背景:在先前关于细胞周期蛋白依赖性激酶4/6(CDK4/6)抑制剂联合内分泌治疗在晚期乳腺癌中应用的研究中,总生存期(OS)结局不一致.本系统评价和荟萃分析旨在进一步评价CDK4/6抑制剂联合内分泌治疗对激素受体(HR)阳性和人表皮生长因子受体2(HER2)阴性晚期乳腺癌患者的临床疗效和安全性。
方法:在PubMed的数据库中搜索了比较CDK4/6抑制剂加内分泌治疗和单独内分泌治疗在HR阳性和HER2阴性晚期乳腺癌患者中的随机对照试验(RCT),Embase,科克伦图书馆,中国国家知识基础设施(CNKI),万方和中国科技期刊数据库(VIP)截至2022年11月。OS的危险比(HR)和置信区间(CI),无进展生存期(PFS),患者接受下一线治疗或任何原因死亡(PFS2)时,从随机分组到首次记录疾病进展的时间,停药后首次后续化疗的时间(TTC),和客观反应率(ORR),临床获益率(CBR),提取安全指标。使用Stata14.0软件进行荟萃分析,使用Cochrane偏倚风险工具2.0评估偏倚风险。
结果:共纳入9项RCTs,4,920名参与者。在内分泌治疗中添加CDK4/6抑制剂可显着延长OS(HR0.76;95%CI:0.69-0.84;P<0.001),无论在一线和二线治疗中的应用如何,与单独的内分泌治疗相比。在PFS中观察到类似的益处(HR0.56;95%CI:0.52-0.60;P<0.001)。此外,CDK4/6抑制剂组改善了ORR的结果[相对危险度(RR)1.43;95%CI:1.27-1.62;P<0.001],CBR(RR1.24;95%CI:1.08-1.41;P<0.01,RR1.11;95%CI:1.06-1.18;P<0.001),PFS2(HR0.68;95%CI:0.60-0.76;P<0.001)和TTC(HR0.65;95%CI:0.58-0.72;P<0.001)。其中一项纳入的RCT具有性能偏差。发表偏倚不显著。
结论:CDK4/6抑制剂联合内分泌治疗能有效延长OS,PFS,PFS2和TTC,并改善HR阳性患者的ORR和CBR,HER2阴性晚期乳腺癌,安全性在可控范围内。
BACKGROUND: In previous studies on the application of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy in advanced breast cancer, the outcomes of overall survival (OS) were inconsistent. This systematic
review and meta-analysis aimed to further evaluate the clinical efficacy and safety of CDK4/6 inhibitors combined with endocrine therapy on patients with hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.
METHODS: Randomized controlled trials (RCTs) comparing CDK4/6 inhibitors plus endocrine therapy and endocrine therapy alone in patients with HR-positive and HER2-negative advanced breast cancer were searched in the databases of PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG and China Science and Technology Journal Database (VIP) up to November 2022. Hazard ratios (HRs) and confidence intervals (CI) of OS, progression-free survival (PFS), the time from randomization to the first recorded disease progression while the patient was receiving next-line therapy or death from any cause (PFS2), time to first subsequent chemotherapy after discontinuation (TTC), and objective response rate (ORR), clinical benefit rate (CBR), safety indicators were extracted. Stata 14.0 software was used for meta analysis and the Cochrane risk-of-bias tool 2.0 was used to evaluate the bias risk.
RESULTS: A total of 9 RCTs with 4,920 participants were included. The addition of CDK4/6 inhibitors to endocrine therapy significantly prolonged OS (HR 0.76; 95% CI: 0.69-0.84; P<0.001), regardless of the application in first-line and second-line treatment, compared with endocrine therapy alone. Similar benefit was observed in PFS (HR 0.56; 95% CI: 0.52-0.60; P<0.001). Moreover, the CDK4/6 inhibitors group improved results of ORR [relative risk (RR) 1.43; 95% CI: 1.27-1.62; P<0.001], CBR (RR 1.24; 95% CI: 1.08-1.41; P<0.01 and RR 1.11; 95% CI: 1.06-1.18; P<0.001), PFS2 (HR 0.68; 95% CI: 0.60-0.76; P<0.001) and TTC (HR 0.65; 95% CI: 0.58-0.72; P<0.001). One of the included RCTs had performance bias. Publication bias was not significant.
CONCLUSIONS: CDK4/6 inhibitors combined with endocrine therapy effectively prolong OS, PFS, PFS2, and TTC, and also improve ORR and CBR in patients with HR-positive, HER2-negative advanced breast cancer, and the safety was within the controllable range.