Breast Disease Diagnosis and Treatment Center of Affiliated Hospital of Qinghai University & Affiliated Cancer Hospital of Qinghai University, Xining, China.
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), The VIPII Gastrointestinal Cancer Division of the Medical Department, Peking University Cancer Hospital and Institute, Beijing, China.
JAMA Netw Open. 2020 Oct 1;3(10):e2020312. doi: 10.1001/jamanetworkopen.2020.20312.
One of the most recent treatment regimens used for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative metastatic breast cancer is treatment with the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and endocrine therapy (ET).
To assess overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events, especially grades 3 and 4 adverse events, among patients with HR-positive, ERBB2-negative metastatic breast cancer who were treated with CDK4/6 inhibitors plus ET vs ET alone.
A systematic search of PubMed, Embase, the main oncology conference of the European Society of Medical Oncology, and the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium databases for randomized clinical trials of CDK4/6 inhibitors plus ET vs ET for HR-positive, ERBB2-negative metastatic breast cancer. Searches were performed up to March 30, 2020.
A total of 472 records were assessed in PubMed and Embase by 2 authors, including studies, international meeting reports, and reviews. Inclusion criteria were English-language phase 2 or 3 randomized clinical trials of HR-positive, ERBB2-negative metastatic breast cancer, with patients randomly assigned to receive CDK4/6 inhibitors plus ET or ET alone, and having OS or PFS outcomes. The exclusion criteria were phase 1 trials, retrospective studies, or studies without survival outcomes. Excluding the references, 16 articles were relevant. After excluding studies based on exclusion criteria, 9 studies were considered eligible for this meta-analysis.
Two researchers independently extracted data and assessed potential bias. Data assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. The results were pooled using a fixed-effect model.
Study heterogeneity was assessed using the I2 statistic. Hazard ratios (HRs) and 95% CIs were used to evaluate PFS, OS, and subgroup analyses. Overall response and 95% CIs were used to evaluate the objective response rate and grade 3 or 4 adverse events. The primary outcome was OS.
In total, 9 studies that included a total of 5043 patients with metastatic breast cancer were assessed in this meta-analysis. Overall, the addition of CDK4/6 inhibitors to ET was associated with a statistically significant benefit to OS (HR, 1.33; 95% CI, 1.19-1.48; P < .001). Compared with ET alone, treatment with CDK4/6 inhibitors plus ET was associated with improved OS for the following subgroups: first-line therapy (HR, 1.35; 95% CI, 1.18-1.54; P < .001), second-line therapy (HR, 1.30; 95% CI, 1.09-1.54; P < .001), premenopausal women (HR, 1.32; 95% CI, 1.04-1.66; P < .001), postmenopausal women (HR, 1.34; 95% CI, 1.18-1.52; P < .001), visceral metastasis (HR, 1.31; 95% CI, 1.12-1.53; P < .001), bone-only metastasis (HR, 1.22; 95% CI, 0.88-1.68; P < .001), age younger than 65 years (HR, 1.25; 95% CI, 1.06-1.49; P < .001), and age 65 years or older (HR, 1.38; 95% CI, 1.11-1.72; P < .001). The addition of CDK4/6 inhibitors to ET was also associated with significant PFS benefit (HR, 1.84; 95% CI, 1.70-1.98; P < .001) and objective response rate benefit (odds ratio, 2.02; 95% CI, 1.61-2.53; P < .001). However, the use of CDK4/6 inhibitors in combination with ET was associated with significantly increased risk of grade 3 or 4 adverse events compared with ET alone, including neutropenia (HR, 57.05; 95% CI, 38.26-85.05; P < .001), leukopenia (HR, 36.36; 95% CI, 19.35-68.34; P < .001), and diarrhea (HR, 4.97; 95% CI, 2.84-8.69; P < .001).
This meta-analysis indicated that, compared with ET alone, treatment with CDK4/6 inhibitors plus ET was associated with significantly improved OS, PFS, and objective response rate among patients with HR-positive, ERBB2-negative metastatic breast cancer.
