期刊
BRITISH JOURNAL OF CANCER
卷 104, 期 12, 页码 1828-1835出版社
SPRINGERNATURE
DOI: 10.1038/bjc.2011.156
关键词
histone deacetylase; HDAC; HDAC inhibitors; breast cancer; oestrogen receptor; anti-oestrogen therapy
类别
资金
- Merck Sharp Dohme Corp
BACKGROUND: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points. METHODS: Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated. RESULTS: In all, 43 patients (median age 56 years (31-71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease 424 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response. CONCLUSION: The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination. British Journal of Cancer (2011) 104, 1828-1835. doi:10.1038/bjc.2011.156 www.bjcancer.com Published online 10 May 2011 (C) 2011 Cancer Research UK
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