Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA 20110, USA.
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Cell Rep Med. 2023 Dec 19;4(12):101312. doi: 10.1016/j.xcrm.2023.101312. Epub 2023 Dec 11.
Molecular subtyping of breast cancer is based mostly on HR/HER2 and gene expression-based immune, DNA repair deficiency, and luminal signatures. We extend this description via functional protein pathway activation mapping using pre-treatment, quantitative expression data from 139 proteins/phosphoproteins from 736 patients across 8 treatment arms of the I-SPY 2 Trial (ClinicalTrials.gov: NCT01042379). We identify predictive fit-for-purpose, mechanism-of-action-based signatures and individual predictive protein biomarker candidates by evaluating associations with pathologic complete response. Elevated levels of cyclin D1, estrogen receptor alpha, and androgen receptor S650 associate with non-response and are biomarkers for global resistance. We uncover protein/phosphoprotein-based signatures that can be utilized both for molecularly rationalized therapeutic selection and for response prediction. We introduce a dichotomous HER2 activation response predictive signature for stratifying triple-negative breast cancer patients to either HER2 or immune checkpoint therapy response as a model for how protein activation signatures provide a different lens to view the molecular landscape of breast cancer and synergize with transcriptomic-defined signatures.
乳腺癌的分子亚型主要基于 HR/HER2 和基于基因表达的免疫、DNA 修复缺陷和管腔特征。我们通过使用来自 I-SPY 2 试验的 8 个治疗臂的 736 名患者的 139 种蛋白质/磷酸化蛋白质的预处理、定量表达数据，通过功能蛋白通路激活图谱来扩展这一描述（ClinicalTrials.gov：NCT01042379）。我们通过评估与病理完全缓解的关联，确定了有预测作用的、基于作用机制的特征和个体预测性蛋白生物标志物候选物。细胞周期蛋白 D1、雌激素受体α和雄激素受体 S650 的水平升高与无反应相关，是整体耐药的生物标志物。我们揭示了基于蛋白质/磷酸化蛋白质的特征，这些特征既可以用于合理的分子治疗选择，也可以用于预测反应。我们引入了一个二项 HER2 激活反应预测特征，用于将三阴性乳腺癌患者分层为 HER2 或免疫检查点治疗反应，这是一个如何通过蛋白质激活特征提供观察乳腺癌分子景观的不同视角并与转录组定义的特征协同作用的模型。
