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本帖最后由 seacat 于 2012-11-5 14:45 编辑
A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer.
Munster PN, Thurn KT, Thomas S, Raha P, Lacevic M, Miller A, Melisko M, Ismail-Khan R, Rugo H, Moasser M, Minton SE.
SourceDivision of Hematology and Oncology, University of California, San Francisco, 1600 Divisadero, Rm A719 Box 1711, San Francisco, CA 94143, USA. pmunster@medicine.ucsf.edu
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 >24 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.
ER阳性的病人，内分泌治疗（他莫昔芬或芳香酶抑制剂）进展后，每4周的前3周口服400mg/d伏立诺他，同时口服他莫昔芬20mg/d。结果客观有效率是19%，临床获益率40%，中位反应期10个月。
伏立诺他联合他莫昔芬治疗ER阴性病人的实验正在开展，密切关注。
伏立诺他是已经在美国上市的药物，YL药也能在国内买到。 |
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发表于 2012-11-5 12:56:32
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