组蛋白去乙酰化酶抑制剂联合依西美坦治疗HR+/HER2-晚期转移性乳腺癌有效性和安全性的Meta分析

A meta-analysis of the efficacy and safety of HDAC inhibitors combined with exemestane in the treatment of HR+/HER2- advanced Metastatic breast cancer

摘要

目的: 系统评价组蛋白去乙酰化酶抑制剂(histone deacetylaseinhibitors, HDACi)联合依西美坦对比依西美坦单药治疗激素受体阳性(hormone receptor-positive, HR+)、人表皮生长因子受体2阴性(human epidermal growth factor receptor 2-negative, HER2-)乳腺癌患者的有效性和安全性。方法: 计算机检索PubMed、Cochrane Library、Embase、万方数据、中国知网和维普网等中英文数据库,收集公开发表的关于HDACi联合依西美坦对比依西美坦单药治疗HR+/HER2-乳腺癌的随机对照试验(randomized controlled trials, RCT),检索时限从建库至2025年7月10日。由2名研究者独立筛选文献、提取资料并评价纳入研究的偏倚风险。采用RevMan 5.4.1 软件进行Meta分析。结果: 最终纳入5项RCT,共计1 588例患者。Meta分析结果显示:HDACi联合依西美坦组患者在无进展生存期[风险比(hazard ratio,HR)=0.77,95%CI (0.67,0.89),P=0.000 2]、客观缓解率[比值比(odds ratio, OR)=1.69,95%CI (1.15,2.50),P=0.008]和临床获益率[OR=1.39,95%CI (1.05,1.85),P=0.02]方面明显优于依西美坦单药组,其差异有统计学意义。然而,与单药组相比,联用方案组的总生存期无明显改善[HR=0.91,95%CI (0.63,1.30),P=0.60]。在安全性方面,Meta分析显示,HDACi联合依西美坦组≥3级不良事件总发生率显著高于单药组[OR=7.16,95%CI (4.37,11.74),P<0.000 01]。结论: 现有证据表明,对于HR+/HER2-乳腺癌患者,HDACi联合依西美坦相比依西美坦单药治疗可显著延长无进展生存期并提高客观缓解率及临床获益率,但同时也显著增加了≥3级不良事件的发生风险,尤其是血液学毒性和疲劳。临床决策需充分权衡疗效获益与安全风险。

Abstract

Objective: To systematically evaluate the efficacy and safety of histone deacetylase inhibitors (HDACi) combined with exemestane compared with exemestane alone in the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Methods: Electronic databases including PubMed, Cochrane Library, Embase, Wanfang Data, CNKI, and VIP were searched for randomized controlled trials (RCTs) comparing HDACi combined with exemestane versus exemestane alone in the treatment of HR+/HER2- breast cancer. The search period began from database inception to July 10, 2025. Two reviewers independently screened the literature, extracted data, and assessed the risk of bias in the included studies. Meta-analysis was performed using RevMan 5.4.1 software. Results: Five RCTs involving 1 588 patients were included. The meta-analysis showed that HDACi plus exemestane group had significantly better progression-free survival [HR=0.77, 95%CI (0.67, 0.89), P=0.000 2], objective response rate [OR=1.69, 95%CI (1.15, 2.50), P=0.008], and clinical benefit rate [OR=1.39, 95%CI (1.05, 1.85), P=0.02] than the exemestane alone group. However, there was no significant difference in overall survival between the two groups [HR=0.91, 95%CI (0.63, 1.30), P=0.60]. Regarding safety, the meta-analysis showed that the overall incidence of ≥grade 3 adverse events was significantly higher in the HDACi plus exemestane group compared to the monotherapy group [OR=7.16, 95% CI (4.37, 11.74), P<0.000 01]. Conclusion: Current evidence suggests that in HR+/HER2- breast cancer patients, HDACi combined with exemestane significantly prolongs progression-free survival and improves objective response rate and clinical benefit compared to exemestane alone, but also significantly increases the risk of ≥grade 3 adverse events, particularly hematological toxicity and fatigue. Clinicians should carefully weigh the benefits of efficacy against the risks of adverse events when making decisions.

关键词

乳腺癌 / 组蛋白去乙酰化酶抑制剂 / 依西美坦 / 激素受体阳性 / HER2阴性 / Meta分析

Key words

breast cancer / histone deacetylase inhibitor / exemestane / hormone receptor positive / HER2 negative / Meta-analysis

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基金资助

河北省重点研发计划生物医药创新专项资助项目(23377707D)