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癌细胞的有丝分裂周期分为5个阶段：静止期G0、DNA合成前期G1、DNA合成期S、DNA合成后期G2、分裂期M，这些不同阶段受到不同的周期蛋白控制。其中，周期蛋白D1负责控制G1期进入S期。在雌激素和雌激素受体的过度刺激下，周期蛋白D1与周期蛋白依赖性激酶CDK4和CDK6结合，将抑癌蛋白Rb磷酸化而失去抑癌作用，导致癌细胞由G1期进入S期失控，从而陷入疯狂复制的死循环。对于内分泌治疗耐药的激素受体阳性乳腺癌患者，CDK4和CDK6抑制剂可有效阻断该死循环。 目前，已有三种CDK抑制剂（哌柏西利、阿贝西利、瑞博西利）被批准联合内分泌治疗用于激素受体阳性HER2阴性晚期乳腺癌患者的一线或二线治疗。2019年，英国《柳叶刀》肿瘤学分册发表美国食品药品监督管理局的研究报告，对CDK抑制剂联合内分泌治疗用于激素受体阳性HER2阴性晚期乳腺癌患者的无进展生存结局进行了汇总分析，结果表明全部重要的临床病理亚组都能获益。随着越来越多的临床研究已经公布总生存结局，故有必要对总生存结局进行汇总分析。 2021年10月14日，英国《柳叶刀》肿瘤学分册在线发表美国食品药品监督管理局药品审评研究中心的研究报告，首次对CDK抑制剂联合雌激素受体降解剂氟维司群治疗激素受体阳性HER2阴性晚期乳腺癌患者的总生存结局进行了汇总分析。 该探索性分析对2020年8月1日前提交并获得美国食品药品监督管理局批准上市的CDK抑制剂或安慰剂联合氟维司群治疗乳腺癌随机对照三期临床研究患者个体数据进行汇总分析：
全部被分析的患者年龄≥18岁，美国东部肿瘤学协作组体力状态评分为0～1，激素受体阳性HER2阴性晚期乳腺癌，并接受至少一次CDK4抑制剂或安慰剂联合氟维司群。通过生存曲线推算中位总生存，通过多因素比例风险回归模型推算不同因素的总死亡风险比及其95%置信区间。对既往全身内分泌治疗线数（一线或内分泌初治与二线及以上）以及不同的临床病理特征亚组进行汇总比较。由于潜在患者异质性，当汇总人群包括跨线治疗患者时，未按组报告推算中位总生存。全部结果为探索性和假设生成。 结果，3项研究合计1960例患者于2013年10月7日～2016年6月10日被随机分组，其中12例患者未治疗、1296例（66%）患者被随机分入CDK抑制剂组、652例（33%）被随机分入安慰剂组。 对于接受治疗的全部1948例患者，中位随访43.7个月（四分位：37.8～47.7）期间死亡935例（48%），CDK抑制剂组与安慰剂组相比：
对于其中2项研究的396例一线治疗患者，中位随访39.4个月（四分位：37.0～42.2）期间死亡123例（31%），CDK抑制剂组与安慰剂组相比：
对于其中3项研究的1552例二线治疗患者，中位随访45.1个月（95%置信区间：39.2～48.5）期间死亡812例（52%），CDK抑制剂组与安慰剂组相比：
对于其他临床病理特征亚组，除了年轻亚组、亚裔亚组、初诊转移亚组，氟维司群＋CDK抑制剂与氟维司群＋安慰剂相比，总生存获益一致。 因此，该研究结果表明，对于全部汇总患者和大多数临床病理特征亚组，氟维司群＋CDK抑制剂与氟维司群＋安慰剂相比，总生存都可获益。这些结果支持CDK抑制剂＋氟维司群治疗激素受体阳性HER2阴性晚期乳腺癌患者的现有治疗标准。 相关链接 Lancet Oncol. 2021 Oct 14. Online ahead of print. Overall survival in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer treated with a cyclin-dependent kinase 4/6 inhibitor plus fulvestrant: a US Food and Drug Administration pooled analysis. Jennifer J Gao, Joyce Cheng, Tatiana M Prowell, Erik Bloomquist, Shenghui Tang, Suparna B Wedam, Melanie Royce, Danielle Krol, Christy Osgood, Gwynn Ison, Rajeshwari Sridhara, Richard Pazdur, Julia A Beaver, Laleh Amiri-Kordestani. Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA. BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant. METHODS: In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating. FINDINGS: Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0.77 (95% CI 0.68-0.88), with a median follow-up of 43.7 months (IQR 37.8-47.7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7.1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0.74 (95% CI 0.52-1.07), with a median follow-up of 39.4 months (IQR 37.0-42.2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50.9-not estimable) in the CDKI group and was 45.7 months (95% CI 41.7-not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0.77 (95% CI 0.67-0.89), with a median follow-up of 45.1 months (95% CI 39.2-48.5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7.0 months, favouring CDKIs. INTERPRETATION: The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer. DOI: 10.1016/S1470-2045(21)00472-1
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