 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 twostage 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.

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