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

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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.

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Acknowledgments

Supported by United States Department of Health and Human Service grant P30-CA113330 and by a grant from Merck, Inc. The authors thank Angelo Massari for his assistance in reviewing the data

Conflict of interest

The authors declare no conflict of interest. They have no financial relationship with the organization that sponsored the research.

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Authors and Affiliations

  1. Department of Oncology, Montefiore Medical Center-Weiler Division, 2 South, Room 47-48, 1825 Eastchester Road, Bronx, NY, 10461, USA

    Yifan Tu, Christine M. Pellegrino, Eleni Andreopoulou, Della Makower, Karen Fehn, Susan Fineberg, Leslie L. Montgomery, Lisa S. Wiechmann & Joseph A. Sparano

  2. Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Yifan Tu, Christine M. Pellegrino, Eleni Andreopoulou, Della Makower, Karen Fehn, Susan Fineberg, Abdissa Negassa, Leslie L. Montgomery, Lisa S. Wiechmann & Joseph A. Sparano

  3. Columbia University College of Physicians and Surgeons, New York, NY, USA

    Dawn L. Hershman & Kevin Kalinsky

  4. Houston Methodist Research Institute, Houston, TX, USA

    Kapil Bhalla & Warren Fiskus

  5. Fox Chase Cancer Center, Philadelphia, PA, USA

    R. Katherine Alpaugh & Min Huang

Authors
  1. Yifan Tu
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  2. Dawn L. Hershman
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  3. Kapil Bhalla
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  4. Warren Fiskus
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  5. Christine M. Pellegrino
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  7. Della Makower
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  8. Kevin Kalinsky
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  9. Karen Fehn
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  10. Susan Fineberg
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  11. Abdissa Negassa
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  12. Leslie L. Montgomery
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  13. Lisa S. Wiechmann
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  14. R. Katherine Alpaugh
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  15. Min Huang
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  16. Joseph A. Sparano
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Correspondence to Joseph A. Sparano.

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Tu, Y., Hershman, D.L., Bhalla, K. et al. 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 Res Treat 146, 145–152 (2014). https://doi.org/10.1007/s10549-014-3008-5

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  • DOI: https://doi.org/10.1007/s10549-014-3008-5

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