Breast Cancer Research and Treatment

, Volume 146, Issue 1, pp 145–152 | Cite as

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 Makower
  • Kevin Kalinsky
  • Karen Fehn
  • Susan Fineberg
  • Abdissa Negassa
  • Leslie L. Montgomery
  • Lisa S. Wiechmann
  • R. Katherine Alpaugh
  • Min Huang
  • Joseph A. Sparano
Clinical trial

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/m2) 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.

Keywords

HDAC inhibitor Vorinostat Breast cancer Neoadjuvant chemotherapy 

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Yifan Tu
    • 1
    • 2
  • Dawn L. Hershman
    • 3
  • Kapil Bhalla
    • 4
  • Warren Fiskus
    • 4
  • Christine M. Pellegrino
    • 1
    • 2
  • Eleni Andreopoulou
    • 1
    • 2
  • Della Makower
    • 1
    • 2
  • Kevin Kalinsky
    • 3
  • Karen Fehn
    • 1
    • 2
  • Susan Fineberg
    • 1
    • 2
  • Abdissa Negassa
    • 2
  • Leslie L. Montgomery
    • 1
    • 2
  • Lisa S. Wiechmann
    • 1
    • 2
  • R. Katherine Alpaugh
    • 5
  • Min Huang
    • 5
  • Joseph A. Sparano
    • 1
    • 2
  1. 1.Department of OncologyMontefiore Medical Center-Weiler DivisionBronxUSA
  2. 2.Albert Einstein Cancer CenterAlbert Einstein College of MedicineBronxUSA
  3. 3.Columbia University College of Physicians and SurgeonsNew YorkUSA
  4. 4.Houston Methodist Research InstituteHoustonUSA
  5. 5.Fox Chase Cancer CenterPhiladelphiaUSA

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