A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer

Yifan Tu, Dawn L. Hershman, Kapil Bhalla, Warren Fiskus, Christine M. Pellegrino, Eleni Andreopoulou, Della F. Makower, Kevin Kalinsky, Karen Fehn, Susan A. Fineberg, Abdissa Negassa, Leslie L. Montgomery, Lisa S. Wiechmann, R. Katherine Alpaugh, Min Huang, Joseph A. Sparano

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m 2) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m2 every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo.

Original languageEnglish (US)
Pages (from-to)145-152
Number of pages8
JournalBreast Cancer Research and Treatment
Volume146
Issue number1
DOIs
StatePublished - 2014

Fingerprint

Histone Deacetylase Inhibitors
Paclitaxel
Doxorubicin
Cyclophosphamide
Breast Neoplasms
Confidence Intervals
Tubulin
Acetylation
Taxoids
Proteins
Histone Deacetylases
Chromatin Assembly and Disassembly
Heterografts
Neoplasms
vorinostat
Cell Line
Enzymes
Genes
Trastuzumab

Keywords

  • Breast cancer
  • HDAC inhibitor
  • Neoadjuvant chemotherapy
  • Vorinostat

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer. / Tu, Yifan; Hershman, Dawn L.; Bhalla, Kapil; Fiskus, Warren; Pellegrino, Christine M.; Andreopoulou, Eleni; Makower, Della F.; Kalinsky, Kevin; Fehn, Karen; Fineberg, Susan A.; Negassa, Abdissa; Montgomery, Leslie L.; Wiechmann, Lisa S.; Alpaugh, R. Katherine; Huang, Min; Sparano, Joseph A.

In: Breast Cancer Research and Treatment, Vol. 146, No. 1, 2014, p. 145-152.

Research output: Contribution to journalArticle

Tu, Y, Hershman, DL, Bhalla, K, Fiskus, W, Pellegrino, CM, Andreopoulou, E, Makower, DF, Kalinsky, K, Fehn, K, Fineberg, SA, Negassa, A, Montgomery, LL, Wiechmann, LS, Alpaugh, RK, Huang, M & Sparano, JA 2014, 'A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer', Breast Cancer Research and Treatment, vol. 146, no. 1, pp. 145-152. https://doi.org/10.1007/s10549-014-3008-5
Tu, Yifan ; Hershman, Dawn L. ; Bhalla, Kapil ; Fiskus, Warren ; Pellegrino, Christine M. ; Andreopoulou, Eleni ; Makower, Della F. ; Kalinsky, Kevin ; Fehn, Karen ; Fineberg, Susan A. ; Negassa, Abdissa ; Montgomery, Leslie L. ; Wiechmann, Lisa S. ; Alpaugh, R. Katherine ; Huang, Min ; Sparano, Joseph A. / A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer. In: Breast Cancer Research and Treatment. 2014 ; Vol. 146, No. 1. pp. 145-152.
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AU - Kalinsky, Kevin

AU - Fehn, Karen

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AU - Negassa, Abdissa

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