Biomarker modulation following short-term vorinostat in women with newly diagnosed primary breast cancer.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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 Oncotype 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.

RESULTS:

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 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed.

CONCLUSIONS:

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.

• Authors: Vered Stearns, Lisa K Jacobs, Maryjo Fackler, Theodore N Tsangaris, Michelle A Rudek, Michaela Higgins, Julie Lange, Zandra Cheng, Shannon A Slater, Stacie C Jeter, Penny Powers, Susanne Briest, Calvin Chao, Carl Yoshizawa, Elizabeth Sugar, Igor Espinoza-Delgado, Saraswati Sukumar, Edward Gabrielson, Nancy E Davidson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 14 Pg. 4008-16 (Jul 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23719261 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• CCNB1 protein, human
• Cell Cycle Proteins
• Cyclin B1
• Hydroxamic Acids
• Inhibitor of Apoptosis Proteins
• Ki-67 Antigen
• MYBL2 protein, human
• Survivin
• Trans-Activators
• Vorinostat
• AURKA protein, human
• Aurora Kinase A

Topics

• Adult
• Aged
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Aurora Kinase A (genetics, metabolism)
• Breast Neoplasms (drug therapy, metabolism, surgery)
• Carcinoma, Ductal, Breast (drug therapy, metabolism, surgery)
• Cell Cycle Proteins (genetics, metabolism)
• Combined Modality Therapy
• Cyclin B1 (genetics, metabolism)
• Female
• Humans
• Hydroxamic Acids (pharmacokinetics, therapeutic use)
• Inhibitor of Apoptosis Proteins (genetics, metabolism)
• Ki-67 Antigen (genetics, metabolism)
• Middle Aged
• Prospective Studies
• Survivin
• Trans-Activators (genetics, metabolism)
• Transcriptome
• Vorinostat