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Erschienen in: Breast Cancer Research and Treatment 1/2014

01.07.2014 | Clinical trial

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

verfasst von: 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

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 1/2014

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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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Metadaten
Titel
A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer
verfasst von
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
Publikationsdatum
01.07.2014
Verlag
Springer US
Erschienen in
Breast Cancer Research and Treatment / Ausgabe 1/2014
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-014-3008-5

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