학술논문
Protein signaling and drug target activation signatures to guide therapy prioritization: Therapeutic resistance and sensitivity in the I-SPY 2 Trial
Document Type
article
Author
Gallagher, Rosa I; Wulfkuhle, Julia; Wolf, Denise M; Brown-Swigart, Lamorna; Yau, Christina; O’Grady, Nicholas; Basu, Amrita; Lu, Ruixiao; Campbell, Michael J; Magbanua, Mark J; Coppé, Jean-Philippe; Investigators, I-SPY 2; Asare, Smita M; Sit, Laura; Matthews, Jeffrey B; Perlmutter, Jane; Hylton, Nola; Liu, Minetta C; Symmans, W Fraser; Rugo, Hope S; Isaacs, Claudine; DeMichele, Angela M; Yee, Douglas; Pohlmann, Paula R; Hirst, Gillian L; Esserman, Laura J; van ‘t Veer, Laura J; Petricoin, Emanuel F
Source
Cell Reports Medicine. 4(12)
Subject
Language
Abstract
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.