Phase I-II study of the histone deacetytase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer.

598 Background: HDACs regulate chromatin remodeling and gene transcription. Vorinostat (V) is a panHDAC inhibitor that sensitizes breast cancer (BC) cells to taxanes and trastuzumab. Methods: 55 patients (pts) with clinical stage IIA-IIIC BC received 12 weekly doses of paclitaxel (P)(80 mg/m2) plus V on days 1-3 (200 mg BID [N=4], 300 mg BID [N=51]) of each P dose plus trastuzumab (if HER2-positive), followed by doxorubicin/cyclophosphamide (AC-60/600 mg/m2 every 2 weeks and pegfilgrastim), The trial was powered to detect an improvement in pathologic complete response (pCR) rate from 30% to 55% (α=0.10, β=0.10) in stratum A (HER2+) and stratum B (triple negative), and from 15% to 40% in stratum C (ER+, HER2-). Immunohistochemistry was done on pretreatment core biopsies for HDAC6, p27, p21, Hsp70, and Ki67, and 3 pts had biopsies done before and after the third V dose for Western blot analysis. Results: There were no dose limiting toxicities at either V dose level. Breast/nodal pCR occurred in 13/24 evalua...