CDK4/6抑制剂（CDK4/6i）和内分泌治疗联合治疗可显着改善雌激素受体阳性（ER）转移性乳腺癌患者的预后，但不可避免地会出现耐药性，从而导致疾病进展。在此，我们的目的是确定与 CDK4/6i 和内分泌治疗耐药联合相关的基因组改变，并跟踪纵向循环肿瘤 DNA (ctDNA) 中的特定突变水平，以早期检测进展。我们对 86 名 ER 转移性乳腺癌患者进行了全外显子组测序或靶向测序，对在开始 CDK4/6i 和内分泌联合治疗之前以及疾病进展时获得的配对肿瘤 (N = 8) 或血液样本 (N = 5) 进行了全外显子组测序或靶向测序。进展过程中致癌基因的突变很少见，而生长调节基因的扩增则更为频繁。最常见的获得性改变是 PIK3CA 和 TP53 突变以及 PDK1 扩增。突变 PIK3CA 或私人突变的纵向 ctDNA 动态显示，10 名患者中有 8 名 (80%) 在进展时突变水平增加。令人印象深刻的是，在成像前 4-17 个月检测到 PIK3CA 突变 ctDNA 水平上升。我们的数据为支持纵向 ctDNA 分析实时监测 CDK4/6i 反应和早期检测晚期乳腺癌进展提供了越来越多的证据。此外，我们的分析表明，生长相关基因的扩增可能导致 CDK4/6i 和内分泌治疗耐药性相结合。© 2024 作者。约翰·威利出版的《国际癌症杂志》

Combined CDK4/6 inhibitor (CDK4/6i) and endocrine therapy significantly improves outcome for patients with estrogen receptor-positive (ER+) metastatic breast cancer, but drug resistance and thus disease progression inevitably occur. Herein, we aimed to identify genomic alterations associated with combined CDK4/6i and endocrine therapy resistance, and follow the levels of specific mutations in longitudinal circulating tumor DNA (ctDNA) for early detection of progression. From a cohort of 86 patients with ER+ metastatic breast cancer we performed whole exome sequencing or targeted sequencing of paired tumor (N = 8) or blood samples (N = 5) obtained before initiation of combined CDK4/6i and endocrine therapy and at disease progression. Mutations in oncogenic genes at progression were rare, while amplifications of growth-regulating genes were more frequent. The most frequently acquired alterations observed were PIK3CA and TP53 mutations and PDK1 amplification. Longitudinal ctDNA dynamics of mutant PIK3CA or private mutations revealed increased mutation levels at progression in 8 of 10 patients (80%). Impressively, rising levels of PIK3CA-mutated ctDNA were detected 4-17 months before imaging. Our data add to the growing evidence supporting longitudinal ctDNA analysis for real-time monitoring of CDK4/6i response and early detection of progression in advanced breast cancer. Further, our analysis suggests that amplification of growth-related genes may contribute to combined CDK4/6i and endocrine therapy resistance.© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.