内分泌疗法（ET）与CDK4/6抑制联合常规用于HR+/HER2-转移性乳腺癌（MBC）患者的一线治疗。然而，30-40%的患者很快就发展成疾病进展。在这项开放标签的多中心临床试验中，我们利用基于蛋白质/磷酸蛋白的假说驱动方法，在治疗前组织活检中鉴定了ET加CDK4/6抑制的反应预测标记。通过反相蛋白微阵列从微切割肿瘤上皮和周围的基质/免疫细胞中生成通路中心的信号剖面。与反应者（p=0.02）相比，CDK4/6下游底物Rb（S780）和FoxM1（T600）的磷酸化水平在进展性疾病（PD）患者中更高。在肿瘤上皮和基质/免疫细胞中检测到系统性PI3K/AKT/mTOR激活，这种激活并不能仅仅由基因组变化解释。随着FDA批准的靶向化合物数量的增加，功能性基于蛋白质的信号分析可能成为MBC患者反应预测和治疗选择的关键组成部分。©2023年作者。

Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2- metastatic breast cancer (MBC) patients. However, 30-40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders (p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients.© 2023. The Author(s).