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

Roisin M. Connolly, Huili Li, Rachel C. Jankowitz, Zhe Zhang, Michelle A. Rudek, 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 A. 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

Fingerprint

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

Cite this

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 M.; Li, Huili; Jankowitz, Rachel C.; Zhang, Zhe; Rudek, Michelle A.; 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 A.; Stearns, Vered.

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

Research output: Contribution to journalArticle

Connolly, RM, Li, H, Jankowitz, RC, Zhang, Z, Rudek, MA, 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, CA & 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. DOI: 10.1158/1078-0432.CCR-16-1729
Connolly, Roisin M. ; Li, Huili ; Jankowitz, Rachel C. ; Zhang, Zhe ; Rudek, Michelle A. ; 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 A. ; 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
@article{15a1208934de435298fd4dd12712dab3,
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 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.",
author = "Connolly, {Roisin M.} and Huili Li and Jankowitz, {Rachel C.} and Zhe Zhang and Rudek, {Michelle A.} and Jeter, {Stacie C.} and Slater, {Shannon A.} and Penny Powers and Wolff, {Antonio C.} and Fetting, {John H.} and Adam Brufsky and Richard Piekarz and Nita Ahuja and Laird, {Peter W.} and Hui Shen and Weisenberger, {Daniel J.} and Leslie Cope and Herman, {James G.} and George Somlo and Garcia, {Agustin A.} and Jones, {Peter A.} and Baylin, {Stephen B.} and Davidson, {Nancy E.} and Zahnow, {Cynthia A.} and Vered Stearns",
year = "2017",
month = "6",
day = "1",
doi = "10.1158/1078-0432.CCR-16-1729",
language = "English (US)",
volume = "23",
pages = "2691--2701",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - Combination epigenetic therapy in advanced breast cancer with 5-azacitidine and entinostat

T2 - Clinical Cancer Research

AU - Connolly,Roisin M.

AU - Li,Huili

AU - Jankowitz,Rachel C.

AU - Zhang,Zhe

AU - Rudek,Michelle A.

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 A.

AU - Stearns,Vered

PY - 2017/6/1

Y1 - 2017/6/1

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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85020261481&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020261481&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-16-1729

DO - 10.1158/1078-0432.CCR-16-1729

M3 - Article

VL - 23

SP - 2691

EP - 2701

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 11

ER -