TY - JOUR
T1 - Biomarker modulation following short-term vorinostat in women with newly diagnosed primary breast cancer
AU - Stearns, Vered
AU - Jacobs, Lisa K.
AU - Fackler, Mary Jo
AU - Tsangaris, Theodore N.
AU - Rudek, Michelle A.
AU - Higgins, Michaela
AU - Lange, Julie
AU - Cheng, Zandra
AU - Slater, Shannon A.
AU - Jeter, Stacie C.
AU - Powers, Penny
AU - Briest, Susanne
AU - Chao, Calvin
AU - Yoshizawa, Carl
AU - Sugar, Elizabeth
AU - Espinoza-Delgado, Igor
AU - Sukumar, Saraswati
AU - Gabrielson, Edward
AU - Davidson, Nancy E.
PY - 2013/7/15
Y1 - 2013/7/15
N2 - 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 postvorinostat with changes in expression in untreated controls, and changes in gene methylation between preand 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 proliferationassociated 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.
AB - 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 postvorinostat with changes in expression in untreated controls, and changes in gene methylation between preand 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 proliferationassociated 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.
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U2 - 10.1158/1078-0432.CCR-13-0033
DO - 10.1158/1078-0432.CCR-13-0033
M3 - Article
C2 - 23719261
AN - SCOPUS:84881143035
SN - 1078-0432
VL - 19
SP - 4008
EP - 4016
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -