1. Protein signaling and drug target activation signatures to guide therapy prioritization: Therapeutic resistance and sensitivity in the I-SPY 2 Trial
- Author
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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, and Petricoin, Emanuel F
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Women's Health ,Precision Medicine ,Breast Cancer ,Genetics ,Clinical Research ,Cancer ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Good Health and Well Being ,Humans ,Drug Resistance ,Neoplasm ,Neoadjuvant Therapy ,Triple Negative Breast Neoplasms ,Biomarkers ,Gene Expression Profiling ,I-SPY 2 Investigators ,LCM ,RPPA ,biomarker ,breast cancer ,clinical trial ,drug target ,neoadjuvant ,phosphoprotein ,protein ,resistance ,Biomedical and clinical sciences - 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.
- Published
- 2023