最近用于治疗激素受体（HR）阳性、ERBB2（以前称为 HER2）阴性转移性乳腺癌的治疗方案之一是使用细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）抑制剂和内分泌治疗（ET）。
评估 HR 阳性、ERBB2 阴性转移性乳腺癌患者接受 CDK4/6 抑制剂加 ET 与单独 ET 治疗的总生存期（OS）、无进展生存期（PFS）、客观缓解率和不良事件，特别是 3 级和 4 级不良事件。
对 PubMed、Embase、欧洲肿瘤内科学会主要肿瘤会议、美国临床肿瘤学会和圣安东尼奥乳腺癌研讨会数据库进行了系统检索，以查找 CDK4/6 抑制剂加 ET 与 ET 用于 HR 阳性、ERBB2 阴性转移性乳腺癌的随机临床试验。检索截止日期为 2020 年 3 月 30 日。
通过两名作者对 PubMed 和 Embase 中的 472 条记录进行评估，包括研究、国际会议报告和综述。纳入标准为接受 CDK4/6 抑制剂加 ET 或 ET 单药治疗的 HR 阳性、ERBB2 阴性转移性乳腺癌的 2 期或 3 期随机临床试验，并且具有 OS 或 PFS 结果。排除标准为 1 期试验、回顾性研究或无生存结果的研究。排除参考文献后，有 16 篇文章相关。根据排除标准排除研究后，有 9 项研究被认为符合本荟萃分析的条件。
两名研究人员独立提取数据并评估潜在偏倚。数据评估遵循系统评价和荟萃分析报告的首选报告项目指南。使用固定效应模型对结果进行汇总。
使用 I2 统计评估研究异质性。风险比（HR）和 95%置信区间（CI）用于评估 PFS、OS 和亚组分析。总缓解率和 95%CI 用于评估客观缓解率和 3 级或 4 级不良事件。主要结局为 OS。
本荟萃分析共纳入了 9 项研究，共纳入了 5043 例转移性乳腺癌患者。总的来说，与单独 ET 相比，CDK4/6 抑制剂加 ET 治疗与 OS 显著改善相关（HR，1.33；95%CI，1.19-1.48；P<0.001）。与单独 ET 相比，CDK4/6 抑制剂加 ET 治疗在以下亚组中具有改善 OS 的作用：一线治疗（HR，1.35；95%CI，1.18-1.54；P<0.001）、二线治疗（HR，1.30；95%CI，1.09-1.54；P<0.001）、绝经前妇女（HR，1.32；95%CI，1.04-1.66；P<0.001）、绝经后妇女（HR，1.34；95%CI，1.18-1.52；P<0.001）、内脏转移（HR，1.31；95%CI，1.12-1.53；P<0.001）、骨转移（HR，1.22；95%CI，0.88-1.68；P<0.001）、年龄<65 岁（HR，1.25；95%CI，1.06-1.49；P<0.001）和年龄≥65 岁（HR，1.38；95%CI，1.11-1.72；P<0.001）。CDK4/6 抑制剂加 ET 治疗还与显著的 PFS 获益相关（HR，1.84；95%CI，1.70-1.98；P<0.001）和客观缓解率获益相关（优势比，2.02；95%CI，1.61-2.53；P<0.001）。然而，与单独 ET 相比，CDK4/6 抑制剂加 ET 治疗与 3 级或 4 级不良事件的风险显著增加相关，包括中性粒细胞减少症（HR，57.05；95%CI，38.26-85.05；P<0.001）、白细胞减少症（HR，36.36；95%CI，19.35-68.34；P<0.001）和腹泻（HR，4.97；95%CI，2.84-8.69；P<0.001）。
本荟萃分析表明，与单独 ET 相比，CDK4/6 抑制剂加 ET 治疗可显著改善 HR 阳性、ERBB2 阴性转移性乳腺癌患者的 OS、PFS 和客观缓解率。
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