Department of Internal Medicine, Hacettepe University, Ankara, Turkey.
Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey.
Support Care Cancer. 2022 Nov;30(11):9071-9078. doi: 10.1007/s00520-022-07320-y. Epub 2022 Aug 16.
The combination of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors plus endocrine therapy (ET) improved the survival outcomes and became the standard of care in the treatment of metastatic hormone-positive breast cancer. However, these combinations increased the risk of neutropenia compared with ET alone. While the infection-related mortalities did not seem to be increased, the exact risk of infections with CDK 4/6 inhibitor and ET combinations is relatively understudied. Therefore, we performed a meta-analysis of CDK 4/6 inhibitor clinical trials to assess the infection risk of adding CDK4/6 inhibitors to ET.
We systemically searched the PubMed database for relevant clinical trials. For each study, all grade and grade 3 or higher infections, upper respiratory tract infections (URTI), urinary tract infections (UTI), pneumonia, and febrile neutropenia rates were recorded whenever available. The hazard ratios (HR) with a 95% confidence interval (CI) of infection risk were calculated via the generic inverse-variance method with a random-effects model.
Nine eligible studies were included in the analyses (MONALEESA-2,3,7, MONARCH-2,3, MONARCH plus, PALOMA-1,2,3). In the meta-analysis of these studies, CDK 4/6 inhibitors plus ET arms were associated with increased all grade infections (HR 1.77, 95% CI 1.56-2.01, p < 0.00001), grade 3 or higher infections, (HR 1.77, 95% CI 1.28-2.43, p = 0.0005), UTIs (HR 1.59, 95% CI 1.19-2.12, p = 0.002), and febrile neutropenia (HR 4.28, 95% CI 1.73-10.62, p = 0.002).
In this meta-analysis, we observed that adding CDK4/6 inhibitors to ET significantly increased the risk of all grade, grade 3 or higher infections, and urinary tract infections. We propose that closer follow-up for infections should be considered for metastatic breast cancer patients using CDK 4/6 inhibitors. This may help clinicians to recognize infections earlier which prevents early death from infection.
细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）抑制剂联合内分泌治疗（ET）改善了生存结局，成为治疗转移性激素阳性乳腺癌的标准治疗方法。然而，与单独 ET 相比，这些联合用药增加了中性粒细胞减少症的风险。尽管感染相关死亡率似乎没有增加，但 CDK4/6 抑制剂和 ET 联合用药的感染风险的确切风险相对研究较少。因此，我们对 CDK4/6 抑制剂的临床试验进行了荟萃分析，以评估将 CDK4/6 抑制剂加入 ET 中治疗的感染风险。
我们系统地在 PubMed 数据库中搜索相关的临床试验。对于每一项研究，记录所有级别和 3 级或更高级别的感染、上呼吸道感染（URTI）、尿路感染（UTI）、肺炎和发热性中性粒细胞减少症的发生率，只要有数据可用。通过随机效应模型的通用逆方差法计算感染风险的危险比（HR）及其 95%置信区间（CI）。
9 项符合条件的研究被纳入分析（MONALEESA-2、3、7、MONARCH-2、3、MONARCH plus、PALOMA-1、2、3）。在这些研究的荟萃分析中，CDK4/6 抑制剂联合 ET 组与所有级别感染（HR 1.77，95%CI 1.56-2.01，p<0.00001）、3 级或更高级别的感染（HR 1.77，95%CI 1.28-2.43，p=0.0005）、UTI（HR 1.59，95%CI 1.19-2.12，p=0.002）和发热性中性粒细胞减少症（HR 4.28，95%CI 1.73-10.62，p=0.002）的风险增加有关。
在这项荟萃分析中，我们观察到将 CDK4/6 抑制剂加入 ET 中治疗显著增加了所有级别、3 级或更高级别的感染和尿路感染的风险。我们建议，使用 CDK4/6 抑制剂治疗转移性乳腺癌的患者应更密切地监测感染情况。这可能有助于临床医生更早地识别感染，从而防止因感染而早期死亡。
