Data from Biomarker Modulation following Short-Term Vorinostat in Women with Newly Diagnosed Primary Breast Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not.</p><p><b>Experimental Design:</b> Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Onco<i>type</i> DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples.</p><p><b>Results:</b> Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (<i>P</i> = 0.003), STK15 (<i>P</i> = 0.005), and Cyclin B1 (<i>P</i> = 0.03) following vorinostat, but not in other genes by the Onco<i>type</i> DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed.</p><p><b>Conclusions:</b> Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer. <i>Clin Cancer Res; 19(14); 4008–16. ©2013 AACR</i>.</p></div>