Azim Hamdy A, Elghazawy Hagar, Shohdy Kyrillus S, Lasheen Shaimaa, Elghazawy Mahmoud, Ghazy Ramy Mohamed, Abdelnasser Dalia, Kassem Loay
Clinical Oncology Department, Cairo University, Cairo, Egypt.
Clinical Oncology Department, Ain Shams University, Cairo, Egypt.
JCO Precis Oncol. 2025 Aug;9:e2400841. doi: 10.1200/PO-24-00841. Epub 2025 Aug 6.
The prognostic significance of mutation and alteration (Alt) in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) breast cancer (BC) treated with endocrine therapy (ET) ± cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) remains unresolved. This meta-analysis aimed to define their influence on therapy outcomes in the early and metastatic stages.
We systematically searched PubMed, Cochrane, and Google Scholar databases. Primary end points included disease-free (or progression-free) survival (DFS/PFS) and overall survival (OS) according to mutation or status. A separate analysis of individual-patient data for metastatic HR+/HER2- BC extracted from MSK-MET project was performed.
Twenty-two studies comprising 34,960 patients were eligible for meta-analysis. In the early setting, in eight studies (n = 7,857 patients with HR+ BC received ET), () was associated with a marginally significant worse DFS (hazard ratio, 1.64 [95% CI, 1 to 2.69]; = .05) and a significantly worse OS (hazard ratio, 1.52 [95% CI, 1.20 to 1.92]; = .0006) versus wild-type (). In the metastatic setting, in 11 studies (n = 12,670 patients received ET+ CDK4/6i), mutation was associated with a significantly worse PFS (hazard ratio, 1.87 [95% CI, 1.45 to 2.41]; < .00001) and OS (hazard ratio, 1.38 [95% CI, 1.15 to 1.65]; = .0005) versus . The individual-patient data confirmed the poorer prognosis of and , but not , and a significant co-occurrence of loss of heterozygosity () among carriers.
The current analysis adds to the body of evidence supporting the inferior outcomes of ET± CDK4/6i in compared with . Given its significant coexistence with LOH, BC seems uniquely resistant to ET± CDK4/6i, a point that is profoundly different from sporadic or even HR+/HER2- BC.
对于接受内分泌治疗（ET）±细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）治疗的激素受体阳性（HR+）/人表皮生长因子受体2阴性（HER2-）乳腺癌（BC）患者，其基因突变和改变（Alt）的预后意义仍未明确。本荟萃分析旨在确定它们对早期和转移阶段治疗结果的影响。
我们系统检索了PubMed、Cochrane和谷歌学术数据库。主要终点包括根据基因突变或状态的无病（或无进展）生存期（DFS/PFS）和总生存期（OS）。对从MSK-MET项目中提取的转移性HR+/HER2-BC患者的个体数据进行了单独分析。
22项研究共34960例患者符合荟萃分析条件。在早期阶段，八项研究（n = 7857例接受ET的HR+ BC患者）中，与野生型相比，（）与DFS略差相关（风险比，1.64 [95% CI，1至2.69]；P = 0.05），且与OS显著较差相关（风险比，1.52 [95% CI，1.20至1.92]；P = 0.0006）。在转移阶段，11项研究（n = 12670例接受ET + CDK4/6i的患者）中，与相比，基因突变与PFS显著较差相关（风险比，1.87 [95% CI，1.45至2.41]；P < 0.00001）和OS（风险比，1.38 [95% CI，1.15至1.65]；P = 0.0005）。个体数据证实了和的预后较差，但未证实的预后较差，且在携带者中存在显著的杂合性缺失（）共现情况。
当前分析增加了支持与相比，ET±CDK4/6i在中疗效较差的证据。鉴于其与杂合性缺失显著共存，BC似乎对ET±CDK4/6i具有独特的抗性，这一点与散发性甚至HR+/HER2-BC有很大不同。
