A pilot study evaluating surrogates of response to short-term vorinostat in women with newly diagnosed breast cancer

Abstract

e14508 Background: Epigenetic modifications contribute to breast cancer initiation and progression and may be reversible, thus representing an attractive area for new drug investigation. In preclinical breast cancer models, the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) induces cell cycle arrest, apoptosis and differentiation. Methods: We evaluated the safety and tolerability of short term vorinostat in women with a primary clinical stage I-III histologically confirmed carcinoma of the breast on a core needle biopsy. Participants received vorinostat 300 mg PO bid for a total of 6 doses, the last dose 2 hours prior to surgery or biopsy. Peripheral blood mononuclear cells were collected at baseline and following the last vorinostat dose to determine histone acetylation. Baseline and post-treatment tumor specimens were collected for analysis of histone acetylation, candidate gene methylation and expression. Tissues were also collected from untreated controls. Paired t-tests and Fisher's exact tests were used to evaluate changes from baseline for continuous and categorical data, respectively. Results: From March 2006 to October 2008, 25 women signed an informed consent and initiated study drug. Median age was 55 and 80% had hormone receptor positive tumors. Twenty-two women took all 6 prescribed doses. One participant took 4 and one 5 doses due to insurance clearance delay; one received a single dose due to fatigue and abdominal pain. Study-related surgical delays did not occur. Grade 1 toxicities included diarrhea (28%), low white blood cell count (24%), and fatigue, taste alterations and nausea (16% each). Tissue and blood samples were successfully collected. Tissue was also collected from 25 untreated controls. No significant change was observed in the proliferation marker Ki67 following 3 days of agent administration. Modulation of apoptosis, histone acetylation and gene methylation will be presented. Conclusions: Short-term administration of vorinostat is feasible, safe, and allows for studies of biomarker modulation. The results will be used to design future studies in which vorinostat will be administered in combination with other targeted therapies or with other epigenetic modifiers. [Table: see text]