Buonaiuto Roberto, Caltavituro Aldo, Tafuro Margherita, Longobardi Alessandra, Pavone Giuliana, De Santis Pierluigi, Caputo Roberta, De Angelis Carmine, Del Mastro Lucia, Puglisi Fabio, Giuliano Mario, Arpino Grazia, Pagliuca Martina, De Laurentiis Michelino
Oncology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy; Clinical and Translational Oncology, Scuola Superiore Meridionale, Naples, Italy.
Oncology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.
Breast. 2025 Feb;79:103833. doi: 10.1016/j.breast.2024.103833. Epub 2024 Nov 4.
The combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard of care for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (aBC). While the efficacy and safety profiles of CDK4/6i and ET have been extensively evaluated in phase II and III trials worldwide, it remains unclear whether the response to CDK4/6i and toxicity profile vary among Asian and non-Asian patients. Therefore, we aimed to assess the treatment efficacy of ET with and without CDK4/6i by comparing outcomes in Asian and non-Asian subgroups included in these clinical trials. In addition, we evaluated the toxicity profiles of the treatments by estimating the risk of treatment-related adverse events (AEs).
We conducted a meta-analysis including the most recent randomized trial data systematically searched from PubMed, Embase, Web of Science, Cochrane CENTRAL (from inception to May 31st, 2024) or presented in abstracts or oral presentations at the ESMO, ASCO, and SABCS international congresses. We included studies comparing CDK4/6i (palbociclib, ribociclib, abemaciclib, dalpiciclib) + ET versus placebo + ET. Progression-free survival (PFS) and overall survival (OS), hazard ratios (HR), and 95 % confidence intervals (CI) were extracted for the two subgroups of interest. To evaluate the treatment-related toxicity profiles, we extracted the number of side effects to estimate the risk of treatment-emergent AEs.
Eleven studies (n = 5129) were included in this meta-analysis. The addition of CDK4/6i to ET consistently improved PFS in both Asian (HR = 0.52, 95 % CI 0.47-0.60; p < 0.001) and non-Asian (HR = 0.58, 95 % CI 0.52-0.64; p < 0.001) groups. Similarly, the combination of CDK4/6i + ET led to an OS improvement in both Asian (HR = 0.75, 95 % CI 0.62-0.91; p = 0.003) and non-Asian (HR = 0.81, 95 % CI 0.73-0.89; p < 0.001) patients. The risk of treatment related toxicity was higher in the CDK4/6i + ET arm in both Asian and non-Asian groups. Interestingly, a numerically higher rate of treatment-related hematological toxicity was observed in Asian patients, although no significant interethnic difference was found in the relative risk of these events.
The combination of CDK4/6i and ET significantly improves PFS and OS compared to ET alone in both Asian and non-Asian patients with HR+/HER2-aBC. Although the magnitude of benefit appears to be independent of ethnicity, future clinical trials should devise a standardized method for stratifying patients by ethnicity to more effectively assess potential differences in treatment benefits.
PROSPERO registration number: CRD42024543217.
细胞周期蛋白依赖性激酶4和6抑制剂（CDK4/6i）与内分泌治疗（ET）联合使用是激素受体阳性/人表皮生长因子受体2阴性（HR+/HER2-）晚期乳腺癌（aBC）患者的标准治疗方案。虽然CDK4/6i和ET的疗效和安全性在全球范围内的II期和III期试验中已得到广泛评估，但亚洲和非亚洲患者对CDK4/6i的反应及毒性特征是否存在差异仍不清楚。因此，我们旨在通过比较这些临床试验中亚洲和非亚洲亚组的结果，评估联合或不联合CDK4/6i的ET的治疗效果。此外，我们通过估计治疗相关不良事件（AE）的风险来评估治疗的毒性特征。
我们进行了一项荟萃分析，纳入了从PubMed、Embase、科学网、Cochrane CENTRAL（从创刊至2024年5月31日）系统检索到的最新随机试验数据，或在欧洲肿瘤内科学会（ESMO）、美国临床肿瘤学会（ASCO）和圣安东尼奥乳腺癌研讨会（SABCS）国际大会上发表的摘要或口头报告中的数据。我们纳入了比较CDK4/6i（哌柏西利、瑞博西尼、阿贝西利、达尔西利）+ET与安慰剂+ET的研究。提取了两个感兴趣亚组的无进展生存期（PFS）、总生存期（OS）、风险比（HR）和95%置信区间（CI）。为了评估治疗相关的毒性特征，我们提取了副作用的数量以估计治疗中出现的AE的风险。
该荟萃分析纳入了11项研究（n = 5129）。在亚洲组（HR = 0.52，95% CI 0.47 - 0.60；p < 0.001）和非亚洲组（HR = 0.58，95% CI 0.52 - 0.64；p < 0.001）中，CDK4/6i联合ET均持续改善了PFS。同样，CDK4/6i + ET联合治疗在亚洲患者（HR = 0.75，95% CI 0.62 - 0.91；p = 0.003）和非亚洲患者（HR = 0.81，95% CI 0.73 - 0.89；p < 0.001）中均使OS得到改善。在亚洲和非亚洲组中，CDK4/6i + ET组的治疗相关毒性风险均更高。有趣的是，亚洲患者中治疗相关血液学毒性的发生率在数值上更高，尽管在这些事件的相对风险中未发现显著的种族间差异。
与单独使用ET相比，CDK4/6i与ET联合使用在亚洲和非亚洲HR+/HER2- aBC患者中均显著改善了PFS和OS。尽管获益程度似乎与种族无关，但未来的临床试验应设计一种按种族对患者进行分层的标准化方法，以更有效地评估治疗获益的潜在差异。
PROSPERO注册号：CRD42024543217。
