title: A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer.
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/m(2) 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.
authors.affiliation: Department of Oncology, Montefiore Medical Center-Weiler Division, 2 South, Room 47-48, 1825 Eastchester Road, Bronx, NY, 10461, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Tu
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Hershman
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
authors.forename: Warren
authors.initials: W
authors.lastname: Fiskus
authors.forename: Christine M
authors.initials: CM
authors.lastname: Pellegrino
authors.forename: Eleni
authors.initials: E
authors.lastname: Andreopoulou
authors.forename: Della
authors.initials: D
authors.lastname: Makower
authors.forename: Kevin
authors.initials: K
authors.lastname: Kalinsky
authors.forename: Karen
authors.initials: K
authors.lastname: Fehn
authors.forename: Susan
authors.initials: S
authors.lastname: Fineberg
authors.forename: Abdissa
authors.initials: A
authors.lastname: Negassa
authors.forename: Leslie L
authors.initials: LL
authors.lastname: Montgomery
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Wiechmann
authors.forename: R Katherine
authors.initials: RK
authors.lastname: Alpaugh
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D015870:Gene Expression; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D014408:Biomarkers, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006877:Hydroxamic Acids; D019394:Ki-67 Antigen; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000077337:Vorinostat; D004317:Doxorubicin; D003520:Cyclophosphamide; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D017239:Paclitaxel