Yeruva Sri Lakshmi Hyndavi, Zhao Fengmin, Miller Kathy D, Tevaarwerk Amye J, Wagner Lynne I, Gray Robert J, Sparano Joseph A, Connolly Roisin M
1Department of Medicine, Howard University Hospital, Washington, DC USA.
2Dana Farber Cancer Institute, Boston, MA USA.
NPJ Breast Cancer. 2018 Jan 11;4:1. doi: 10.1038/s41523-017-0053-3. eCollection 2018.
Endocrine therapies are effective in the treatment of hormone receptor (HR)-positive breast cancer, however, de novo or acquired treatment resistance is a significant clinical problem. A potential mechanism of resistance involves changes in gene expression secondary to epigenetic modifications, which might be reversed with the use of histone deacetylase (HDAC) inhibitors such as entinostat. The ENCORE 301 phase II randomized, placebo-controlled study demonstrated a significant improvement in progression-free survival (PFS) and overall survival (OS), with the addition of entinostat to exemestane in patients with HR-positive advanced breast cancer with disease progression after prior non-steroidal aromatase inhibitor (AI). These results prompted the development of E2112, a phase III registration trial which is investigating entinostat/placebo in combination with exemestane in patients with locally advanced or metastatic breast cancer who have experienced disease progression after a non-steroidal AI. E2112 aims to validate the preclinical and clinical findings supporting the role of HDAC inhibitors in overcoming resistance to endocrine therapy in breast cancer, and ultimately improve outcomes for patients with advanced breast cancer.
内分泌疗法在激素受体（HR）阳性乳腺癌的治疗中有效，然而，原发性或获得性治疗耐药是一个重大的临床问题。一种潜在的耐药机制涉及表观遗传修饰继发的基因表达变化，使用诸如恩替诺特之类的组蛋白去乙酰化酶（HDAC）抑制剂可能会逆转这种变化。ENCORE 301 II期随机、安慰剂对照研究表明，对于既往接受非甾体芳香化酶抑制剂（AI）治疗后疾病进展的HR阳性晚期乳腺癌患者，在依西美坦基础上加用恩替诺特可显著改善无进展生存期（PFS）和总生存期（OS）。这些结果促使开展了E2112研究，这是一项III期注册试验，正在研究恩替诺特/安慰剂联合依西美坦用于局部晚期或转移性乳腺癌且在接受非甾体AI治疗后疾病进展的患者。E2112旨在验证支持HDAC抑制剂在克服乳腺癌内分泌治疗耐药中作用的临床前和临床研究结果，并最终改善晚期乳腺癌患者的预后。
